Parents and adolescents preferences for asthma control: a best-worst scaling choice experiment using an orthogonal main effects design

Background: The preferences of parents and children with asthma influence their ability to manage a child’s asthma and achieve good control. Potential differences between parents and adolescents with respect to specific parameters of asthma control are not considered in clinical asthma guidelines. The objective was to measure and compare the preferences of parents and adolescents with asthma with regard to asthma control parameters using best worst scaling (BWS). Methods: Fifty-two parents of children with asthma and 44 adolescents with asthma participated in a BWS study to quantify preferences regarding night-time symptoms, wheezing/chest tightening, changes in asthma medications, emergency visits and physical activity limitations. Conditional logit regression was used to determine each group’s utility for each level of each asthma control parameter. Results: Parents displayed the strongest positive preference for the absence of night-time symptoms (β = 2.09, p < 0.00001) and the strongest negative preference for 10 emergency room visits per year (β = −2.15, p < 0.00001). Adolescents displayed the strongest positive preference for the absence of physical activity limitations (β = 2.17, p < 0.00001) and the strongest negative preference for ten physical activity limitations per month (β = −1.97). Both groups were least concerned with changes to medications. Conclusion: Parents and adolescents placed different weights on the importance of asthma control parameters and each group displayed unique preferences. Understanding the relative importance placed on each parameter by parents and adolescents is essential for designing effective patient-focused disease management plans. Electronic supplementary material The online version of this article (doi:10.1186/s12890-015-0141-9) contains supplementary material, which is available to authorized users

The epigenetic landscape of T cell exhaustion.

Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Decentralized Automated Dispensing Devices: Systematic Review of Clinical and Economic Impacts in Hospitals

ABSTRACTBackground: Technologies have been developed over the past 20 years to automate the stages of drug distribution in hospitals, including ordering, dispensing, delivery, and administration of medications, in attempts to decrease medication error rates. Decentralized automated dispensing devices (ADDs) represent one such technology that is being adopted by hospitals across Canada, but the touted benefits, in terms of improved patient safety and cost savings, are increasingly being questioned.Objective: To summarize and evaluate the existing literature reporting the clinical and economic impacts of using decentralized ADDs in hospitals.Data Sources: A literature search was conducted in MEDLINE, Embase, and all evidence-based medicine databases for the years 1992 to 2012 to identify English-language articles reporting on the use of ADDs in hospital wards. Study Selection and Data Extraction: All randomized controlled trials, observational studies, before-and-after studies, time series analyses, cost-effectiveness and cost–benefit analyses, and review articles were considered for inclusion. Studies evaluating pharmacy-based ADDs, such as bar code–based medication dispensing carousels, automated dispensing shelves, and combinations of various dispensing modalities, were excluded.Data Synthesis: Of 175 studies initially identified, 8 were retained for evidence synthesis. It appears that ADDs were effective in reducing medication storage errors and the time that nurses spent taking inventory of narcotics and controlled substances. There was no definitive evidence that using ADDs increased the time that nurses or pharmacists spent with patients, reduced medication errors resulting in patient harm, or reduced costs in Canadian hospitals. However, pharmacy technicians spent more time stocking the machines.Conclusion: ADDs have limited potential to decrease medication errors and increase efficiencies, but their impact is highly institution-specific, and use of this technology requires proper integration into an institution’s medication distribution process. Before deploying this technology, it is recommended that  Canadian hospitals carefully examine their current systems and the benefits they hope to gain with the changes. RÉSUMÉContexte : Au cours des vingt dernières années, des  technologies ont été développées afin d’automatiser les étapes de la distribution des médicaments dans les hôpitaux, notamment pour ce qui est de l’émission d’ordonnances et de la dispensation, de la délivrance et de l’administration des médicaments, le tout dans le but de réduire le nombre d’erreurs de médication. Les cabinets automatisés décentralisés (CAD) font partie de ces technologies qui sont adoptées par les hôpitaux du Canada, mais leurs bienfaits très publicisés, en ce qui a trait à l’amélioration de la sécurité des patients et aux économies pouvant être réalisées, sont de plus en plus remis en question.Objectif : Résumer et évaluer la littérature faisant état des retombées cliniques et économiques de l’utilisation de CAD dans les hôpitaux. Sources des données : Une recherche documentaire a été effectuée dans MEDLINE, Embase ainsi que dans l’ensemble des bases de données médicales fondées sur des preuves pour la période allant de 1992 à 2012 afin de trouver les articles rédigés en anglais qui font état de l’utilisation des CAD dans les services d’hôpitaux.Sélection des études et extraction des données : Cette revue a pris en considération toutes les études cliniques aléatoires, les études observationnelles, les études avant-après, les analyses de séries chronologiques, les analyses coût-avantage et coût-efficacité, et les articles de synthèse. Les études évaluant les CAD en usage dans les pharmacies, robots parmi lesquels on compte les carrousels de distribution de médicaments utilisant des codes-barres, les rayonnages de distribution automatisés et les combinaisons de différents moyens de distribution, n’ont pas été retenues.Synthèse des données : Des 175 études d’abord recensées, huit ont été retenues pour la synthèse des données probantes. Les CAD semblent avoir été utiles pour réduire le nombre d’erreurs d’entreposage de médicaments ainsi que le temps nécessaire au personnel infirmier pour faire l’inventaire des narcotiques et des substances contrôlées. Aucune donnée probante ne permet d’affirmer que le temps passé par le personnel infirmier et les pharmaciens auprès des patients a augmenté, que le nombre d’erreurs de médication causant du tort aux patients a baissé ou que les coûts des hôpitaux canadiens ont chuté grâce à l’utilisation des CAD. Par contre, les techniciens en pharmacie ont passé plus de temps à remplir les machines.Conclusion : Les CAD présentent un faible potentiel de réduction du nombre d’erreurs de médication et d’augmentation de l’efficacité des ressources. Cependant, leur incidence est propre à chaque établissement et l’utilisation de cette technologie nécessite une intégration réfléchie dans le processus de distribution des médicaments d’un établissement. Avant de mettre en place cette technologie, il est recommandé aux hôpitaux canadiens de bien étudier leurs systèmes actuels et de réfléchir aux avantages qu’ils espèrent obtenir par ce changement