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- Arking, D. E., et al.
(author)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Journal article (peer-reviewed)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 5. |
- van Setten, Jessica, et al.
(author)
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PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
- 2018
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genomewide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are overrepresented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of similar to 105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
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| 9. |
- Cunningham, S. G., et al.
(author)
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Core Standards of the EUBIRO Project Defining a European Diabetes Data Dictionary for Clinical Audit and Healthcare Delivery
- 2016
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In: Methods of Information in Medicine. - : Georg Thieme Verlag KG. - 0026-1270 .- 2511-705X. ; 55:2, s. 166-176
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Journal article (peer-reviewed)abstract
- Background: A set of core diabetes indicators were identified in a clinical review of current evidence for the EUBIROD project. In order to allow accurate comparisons of diabetes indicators, a standardised currency for data storage and aggregation was required. We aimed to define a robust European data dictionary with appropriate clinical definitions that can be used to analyse diabetes outcomes and provide the foundation for data collection from existing electronic health records for diabetes. Methods: Existing clinical datasets used by 15 partner institutions across Europe were collated and common data items analysed for consistency in terms of recording, data definition and units of measurement. Where necessary, data mappings and algorithms were specified in order to allow partners to meet the standard definitions. A series of descriptive elements were created to document metadata for each data item, including recording, consistency, completeness and quality. Results: While datasets varied in terms of consistency, it was possible to create a common standard that could be used by all. The minimum dataset defined 53 data items that were classified according to their feasibility and validity. Mappings and standardised definitions were used to create an electronic directory for diabetes care, providing the foundation for the EUBIROD data analysis repository, also used to implement the diabetes registry and model of care for Cyprus. Conclusions: The development of data dictionaries and standards can be used to improve the quality and comparability of health information. A data dictionary has been developed to be compatible with other existing data sources for diabetes, within and beyond Europe.
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| 10. |
- Piras, F, et al.
(author)
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White matter microstructure and its relation to clinical features of obsessive-compulsive disorder: findings from the ENIGMA OCD Working Group
- 2021
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In: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1, s. 173-
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Journal article (peer-reviewed)abstract
- Microstructural alterations in cortico-subcortical connections are thought to be present in obsessive–compulsive disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Here we investigated microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. We analyzed diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA OCD Working Group, in a cross-sectional case-control magnetic resonance study. We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen’s d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Adult OCD patients showed significant FA reduction in the sagittal stratum (d = −0.21, z = −3.21, p = 0.001) and posterior thalamic radiation (d = −0.26, z = −4.57, p < 0.0001). In the sagittal stratum, lower FA was associated with a younger age of onset (z = 2.71, p = 0.006), longer duration of illness (z = −2.086, p = 0.036), and a higher percentage of medicated patients in the cohorts studied (z = −1.98, p = 0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to controls. Our findings of microstructural alterations in projection and association fibers to posterior brain regions in OCD are consistent with models emphasizing deficits in connectivity as an important feature of this disorder.
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| 13. |
- Cunningham, S G, et al.
(author)
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Core Standards of the EUBIROD Project. Defining a European Diabetes Data Dictionary for Clinical Audit and Healthcare Delivery.
- 2016
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In: Methods of information in medicine. - 2511-705X. ; 55:2, s. 166-76
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Journal article (peer-reviewed)abstract
- A set of core diabetes indicators were identified in a clinical review of current evidence for the EUBIROD project. In order to allow accurate comparisons of diabetes indicators, a standardised currency for data storage and aggregation was required. We aimed to define a robust European data dictionary with appropriate clinical definitions that can be used to analyse diabetes outcomes and provide the foundation for data collection from existing electronic health records for diabetes.Existing clinical datasets used by 15 partner institutions across Europe were collated and common data items analysed for consistency in terms of recording, data definition and units of measurement. Where necessary, data mappings and algorithms were specified in order to allow partners to meet the standard definitions. A series of descriptive elements were created to document metadata for each data item, including recording, consistency, completeness and quality.While datasets varied in terms of consistency, it was possible to create a common standard that could be used by all. The minimum dataset defined 53 data items that were classified according to their feasibility and validity. Mappings and standardised definitions were used to create an electronic directory for diabetes care, providing the foundation for the EUBIROD data analysis repository, also used to implement the diabetes registry and model of care for Cyprus.The development of data dictionaries and standards can be used to improve the quality and comparability of health information. A data dictionary has been developed to be compatible with other existing data sources for diabetes, within and beyond Europe.
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| 18. |
- Matino, D., et al.
(author)
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Switching clotting factor concentrates: considerations in estimating the risk of immunogenicity
- 2014
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In: Haemophilia. - : Wiley. - 1351-8216. ; 20:2, s. 200-206
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Journal article (peer-reviewed)abstract
- The development of neutralizing antibodies to factor VIII (FVIII) is the most serious complication of therapy for haemophilia A. There is now excellent documentation that a large number of both genetic and environmental factors contribute to the risk of FVIII inhibitor incidence. One of the environmental factors that has been proposed as an influence on this complication is the occurrence of FVIII product switching. There are only a small number of clinical studies that have addressed this question, and thus, the amount of objective information available to assess this association is limited. In this review, in addition to summarizing past evidence pertinent to this subject, we present the results of a complementary strategy, a Delphi analysis, to add to the considerations of product switching and FVIII immunogenicity. With the imminent arrival in the clinic of several new FVIII products, the haemophilia community must be prepared to collect prospectively controlled data to better address this important management issue.
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| 19. |
- Alper, BS, et al.
(author)
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Defining certainty of net benefit: a GRADE concept paper
- 2019
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In: BMJ open. - : BMJ. - 2044-6055. ; 9:6, s. e027445-
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Journal article (peer-reviewed)abstract
- Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology is used to assess and report certainty of evidence and strength of recommendations. This GRADE concept article is not GRADE guidance but introduces certainty of net benefit, defined as the certainty that the balance between desirable and undesirable health effects is favourable. Determining certainty of net benefit requires considering certainty of effect estimates, the expected importance of outcomes and variability in importance, and the interaction of these concepts. Certainty of net harm is the certainty that the net effect is unfavourable. Guideline panels using or testing this approach might limit strong recommendations to actions with a high certainty of net benefit or against actions with a moderate or high certainty of net harm. Recommendations may differ in direction or strength from that suggested by the certainty of net benefit or harm when influenced by cost, equity, acceptability or feasibility.
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| 21. |
- Hultcrantz, Monica, et al.
(author)
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The GRADE Working Group clarifies the construct of certainty of evidence
- 2017
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In: Journal of Clinical Epidemiology. - : Pergamon Press. - 0895-4356 .- 1878-5921. ; 87, s. 4-13
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Journal article (peer-reviewed)abstract
- Objective: To clarify the grading of recommendations assessment, development and evaluation (GRADE) definition of certainty of evidence and suggest possible approaches to rating certainty of the evidence for systematic reviews, health technology assessments, and guidelines. Study Design and Setting: This work was carried out by a project group within the GRADE Working Group, through brainstorming and iterative refinement of ideas, using input from workshops, presentations, and discussions at GRADE Working Group meetings to produce this document, which constitutes official GRADE guidance. Results: Certainty of evidence is best considered as the certainty that a true effect lies on one side of a specified threshold or within a chosen range. We define possible approaches for choosing threshold or range. For guidelines, what we call a fully contextualized approach requires simultaneously considering all critical outcomes and their relative value. Less-contextualized approaches, more appropriate for systematic reviews and health technology assessments, include using specified ranges of magnitude of effect, for example, ranges of what we might consider no effect, trivial, small, moderate, or large effects. Conclusion: It is desirable for systematic review authors, guideline panelists, and health technology assessors to specify the threshold or ranges they are using when rating the certainty in evidence. (C) 2017 The Authors. Published by Elsevier Inc.
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| 22. |
- Iorio, A., et al.
(author)
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Characterization of hydration water in supercooled water-trehalose solutions : The role of the hydrogen bonds network
- 2019
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In: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 151:4
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Journal article (peer-reviewed)abstract
- The structural and dynamical properties of hydration water in aqueous solutions of trehalose are studied with molecular dynamics simulation. We simulate the systems in the supercooled region to investigate how the interaction with the trehalose molecules modifies the hydrogen bond network, the structural relaxation, and the diffusion properties of hydration water. The analysis is performed by considering the radial distribution functions, the residence time of water molecules in the hydration shell, the two body excess entropy, and the hydrogen bond water-water and water-trehalose correlations of the hydration water. The study of the two body excess entropy shows the presence of a fragile to strong crossover in supercooled hydration water also found in the relaxation time of the water-water hydrogen bond correlation function, and this is in agreement with predictions of the mode coupling theory and of previous studies of the oxygen-oxygen density correlators [A. Iorio et al., J. Mol. Liq. 282, 617 (2019); Sci. China: Phys., Mech. Astron. 62, 107011 (2019)]. The water-trehalose hydrogen bond correlation function instead evidences a strong to strong crossover in the relaxation time, and this crossover is related to a trehalose dynamical transition. This signals the role that the strong interplay between the soluted molecules and the surrounding solvent has in determining the dynamical transition common to both components of the system that happens upon cooling and that is similar to the well known protein dynamical transition. We connect our results with the cryoprotecting role of trehalose molecules.
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| 23. |
- Iorio Di, C T, et al.
(author)
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Cross-border flow of health information: is 'privacy by design' enough? Privacy performance assessment in EUBIROD.
- 2013
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In: European Journal of Public Health. - : Oxford University Press (OUP). - 1101-1262 .- 1464-360X. ; 23:2, s. 247-53
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Journal article (peer-reviewed)abstract
- Background: The EUBIROD project aims to perform a cross-border flow of diabetes information across 19 European countries using the BIRO information system, which embeds privacy principles and data protection mechanisms in its architecture (privacy by design). A specific task of EUBIROD was to investigate the variability in the implementation of the EU Data Protection Directive (DPD) across participating centres. Methods: Compliance with privacy requirements was assessed by means of a specific questionnaire administered to all participating diabetes registers. Items included relevant issues e.g. patient consent, accountability of data custodian, communication (openness) and complaint procedures (challenging compliance), authority to disclose, accuracy, access and use of personal information, and anonymization. The identification of an ad hoc scoring system and statistical software allowed an overall quali-quantitative analysis and independent evaluation of questionnaire responses, automated through a dedicated IT platform (‘privacy performance assessment’). Results: A total of 18 diabetes registers from different countries completed the survey. Over 50% of the registers recorded a maximum score for accountability, openness, anonymization and challenging compliance. Low average values were found for disclosure and disposition, access, consent, use of personal information and accuracy. A high heterogeneity was found for anonymization, consent, accuracy and access. Conclusions: The novel method of privacy performance assessment realized in EUBIROD may improve the respect of privacy in each data source, reduce overall variability in the implementation of privacy principles and favour a sound and legitimate cross-border exchange of high quality data across Europe.
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