Aeilko H Zwinderman

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands

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Publications (816)4488.34 Total impact

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    ABSTRACT: Patients with Marfan syndrome (MFS) have a highly variable occurrence of aortic complications. Aortic tortuosity is often present in MFS and may help to identify patients at risk for aortic complications. 3D-visualization of the total aorta by MR imaging was performed in 211 adult MFS patients (28% with prior aortic root replacement) and 20 controls. A method to assess aortic tortuosity (aortic tortuosity index: ATI) was developed and reproducibility was tested. The relation between ATI and age, and body size and aortic dimensions at baseline was investigated. Relations between ATI at baseline and the occurrence of a clinical endpoint (aortic dissection, and/or aortic surgery) and aortic dilatation rate during 3years of follow-up were investigated. ATI intra- and interobserver agreements were excellent (ICC: 0.968 and 0.955, respectively). Mean ATI was higher in 28 age-matched MFS patients than in the controls (1.92±0.2 vs. 1.82±0.1, p=0.048). In the total MFS cohort, mean ATI was 1.87±0.20, and correlated with age (r=0.281, p<0.001), aortic root diameter (r=0.223, p=0.006), and aortic volume expansion rate (r=0.177, p=0.026). After 49.3±8.8months follow-up, 33 patients met the combined clinical endpoint (7 dissections) with a significantly higher ATI at baseline than patients without endpoint (1.98±0.2 vs. 1.86±0.2, p=0.002). Patients with an ATI>1.95 had a 12.8 times higher probability of meeting the combined endpoint (log rank-test, p<0.001) and a 12.1 times higher probability of developing an aortic dissection (log rank-test, p=0.003) compared to patients with an ATI<1.95. Increased ATI is associated with a more severe aortic phenotype in MFS patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    International journal of cardiology 09/2015; 194. DOI:10.1016/j.ijcard.2015.05.072 · 6.18 Impact Factor
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    ABSTRACT: Introduction: Patients with Marfan syndrome - caused by FBN1 mutations - have an increased risk of life-threatening aortic complications. It has been shown that losartan reduces aortic dilation rate in these patients. The response to losartan treatment, however, was highly variable between individuals. Here we investigate whether there is a difference in Losartan effectiveness in genetically classified subgroups. Methods: In this predefined sub-study of the COMPARE trial, we classified FBN1 mutations into: 1) Dominant negative mutations leading to a mutated fibrillin-1 protein incorporated in the extracellular matrix, 2) Haploinsufficient mutations leading to decreased amount of normal fibrillin-1 protein. The response to losartan therapy based on aortic root dilatation rate was compared between the two groups. Results: Baseline characteristics between treatment groups were similar. Overall, losartan significantly reduced aortic root dilatation rate. However, losartan only reduced aortic root dilatation rate in haploinsufficient patients and not in dominant negative patients. Conclusion: Marfan patients with haploinsufficient FBN1 mutations are more responsive to losartan therapy with respect to inhibition of aortic root dilatation rate compared to dominant negative patients. In order to predict response on losartan therapy, mutation classification should be performed for all Marfan patients. More research for novel treatment strategies is needed in Marfan patients with a dominant negative FBN1 mutation.
    European Society for Human Genetics, Glasgow UK; 06/2015
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    ABSTRACT: Radiotherapy is a well-known cause of adverse events (AEs). To reduce AEs, an innovative local treatment was developed in Amsterdam: Ablative surgery, MOuld brachytherapy and surgical REconstruction (AMORE). (1) to determine the prevalence of AEs in HNRMS survivors and (2) to compare AEs between survivors treated with the international standard: external beam radiotherapy (EBRT-based: London) and survivors treated with AMORE if feasible, otherwise EBRT (AMORE-based: Amsterdam). All HNRMS survivors, treated in London or Amsterdam between January 1990 and December 2010 (n=153), and alive ⩾2years post-treatment were eligible (n=113). A predefined list of AEs was assessed in a multidisciplinary clinic and graded according to the Common Terminology Criteria for Adverse Events. Eighty HNRMS survivors attended the clinic (median follow-up 10.5years); 63% experienced ⩾1 severe or disabling event, and 76% had ⩾5 AEs (any grade). Survivors with EBRT-based treatment were, after adjustment for site, age at diagnosis, and follow-up duration, at increased risk to develop any grade 3/4 event or ⩾5 AEs (any grade) compared with survivors with AMORE-based treatments (p=0.032 and 0.01, respectively). Five year overall survival (source population) after EBRT-based treatment was 75.0%, after AMORE-based treatment 76.9%, p=0.56. This study may serve as a baseline inventory and can be used in future studies for prospective assessments of AEs following the introduction of novel local treatment modalities. AMORE-based local treatment resulted in similar overall survival and a reduction of AEs secondary to local treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 05/2015; 51(11). DOI:10.1016/j.ejca.2015.02.010 · 4.82 Impact Factor
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    ABSTRACT: Small-study effects and time trends have been identified in meta-analyses of randomized trials. We evaluated whether these effects are also present in meta-analyses of diagnostic test accuracy studies. A systematic search identified test accuracy meta-analyses published between May and September 2012. In each meta-analysis, the strength of the associations between estimated accuracy of the test (diagnostic odds ratio (DOR), sensitivity, and specificity) and sample size and between accuracy estimates and time since first publication were evaluated using meta-regression models. The regression coefficients over all meta-analyses were summarized using random effects meta-analysis. Forty-six meta-analyses and their corresponding primary studies (N = 859) were included. There was a non-significant relative change in the DOR of 1.01 per 100 additional participants (95% CI 1.00 to 1.03; P = 0.07). In the subgroup of imaging studies, there was a relative increase in sensitivity of 1.13 per 100 additional diseased subjects (95% CI 1.05 to 1.22; P = 0.002). The relative change in DOR with time since first publication was 0.94 per 5 years (95% CI 0.80 to 1.10; P = 0.42). Sensitivity was lower in studies published later (relative change 0.89, 95% CI 0.80 to 0.99; P = 0.04). Small-study effects and time trends do not seem to be as pronounced in meta-analyses of test accuracy studies as they are in meta-analyses of randomized trials. Small-study effects seem to be reversed in imaging, where larger studies tend to report higher sensitivity.
    05/2015; 4(1):66. DOI:10.1186/s13643-015-0049-8
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    ABSTRACT: Although the ubiquitous detection of polybrominated diphenyl ether (PBDE) and organophosphate flame retardants (PFRs) in indoor dust have raised health concerns, only very few epidemiological studies have assessed their impact on human health. Inhalation of dust is an important exposure route of FRs, especially in children and can be hazardous for the respiratory health. Moreover, PFRs are structurally similar to organophosphate pesticides, which have been associated with allergic asthma. Thus, we investigated whether the concentrations of PFR and PBDEs in indoor dust are associated with development of childhood asthma. We selected 110 children who developed asthma at 4 or at 8 years old and 110 matched controls from a large prospective birth cohort (BAMSE-Barn, Allergy, Milieu Stockholm Epidemiology). We analysed the concentration of 7 PFRs and 21 PBDEs in dust collected around two months after birth from the mother's mattress. The abundance rank in dust was as follows: TBOEP>TPHP>mmp-TMPP>EHDPHP~TDCIPP>TCEP~TCIPP~BDE-209>BDE-99>BDE-47>BDE-153>BDE-183>BDE-100. There was no positive association between FRs in mattress dust and the development of childhood asthma. In contrast, mother's mattress dust collected of children who would develop asthma contained significant lower levels of TPHP and mmp-TMPP. This study provides data on a wide range of PFRs and PBDEs in dust samples and development of asthma in children. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Indoor Air 05/2015; DOI:10.1111/ina.12221 · 4.20 Impact Factor
  • American Journal of Respiratory and Critical Care Medicine 05/2015; 191(9):1086-1088. DOI:10.1164/rccm.201411-2010LE · 11.99 Impact Factor
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    ABSTRACT: A number of randomized trials are underway, which will address the effects of angiotensin receptor blockers (ARBs) on aortic root enlargement and a range of other end points in patients with Marfan syndrome. If individual participant data from these trials were to be combined, a meta-analysis of the resulting data, totaling approximately 2,300 patients, would allow estimation across a number of trials of the treatment effects both of ARB therapy and of β-blockade. Such an analysis would also allow estimation of treatment effects in particular subgroups of patients on a range of end points of interest and would allow a more powerful estimate of the effects of these treatments on a composite end point of several clinical outcomes than would be available from any individual trial. A prospective, collaborative meta-analysis based on individual patient data from all randomized trials in Marfan syndrome of (i) ARBs versus placebo (or open-label control) and (ii) ARBs versus β-blockers will be performed. A prospective study design, in which the principal hypotheses, trial eligibility criteria, analyses, and methods are specified in advance of the unblinding of the component trials, will help to limit bias owing to data-dependent emphasis on the results of particular trials. The use of individual patient data will allow for analysis of the effects of ARBs in particular patient subgroups and for time-to-event analysis for clinical outcomes. The meta-analysis protocol summarized in this report was written on behalf of the Marfan Treatment Trialists' Collaboration and finalized in late 2012, without foreknowledge of the results of any component trial, and will be made available online ( Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    American heart journal 05/2015; 169(5):605-612. DOI:10.1016/j.ahj.2015.01.011 · 4.56 Impact Factor
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    ABSTRACT: AIMS: The identification of sex differences in the prognosis of adults with a secundum atrial septal defect (ASD2) could help tailor their clinical management, as it has in other cardiovascular diseases. We investigated whether disparity between the sexes exists in long-term outcome of adult ASD2 patients. METHODS AND RESULTS: Patients with ASD2 classified as the primary defect were selected from the Dutch national registry of adult congenital heart disease. Survival stratified by sex was compared with a sex-matched general population. In a total of 2207 adult patients (mean age at inclusion 44.8 years, 33.0% male), 102 deaths occurred during a cumulative follow-up of 13 584 patient-years. Median survival was 79.7 years for men and 85.6 years for women with ASD2. Compared with the age- and sex-matched general population, survival was lower for male, but equal for female patients (P = 0.015 and 0.766, respectively). Logistic regression analyses showed that men had a higher risk of conduction disturbances (OR = 1.63; 95% CI, 1.22-2.17) supraventricular dysrhythmias (OR = 1.41; 1.12-1.77), cerebrovascular thromboembolic events (OR = 1.53; 1.10-2.12), and heart failure (OR = 1.91; 1.06-3.43). CONCLUSION: In contrast to women, adult men with an ASD2 have worse survival than a sex-matched general population. Male patients also have a greater risk of morbidity during adult life. Sex disparity in survival and morbidity suggests the need for a sex-specific clinical approach towards these patients.
    European Heart Journal 04/2015; DOI:10.1093/eurheartj/ehv097 · 14.72 Impact Factor
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    ABSTRACT: Intensive glucose control, often involving insulin treatment, failed to improve cardiovascular outcomes in several clinical trials. Observational studies reported an association between insulin use and cardiovascular disease (CVD) risk. It has therefore been suggested that insulin adversely affects CVD risk. To investigate the feasibility of this hypothesis, we studied the association between insulin dose and CVD risk in type 2 diabetes. A case-control study was conducted of new users of oral antidiabetics who were prescribed insulin, using the Dutch Pharmo database. Cases were hospitalized for a cardiovascular event (CVE) and matched 1:2 to patients who were not hospitalized for a CVE, by sex, age, duration of diabetes and type of oral antidiabetic. Patients were divided into tertiles according to mean daily insulin dose. Conditional logistic regression analyses were used to explore the association between insulin exposure and CVE risk. We included 836 patients (517 (62%) male, mean age 66 years). After adjusting for available potential confounders, including HbA1c and triglycerides, insulin exposure was positively related to CVE risk (odds ratios for high (≥53.0 U/day) and intermediate (24.3-52.9 U/day) vs. low exposure (≤24.2 U/day): 3.00 [95% confidence interval (CI) 1.70 to 5.28] and 2.03 [95% CI 1.17 to 3.52]. Our findings are in line with the suggestion that high-dose insulin therapy adversely affects CVD risk, but need to be interpreted with caution due to the observational nature of the study. The role of particularly high-dose insulin in the progression of CVD warrants further investigation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 03/2015; 240(2):318-323. DOI:10.1016/j.atherosclerosis.2015.03.040 · 3.97 Impact Factor
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    ABSTRACT: seCundum atrial septal defeCt is assoCiated with reduCed survival in adult men Moderated Poster Contributions Congenital Heart Disease Moderated Poster Theater, Poster Hall B1 Saturday, March 14, 2015, 11:45 a.m.-11:55 a.m. Session Title: Congenital Heart Disease: Quality & Outcomes Abstract Category: 10. Congenital Heart Disease: Adult Background: We investigated whether gender disparity exists in long-term outcome of adult ASD2 patients, as this might call for a gender-specific approach toward these patients.
    J Am Coll Cardiol, San Diego; 03/2015
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    ABSTRACT: Hazelnut allergy is birch pollen-driven in Northern/Western Europe and lipid transfer protein-driven in Spain and Italy. Little is known about other regions and other allergens. Establishing a molecular map of hazelnut allergy across Europe. In 12 European cities, subjects reporting reactions to hazelnut (n = 731) were evaluated and sensitization to 24 foods, 12 respiratory allergen sources, and latex was tested by using skin prick test and ImmunoCAP. A subset (124 of 731) underwent a double-blind placebo-controlled food challenge to hazelnut. Sera of 423 of 731 subjects were analyzed for IgE against 7 hazelnut allergens and cross-reactive carbohydrate determinants by ImmunoCAP. Hazelnut allergy was confirmed in 70% of those undergoing double-blind placebo-controlled food challenges. Birch pollen-driven hazelnut sensitization (Cor a 1) dominated in most cities, except in Reykjavik, Sofia, Athens, and Madrid, where reporting of hazelnut allergy was less frequent anyhow. In Athens, IgE against Cor a 8 dominated and strongly correlated with IgE against walnut, peach, and apple and against Chenopodium, plane tree, and mugwort pollen. Sensitization to seed storage proteins was observed in less than 10%, mainly in children, and correlated with IgE to nuts, seeds, and legumes. IgE to Cor a 12, observed in all cities (10% to 25%), correlated with IgE to nuts, seeds, and pollen. In adulthood, the importance of hazelnut sensitization to storage proteins, oleosin (Cor a 12), and Cor a 8 is diluted by the increased role of birch pollen cross-reactivity with Cor a 1. Cor a 8 sensitization in the Mediterranean is probably driven by diet in combination with pollen exposure. Hazelnut oleosin sensitization is prevalent across Europe; however, the clinical relevance remains to be established. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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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. -; Unique Identifier: NTR1423.
    Circulation Cardiovascular Genetics 01/2015; 8(2). 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.
    Journal of Allergy and Clinical Immunology 01/2015; 135(3). DOI:10.1016/j.jaci.2014.11.033 · 11.25 Impact Factor
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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, 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 · 45.22 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.
    Journal of Clinical Oncology 01/2015; 33(7). DOI:10.1200/JCO.2014.57.4756 · 17.88 Impact Factor
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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; 68(3). DOI:10.1016/j.jclinepi.2014.10.005 · 5.48 Impact Factor

Publication Stats

24k Citations
4,488.34 Total Impact Points


  • 2015
    • University Medical Center Utrecht
      • Julius Center for Health Sciences and Primary Care
      Utrecht, Utrecht, Netherlands
  • 2012–2015
    • Netherlands Bioinformatics Centre
      Nymegen, Gelderland, Netherlands
  • 2003–2015
    • University of Amsterdam
      • • Department of Clinical Epidemiology and Biostatistics
      • • Department of Neurology
      Amsterdamo, North Holland, Netherlands
  • 1992–2015
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Department of Clinical Epidemiology and Biostatistics
      • • Department of Cardiology and Cardio-thoracic Surgery
      • • Department of Medical Biochemistry
      • • Academic Medical Center
      • • Department of Vascular Medicine
      Amsterdamo, North Holland, Netherlands
  • 2003–2013
    • 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
  • 2005–2012
    • Collège de France
      Lutetia Parisorum, Île-de-France, France
    • Sapienza University of Rome
      Roma, Latium, Italy
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
  • 2000–2012
    • Albert Schweitzer Ziekenhuis
      Dordt, South Holland, Netherlands
  • 2011
    • Ludwig-Maximilian-University of Munich
      • Department of Neurology
      München, Bavaria, Germany
  • 1990–2009
    • Leiden University
      • Leiden Amsterdam Center for Drug Research
      Leyden, South Holland, Netherlands
  • 2008
    • AMC Health
      New York, New York, United States
  • 2004–2005
    • University of Groningen
      Groningen, Groningen, Netherlands
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
    • Universiteit Twente
      Enschede, Overijssel, 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
  • 1997–2001
    • Martini Ziekenhuis
      Groningen, Groningen, Netherlands
  • 1995–1999
    • Netherlands Institute for Space Research, Utrecht
      Utrecht, Utrecht, 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