Cytosolic 5'-triphosphate ended viral leader transcript of measles virus as activator of the RIG I-mediated interferon response.

International audienceBACKGROUND: Double stranded RNA (dsRNA) is widely accepted as an RNA motif recognized as a danger signal by the cellular sentries. However, the biology of non-segmented negative strand RNA viruses, or Mononegavirales, is hardly compatible with the production of such dsRNA. METHODOLOGY AND PRINCIPAL FINDINGS: During measles virus infection, the IFN-beta gene transcription was found to be paralleled by the virus transcription, but not by the virus replication. Since the expression of every individual viral mRNA failed to activate the IFN-beta gene, we postulated the involvement of the leader RNA, which is a small not capped and not polyadenylated RNA firstly transcribed by Mononegavirales. The measles virus leader RNA, synthesized both in vitro and in vivo, was efficient in inducing the IFN-beta expression, provided that it was delivered into the cytosol as a 5'-trisphosphate ended RNA. The use of a human cell line expressing a debilitated RIG-I molecule, together with overexpression studies of wild type RIG-I, showed that the IFN-beta induction by virus infection or by leader RNA required RIG-I to be functional. RIG-I binds to leader RNA independently from being 5-trisphosphate ended; while a point mutant, Q299A, predicted to establish contacts with the RNA, fails to bind to leader RNA. Since the 5'-triphosphate is required for optimal RIG-I activation but not for leader RNA binding, our data support that RIG-I is activated upon recognition of the 5'-triphosphate RNA end. CONCLUSIONS/SIGNIFICANCE: RIG-I is proposed to recognize Mononegavirales transcription, which occurs in the cytosol, while scanning cytosolic RNAs, and to trigger an IFN response when encountering a free 5'-triphosphate RNA resulting from a mislocated transcription activity, which is therefore considered as the hallmark of a foreign invader

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Comparaison des tubes à double lumière gauche avec ou sans ergot lors des interventions de chirurgie thoracique

Introduction : Une des particularités de la chirurgie thoracique est la nécessité de réaliser une ventilation unipulmonaire dont la technique de référence est l'utilisation de tube à double lumière gauche (TDL-G). Ces TDL-G sont disponibles avec ou sans ergot, celui-ci devant faciliter le positionnement et limitant les mobilisations peropératoires. Néanmoins, du fait de leur possible morbidité et depuis l'introduction systématique de la fibroscopie bronchique pour contrôler la position des TDL, l’intérêt de l’ergot est remis en cause. Cette étude compare les bénéfices et les risques liés à l’utilisation des TDL-G avec et sans ergot. Matériel et méthodes : Il s’agit d’une étude monocentrique, randomisée comparant un groupe de patients intubés avec une sonde avec ergot versus sans ergot. L'objectif principal est de comparer la facilité d'insertion de ces deux tubes, les objectifs secondaires évaluent leurs balances avantages/inconvénients (évaluation fibroscopique peropératoire et à J1).Résultats : 184 patients ont été inclus, 92 dans chaque groupe. Nous ne retrouvons pas de différence significative en termes de délai de mise en place (68 sec « avec ergot » vs 80 sec « sans ergot » (P=0,47)). Le taux de bon positionnement est équivalent avec ou sans ergot que ce soit après l'intubation (64% vs 63%) ou le positionnement en décubitus latéral (79% vs 72%). La morbidité (lésions glottiques, trachéo-bronchiques et l'EVA pharyngées à J0/J1) est équivalente. Discussion : Le TDL-G avec ergot n'est pas supérieur au TDL-G sans ergot ; l'ergot ne semble pas responsable d'une surmorbidité

Trauma reloaded: Trauma registry in the era of data science

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Doubly robust treatment effect estimation with missing attributes

International audienceMissing attributes are ubiquitous in causal inference, as they are in most applied statistical work. In this paper, we consider various sets of assumptions under which causal inference is possible despite missing attributes and discuss corresponding approaches to average treatment effect estimation, including generalized propensity score methods and multiple imputation. Across an extensive simulation study, we show that no single method systematically out-performs others. We find, however, that doubly robust modifications of standard methods for average treatment effect estimation with missing data repeatedly perform better than their non-doubly robust baselines; for example, doubly robust generalized propensity score methods beat inverse-weighting with the generalized propensity score. This finding is reinforced in an analysis of an observations study on the effect on mortality of tranexamic acid administration among patients with traumatic brain injury in the context of critical care management. Here, doubly robust estimators recover confidence intervals that are consistent with evidence from randomized trials, whereas non-doubly robust estimators do not

Machine Learning Augmented Causal Inference To Estimate The Treatment Effect of Tranexamic Acid In Traumatic Brain Injury

Background: The CRASH-3 trial provides a high level of evidence on the question whether to administer Tranexamic Acid (TXA) for Traumatic brain injury (TBI). For numerous other research questions, the available evidence will not correspond to such a level of evidence and will rely on observational evidence only. The development of methodological alternatives to analyze observational data is necessary. The Crash-3trial provided the opportunity to explore the effect of TXA on TBI mortality with two distinct causal inference methods using incomplete observational data.Methods: Two causal inference techniques, inverse propensity weighting (IPW) and doubly robust method (DR), associated with machine learning method techniques to handle missing data, explored the effect of TXA administration on 30-day head injury related death expressed in registry data. The effect was expressed as Average Treatment Effect (ATE). TBI was defined as a head Abbreviated Injury Score >2. The hypothesis expected the results to concur with the results obtained with the CRASH-3 benchmark trial.Results: Between September 2010 and February 2019, from a total of 20037 registry cases 8269 corresponded to the definition of TBI. A total of 683 received TXA and 7565 did not. The observed head-injury related 30-day hospital mortality rate in the group TXA was 30% (205/683) compared to 15% in the group no-TXA (1102/7565, p<0.001). Causal inference with the IPW approach indicates an ATE with a higher mortality after TXA independently of the approach applied to manage missing data (ATE 0.10 (95% IC [0.06, 0.14]) or 0.09 (95% IC [0.03, 0.15])). ATE obtained with DR did not show any effect on mortality independently of the approach applied to missing data (ATE -0.01 (95% IC [-0.05, 0.03]) or -0.01 (95% IC [-0.07, 0.05])). No effect was observed in predefined subgroups.Conclusions: This study demonstrated the feasibility to apply causal inference techniques in incomplete observational data. DR based on a stronger theoretical background compared to IPW, did not show a significant association of TXA administration with in-hospital mortality. This result provides a strong incentive to explore augmented causal inference techniques on incomplete observational data coupled with techniques to handle missing values

Sulcal-based morphometry in Parkinson’s disease: a study of reliability and disease effects

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COBI (COntinuous hyperosmolar therapy for traumatic Brain-Injured patients) trial protocol: a multicentre randomised open-label trial with blinded adjudication of primary outcome

International audienceIntroduction: Traumatic brain injury (TBI) is a major cause of death and severe prolonged disability. Intracranial hypertension (ICH) is a critical risk factor of bad outcomes after TBI. Continuous infusion of hyperosmolar therapy has been proposed for the prevention and the treatment of ICH. Whether an early administration of continuous hyperosmolar therapy improves long-term outcomes of patients with TBI is uncertain. The aim of the COBI study (number clinicaltrial.gov 03143751, pre-results stage) is to assess the efficiency and the safety of continuous hyperosmolar therapy in patients with TBI.Methods and analysis: The COBI (COntinuous hyperosmolar therapy in traumatic Brain-Injured patients) trial is a multicentre, randomised, controlled, open-label, two-arms study with blinded adjudication of primary outcome. Three hundred and seventy patients hospitalised in intensive care unit with a TBI (Glasgow Coma Scale ≤12 and abnormal brain CT scan) are randomised in the first 24 hours following trauma to standard care or continuous hyperosmolar therapy (20% NaCl) plus standard care. Continuous hyperosmolar therapy is maintained for at least 48 hours in the treatment group and continued for as long as is necessary to prevent ICH. The primary outcome is the score on the Extended Glasgow Outcome Scale at 6 months. The treatment effect is estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common OR.Ethics and dissemination: The COBI trial protocol has been approved by the ethics committee of Paris Ile de France VIII and will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results of this study will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals. The COBI trial is the first randomised controlled trial powered to investigate whether continuous hyperosmolar therapy in patients with TBI improve long-term recovery.Trial registration number Trial registration number is NCT03143751