Aeilko H Zwinderman

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands

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Publications (782)4137.9 Total impact

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    ABSTRACT: Patients with CHD-PAH have a limited prognosis. In daily practice, combination therapy is often initiated after a clinical event. Although clinical events have been associated with a poor prognosis in idiopathic PAH, data on this association are limited in CHD-PAH. The aim of this study was to determine whether baseline characteristics and clinical events associate with mortality in patients with pulmonary hypertension (PAH) due to congenital heart disease (CHD). In total 91 consecutive adults (42±14year) with CHD-PAH were referred for therapy between January 2005 and June 2013. Cox proportional hazard analysis was performed to identify determinants of mortality, including clinical events as time dependent covariates. Twenty-four patients (nine with Down) died during the median follow-up of 4.7 (range 0.1-7.9) years. The one and eight year mortality rates were 7.3% and 37.3%, respectively. Clinical events included admission for heart failure (n=9), arrhythmias (n=9), haemoptysis (n=5), change to a worse NYHA class (n=16), vascular events (n=1), syncope (n=1) and need for red blood cell depletion (n=4). In univariate analysis, both baseline characteristics and clinical events were associated with mortality. In multivariate analysis, only baseline NT-pro-BNP serum level≥500ng/L and TAPSE<15mm at echocardiography were significant determinants of mortality. None of the clinical events remained significant. Patients with both a NT-pro-BNP serum level≥500ng/L and TAPSE<15mm at echocardiography have a nine fold higher mortality rate than patients without both risk factors. Prognosis is still poor in contemporary patients with CHD-PAH. Both baseline NT-pro-BNP serum level and right ventricular function are superior to clinical events in prognostication. These two baseline characteristics should have a major impact on therapeutic management in patients with CHD-PAH, such as initiation of combination therapy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    International Journal of Cardiology 02/2015; 181. DOI:10.1016/j.ijcard.2014.11.222 · 6.18 Impact Factor
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    ABSTRACT: Background Myoclonus-dystonia (M-D) is a hyperkinetic movement disorder with predominant myoclonic symptoms combined with dystonia of the upper part of the body. A proportion of M-D cases are caused by mutations in the epsilon-sarcoglycan gene. In remaining M-D patients, no genetic factor has been established, indicating genetic heterogeneity.Methods Patients were included in a prospective clinical database and recruited from referral centers and general neurology clinics in The Netherlands. To investigate new genetic causal factors in M-D syndrome, we performed homozygosity mapping combined with exome sequencing in a three-generation M-D family and genetically screened 24 additional patients with M-D.ResultsWe found co-segregation of the rare missense variant Thr1904Met in the RELN gene. By additional screening of an M-D cohort, we identified co-segregation of RELN variants in two families (Thr1904Met, Ile1217Met) and identified two sporadic RELN mutation carriers (Pro1703Arg, Leu411Ile). Taken together, five of 25 SGCE-negative M-D patients carried RELN rare missense variants.Conclusion We propose that RELN mutations contribute to the genetic heterogeneity of M-D. Reelin is a large secreted glycoprotein that plays essential roles in the cytoarchitecture of laminated brain structures and modulation of synaptic transmission and plasticity. © 2015 International Parkinson and Movement Disorder Society
    Movement Disorders 02/2015; 30(3):n/a-n/a. DOI:10.1002/mds.26070 · 5.63 Impact Factor
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    ABSTRACT: Aortic dissections involving the descending aorta are a major clinical problem in patients with Marfan syndrome. The purpose of this study was to identify clinical parameters associated with type B aortic dissection and to develop a risk model to predict type B aortic dissection in patients with Marfan syndrome. Patients with the diagnosis of Marfan syndrome and magnetic resonance imaging or computed tomographic imaging of the aorta were followed for a median of 6 years for the occurrence of type B dissection or the combined end point of type B aortic dissection, distal aortic surgery, and death. A model using various clinical parameters as well as genotyping was developed to predict the risk for type B dissection in patients with Marfan syndrome. Between 1998 and 2013, 54 type B aortic dissections occurred in 600 patients with Marfan syndrome (mean age 36 ± 14 years, 52% male). Independent variables associated with type B aortic dissection were prior prophylactic aortic surgery (hazard ratio: 2.1; 95% confidence interval: 1.2 to 3.8; p = 0.010) and a proximal descending aorta diameter ≥27 mm (hazard ratio: 2.2; 95% confidence interval: 1.1 to 4.3; p = 0.020). In the risk model, the 10-year occurrence of type B aortic dissection in low-, moderate-, and high-risk patients was 6%, 19%, and 34%, respectively. Angiotensin II receptor blocker therapy was associated with fewer type B aortic dissections (hazard ratio: 0.3; 95% confidence interval: 0.1 to 0.9; p = 0.030). Patients with Marfan syndrome with prior prophylactic aortic surgery are at substantial risk for type B aortic dissection, even when the descending aorta is only slightly dilated. Angiotensin II receptor blocker therapy may be protective in the prevention of type B aortic dissections. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
    Journal of the American College of Cardiology 01/2015; 65(3):246-54. DOI:10.1016/j.jacc.2014.10.050 · 15.34 Impact Factor
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    ABSTRACT: -It has been shown that losartan reduces aortic dilatation in patients with Marfan syndrome. However, treatment response is highly variable. This study investigates losartan effectiveness in genetically classified subgroups. -In this predefined sub-study of COMPARE, Marfan patients were randomized to daily receive losartan 100mg or no losartan. Aortic root dimensions were measured by magnetic resonance imaging at baseline and after 3 years. FBN1 mutations were classified based on fibrillin-1 protein effect into 1) 'Haploinsufficiency', decreased amount of normal fibrillin-1, 2) 'Dominant negative', normal fibrillin-1 abundance with mutant fibrillin-1 incorporated in the matrix. A pathogenic FBN1 mutation was found in 117 patients, of whom 79 patients were positive for a dominant negative mutation (67.5%) and 38 for a mutation causing haploinsufficiency (32.5%). Baseline characteristics between treatment groups were similar. Overall, losartan significantly reduced aortic root dilatation rate (no losartan: 1.3±1.5mm/3years, n=59, versus losartan: 0.8±1.4mm/3years, n=58, p=0.009). However, losartan only reduced aortic root dilatation rate in haploinsufficient patients (no losartan: 1.8±1.5mm/3years, n=21, versus losartan 0.5±0.8mm/3years, n=17, p=0.001) and not in dominant negative patients (no losartan: 1.2±1.7mm/3years, n=38, versus losartan 0.8±1.3mm/3years, n=41, p=0.197). -Marfan patients with haploinsufficient FBN1 mutations appear to be more responsive to losartan therapy for inhibition of aortic root dilatation rate compared to dominant negative patients. Additional treatment strategies are needed in Marfan patients with dominant negative FBN1 mutations. -http://www.trialregister.nl/trialreg/index.asp; Unique Identifier: NTR1423.
    Circulation Cardiovascular Genetics 01/2015; DOI:10.1161/CIRCGENETICS.114.000950 · 5.34 Impact Factor
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    ABSTRACT: Low levels of vitamin D are associated with asthma severity, airway remodeling, and exacerbation rate increase, especially in nonatopic asthma. Reduced steroid responsiveness or impaired antimicrobial defense might be underlying mechanisms. We sought to evaluate the effect of vitamin D supplementation on eosinophilic and neutrophilic airway inflammation in patients with nonatopic asthma. In a double-blind, randomized, placebo-controlled trial, we investigated the effect of long-acting vitamin D3 (400,000 IU) on sputum neutrophils and eosinophils in 44 patients with nonatopic asthma with neutrophilic (≥53%) and/or eosinophilic (≥3%) airway inflammation. Sputum induction was performed at baseline and after 9 weeks. Other measurements included questionnaires, blood samples, and pulmonary function. Treatment with vitamin D did not significantly affect sputum neutrophils or eosinophils compared with treatment with placebo in the total group. Regarding sputum eosinophils, the effect of vitamin D appeared to be dependent on baseline sputum eosinophil levels (interaction P = .015). In patients with eosinophil levels of 26.2% or more (median in patients with sputum eosinophilia, >3%), eosinophils decreased from a median of 41.0% to 11.8% after vitamin D treatment as compared with an increase from 51.8% to 63.3% in patients receiving placebo (P = .034). Vitamin D treatment also resulted in slightly better Asthma Control Questionnaire scores (P = .08). Vitamin D supplementation reduced eosinophilic airway inflammation in patients with nonatopic asthma with severe eosinophilic airway inflammation, but did not affect sputum neutrophils. Also, a small effect on asthma control was observed. These findings suggest that vitamin D might have potential as an add-on treatment option in eosinophilic asthma. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke. In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176. Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82-1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group. Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke. Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet 01/2015; DOI:10.1016/S0140-6736(14)62456-9 · 39.21 Impact Factor
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    ABSTRACT: Vitiligo-like depigmentation in patients with melanoma may be associated with more favorable clinical outcome. We conducted a systematic review of patients with stage III to IV melanoma treated with immunotherapy to determine the cumulative incidence of vitiligo-like depigmentation and the prognostic value of vitiligo development on survival. We systemically searched and selected all studies on melanoma immunotherapy that reported on autoimmune toxicity and/or vitiligo between 1995 and 2013. Methodologic quality of each study was appraised using adapted criteria for systematic reviews in prognostic studies. Random-effect models were used to calculate summary estimates of the cumulative incidence of vitiligo-like depigmentation across studies. The prognostic value of vitiligo-like depigmentation on survival outcome was assessed using random-effects Cox regression survival analyses. One hundred thirty-seven studies were identified comprising 139 treatment arms (11 general immune stimulation, 84 vaccine, 28 antibody-based, and 16 adoptive transfer) including a total of 5,737 patients. The overall cumulative incidence of vitiligo was 3.4% (95% CI, 2.5% to 4.5%). In 27 studies reporting individual patient data, vitiligo development was significantly associated with both progression-free-survival (hazard ratio [HR], 0.51; 95% CI, 0.32 to 0.82; P < .005) and overall survival (HR, 0.25; 95% CI, 0.10 to 0.61; P < .003), indicating that these patients have two to four times less risk of disease progression and death, respectively, compared with patients without vitiligo development. Although vitiligo occurs only in a low percentage of patients with melanoma treated with immunotherapy, our findings suggest clear survival benefit in these patients. Awareness of vitiligo induction in patients with melanoma is important as an indicator of robust antimelanoma immunity and associated improved survival. © 2015 by American Society of Clinical Oncology.
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    ABSTRACT: Little is known about the impact of acute HCV co-infection on HIV-1 disease progression. We investigated CD4 cell count and HIV RNA concentration changes after HCV infection in individuals chronically infected with HIV-1. We selected individuals that had a last negative and first positive HCV RNA test less than 1 year apart. Bivariate linear mixed effects regression was used to model trends in HIV RNA level and CD4 cell count from 2 years before the last negative HCV RNA test until the first of the following dates: start of anti-HCV medication, change in cART status and end of follow-up. At the estimated time of HCV co-infection, out of 89 individuals, 63 (71%) were cART-treated and 26 (29%) were not on cART. In persons on cART, median CD4 cell count declined from 587 to 508 cells/mm (p<0.0001) during the first 5 months after HCV infection and returned to 587 cells/mm after 2.2 years. Also, the probability of an HIV RNA >50 copies/ml peaked to 18.6% at HCV co-infection , with lower probabilities 6 months before (3.5%, p=0.006 compared to peak probability) and after (2.9%, p=0.009). In persons not on cART, no significant impact of HCV co-infection on trends in HIV RNA level or CD4 cell count were observed. Acute HCV infection in cART-treated, chronically HIV-infected patients was associated with a temporary decrease in CD4 cell counts and increased risk of HIV viraemia >50 copies/ ml. This may increase the risk of further HIV transmission.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 12/2014; DOI:10.1097/QAI.0000000000000514 · 4.39 Impact Factor
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    ABSTRACT: In comparative systematic reviews of diagnostic accuracy, inconsistencies between direct and indirect comparisons may lead to bias. We investigated whether using individual patient data (IPD) can adjust for this form of bias. We included IPD of 3 ovarian reserve tests from 32 studies. Inconsistency was defined as a statistically significant difference in relative accuracy or different comparative results between the direct and indirect evidence. We adjusted for the effect of threshold and reference standard, as well as for patient-specific variables. Anti-Müllerian hormone (AMH) and follicle stimulation hormone (FSH) differed significantly in sensitivity (-0.1563, P = 0.04). AMH and antral follicle count (AFC) differed significantly in sensitivity (0.1465, P < 0.01). AMH and AFC differed significantly in specificity (-0.0607, P = 0.02). The area under the curve (AUC) differed significantly between AFC and FSH (0.0948, P < 0.01) in the direct comparison but not (0.0678, P = 0.09) in the indirect comparison. The AUCs of AFC and AMH differed significantly (-0.0830, P < 0.01) in the indirect comparison but not (-0.0176, P = 0.29) in the direct comparison. These differences remained after adjusting for indirectness. Estimates of comparative accuracy obtained through indirect comparisons are not always consistent with those obtained through direct comparisons. Using IPD to adjust for indirectness did not successfully remove the bias in this case study. Copyright © 2014 Elsevier Inc. All rights reserved.
    Journal of Clinical Epidemiology 12/2014; DOI:10.1016/j.jclinepi.2014.10.005 · 5.48 Impact Factor
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    ABSTRACT: Background Recently, we demonstrated that losartan reduced the aortic root dilatation rate (AoDR) in adults with Marfan syndrome (MFS); however, responsiveness was diverse. The aim was to determine the role of transforming growth factor-β (TGF-β) as therapeutic biomarker for effectiveness of losartan on AoDR. Methods Baseline plasma TGF-β levels of 22 healthy controls and 99 MFS patients, and TGF-β levels after 1 month of losartan treatment in 42 MFS patients were measured. AoDR was assessed by magnetic resonance imaging at baseline and after 3 years of follow-up. Results Patients with MFS had higher TGF-β levels compared with healthy controls (121 pg/ml versus 54 pg/mL, p = 0.006). After 1 month of therapy, losartan normalised the TGF-β level in 15 patients (36%); the other 27 patients (64%) showed a significant increase of TGF-β. After 3 years of losartan therapy, patients with a decrease in TGF-β had significantly higher AoDR compared with patients with increased TGF-β (1.5 mm/3 years versus 0.5 mm/3 years, p = 0.04). Patients showing a decrease in TGF-β after losartan therapy had significantly elevated baseline TGF-β levels compared with patients with increased TGF-β (189 pg/ml versus 94 pg/ml, p = 0.05). Conclusion Patients responding to losartan therapy with a reduction of the plasma TGF-β level had higher baseline TGF-β levels and a higher AoDR. Most likely, TGF-β levels may be considered to be a readout of the disease state of the aorta. We propose that increased angiotensin II is the initiator of aorta dilatation and is responsible for increased TGF-β levels in MFS. The concept of TGF-β as initiator of aortic dilatation in MFS patients should be nuanced.
    Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 10/2014; 23(2). DOI:10.1007/s12471-014-0622-0 · 2.26 Impact Factor
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    ABSTRACT: In prognostic studies, the lasso technique is attractive since it improves the quality of predictions by shrinking regression coefficients, compared to predictions based on a model fitted via unpenalized maximum likelihood. Since some coefficients are set to zero, parsimony is achieved as well. It is unclear whether the performance of a model fitted using the lasso still shows some optimism. Bootstrap methods have been advocated to quantify optimism and generalize model performance to new subjects. It is unclear how resampling should be performed in the presence of multiply imputed data.
    BMC Medical Research Methodology 10/2014; 14(1):116. DOI:10.1186/1471-2288-14-116 · 2.17 Impact Factor
  • Jammbe Z. Musoro, Ronald B. Geskus, Aeilko H. Zwinderman
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    ABSTRACT: This paper presents an extension of the joint modeling strategy for the case of multiple longitudinal outcomes and repeated infections of different types over time, motivated by postkidney transplantation data. Our model comprises two parts linked by shared latent terms. On the one hand is a multivariate mixed linear model with random effects, where a low-rank thin-plate spline function is incorporated to collect the nonlinear behavior of the different profiles over time. On the other hand is an infection-specific Cox model, where the dependence between different types of infections and the related times of infection is through a random effect associated with each infection type to catch the within dependence and a shared frailty parameter to capture the dependence between infection types. We implemented the parameterization used in joint models which uses the fitted longitudinal measurements as time-dependent covariates in a relative risk model. Our proposed model was implemented in OpenBUGS using the MCMC approach.
    Biometrical Journal 10/2014; DOI:10.1002/bimj.201300167 · 1.15 Impact Factor
  • Wouter Ouwerkerk, Adriaan A. Voors, Aeilko H. Zwinderman
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    ABSTRACT: The present paper systematically reviews and compares existing prediction models in order to establish the strongest variables, models, and model characteristics in patients with heart failure predicting outcome. To improve decision making accurately predicting mortality and heart-failure hospitalization in patients with heart failure can be important for selecting patients with a poorer prognosis or nonresponders to current therapy, to improve decision making. MEDLINE/PubMed was searched for papers dealing with heart failure prediction models. To identify similar models on the basis of their variables hierarchical cluster analysis was performed. Meta-analysis was used to estimate the mean predictive value of the variables and models; meta-regression was used to find characteristics that explain variation in discriminating values between models. We identified 117 models in 55 papers. These models used 249 different variables. The strongest predictors were blood urea nitrogen and sodium. Four subgroups of models were identified. Mortality was most accurately predicted by prospective registry-type studies using a large number of clinical predictor variables. Mean C-statistic of all models was 0.66 ± 0.0005, with 0.71 ± 0.001, 0.68 ± 0.001 and 0.63 ± 0.001 for models predicting mortality, heart failure hospitalization, or both, respectively. There was no significant difference in discriminating value of models between patients with chronic and acute heart failure. Prediction of mortality and in particular heart failure hospitalization in patients with heart failure remains only moderately successful. The strongest predictors were blood urea nitrogen and sodium. The highest C-statistic values were achieved in a clinical setting, predicting short-term mortality with the use of models derived from prospective cohort/registry studies with a large number of predictor variables.
    10/2014; DOI:10.1016/j.jchf.2014.04.006
  • M. H. P. Hof, A. H. Zwinderman
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    ABSTRACT: Combining information from two data sources depends on finding records that belong to the same individual (matches). Sometimes, unique identifiers per individual are not available, and we have to rely on partially identifying variables that are registered in both data sources. A risk of relying on these variables is that some records from both datasets are wrongly linked to each other, which introduces bias in further regression analyses. In this paper, we propose a mixture model where we treat the indicator whether records belong to the same individual as missing. Each pair of records from both datasets contributes independently to a pairwise pseudo-likelihood, which we maximize with an expectation–maximization algorithm. Each part of the pseudo-likelihood is parameterized by the appropriate (parametric) density function. Moreover, some structures of the data allow for simplifying assumptions, which makes the pseudo-likelihood considerably easier to parameterize. Because the optimization requires a product over all combinations of records from both datasets, we suggest a procedure that summarizes information from highly unlikely matches. With simulations, we showed that the new approach produces accurate estimates in different linkage scenarios. Moreover, the estimator remained accurate in scenarios where previously proposed analysis approaches give biased results. We applied the method to estimation of the association between pregnancy duration of the first and second born children from the same mother from a register without mother identifier. Copyright © 2014 John Wiley & Sons, Ltd.
    Statistics in Medicine 10/2014; 34(1). DOI:10.1002/sim.6315 · 2.04 Impact Factor
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    ABSTRACT: Infections occur in 30% of stroke patients and are associated with unfavorable outcomes. Preventive antibiotic therapy lowers the infection rate after stroke, but the effect of preventive antibiotic treatment on functional outcome in patients with stroke is unknown. The PASS is a multicenter, prospective, phase three, randomized, open-label, blinded end-point (PROBE) trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to standard stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. The aim of this study is to assess whether preventive antibiotic treatment improves functional outcome at 3 months by preventing infections. This paper presents in detail the statistical analysis plan (SAP) of the Preventive Antibiotics in Stroke Study (PASS) and was submitted while the investigators were still blinded for all outcomes.
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    ABSTRACT: Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. In the FBN1C1039G/+ Marfan mouse model, losartan decreases aortic root dilatation. We recently confirmed this beneficial effect of losartan in adult patients with Marfan syndrome. The straightforward translation of this mouse model to man is reassuring to test novel treatment strategies. A number of studies have shown signs of inflammation in aortic tissue of Marfan patients. This study examined the efficacy of anti-inflammatory therapies in attenuating aortic root dilation in Marfan syndrome and compared effects to the main preventative agent, losartan.
    PLoS ONE 09/2014; 9(9):e107221. DOI:10.1371/journal.pone.0107221 · 3.53 Impact Factor
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    ABSTRACT: Background: Patients who visit their General Practitioner (GP) very frequently over extended periods of time often have multimorbidity and are costly in primary and specialist healthcare. We investigated the impact of patient-level psychosocial and GP-level factors on the persistence of frequent attendance (FA) in primary care. Methods: Two-year prospective cohort study in 623 incident adult frequent attenders (N90th attendance centile; age and sex-adjusted) in 2009. Information was collected through questionnaires (patients, GPs) and GPs' patient data. We used multilevel, ordinal logistic regression analysis, controlling for somatic illness and demographic fac-tors with FA in 2010 and/or 2011 as the outcome. Results: Other anxiety (odds ratio (OR) 2.00; 95% confidence interval from 1.29 to 3.10) over 3 years and the number of life events in 3 years (OR 1.06; 1.01–1.10 per event; range of 0 to 12) and, at baseline, panic disorder (OR 5.40; 1.67–17.48), other anxiety (OR 2.78; 1.04–7.46), illness behavior (OR 1.13; 1.05–1.20 per point; 28-point scale) and lack of mastery (OR 1.08; 1.01–1.15 per point; 28-point scale) were associated with persistence of FA. We found no evidence of synergistic effects of somatic, psychological and social problems. We found no strong evidence of effects of GP characteristics. Conclusion: Panic disorder, other anxiety, negative life events, illness behavior and lack of mastery are indepen-dently associated with persistence of frequent attendance. Effective intervention at these factors, apart from their intrinsic benefits to these patients, may reduce attendance rates, and healthcare expenditures in primary and specialist care.
    Journal of Psychosomatic Research 08/2014; j.jpsychores.2014.08.003.. DOI:10.1016/j.jpsychores.2014.08.003 · 2.84 Impact Factor
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    ABSTRACT: 2. The history of diagnosing Marfan syndrome 3. The FBN1 gene 4. Overview of literature 5. Different types of FBN1 mutations 6. Conclusion 7. Expert opinion Introduction: Marfan syndrome (MFS) is a connective tissue disorder with highly variable features in cardiovascular, ocular and skeletal systems. MFS is generally caused by one of the 2900-plus described different genetic mutations in the fibrillin-1 gene (FBN1). Areas covered: By revising the Ghent criteria in 2010, more weight has been given to genetic testing in the diagnosis of MFS. We provide an overview of correlations between different mutation types and clinical MFS features by using the Universal Mutation Database (UMD). Expert opinion: In this paper, we classified FBN1 mutations based on their action on DNA level and we found the following genotype--phenotype corre-lations: i) cysteine mutations are associated with ectopia lentis; ii) introduc-tion of a cysteine leads to less severe involvement of cardiovascular and skeletal system; iii) whole gene deletions and premature termination codon (PTC) mutations are associated with increased skeletal and cardiovascular involvement, but lower prevalence of ectopia lentis and iv) intronic mutations lead to MFS by exon skipping, small insertions/deletions and PTC mutations. Classification based on mutation effect at protein level (reduced vs truncated/deformed fibrillin-1) may partly explain genotype--phenotype asso-ciation and warrants further investigation for individualized prognosis and treatment.
    08/2014; 2(10). DOI:10.1517/21678707.2014.950223
  • N van Geloven, R B Geskus, B W Mol, A H Zwinderman
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    ABSTRACT: When estimating the probability of natural conception from observational data on couples with an unfulfilled child wish, the start of assisted reproductive therapy (ART) is a competing event that cannot be assumed to be independent of natural conception. In clinical practice, interest lies in the probability of natural conception in the absence of ART, as this probability determines the need for therapy. We thus want to estimate the marginal cumulative pregnancy distribution. Without assumptions on the dependence structure between the two competing events, this marginal distribution is not identifiable. We first use inverse probability of censoring weighting assuming that the factors influencing the choice to start ART are known. Then, we parameterize the event distributions for conception and for start of ART and use copulas to account for the dependency between both events. By using these two ways of correcting for the dependent risk of treatment, we obtain a plausible estimation region for the cumulative pregnancy curve and for the prognostic effect of tubal tests. Copyright © 2014 John Wiley & Sons, Ltd.
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    ABSTRACT: Objectives: To investigate how the summary estimates in diagnostic test accuracy (DTA) systematic reviews are affected when searches are limited to MEDLINE. Study Design and Setting: A systematic search was performed to identify DTA reviews that had conducted exhaustive searches and included a meta-analysis. Primary studies included in selected reviews were assessed to determine whether they were indexed on MEDLINE. The effect of omitting non-MEDLINE studies from meta-analyses was investigated by calculating the summary relative diagnostic odds ratio (RDORs) = DORMEDLINE (only)/DORall (studies). We also calculated the summary difference in sensitivity and specificity between all studies and only MEDLINE-indexed studies. Results: Ten reviews contributing 15 meta-analyses met inclusion criteria for quantitative analysis. The RDOR comparing MEDLINE-only studies with all studies was 1.04 (95% confidence interval [CI], 0.95, 1.15). Summary estimates of sensitivity and specificity remained almost unchanged (difference in sensitivity: -0.08%; 95% CI -1% to 1%; difference in specificity: -0.1%; 95% CI -0.8% to 1%). Conclusion: Restricting to studies indexed on MEDLINE did not influence the summary estimates of the meta-analyses in our sample. In certain circumstances, for instance, when resources are limited, it may be appropriate to restrict searches to MEDLINE. However, the impact on individual reviews cannot be predicted.
    Journal of Clinical Epidemiology 07/2014; 67(11). DOI:10.1016/j.jclinepi.2014.05.008 · 5.48 Impact Factor

Publication Stats

23k Citations
4,137.90 Total Impact Points

Institutions

  • 2015
    • University Medical Center Utrecht
      • Julius Center for Health Sciences and Primary Care
      Utrecht, Utrecht, Netherlands
  • 2013–2015
    • Netherlands Bioinformatics Centre
      Nymegen, Gelderland, Netherlands
  • 1998–2015
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Department of Clinical Epidemiology and Biostatistics
      • • Department of Cardiology and Cardio-thoracic Surgery
      • • Academic Medical Center
      • • Department of Medical Biochemistry
      • • Department of Vascular Medicine
      Amsterdamo, North Holland, Netherlands
  • 2003–2014
    • University of Amsterdam
      • • Department of Clinical Epidemiology and Biostatistics
      • • Department of Neurology
      Amsterdamo, North Holland, Netherlands
  • 1992–2014
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
  • 1990–2013
    • Leiden University Medical Centre
      • • Department of Cardiology
      • • Department of Neurology
      • • Department of Rheumatology
      • • Department of Nephrology
      • • Department of Urology
      Leyden, South Holland, Netherlands
  • 2000–2012
    • Albert Schweitzer Ziekenhuis
      Dordt, South Holland, Netherlands
  • 2011
    • Ludwig-Maximilian-University of Munich
      • Department of Neurology
      München, Bavaria, Germany
  • 2005–2010
    • Collège de France
      Lutetia Parisorum, Île-de-France, France
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
  • 1990–2009
    • Leiden University
      • Leiden Amsterdam Center for Drug Research
      Leyden, South Holland, Netherlands
  • 2004–2005
    • University of Groningen
      Groningen, Groningen, Netherlands
    • Universiteit Twente
      Enschede, Overijssel, Netherlands
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Medisch Centrum Leeuwarden
      Leewarden, Friesland, Netherlands
  • 2002
    • Medisch Spectrum Twente
      • Rheumatology Department
      Enschede, Overijssel, Netherlands
  • 2001
    • University of British Columbia - Vancouver
      • Centre for Molecular Medicine and Therapeutics
      Vancouver, British Columbia, Canada
  • 1999–2001
    • Centraal Bureau voor de Statistiek
      's-Gravenhage, South Holland, Netherlands
  • 1995–1999
    • Netherlands Institute for Space Research, Utrecht
      Utrecht, Utrecht, Netherlands
  • 1997
    • Martini Ziekenhuis
      Groningen, Groningen, Netherlands
  • 1990–1996
    • St. Antonius Ziekenhuis
      • • Department of Cardiology
      • • Department of Nuclear Medicine
      Nieuwegen, Utrecht, Netherlands
  • 1993
    • Canisius-Wilhelmina Ziekenhuis
      Nymegen, Gelderland, Netherlands
  • 1991
    • Diakonessenhuis Utrecht
      Utrecht, Utrecht, Netherlands