A Bayesian Secondary Analysis in an Asthma Study

A recent study published in the New England Journal of Medicine by the Asthma Clinical Research Network (ACRN) compared three different treatments for their effectiveness in treating adults with uncontrolled asthma. This paper will describe the study design and its results, then detail the beginnings of a secondary analysis using Bayesian methods to estimate the parameters of interest. The methods will be explained, and the preliminary estimates given and contextualized. The paper will conclude with a discussion of the next steps and the goals for further analysis of the data in this study

Eccentric muscle challenge shows osteopontin polymorphism modulation of muscle damage.

A promoter polymorphism of the osteopontin (OPN) gene (rs28357094) has been associated with multiple inflammatory states, severity of Duchenne muscular dystrophy (DMD) and muscle size in healthy young adults. We sought to define the mechanism of action of the polymorphism, using allele-specific in vitroreporter assays in muscle cells, and a genotype-stratified intervention in healthy controls. In vitro reporter constructs showed the G allele to respond to estrogen treatment, whereas the T allele showed no transcriptional response. Young adult volunteers (n = 187) were enrolled into a baseline study, and subjects with specific rs28357094 genotypes enrolled into an eccentric muscle challenge intervention [n = 3 TT; n = 3 GG/GT (dominant inheritance model)]. Female volunteers carrying the G allele showed significantly greater inflammation and increased muscle volume change as determined by magnetic resonance imaging T1- and T2-weighted images after eccentric challenge, as well as greater decrement in biceps muscle force. Our data suggest a model where the G allele enables enhanced activities of upstream enhancer elements due to loss of Sp1 binding at the polymorphic site. This results in significantly greater expression of the pro-inflammatory OPN cytokine during tissue remodeling in response to challenge in G allele carriers, promoting muscle hypertrophy in normal females, but increased damage in DMD patients

Identification of Class I HLA T Cell Control Epitopes for West Nile Virus

The recent West Nile virus (WNV) outbreak in the United States underscores the importance of understanding human immune responses to this pathogen. Via the presentation of viral peptide ligands at the cell surface, class I HLA mediate the T cell recognition and killing of WNV infected cells. At this time, there are two key unknowns in regards to understanding protective T cell immunity: 1) the number of viral ligands presented by the HLA of infected cells, and 2) the distribution of T cell responses to these available HLA/viral complexes. Here, comparative mass spectroscopy was applied to determine the number of WNV peptides presented by the HLA-A*11:01 of infected cells after which T cell responses to these HLA/WNV complexes were assessed. Six viral peptides derived from capsid, NS3, NS4b, and NS5 were presented. When T cells from infected individuals were tested for reactivity to these six viral ligands, polyfunctional T cells were focused on the GTL9 WNV capsid peptide, ligands from NS3, NS4b, and NS5 were less immunogenic, and two ligands were largely inert, demonstrating that class I HLA reduce the WNV polyprotein to a handful of immune targets and that polyfunctional T cells recognize infections by zeroing in on particular HLA/WNV epitopes. Such dominant HLA/peptide epitopes are poised to drive the development of WNV vaccines that elicit protective T cells as well as providing key antigens for immunoassays that establish correlates of viral immunity. © 2013 Kaabinejadian et al

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia.

Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice

Associations with photoreceptor thickness measures in the UK Biobank.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness

ACC/AHA/SCAI/AMA–Convened PCPI/NCQA 2013 Performance Measures for Adults Undergoing Percutaneous Coronary Intervention A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures, the Society for Cardiovascular Angiography and Interventions, the American Medical Association–Convened Physician Consortium for Performance Improvement, and the National Committee for Quality Assurance

Journal of the American College of Cardiology Ó 2014 by the American College of Cardiology Foundation, American Heart Association, Inc., American Medical Association, and National Committee for Quality Assurance Published by Elsevier Inc. Vol. 63, No. 7, 2014 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.12.003 PERFORMANCE MEASURES ACC/AHA/SCAI/AMA–Convened PCPI/NCQA 2013 Performance Measures for Adults Undergoing Percutaneous Coronary Intervention A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures, the Society for Cardiovascular Angiography and Interventions, the American Medical Association–Convened Physician Consortium for Performance Improvement, and the National Committee for Quality Assurance Developed in Collaboration With the American Association of Cardiovascular and Pulmonary Rehabilitation and Mended Hearts Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and Mended Hearts WRITING COMMITTEE MEMBERS Brahmajee K. Nallamothu, MD, MPH, FACC, FAHA, Co-Chair*; Carl L. Tommaso, MD, FACC, FAHA, FSCAI, Co-Chairy; H. Vernon Anderson, MD, FACC, FAHA, FSCAI*; Jeffrey L. Anderson, MD, FACC, FAHA, MACP*; Joseph C. Cleveland, J R , MDz; R. Adams Dudley, MD, MBA; Peter Louis Duffy, MD, MMM, FACC, FSCAIy; David P. Faxon, MD, FACC, FAHA*; Hitinder S. Gurm, MD, FACC; Lawrence A. Hamilton, Neil C. Jensen, MHA, MBA; Richard A. Josephson, MD, MS, FACC, FAHA, FAACVPRx; David J. Malenka, MD, FACC, FAHA*; Calin V. Maniu, MD, FACC, FAHA, FSCAIy; Kevin W. McCabe, MD; James D. Mortimer, Manesh R. Patel, MD, FACC*; Stephen D. Persell, MD, MPH; John S. Rumsfeld, MD, PhD, FACC, FAHAjj; Kendrick A. Shunk, MD, PhD, FACC, FAHA, FSCAI*; Sidney C. Smith, J R , MD, FACC, FAHA, FACP{; Stephen J. Stanko, MBA, BA, AA#; Brook Watts, MD, MS *ACC/AHA Representative. ySociety of Cardiovascular Angiography and Interventions Representative. zSociety of Thoracic Surgeons Representative. xAmerican Association of Cardiovascular and Pulmonary Rehabilitation Representative. kACC/AHA Task Force on Performance Measures Liaison. {National Heart Lung and Blood Institute Representative. #Mended Hearts Representative. The measure specifications were approved by the American College of Cardiology Board of Trustees, American Heart Association Science Advisory and Coordinating Committee, in January 2013 and the American Medical Association–Physician Consortium for Performance Improvement in February 2013. This document was approved by the American College of Cardiology Board of Trustees and the American Heart Association Science Advisory and Coordinating Committee in October 2013, and the Society of Cardiovascular Angiography and Interventions in December 2013. The American College of Cardiology requests that this document be cited as follows: Nallamothu BK, Tommaso CL, Anderson HV, Anderson JL, Cleveland JC, Dudley RA, Duffy PL, Faxon DP, Gurm HS, Hamilton LA, Jensen NC, Josephson RA, Malenka DJ, Maniu CV, McCabe KW, Mortimer JD, Patel MR, Persell SD, Rumsfeld JS, Shunk KA, Smith SC, Stanko SJ, Watts B. ACC/AHA/SCAI/AMA–Convened PCPI/NCQA 2013 perfor- mance measures for adults undergoing percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures, the Society for Cardiovascular Angiography and Interventions, the American Medical Association–Convened Physician Consortium for Performance Improvement, and the National Committee for Quality Assurance. J Am Coll Cardiol 2014;63:722–45. This article has been copublished in Circulation. Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.cardiosource.org) and the American Heart Asso- ciation (http://my.americanheart.org). For copies of this document, please contact Elsevier Inc. Reprint Department, fax (212) 633-3820, e-mail [email protected]. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American College of Cardiology. Requests may be completed online via the Elsevier site (http://www.elsevier.com/authors/obtaining- permission-to-re-use-elsevier-material). This Physician Performance Measurement Set (PPMS) and related data specifications were developed by the Physician Consortium for Performance Improvement (the Consortium), including the American College of Cardiology (ACC), the American Heart Association (AHA), and the American Medical Association (AMA), to facilitate quality-improvement activities by physicians. The performance measures contained in this PPMS are not clinical guidelines, do not establish a standard of medical care, and have not been tested for all potential applications. Although copyrighted, they can be reproduced and distributed, without modification, for noncommercial purposesdfor example, use by health care pro

The New Horizons Spacecraft

The New Horizons spacecraft was launched on 19 January 2006. The spacecraft was designed to provide a platform for seven instruments that will collect and return data from Pluto in 2015. The design drew on heritage from previous missions developed at The Johns Hopkins University Applied Physics Laboratory (APL) and other missions such as Ulysses. The trajectory design imposed constraints on mass and structural strength to meet the high launch acceleration needed to reach the Pluto system prior to the year 2020. The spacecraft subsystems were designed to meet tight mass and power allocations, yet provide the necessary control and data handling finesse to support data collection and return when the one-way light time during the Pluto flyby is 4.5 hours. Missions to the outer solar system require a radioisotope thermoelectric generator (RTG) to supply electrical power, and a single RTG is used by New Horizons. To accommodate this constraint, the spacecraft electronics were designed to operate on less than 200 W. The spacecraft system architecture provides sufficient redundancy to provide a probability of mission success of greater than 0.85, even with a mission duration of over 10 years. The spacecraft is now on its way to Pluto, with an arrival date of 14 July 2015. Initial inflight tests have verified that the spacecraft will meet the design requirements.Comment: 33 pages, 13 figures, 4 tables; To appear in a special volume of Space Science Reviews on the New Horizons missio

Behavioural and demographic predictors of adherence to three consecutive faecal occult blood test screening opportunities: a population study

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background Social cognitive variables are often examined for their association with initial participation in colorectal cancer screening. Few studies have examined the association of these variables with adherence to multiple screening offers i.e., rescreening. This study aimed to describe patterns of participatory behaviour after three rounds of screening using faecal immunochemical tests (FIT) and to determine social cognitive, demographic and background variables predictive of variations in adherence. Methods Participants were 1,540 men and women aged 50 to 75 living in South Australia who completed a behavioural survey measuring demographic (for example, age, gender) and social cognitive variables relevant to FIT screening (for example, perceived barriers, benefits, self-efficacy). The survey was followed by three, free FIT screening offers mailed on an annual basis from 2008 to 2010. Patterns of participation after three screening rounds were described as one of five screening behaviours; 1) consistent re-participation (adherent with all screening rounds), 2) consistent refusal (adherent with no screening rounds), 3) drop out (adherent with earlier but not later rounds), 4) intermittent re-participation (adherent with alternate rounds) and 5) delayed entry (adherent with later but not initial round(s)). Univariate (Chi Square and Analysis of Variance) and multivariate (Generalised Estimating Equations) analyses were conducted to determine variables predictive of each category of non-adherence (those that did not participate in every screening offer, groups 2, 3, 4 and 5) relative to consistent re-participation. Results Significant social cognitive predictors of non-adherence were; less self-efficacy (drop out and consistent refusal), greater perceived barriers (drop out) and lower levels of response efficacy (consistent refusal). Demographic predictors of non-adherence included; male gender (delayed entry), younger age (intermittent, delayed and consistent refusal), less frequent GP visits (intermittent re-participation) and lack of adequate health insurance (drop out). Less satisfaction with screening at baseline predicted drop out, consistent refusal and delayed entry. Conclusions Different combinations of demographic and behavioural variables predicted different patterns of rescreening adherence. Rescreening interventions may benefit from a targeted approach that considers the different needs of the population subgroups. Satisfaction with past FOBT screening measured prior to the study screening offers was an important predictor of adherence

Demographic, social cognitive and social ecological predictors of intention and participation in screening for colorectal cancer

Extent: 10p.Background: Previous research points to differences between predictors of intention to screen for colorectal cancer (CRC) and screening behavior, and suggests social ecological factors may influence screening behavior. The aim of this study was to compare the social cognitive and social ecological predictors of intention to screen with predictors of participation. Methods: People aged 50 to 74 years recruited from the electoral roll completed a baseline survey (n = 376) and were subsequently invited to complete an immunochemical faecal occult blood test (iFOBT). Results: Multivariate analyses revealed five predictors of intention to screen and two predictors of participation. Perceived barriers to CRC screening and perceived benefits of CRC screening were the only predictor of both outcomes. There was little support for social ecological factors, but measurement problems may have impacted this finding. Conclusions: This study has confirmed that the predictors of intention to screen for CRC and screening behaviour, although overlapping, are not the same. Research should focus predominantly on those factors shown to predict participation. Perceptions about the barriers to screening and benefits of screening are key predictors of participation, and provide a focus for intervention programs.Tess A Gregory, Carlene Wilson, Amy Duncan, Deborah Turnbull, Stephen R Cole and Graeme Youn

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