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Van Der Post R.S.,Radboud University Nijmegen | Vogelaar I.P.,Radboud University Nijmegen | Manders P.,Radboud University Nijmegen | Van Der Kolk L.E.,Netherlands Cancer Institute | And 13 more authors.
Gastroenterology | Year: 2015

Background & Aims Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1, and assessed their outcomes. The criteria were as follows: families with 2 or more cases of gastric cancer, with at least 1 patient diagnosed with diffuse gastric cancer (DGC) before age 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50. Methods We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in The Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; there were 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan-Meier method and Cox regression analysis were used to evaluate the overall survival of patients with and without CDH1 mutations. Results In a cohort study in The Netherlands, the HDGC criteria identified individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, or in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 year and 4% survived for 5 years; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 year and 13% survived for 5 years (P =.014 for comparative survival analysis between patients with and without a CDH1 mutation). Conclusions All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations. © 2015 by the AGA Institute. Source

Visser M.S.,Erasmus Medical Center | Zonneveld L.N.L.,Erasmus Medical Center | Zonneveld L.N.L.,Academic Medical CenterAmsterdam | Van't Spijker A.,Erasmus Medical Center | And 2 more authors.
Value in Health | Year: 2015

Objective The aim of the study was to evaluate the cost-effectiveness of a cognitive-behavioral group training compared with a wait-list control for patients with unexplained physical symptoms (UPS). Methods A probabilistic decision-analytic Markov model was developed with three health states (poor health, average health, and death) based on a cutoff score of the Physical Component Summary of the short-form 36 health survey. To assess the cost-effectiveness in terms of cost per quality-adjusted life-year (QALY), a societal perspective was adopted. The model consisted of cycles of 3 months and a time horizon of 4 years. Data for the model were derived from a randomized controlled trial, in which 162 patients with UPS were randomized either to cognitive-behavioral group training or to the wait-list control. Data were assessed at baseline and after the training of 3 months or after a wait-list period of 3 months. In addition, the training group was followed in an uncontrolled phase and assessed at 3 months and 1 year after the training. Results After 4 years, the group training was in terms of cost-effectiveness "dominant" compared with the wait-list control; there was a positive effect of 0.06 QALYs and a €828 reduction in costs. The cost-effectiveness improved with a longer time horizon. A threshold of a€30,000/QALY was passed after 18 months. The group training was cost saving after 33 months. Conclusions Cognitive-behavioral group training is a cost-effective treatment compared with the wait-list control for patients with UPS. © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Source

Mesman E.,University Utrecht | Birmaher B.B.,University of Pittsburgh | Goldstein B.I.,University of Toronto | Goldstein T.,University of Pittsburgh | And 12 more authors.
Journal of Affective Disorders | Year: 2016

Objective Accumulating evidence suggests cross-national differences in adults with bipolar disorder (BD), but also in the susceptibility of their offspring (bipolar offspring). This study aims to explore and clarify cross-national variation in the prevalence of categorical and dimensional psychopathology between bipolar offspring in the US and The Netherlands. Methods We compared levels of psychopathology in offspring of the Pittsburgh Bipolar Offspring Study (n=224) and the Dutch Bipolar Offspring Study (n=136) (age 10–18). Categorical psychopathology was ascertained through interviews using the Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS-PL), dimensional psychopathology by parental reports using the Child Behavior Checklist (CBCL). Results Higher rates of categorical psychopathology were observed in the US versus the Dutch samples (66% versus 44%). We found no differences in the overall prevalence of mood disorders, including BD-I or -II, but more comorbidity in mood disorders in US versus Dutch offspring (80% versus 34%). The strongest predictors of categorical psychopathology were maternal BD (OR: 1.72, p<.05), older age of the offspring (OR: 1.19, p<.05), and country of origin (US; OR: 2.17, p<.001). Regarding comorbidity, only country of origin (OR: 7.84, p<.001) was a significant predictor. In general, we found no differences in dimensional psychopathology based on CBCL reports. Limitations Preliminary measure of inter-site reliability. Conclusions We found cross-national differences in prevalence of categorical diagnoses of non-mood disorders in bipolar offspring, but not in mood disorder diagnoses nor in parent-reported dimensional psychopathology. Cross-national variation was only partially explained by between-sample differences. Cultural and methodological explanations for these findings warrant further study. © 2016 Elsevier B.V. Source

Guzzardi D.G.,University of Calgary | Barker A.J.,Northwestern University | Van Ooij P.,Northwestern University | Van Ooij P.,Academic Medical CenterAmsterdam | And 15 more authors.
Journal of the American College of Cardiology | Year: 2015

Background Suspected genetic causes for extracellular matrix (ECM) dysregulation in the ascending aorta in patients with bicuspid aortic valves (BAV) have influenced strategies and thresholds for surgical resection of BAV aortopathy. Using 4-dimensional (4D) flow cardiac magnetic resonance imaging (CMR), we have documented increased regional wall shear stress (WSS) in the ascending aorta of BAV patients. Objectives This study assessed the relationship between WSS and regional aortic tissue remodeling in BAV patients to determine the influence of regional WSS on the expression of ECM dysregulation. Methods BAV patients (n = 20) undergoing ascending aortic resection underwent pre-operative 4D flow CMR to regionally map WSS. Paired aortic wall samples (i.e., within-patient samples obtained from regions of elevated and normal WSS) were collected and compared for medial elastin degeneration by histology and ECM regulation by protein expression. Results Regions of increased WSS showed greater medial elastin degradation compared to adjacent areas with normal WSS: decreased total elastin (p = 0.01) with thinner fibers (p = 0.00007) that were farther apart (p = 0.001). Multiplex protein analyses of ECM regulatory molecules revealed an increase in transforming growth factor β-1 (p = 0.04), matrix metalloproteinase (MMP)-1 (p = 0.03), MMP-2 (p = 0.06), MMP-3 (p = 0.02), and tissue inhibitor of metalloproteinase-1 (p = 0.04) in elevated WSS regions, indicating ECM dysregulation in regions of high WSS. Conclusions Regions of increased WSS correspond with ECM dysregulation and elastic fiber degeneration in the ascending aorta of BAV patients, implicating valve-related hemodynamics as a contributing factor in the development of aortopathy. Further study to validate the use of 4D flow CMR as a noninvasive biomarker of disease progression and its ability to individualize resection strategies is warranted. © 2015 American College of Cardiology Foundation. Source

Unlu C.,Sint Lucas Andreas Hospital Amsterdam | Unlu C.,Academic Medical CenterAmsterdam | De Korte N.,Kennemer Gasthuis | Daniels L.,Academic Medical CenterAmsterdam | And 15 more authors.
BMC Surgery | Year: 2010

Background. Conservative treatment of uncomplicated or mild diverticulitis usually includes antibiotic therapy. It is, however, uncertain whether patients with acute diverticulitis indeed benefit from antibiotics. In most guidelines issued by professional organizations antibiotics are considered mandatory in the treatment of mild diverticulitis. This advice lacks evidence and is merely based on experts' opinion. Adverse effects of the use of antibiotics are well known, including allergic reactions, development of bacterial resistance to antibiotics and other side-effects. Methods. A randomized multicenter pragmatic clinical trial comparing two treatment strategies for uncomplicated acute diverticulitis. I) A conservative strategy with antibiotics: hospital admission, supportive measures and at least 48 hours of intravenous antibiotics which subsequently are switched to oral, if tolerated (for a total duration of antibiotic treatment of 10 days). II) A liberal strategy without antibiotics: admission only if needed on clinical grounds, supportive measures only. Patients are eligible for inclusion if they have a diagnosis of acute uncomplicated diverticulitis as demonstrated by radiological imaging. Only patients with stages 1a and 1b according to Hinchey's classification or "mild" diverticulitis according to the Ambrosetti criteria are included. The primary endpoint is time-to-full recovery within a 6-month follow-up period. Full recovery is defined as being discharged from the hospital, with a return to pre-illness activities, and VAS score below 4 without the use of daily pain medication. Secondary endpoints are proportion of patients who develop complicated diverticulitis requiring surgery or non-surgical intervention, morbidity, costs, health-related quality of life, readmission rate and acute diverticulitis recurrence rate. In a non-inferiority design 264 patients are needed in each study arm to detect a difference in time-to-full recovery of 5 days or more with a power of 85% and a confidence level of 95%. With an estimated one percent of patients lost to follow up, a total of 533 patients will be included. Conclusion. A clinically relevant difference of more than 5 days in time-to-full recovery between the two treatment strategies is not expected. The liberal strategy without antibiotics and without the strict requirement for hospital admission is anticipated to be more a more cost-effective approach. Trial registration. Trial registration number: NCT01111253. © 2010 nlü et al; licensee BioMed Central Ltd. Source

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