27 research outputs found
Correction to: Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
Erratum for
Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. [BMC Med Genomics. 2019
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Effect of Clinical Decision Support on Appropriateness of Advanced Imaging Use Among Physicians-in-Training
Clinical decision support (CDS) tools have been shown to reduce inappropriate imaging orders. We hypothesized that CDS may be especially effective for house staff physicians who are prone to overuse of resources.
Our hospital implemented CDS for CT and MRI orders in the emergency department with scores based on the American College of Radiology's Appropriateness Criteria (range, 1-9; higher scores represent more-appropriate orders). Data on CT and MRI orders from April 2013 through June 2016 were categorized as pre-CDS or baseline, post-CDS period 1 (i.e., intervention with active feedback for scores of ≤ 4), and post-CDS period 2 (i.e., intervention with active feedback for scores of ≤ 6). Segmented regression analysis with interrupted time series data estimated changes in scores stratified by house staff and non-house staff. Generalized linear models further estimated the modifying effect of the house staff variable.
Mean scores were 6.2, 6.2, and 6.7 in the pre-CDS, post-CDS 1, and post-CDS 2 periods, respectively (p < 0.05). In the segmented regression analysis, mean scores significantly (p < 0.05) increased when comparing pre-CDS versus post-CDS 2 periods for both house staff (baseline increase, 0.41; 95% CI, 0.17-0.64) and non-house staff (baseline increase, 0.58; 95% CI, 0.34-0.81), showing no differences in effect between the cohorts. The generalized linear model showed significantly higher scores, particularly in the post-CDS 2 period compared with the pre-CDS period (0.44 increase in scores; p < 0.05). The house staff variable did not significantly change estimates in the post-CDS 2 period.
Implementation of active CDS increased overall scores of CT and MRI orders. However, there was no significant difference in effect on scores between house staff and non-house staff
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Minimal PD-1 expression in mouse and human NK cells under diverse conditions.
PD-1 expression is a hallmark of both early antigen-specific T cell activation and later chronic stimulation, suggesting key roles in both naive T cell priming and memory T cell responses. Although significant similarities exist between T cells and NK cells, there are critical differences in their biology and functions reflecting their respective adaptive and innate immune effector functions. Expression of PD-1 on NK cells is controversial despite rapid incorporation into clinical cancer trials. Our objective was to stringently and comprehensively assess expression of PD-1 on both mouse and human NK cells under multiple conditions and using a variety of readouts. We evaluated NK cells from primary human tumor samples, after ex vivo culturing, and from multiple mouse tumor and viral models using flow cytometry, quantitative reverse-transcriptase PCR (qRT-PCR), and RNA-Seq for PD-1 expression. We demonstrate that, under multiple conditions, human and mouse NK cells consistently lack PD-1 expression despite the marked upregulation of other activation/regulatory markers, such as TIGIT. This was in marked contrast to T cells, which were far more prominent within all tumors and expressed PD-1. These data have important implications when attempting to discern NK from T cell effects and to determine whether PD-1 targeting can be expected to have direct effects on NK cell functions
Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
Background Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. Results We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. Conclusion In sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.Correction in: BMC MEDICAL GENOMICS, Volume: 12, Issue: 1, Article Number: 154, DOI: 10.1186/s12920-019-0573-9</p