Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

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.

Monitoring asthma in children.

The goal of asthma treatment is to obtain clinical control and reduce future risks to the patient. To reach this goal in children with asthma, ongoing monitoring is essential. While all components of asthma, such as symptoms, lung function, bronchial hyperresponsiveness and inflammation, may exist in various combinations in different individuals, to date there is limited evidence on how to integrate these for optimal monitoring of children with asthma. The aims of this ERS Task Force were to describe the current practise and give an overview of the best available evidence on how to monitor children with asthma. 22 clinical and research experts reviewed the literature. A modified Delphi method and four Task Force meetings were used to reach a consensus. This statement summarises the literature on monitoring children with asthma. Available tools for monitoring children with asthma, such as clinical tools, lung function, bronchial responsiveness and inflammatory markers, are described as are the ways in which they may be used in children with asthma. Management-related issues, comorbidities and environmental factors are summarised. Despite considerable interest in monitoring asthma in children, for many aspects of monitoring asthma in children there is a substantial lack of evidence.

The unruptured intracranial aneurysm treatment score: a multidisciplinary consensus.

OBJECTIVE We endeavored to develop an unruptured intracranial aneurysm (UIA) treatment score (UIATS) model that includes and quantifies key factors involved in clinical decision-making in the management of UIAs and to assess agreement for this model among specialists in UIA management and research. METHODS An international multidisciplinary (neurosurgery, neuroradiology, neurology, clinical epidemiology) group of 69 specialists was convened to develop and validate the UIATS model using a Delphi consensus. For internal (39 panel members involved in identification of relevant features) and external validation (30 independent external reviewers), 30 selected UIA cases were used to analyze agreement with UIATS management recommendations based on a 5-point Likert scale (5 indicating strong agreement). Interrater agreement (IRA) was assessed with standardized coefficients of dispersion (vr*) (vr* = 0 indicating excellent agreement and vr* = 1 indicating poor agreement). RESULTS The UIATS accounts for 29 key factors in UIA management. Agreement with UIATS (mean Likert scores) was 4.2 (95% confidence interval [CI] 4.1-4.3) per reviewer for both reviewer cohorts; agreement per case was 4.3 (95% CI 4.1-4.4) for panel members and 4.5 (95% CI 4.3-4.6) for external reviewers (p = 0.017). Mean Likert scores were 4.2 (95% CI 4.1-4.3) for interventional reviewers (n = 56) and 4.1 (95% CI 3.9-4.4) for noninterventional reviewers (n = 12) (p = 0.290). Overall IRA (vr*) for both cohorts was 0.026 (95% CI 0.019-0.033). CONCLUSIONS This novel UIA decision guidance study captures an excellent consensus among highly informed individuals on UIA management, irrespective of their underlying specialty. Clinicians can use the UIATS as a comprehensive mechanism for indicating how a large group of specialists might manage an individual patient with a UIA.

Psychometric properties of the Trauma and Distress Scale, TADS, in an adult community sample in Finland

BACKGROUND: There is increasing evidence that a history of childhood abuse and neglect is not uncommon among individuals who experience mental disorder and that childhood trauma experiences are associated with adult psychopathology. Although several interview and self-report instruments for retrospective trauma assessment have been developed, many focus on sexual abuse (SexAb) rather than on multiple types of trauma or adversity. METHODS: Within the European Prediction of Psychosis Study, the Trauma and Distress Scale (TADS) was developed as a new self-report assessment of multiple types of childhood trauma and distressing experiences. The TADS includes 43 items and, following previous measures including the Childhood Trauma Questionnaire, focuses on five core domains: emotional neglect (EmoNeg), emotional abuse (EmoAb), physical neglect (PhyNeg), physical abuse (PhyAb), and SexAb.This study explores the psychometric properties of the TADS (internal consistency and concurrent validity) in 692 participants drawn from the general population who completed a mailed questionnaire, including the TADS, a depression self-report and questions on help-seeking for mental health problems. Inter-method reliability was examined in a random sample of 100 responders who were reassessed in telephone interviews. RESULTS: After minor revisions of PhyNeg and PhyAb, internal consistencies were good for TADS totals and the domain raw score sums. Intra-class coefficients for TADS total score and the five revised core domains were all good to excellent when compared to the interviewed TADS as a gold standard. In the concurrent validity analyses, the total TADS and its all core domains were significantly associated with depression and help-seeking for mental problems as proxy measures for traumatisation. In addition, robust cutoffs for the total TADS and its domains were calculated. CONCLUSIONS: Our results suggest the TADS as a valid, reliable, and clinically useful instrument for assessing retrospectively reported childhood traumatisation.

Isotopic ratios, concentration of noble gases and mineral and bulk composition of extraterrestrial dust particles in Dome Fuji ice core, East Antarctica

Two silicate-rich dust layers were found in the Dome Fuji ice core in East Antarctica, at Marine Isotope Stages 12 and 13. Morphologies, textures, and chemical compositions of constituent particles reveal that they are high-temperature melting products and are of extraterrestrial origin. Because similar layers were found ~2000 km east of Dome Fuji, at EPICA (European Project for Ice Coring in Antarctica)-Dome C, particles must have rained down over a wide area 434 and 481 ka. The strewn fields occurred over an area of at least 3 × 10**6 km**2. Chemical compositions of constituent phases and oxygen isotopic composition of olivines suggest that the upper dust layer was produced by a high-temperature interaction between silicate-rich melt and water vapor due to an impact explosion or an aerial burst of a chondritic meteoroid on the inland East Antarctic ice sheet. An estimated total mass of the impactor, on the basis of particle flux and distribution area, is at least 3 × 10**9 kg. A possible parent material of the lower dust layer is a fragment of friable primitive asteroid or comet. A hypervelocity impact of asteroidal/cometary material on the upper atmosphere and an explosion might have produced aggregates of sub-µm to µm-sized spherules. Total mass of the parent material of the lower layer must exceed 1 × 10**9 kg. The two extraterrestrial horizons, each a few millimeters in thickness, represent regional or global meteoritic events not identified previously in the Southern Hemisphere.