15 research outputs found

    A degranulation assay using Vγ9Vδ2 T cells for the rapid diagnosis of familial hemophagocytic syndromes

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    IntroductionHemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune disorder characterized by uncontrolled lymphocyte and macrophage activation and a subsequent cytokine storm. The timely initiation of immunosuppressive treatment is crucial for survival.MethodsHere, we harnessed Vγ9Vδ2 T cell degranulation to develop a novel functional assay for the diagnosis of HLH. We compared the novel assay with the conventional natural killer (NK) cell stimulation method in terms of efficiency, specificity, and reliability. Our analysis involved 213 samples from 182 individuals, including 23 samples from 12 patients with degranulation deficiency (10 individuals with UNC13D deficiency, 1 with STXBP2 deficiency, and 1 with RAB27A deficiency).ResultsWhile both tests exhibited 100% sensitivity, the Vγ9Vδ2 T cell degranulation assay showed a superior specificity of 86.2% (n=70) compared to the NK cell degranulation assay, which achieved 78.9% specificity (n=213). The Vγ9Vδ2 T cell degranulation assay offered simpler technical requirements and reduced labor intensity, leading to decreased susceptibility to errors with faster processing times.DiscussionThis efficiency stemmed from the sole requirement of dissolving (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) powder, contrasting with the intricate maintenance of K562 cells necessary for the NK cell degranulation assay. With its diminished susceptibility to errors, we anticipate that the assay will require fewer repetitions of analysis, rendering it particularly well-suited for testing infants.ConclusionThe Vγ9Vδ2 T cell degranulation assay is a user-friendly, efficient diagnostic tool for HLH. It offers greater specificity, reliability, and practicality than established methods. We believe that our present findings will facilitate the prompt, accurate diagnosis of HLH and thus enable rapid treatment and better patient outcomes

    Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry : a meta-analysis

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    Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1.92, 95% CI 1 85-1.99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations.Peer reviewe

    PHarmacist Avoidance or Reductions in Medical Costs in Patients Presenting the EMergency Department: PHARM-EM Study

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    Objectives:. To comprehensively classify interventions performed by emergency medicine clinical pharmacists and quantify cost avoidance generated through their accepted interventions. Design:. A multicenter, prospective, observational study was performed between August 2018 and January 2019. Setting:. Community and academic hospitals in the United States. Participants:. Emergency medicine clinical pharmacists. Interventions:. Recommendations classified into one of 38 intervention categories associated with cost avoidance. Measurements and Main Results:. Eighty-eight emergency medicine pharmacists at 49 centers performed 13,984 interventions during 917 shifts that were accepted on 8,602 patients and generated 7,531,862ofcostavoidance.Thequantityofacceptedinterventionsandcostavoidancegeneratedinsixestablishedcategorieswereasfollows:adversedrugeventprevention(1,631interventions;7,531,862 of cost avoidance. The quantity of accepted interventions and cost avoidance generated in six established categories were as follows: adverse drug event prevention (1,631 interventions; 2,225,049 cost avoidance), resource utilization (628; 310,582),individualizationofpatientcare(6,122;310,582), individualization of patient care (6,122; 1,787,170), prophylaxis (24; 22,804),handsoncare(3,533;22,804), hands-on care (3,533; 2,836,811), and administrative/supportive tasks (2,046; 342,881).Meancostavoidancewas342,881). Mean cost avoidance was 538.61 per intervention, 875.60perpatient,and875.60 per patient, and 8,213.59 per emergency medicine pharmacist shift. The annualized cost avoidance from an emergency medicine pharmacist was 1,971,262.Themonetarycostavoidancetopharmacistsalaryratiowasbetween1,971,262. The monetary cost avoidance to pharmacist salary ratio was between 1.4:1 and 10.6:1.Conclusions:.Pharmacistinvolvementinthecareofpatientspresentingtotheemergencydepartmentresultsinsignificantavoidanceofhealthcarecosts,particularlyintheareasofhandsoncareandadversedrugeventprevention.Thepotentialmonetarybenefittocostratioforemergencymedicinepharmacistsisbetween10.6:1. Conclusions:. Pharmacist involvement in the care of patients presenting to the emergency department results in significant avoidance of healthcare costs, particularly in the areas of hands-on care and adverse drug event prevention. The potential monetary benefit-to-cost ratio for emergency medicine pharmacists is between 1.4:1 and $10.6:1

    Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

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    Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10−8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85–1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. Funding Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München–Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council. © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

    Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease

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    Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease

    Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease

    No full text
    Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc

    Combined Forward-Backward Asymmetry Measurements in Top-Antitop Quark Production at the Tevatron

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    Tevatron Combination of Single-Top-Quark Cross Sections and Determination of the Magnitude of the Cabibbo-Kobayashi-Maskawa Matrix Element Vtb\bf V_{tb}

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    We present the final combination of CDF and D0 measurements of cross sections for single-top-quark production in proton-antiproton collisions at a center-of-mass energy of 1.96 TeV. The data correspond to total integrated luminosities of up to 9.7 fb1^{−1} per experiment. The t-channel cross section is measured to be σt_t=2.250.31+0.29_{-0.31}^{+0.29} pb. We also present the combinations of the two-dimensional measurements of the s- vs t-channel cross section. In addition, we give the combination of the s+t channel cross section measurement resulting in σs+t_{s+t}=3.300.40+0.52_{-0.40}^{+0.52} pb, without assuming the standard model value for the ratio σs_st_t. The resulting value of the magnitude of the top-to-bottom quark coupling is |Vtb_{tb}|=1.020.05+0.06_{-0.05}^{+0.06}, corresponding to |Vtb_{tb}|>0.92 at the 95% C.L

    Combined Forward-Backward Asymmetry Measurements in Top-Antitop Quark Production at the Tevatron

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