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      Circulating microRNAs improve bacterial infection diagnosis and overall survival prediction in acute decompensation of liver cirrhosis

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          Summary

          Bacterial infections are the most frequent precipitating event in patients with acute decompensation of cirrhosis (AD) and are associated with high mortality. Early diagnosis is challenging due to cirrhosis-related systemic inflammation. Here we investigated the potential of circulating microRNAs to diagnose bacterial infections and predict survival in cirrhotic patients with AD. High throughput profiling of circulating microRNAs was performed using the Nanostring technology in 57 AD patients and 24 patients with compensated cirrhosis (CC). Circulating miRs profiling showed that: (a) miRs differentially detected in AD vs. CC were mostly down-regulated; (b) a composite score including absolute neutrophil count, C reactive protein and miR-362-3p could diagnose bacterial infection with an excellent performance (AUC of 0.825 [95% CI = 0.671–0.980; p < 0.001]); (c) a composite score including miR-382-5p, miR-592 and MELD-Na improved 6-month survival prediction. Circulating miRs are strongly dysregulated in patients with AD and may help to improve bacterial infection diagnosis and survival prediction.

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          Highlights

          • Plasma miRNAs are down-regulated in AD of cirrhosis

          • miR-362-3p improves bacterial infection diagnosis in AD patients

          • miR-382-5p and miR-592 refine MELD-Na survival prediction in AD patients

          Abstract

          Bacteriology; Cell biology;

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          Most cited references48

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          The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.

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            Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.

            Patients with cirrhosis hospitalized for an acute decompensation (AD) and organ failure are at risk for imminent death and considered to have acute-on-chronic liver failure (ACLF). However, there are no established diagnostic criteria for ACLF, so little is known about its development and progression. We aimed to identify diagnostic criteria of ACLF and describe the development of this syndrome in European patients with AD. We collected data from 1343 hospitalized patients with cirrhosis and AD from February to September 2011 at 29 liver units in 8 European countries. We used the organ failure and mortality data to define ACLF grades, assess mortality, and identify differences between ACLF and AD. We established diagnostic criteria for ACLF based on analyses of patients with organ failure (defined by the chronic liver failure-sequential organ failure assessment [CLIF-SOFA] score) and high 28-day mortality rate (>15%). Of the patients assessed, 303 had ACLF when the study began, 112 developed ACLF, and 928 did not have ACLF. The 28-day mortality rate among patients who had ACLF when the study began was 33.9%, among those who developed ACLF was 29.7%, and among those who did not have ACLF was 1.9%. Patients with ACLF were younger and more frequently alcoholic, had more associated bacterial infections, and had higher numbers of leukocytes and higher plasma levels of C-reactive protein than patients without ACLF (P < .001). Higher CLIF-SOFA scores and leukocyte counts were independent predictors of mortality in patients with ACLF. In patients without a prior history of AD, ACLF was unexpectedly characterized by higher numbers of organ failures, leukocyte count, and mortality compared with ACLF in patients with a prior history of AD. We analyzed data from patients with cirrhosis and AD to establish diagnostic criteria for ACLF and showed that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality rate but also on age, precipitating events, and systemic inflammation. ACLF mortality is associated with loss of organ function and high leukocyte counts. ACLF is especially severe in patients with no prior history of AD. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Estimation of the Youden Index and its associated cutoff point.

              The Youden Index is a frequently used summary measure of the ROC (Receiver Operating Characteristic) curve. It both, measures the effectiveness of a diagnostic marker and enables the selection of an optimal threshold value (cutoff point) for the marker. In this paper we compare several estimation procedures for the Youden Index and its associated cutoff point. These are based on (1) normal assumptions; (2) transformations to normality; (3) the empirical distribution function; (4) kernel smoothing. These are compared in terms of bias and root mean square error in a large variety of scenarios by means of an extensive simulation study. We find that the empirical method which is the most commonly used has the overall worst performance. In the estimation of the Youden Index the kernel is generally the best unless the data can be well transformed to achieve normality whereas in estimation of the optimal threshold value results are more variable.
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                Author and article information

                Contributors
                Journal
                iScience
                iScience
                iScience
                Elsevier
                2589-0042
                20 July 2023
                18 August 2023
                20 July 2023
                : 26
                : 8
                : 107427
                Affiliations
                [1 ]Cancer Research Center of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Lyon, France
                [2 ]Department of Hepatology, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
                [3 ]University of Lyon Claude Bernard 1 (UCLB1), Lyon, France
                [4 ]Department of Internal Medicine, Hôpital Lyon Sud, Hospices Civils de Lyon, Lyon, France
                [5 ]Clinical Research Center, GHN, Hospices Civils de Lyon, Lyon, France
                [6 ]Department of Anesthesiology and Intensive Care, Hôpital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
                [7 ]Université Paris-Cité, Inserm, Centre de recherche sur l’inflammation, UMR 1149, Paris, France
                [8 ]Service d'Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Clichy, France
                [9 ]Department of Medicine SCIAC and the Italian Institute of Technology (IIT) Center for Life Nanosciences (CLNS), University of Rome La Sapienza, Rome, Italy
                Author notes
                []Corresponding author yasmina.chouik@ 123456inserm.fr
                [∗∗ ]Corresponding author massimo.levrero@ 123456inserm.fr
                [10]

                Lead contact

                Article
                S2589-0042(23)01504-3 107427
                10.1016/j.isci.2023.107427
                10415934
                a5c97657-612d-4811-ae32-cac64474af3f
                © 2023 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 20 January 2023
                : 23 May 2023
                : 17 July 2023
                Categories
                Article

                bacteriology,cell biology
                bacteriology, cell biology

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