13 research outputs found
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Landscape of stimulation-responsive chromatin across diverse human immune cells.
A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here we collected assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing data under resting and stimulated conditions for up to 32 immune cell populations. Stimulation caused widespread chromatin remodeling, including response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the importance of these cell states in autoimmunity. Allele-specific read mapping identified variants that alter chromatin accessibility in particular conditions, allowing us to observe evidence of function for a candidate causal variant that is undetected by existing large-scale studies in resting cells. Our results provide a resource of chromatin dynamics and highlight the need to characterize the effects of genetic variation in stimulated cells
English-based Pediatric Emergency Medicine Software Improves Physician Test Performance on Common Pediatric Emergencies: A Multicenter Study in Vietnam
INTRODUCTION: Global health agencies and the Vietnam Ministry of Health have identified pediatric emergency care and health information technology as high priority goals. Clinical decision support (CDS) software provides physicians with access to current literature to answer clinical queries, but there is limited impact data in developing countries. We hypothesized that Vietnamese physicians will demonstrate improved test performance on common pediatric emergencies using CDS technologies despite being in English. METHODS: This multicenter, prospective, pretest-posttest study was conducted in 11 Vietnamese hospitals enrolled a convenience sample of physicians who attended an 80-minute software training on a pediatric CDS software (PEMSoft). Two multiple-choice exams (A, B) were administered before and after the session. Participants, who received Test A as a pretest, received Test B as a posttest, and vice versa. Participants used the CDS software for the posttest. The primary outcome measure was the mean percentage difference in physician scores between the pretest and posttest, as calculated by a paired, two-tailed t-test. RESULTS: For the 203 participants, the mean pretest, posttest, and improvement scores were 37% (95% CI: 35–38%), 70% (95% CI: 68–72%), and 33% (95% CI: 30–36%), respectively, with p<0.0001. This represents an 89% improvement over baseline. Subgroup analysis of practice setting, clinical experience, and comfort level with written English and computers showed that all subgroups equivalently improved their test scores. CONCLUSION: After brief training, Vietnamese physicians can effectively use an English-based CDS software based on improved performance on a written clinical exam. Given this rapid improvement, CDS technologies may serve as a transformative tool in resource-poor environments
English-based Pediatric Emergency Medicine Software Improves Physician Test Performance on Common Pediatric Emergencies: A Multicenter Study in Vietnam
Introduction: Global health agencies and the Vietnam Ministry of Health have identified pediatric emergency care and health information technology as high priority goals. Clinical decision support (CDS) software provides physicians with access to current literature to answer clinical queries, but there is limited impact data in developing countries. We hypothesized that Vietnamese physicians will demonstrate improved test performance on common pediatric emergencies using CDS technologies despite being in English.Methods: This multicenter, prospective, pretest-posttest study was conducted in 11 Vietnamese hospitals enrolled a convenience sample of physicians who attended an 80-minute software training on a pediatric CDS software (PEMSoft). Two multiple-choice exams (A, B) were administered before and after the session. Participants, who received Test A as a pretest, received Test B as a posttest, and vice versa. Participants used the CDS software for the posttest. The primary outcome measure was the mean percentage difference in physician scores between the pretest and posttest, as calculated by a paired, two-tailed t-test.Results: For the 203 participants, the mean pretest, posttest, and improvement scores were 37% (95% CI: 35-38%), 70% (95% CI: 68-72%), and 33% (95% CI: 30-36%), respectively, with p<0.0001. This represents an 89% improvement over baseline. Subgroup analysis of practice setting, clinical experience, and comfort level with written English and computers showed that all subgroups equivalently improved their test scores.Conclusion: After brief training, Vietnamese physicians can effectively use an English-based CDS software based on improved performance on a written clinical exam. Given this rapid improvement, CDS technologies may serve as a transformative tool in resource-poor environments. [West J Emerg Med. 2013;14(5):471–476.
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Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies.
Adoptive transfer of genetically modified immune cells holds great promise for cancer immunotherapy. CRISPR knockin targeting can improve cell therapies, but more high-throughput methods are needed to test which knockin gene constructs most potently enhance primary cell functions in vivo. We developed a widely adaptable technology to barcode and track targeted integrations of large non-viral DNA templates and applied it to perform pooled knockin screens in primary human T cells. Pooled knockin of dozens of unique barcoded templates into the T cell receptor (TCR)-locus revealed gene constructs that enhanced fitness in vitro and in vivo. We further developed pooled knockin sequencing (PoKI-seq), combining single-cell transcriptome analysis and pooled knockin screening to measure cell abundance and cell state ex vivo and in vivo. This platform nominated a novel transforming growth factor β (TGF-β) R2-41BB chimeric receptor that improved solid tumor clearance. Pooled knockin screening enables parallelized re-writing of endogenous genetic sequences to accelerate discovery of knockin programs for cell therapies
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Functional CRISPR dissection of gene networks controlling human regulatory T cell identity.
Human regulatory T (Treg) cells are essential for immune homeostasis. The transcription factor FOXP3 maintains Treg cell identity, yet the complete set of key transcription factors that control Treg cell gene expression remains unknown. Here, we used pooled and arrayed Cas9 ribonucleoprotein screens to identify transcription factors that regulate critical proteins in primary human Treg cells under basal and proinflammatory conditions. We then generated 54,424 single-cell transcriptomes from Treg cells subjected to genetic perturbations and cytokine stimulation, which revealed distinct gene networks individually regulated by FOXP3 and PRDM1, in addition to a network coregulated by FOXO1 and IRF4. We also discovered that HIVEP2, to our knowledge not previously implicated in Treg cell function, coregulates another gene network with SATB1 and is important for Treg cell-mediated immunosuppression. By integrating CRISPR screens and single-cell RNA-sequencing profiling, we have uncovered transcriptional regulators and downstream gene networks in human Treg cells that could be targeted for immunotherapies
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Landscape of stimulation-responsive chromatin across diverse human immune cells.
A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here we collected assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing data under resting and stimulated conditions for up to 32 immune cell populations. Stimulation caused widespread chromatin remodeling, including response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the importance of these cell states in autoimmunity. Allele-specific read mapping identified variants that alter chromatin accessibility in particular conditions, allowing us to observe evidence of function for a candidate causal variant that is undetected by existing large-scale studies in resting cells. Our results provide a resource of chromatin dynamics and highlight the need to characterize the effects of genetic variation in stimulated cells