Publications by authors named "Pascal Andreu"

29 Publications

  • Page 1 of 1

BiG-MAP: an Automated Pipeline To Profile Metabolic Gene Cluster Abundance and Expression in Microbiomes.

mSystems 2021 Oct 28;6(5):e0093721. Epub 2021 Sep 28.

Bioinformatics Group, Wageningen University, Wageningen, the Netherlands.

Microbial gene clusters encoding the biosynthesis of primary and secondary metabolites play key roles in shaping microbial ecosystems and driving microbiome-associated phenotypes. Although effective approaches exist to evaluate the metabolic potential of such bacteria through identification of these metabolic gene clusters in their genomes, no automated pipelines exist to profile the abundance and expression levels of such gene clusters in microbiome samples to generate hypotheses about their functional roles, and to find associations with phenotypes of interest. Here, we describe BiG-MAP, a bioinformatic tool to profile abundance and expression levels of gene clusters across metagenomic and metatranscriptomic data and evaluate their differential abundance and expression under different conditions. To illustrate its usefulness, we analyzed 96 metagenomic samples from healthy and caries-associated human oral microbiome samples and identified 252 gene clusters, including unreported ones, that were significantly more abundant in either phenotype. Among them, we found the operon, a gene cluster known to be associated with tooth decay. Additionally, we found a putative reuterin biosynthetic gene cluster from a Streptococcus strain to be enriched but not exclusively found in healthy samples; metabolomic data from the same samples showed masses with fragmentation patterns consistent with (poly)acrolein, which is known to spontaneously form from the products of the reuterin pathway and has been previously shown to inhibit pathogenic Streptococcus mutans strains. Thus, we show how BiG-MAP can be used to generate new hypotheses on potential drivers of microbiome-associated phenotypes and prioritize the experimental characterization of relevant gene clusters that may mediate them. Microbes play an increasingly recognized role in determining host-associated phenotypes by producing small molecules that interact with other microorganisms or host cells. The production of these molecules is often encoded in syntenic genomic regions, also known as gene clusters. With the increasing numbers of (multi)omics data sets that can help in understanding complex ecosystems at a much deeper level, there is a need to create tools that can automate the process of analyzing these gene clusters across omics data sets. This report presents a new software tool called BiG-MAP, which allows assessing gene cluster abundance and expression in microbiome samples using metagenomic and metatranscriptomic data. Here, we describe the tool and its functionalities, as well as its validation using a mock community. Finally, using an oral microbiome data set, we show how it can be used to generate hypotheses regarding the functional roles of gene clusters in mediating host phenotypes.
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http://dx.doi.org/10.1128/mSystems.00937-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547482PMC
October 2021

Inhaled amikacin versus placebo to prevent ventilator-associated pneumonia: the AMIKINHAL double-blind multicentre randomised controlled trial protocol.

BMJ Open 2021 09 14;11(9):e048591. Epub 2021 Sep 14.

Médecine Intensive Réanimation, CHR d'Orléans, Orleans, France.

Introduction: Pre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia.

Methods And Analysis: Academic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee.

Ethics And Dissemination: The protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals.

Trial Registration Numbers: EudraCT 2016-001054-17 and NCT03149640.
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http://dx.doi.org/10.1136/bmjopen-2020-048591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442072PMC
September 2021

The gutSMASH web server: automated identification of primary metabolic gene clusters from the gut microbiota.

Nucleic Acids Res 2021 07;49(W1):W263-W270

Bioinformatics Group, Wageningen University, 6708PB, Wageningen, The Netherlands.

Anaerobic bacteria from the human microbiome produce a wide array of molecules at high concentrations that can directly or indirectly affect the host. The production of these molecules, mostly derived from their primary metabolism, is frequently encoded in metabolic gene clusters (MGCs). However, despite the importance of microbiome-derived primary metabolites, no tool existed to predict the gene clusters responsible for their production. For this reason, we recently introduced gutSMASH. gutSMASH can predict 41 different known pathways, including MGCs involved in bioenergetics, but also putative ones that are candidates for novel pathway discovery. To make the tool more user-friendly and accessible, we here present the gutSMASH web server, hosted at https://gutsmash.bioinformatics.nl/. The user can either input the GenBank assembly accession or upload a genome file in FASTA or GenBank format. Optionally, the user can enable additional analyses to obtain further insights into the predicted MGCs. An interactive HTML output (viewable online or downloadable for offline use) provides a user-friendly way to browse functional gene annotations and sequence comparisons with reference gene clusters as well as gene clusters predicted in other genomes. Thus, this web server provides the community with a streamlined and user-friendly interface to analyze the metabolic potential of gut microbiomes.
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http://dx.doi.org/10.1093/nar/gkab353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262752PMC
July 2021

Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial.

Lancet 2021 04;397(10281):1293-1300

Réanimation médicale, CHRU de Lille, Hôpital Roger Salengro, Lille, France.

Background: Delaying renal replacement therapy (RRT) for some time in critically ill patients with severe acute kidney injury and no severe complication is safe and allows optimisation of the use of medical devices. Major uncertainty remains concerning the duration for which RRT can be postponed without risk. Our aim was to test the hypothesis that a more-delayed initiation strategy would result in more RRT-free days, compared with a delayed strategy.

Methods: This was an unmasked, multicentre, prospective, open-label, randomised, controlled trial done in 39 intensive care units in France. We monitored critically ill patients with severe acute kidney injury (defined as Kidney Disease: Improving Global Outcomes stage 3) until they had oliguria for more than 72 h or a blood urea nitrogen concentration higher than 112 mg/dL. Patients were then randomly assigned (1:1) to either a strategy (delayed strategy) in which RRT was started just after randomisation or to a more-delayed strategy. With the more-delayed strategy, RRT initiation was postponed until mandatory indication (noticeable hyperkalaemia or metabolic acidosis or pulmonary oedema) or until blood urea nitrogen concentration reached 140 mg/dL. The primary outcome was the number of days alive and free of RRT between randomisation and day 28 and was done in the intention-to-treat population. The study is registered with ClinicalTrial.gov, NCT03396757 and is completed.

Findings: Between May 7, 2018, and Oct 11, 2019, of 5336 patients assessed, 278 patients underwent randomisation; 137 were assigned to the delayed strategy and 141 to the more-delayed strategy. The number of complications potentially related to acute kidney injury or to RRT were similar between groups. The median number of RRT-free days was 12 days (IQR 0-25) in the delayed strategy and 10 days (IQR 0-24) in the more-delayed strategy (p=0·93). In a multivariable analysis, the hazard ratio for death at 60 days was 1·65 (95% CI 1·09-2·50, p=0·018) with the more-delayed versus the delayed strategy. The number of complications potentially related to acute kidney injury or renal replacement therapy did not differ between groups.

Interpretation: In severe acute kidney injury patients with oliguria for more than 72 h or blood urea nitrogen concentration higher than 112 mg/dL and no severe complication that would mandate immediate RRT, longer postponing of RRT initiation did not confer additional benefit and was associated with potential harm.

Funding: Programme Hospitalier de Recherche Clinique.
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http://dx.doi.org/10.1016/S0140-6736(21)00350-0DOI Listing
April 2021

Non-readmission decisions in the intensive care unit: A qualitative study of physicians' experience in a multicentre French study.

PLoS One 2021 14;16(1):e0244919. Epub 2021 Jan 14.

Department of Intensive Care, François Mitterrand University Hospital, Dijon, France.

Purpose: Deciding not to re-admit a patient to the intensive care unit (ICU) poses an ethical dilemma for ICU physicians. We aimed to describe and understand the attitudes and perceptions of ICU physicians regarding non-readmission of patients to the ICU.

Materials And Methods: Multicenter, qualitative study using semi-directed interviews between January and May 2019. All medical staff working full-time in the ICU of five participating centres (two academic and three general, non-academic hospitals) were invited to participate. Participants were asked to describe how they experienced non-readmission decisions in the ICU, and to expand on the manner in which the decision was made, but also on the traceability and timing of the decision. Interviews were recorded, transcribed and analyzed using textual content analysis.

Results: In total, 22 physicians participated. Interviews lasted on average 26±7 minutes. There were 14 men and 8 women, average age was 35±9 years, and average length of ICU experience was 7±5 years. The majority of respondents said that they regretted that the question of non-readmission was not addressed before the initial ICU admission. They acknowledged that the ICU stay did lead to more thorough contemplation of the overall goals of care. Multidisciplinary team meetings could help to anticipate the question of readmission within the patient's care pathway. Participants reported that there is a culture of collegial decision-making in the ICU, although the involvement of patients, families and other healthcare professionals in this process is not systematic. The timing and traceability of non-readmission decisions are heterogeneous.

Conclusions: Non-readmission decisions are a major issue that raises ethical questions surrounding the fact that there is no discussion of the patient's goals of care in advance. Better anticipation, and better communication with the patients, families and other healthcare providers are suggested as areas that could be targeted for improvement.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244919PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808577PMC
May 2021

CXCL10 could drive longer duration of mechanical ventilation during COVID-19 ARDS.

Crit Care 2020 11 2;24(1):632. Epub 2020 Nov 2.

INSERM, LNC UMR 1231, FCS Bourgogne-Franche Comté, LipSTIC LabEx, F-21000, Dijon, France.

Background: COVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. Data regarding the host response within the lung are sparse. The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs. non-COVID-19).

Methods: Bronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-COVID-19 ARDS, and 14 COVID-19 ARDS patients. Clinical data, plasma, and epithelial lining fluid (ELF) concentrations of 45 inflammatory mediators and cell-free mitochondrial DNA were measured and compared.

Results: COVID-19 ARDS patients required mechanical ventilation (MV) for significantly longer, even after adjustment for potential confounders. There was a trend toward higher concentrations of plasma CCL5, CXCL2, CXCL10, CD40 ligand, IL-10, and GM-CSF, and ELF concentrations of CXCL1, CXCL10, granzyme B, TRAIL, and EGF in the COVID-19 ARDS group compared with the non-COVID-19 ARDS group. Plasma and ELF CXCL10 concentrations were independently associated with the number of ventilator-free days, without correlation between ELF CXCL-10 and viral load. Mitochondrial DNA plasma and ELF concentrations were elevated in all ARDS patients, with no differences between the two groups. ELF concentrations of mitochondrial DNA were correlated with alveolar cell counts, as well as IL-8 and IL-1β concentrations.

Conclusion: CXCL10 could be one key mediator involved in the dysregulated immune response. It should be evaluated as a candidate biomarker that may predict the duration of MV in COVID-19 ARDS patients. Targeting the CXCL10-CXCR3 axis could also be considered as a new therapeutic approach.

Trial Registration: ClinicalTrials.gov, NCT03955887.
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http://dx.doi.org/10.1186/s13054-020-03328-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604548PMC
November 2020

Family perceptions of clinical research and the informed consent process in the ICU.

J Crit Care 2020 Sep 28. Epub 2020 Sep 28.

Department of Intensive Care, François Mitterrand, University Hospital, Dijon, France; Clinical Epidemiology, University of Burgundy, INSERM CIC 1432, Dijon, France; Lipness Team, INSERM Research Centre LNC-UMR1231 and LabEx LipSTIC, University of Burgundy, Dijon, France. Electronic address:

Purpose: We investigated experiences of families who provide consent for research on behalf of a loved-one hospitalized in intensive care (ICU).

Methods: Multicentre, qualitative, descriptive study using semi-directive interviews in 3 ICUs. Eligible relatives were aged >18 years, and had provided informed consent for a clinical trial on behalf of a patient hospitalized in ICU. Interviews were conducted from 06/2018 to 06/2019 by a qualified sociologist, recorded and transcribed.

Results: Fifteen relatives were interviewed; average age 50.3 ± 15 years. All emphasized their interest in clinical research, seeing it as a duty. Involving their loved-one in research allowed them to find meaning in the events. Participants underlined that trust in caregivers and communication are determinant. The strict regulation of research was perceived as a guarantee of safety. Participants felt they lacked the intellectual capacity and knowledge to question explanations. The greatest fear was not that they might incur a risk for the patient, but rather, that they might deprive the patient of a chance at a cure.

Conclusion: Acceptance of research opportunities by relatives on behalf of decisionally-incapacitated patients is underpinned by trust in the physicians and the legislative framework. Communication and the quality of information provided by the caregivers are key.
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http://dx.doi.org/10.1016/j.jcrc.2020.09.032DOI Listing
September 2020

Computational genomic discovery of diverse gene clusters harbouring Fe-S flavoenzymes in anaerobic gut microbiota.

Microb Genom 2020 05 12;6(5). Epub 2020 May 12.

Bioinformatics Group, Wageningen University, Wageningen, The Netherlands.

The gut contains an enormous diversity of simple as well as complex molecules from highly diverse food sources, together with host-secreted molecules. This presents a large metabolic opportunity for the gut microbiota, but little is known about how gut microbes are able to catabolize this large chemical diversity. Recently, Fe-S flavoenzymes were found to be key in the transformation of bile acids, catalysing the key step in the 7α-dehydroxylation pathway that allows gut bacteria to transform cholic acid into deoxycholic acid, an exclusively microbe-derived molecule with major implications for human health. While this enzyme family has also been implicated in a limited number of other catalytic transformations, little is known about the extent to which it is of more global importance in gut microbial metabolism. Here, we perform a large-scale computational genomic analysis to show that this enzyme superfamily has undergone a remarkable expansion in Clostridiales, and occurs throughout a diverse array of >1000 different families of putative metabolic gene clusters. Analysis of the enzyme content of these gene clusters suggests that they encode pathways with a wide range of predicted substrate classes, including saccharides, amino acids/peptides and lipids. Altogether, these results indicate a potentially important role of this protein superfamily in the human gut, and our dataset provides significant opportunities for the discovery of novel pathways that may have significant effects on human health.
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http://dx.doi.org/10.1099/mgen.0.000373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371122PMC
May 2020

Early Postoperative Endoscopic Recurrence in Crohn's Disease Is Characterised by Distinct Microbiota Recolonisation.

J Crohns Colitis 2020 Nov;14(11):1535-1546

Department of Chronic Diseases Metabolism and Ageing, KU Leuven, Leuven, Belgium.

Background And Aims: Intestinal microbiota dysbiosis is implicated in Crohn's disease [CD] and may play an important role in triggering postoperative disease recurrence [POR]. We prospectively studied faecal and mucosal microbial recolonisation following ileocaecal resection to identify the predictive value of recurrence-related microbiota.

Methods: Mucosal and/or faecal samples from 121 CD patients undergoing ileocaecal resection were collected at predefined time points before and after surgery. Ileal biopsies were collected from 39 healthy controls. POR was defined by a Rutgeerts score ≥i2b. The microbiota was evaluated by 16S rRNA sequencing. Prediction analysis was performed using C5.0 and Random Forest algorithms.

Results: The mucosa-associated microbiota in CD patients was characterised by a depletion of butyrate-producing species (false discovery rate [FDR] <0.01) and enrichment of Proteobacteria [FDR = 0.009] and Akkermansia spp. [FDR = 0.02]. Following resection, a mucosal enrichment of Lachnospiraceae [FDR <0.001] was seen in all patients but in POR patients, also Fusobacteriaceae [FDR <0.001] increased compared with baseline. Patients without POR showed a decrease of Streptococcaceae [FDR = 0.003] and Actinomycineae [FDR = 0.06]. The mucosa-associated microbiota profile had good discriminative power to predict POR, and was superior to clinical risk factors. At Month 6, patients experiencing POR had a higher abundance of taxa belonging to Negativicutes [FDR = 0.04] and Fusobacteria [FDR = 0.04] compared with patients without POR.

Conclusions: Microbiota recolonisation after ileocaecal resection is different between recurrence and non-recurrence patients, with Fusobacteria as the most prominent player driving early POR. These bacteria involved in the early recolonisation and POR represent a promising therapeutic strategy in the prevention of disease recurrence.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648170PMC
November 2020

Criteria deemed important by the relatives for designating a reference person for patients hospitalized in ICU.

J Crit Care 2020 06 26;57:191-196. Epub 2020 Feb 26.

Department of Intensive Care, Centre Hospitalier de Dieppe, France; Espace de Réflexion Ethique de Normandie, University Hospital Caen, France. Electronic address:

Purpose: We investigated the criteria that patients' relatives deem important for choosing, among themselves, the person best qualified to interact with the caregiving staff.

Methods: Exploratory, observational, prospective, multicentre study between 1st March and 31st October 2018 in 2 intensive care units (ICUs). A 12-item questionnaire was completed anonymously by family members of patients hospitalized in the ICU 3 and 5 days after the patient's admission. Relatives were eligible if they understood French and if no surrogate had been appointed by the patient prior to ICU admission. More than one relative per patient could participate.

Results: In total, 87 relatives of 73 patients completed the questionnaire, average age of relatives was 58 ± 15 years, 46% were the spouse, 30% were children/grandchildren. Items classed as being the most important attributes for a reference person were: good knowledge of the patient's wishes and values; an emotional attachment to the patient; being a family member; and having an adequate understanding of the clinical status and clinical history.

Conclusion: This study identifies the attributes considered by relatives to be most important for designating, among themselves, a reference person for a patient hospitalized in the ICU.
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http://dx.doi.org/10.1016/j.jcrc.2020.02.017DOI Listing
June 2020

Stress ulcer prophylaxis in ICU patients: Answers and questions from the PEPTIC trial.

Anaesth Crit Care Pain Med 2020 Apr 5;39(2):175-177. Epub 2020 Mar 5.

Service de Médecine Intensive Réanimation, CHU Dijon-Bourgogne, 21000 Dijon, France; INSERM, U1231, Équipe Lipness, Université Bourgogne-Franche-Comté, 21000 Dijon, France; INSERM, CIC-EC 1432, Faculté des sciences de la santé, 21000 Dijon, France. Electronic address:

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http://dx.doi.org/10.1016/j.accpm.2020.03.005DOI Listing
April 2020

Influence of deprivation on initial severity and prognosis of patients admitted to the ICU: the prospective, multicentre, observational IVOIRE cohort study.

Ann Intensive Care 2020 Feb 11;10(1):20. Epub 2020 Feb 11.

INSERM, CIC 1432, Module Epidémiologie Clinique, Dijon, France.

Background: The influence of socioeconomic status on patient outcomes is unclear. We assessed the impact of socioeconomic deprivation on severity of illness at intensive care unit (ICU) admission, and on the risk of death at 3 months after ICU admission.

Methods: The IVOIRE study was a prospective, observational, multicentre cohort study in the ICU of 8 participating hospitals in France, including patients aged ≥ 18 years admitted to the ICU and receiving at least one life support therapy for organ failure. The primary outcomes were severity at admission (assessed by SAPSII score), and mortality at 3 months. Socioeconomic data were obtained from interviews with patients or family. Deprivation was assessed using the EPICES score.

Results: Among 1294 patents included between 2013 and 2016, 629 (48.6%) were classed as deprived and differed significantly from non-deprived subjects in terms of sociodemographic characteristics and pre-existing conditions. The mean SAPS II score at admission was 50.1 ± 19.4 in deprived patients and 52.3 ± 17.3 in non-deprived patients, with no significant difference by multivariable analysis (β = - 1.85 [95% CI - 3.86; + 0.16, p = 0.072]). The proportion of death was 31.1% at 3 months, without significant differences between deprived and non-deprived patients, even after adjustment for confounders.

Conclusions: Deprivation is frequent in patients admitted to the ICU and is not associated with disease severity at admission, or with mortality at 3 months between deprived and non-deprived patients. Trial registration The IVOIRE cohort is registered with ClinicalTrials.gov under the identifier NCT01907581, registration date 17/7/2013.
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http://dx.doi.org/10.1186/s13613-020-0637-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013026PMC
February 2020

MIBiG 2.0: a repository for biosynthetic gene clusters of known function.

Nucleic Acids Res 2020 01;48(D1):D454-D458

Bioinformatics Group, Wageningen University, Wageningen, NL, The Netherlands.

Fueled by the explosion of (meta)genomic data, genome mining of specialized metabolites has become a major technology for drug discovery and studying microbiome ecology. In these efforts, computational tools like antiSMASH have played a central role through the analysis of Biosynthetic Gene Clusters (BGCs). Thousands of candidate BGCs from microbial genomes have been identified and stored in public databases. Interpreting the function and novelty of these predicted BGCs requires comparison with a well-documented set of BGCs of known function. The MIBiG (Minimum Information about a Biosynthetic Gene Cluster) Data Standard and Repository was established in 2015 to enable curation and storage of known BGCs. Here, we present MIBiG 2.0, which encompasses major updates to the schema, the data, and the online repository itself. Over the past five years, 851 new BGCs have been added. Additionally, we performed extensive manual data curation of all entries to improve the annotation quality of our repository. We also redesigned the data schema to ensure the compliance of future annotations. Finally, we improved the user experience by adding new features such as query searches and a statistics page, and enabled direct link-outs to chemical structure databases. The repository is accessible online at https://mibig.secondarymetabolites.org/.
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http://dx.doi.org/10.1093/nar/gkz882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145714PMC
January 2020

What are the characteristics that lead physicians to perceive an ICU stay as non-beneficial for the patient?

PLoS One 2019 6;14(9):e0222039. Epub 2019 Sep 6.

Department of Intensive Care, Dieppe General Hospital, Dieppe, France.

Purpose: We sought to describe the characteristics that lead physicians to perceive a stay in the intensive care unit (ICU) as being non-beneficial for the patient.

Materials And Methods: In the first step, we used a multidisciplinary focus group to define the characteristics that lead physicians to consider a stay in the ICU as non-beneficial for the patient. In the second step, we assessed the proportion of admissions that would be perceived by the ICU physicians as non-beneficial for the patient according to our focus group's definition, in a large population of ICU admissions in 4 French ICUs over a period of 4 months.

Results: Among 1075 patients admitted to participating ICUs during the study period, 155 stays were considered non-beneficial for the patient, yielding a frequency of 14.4% [95% confidence interval (CI) 8.9, 19.9]. Average age of these patients was 72 ±12.8 years. Mortality was 43.2% in-ICU [95%CI 35.4, 51.0], 55% [95%CI 47.2, 62.8] in-hospital. The criteria retained by the focus group to define a non-beneficial ICU stay were: patient refusal of ICU care (23.2% [95%CI 16.5, 29.8]), and referring physician's desire not to have the patient admitted (11.6% [95%CI 6.6, 16.6]). The characteristics that led physicians to perceive the stay as non-beneficial were: patient's age (36.8% [95%CI 29.2, 44.4]), unlikelihood of recovering autonomy (61.9% [95%CI 54.3, 69.6]), prior poor quality of life (60% [95%CI 52.3, 67.7]), terminal status of chronic disease (56.1% [95%CI 48.3, 63.9]), and all therapeutic options have been exhausted (35.5% [95%CI 27.9, 43.0]). Factors that explained admission to the ICU of patients whose stay was subsequently judged to be non-beneficial included: lack of knowledge of patient's wishes (52% [95%CI 44.1, 59.9]); decisional incapacity (sedation) (69.7% [95%CI 62.5, 76.9]); inability to contact family (34% [95%CI 26.5, 41.5]); pressure to admit (from family or other physicians) (50.3% [95%CI 42.4, 58.2]).

Conclusions: Non-beneficial ICU stays are frequent. ICU admissions need to be anticipated, so that patients who would yield greater benefit from other care pathways can be correctly oriented in a timely manner.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222039PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730882PMC
March 2020

Corporeal Compression at the Onset of Septic shock (COCOONs): a compression method to reduce fluid balance of septic shock patients.

Sci Rep 2019 08 9;9(1):11566. Epub 2019 Aug 9.

Department of intensive care, François Mitterrand University Hospital, Dijon, France.

Fluid overload in septic intensive care unit (ICU) patients is common and strongly associated with poor outcome. There is currently no treatment for capillary leak, which is mainly responsible for high positive fluid balance (FB) in sepsis. We hypothesized that increasing interstitial pressure with extensive corporeal compression would reduce FB. The objective of this study was to evaluate the feasibility, efficacy, and safety of a compression treatment during sepsis. This pilot, two-center, single-arm trial enrolled critically ill, non-surgical, septic patients receiving mechanical ventilation. The therapeutic intervention was the early application of compression bandages on more than 80% of the body surface. The primary outcome was negative net FB on day 7. The primary endpoint was reached in 29 of 45 patients (64%) with available data, for a planned objective of 26. By day 4, cumulative FB was 7280 ml [3300-9700]. SOFA- and aged-matched patients from a historical cohort had a significantly higher FB at 1, 2 and 7 days. Tolerance was good, although low-stage pressure ulcers were observed in 16 patients (26%). No effect on intra-abdominal pressure or respiratory plateau pressure was observed. In conclusion, corporeal compression demonstrated potential efficacy in limiting FB during septic shock, with acceptable feasibility and tolerance.
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http://dx.doi.org/10.1038/s41598-019-47939-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689006PMC
August 2019

Adhering to the procalcitonin algorithm allows antibiotic therapy to be shortened in patients with ventilator-associated pneumonia.

J Crit Care 2019 10 31;53:125-131. Epub 2019 May 31.

Service de Médecine Intensive-Réanimation, CHU Dijon Bourgogne, 14 rue Paul Gaffarel, B.P. 77908-21079, Dijon, Cedex, France; Université Bourgogne Franche-Comté, Lipness Team UMR 1231 et LabExLipSTIC, 7 boulevard Jeanne d'Arc, 21000 Dijon, France. Electronic address:

Purpose: Ventilator-associated pneumonia (VAP) increases exposure to antibiotics. Physicians are however reluctant to shorten treatment, arguing this could lead to failures and worse outcome. Monitoring procalcitonin (PCT) has proven effective for decreasing exposure to antibiotics in randomized controlled trials, but additional "real-life" studies are needed.

Materials And Methods: All patients with VAP in whom ABT was stopped before death or discharge were included in this 5-year prospective cohort study. Patients in whom ABT was stopped in accordance with the algorithm ("PCT-guided" group: ABT withdrawal strongly encouraged if PCT < 0.5 ng/mL or < 80% peak value) were compared to those with ABT continuation despite PCT decrease ("not PCT-guided" group). The primary endpoint was ABT duration. The secondary endpoint was unfavorable VAP outcome (i.e. death or relapse).

Results: We included 157 of the 316 patients with microbiologically-proven VAP. The algorithm was overruled in 81 patients (51.6%). ABT duration was significantly longer in these patients than in the PCT-guided group (9.5 vs. 8.0 days; p = .02), although baseline and VAP characteristics did not differ. The rate of unfavorable outcomes was comparable (46.9% vs. 51.3%; p = .69).

Conclusions: PCT-guided ABT adherence appears safe for patients with VAP and is likely to reduce exposure to antibiotics.
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http://dx.doi.org/10.1016/j.jcrc.2019.05.022DOI Listing
October 2019

Non-invasive ventilation versus high-flow nasal cannula oxygen therapy with apnoeic oxygenation for preoxygenation before intubation of patients with acute hypoxaemic respiratory failure: a randomised, multicentre, open-label trial.

Lancet Respir Med 2019 04 18;7(4):303-312. Epub 2019 Mar 18.

Biostatistics, INSERM, CIC-1402, Poitiers, France; Faculté de Médecine et de Pharmacie de Poitiers, Université de Poitiers, Poitiers, France.

Background: Non-invasive ventilation has never been compared with high-flow oxygen to determine whether it reduces the risk of severe hypoxaemia during intubation. We aimed to determine if preoxygenation with non-invasive ventilation was more efficient than high-flow oxygen in reducing the risk of severe hypoxaemia during intubation.

Methods: The FLORALI-2 multicentre, open-label trial was done in 28 intensive care units in France. Adult patients undergoing tracheal intubation for acute hypoxaemic respiratory failure (a partial pressure of arterial oxygen [PaO] to fraction of inspired oxygen [FiO] ratio of ≤300 mm Hg) were randomly assigned (1:1; block size, four participants) to non-invasive ventilation or high-flow oxygen during preoxygenation, with stratification by PaO/FiO ratio (≤200 mm Hg vs >200 mm Hg). Key exclusion criteria were intubation for cardiac arrest, altered consciousness (defined as a Glasgow coma score of less than eight points), other contraindications to non-invasive ventilation (recent laryngeal, oesophageal, or gastric surgery, and substantial facial fractures), pulse oximetry not available, pregnant or breastfeeding women, and refusal to participate. The primary outcome was the occurrence of severe hypoxaemia (pulse oximetry <80%) during the procedure, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02668458.

Findings: Between April 15, 2016, and Jan 8, 2017, 2079 patients were intubated in the 28 participating units, and 322 were enrolled. We excluded five patients with no recorded data, two who withdrew consent or were under legal protection, one who was not intubated, and one who had a cardiac arrest. Of the 313 patients included in the intention-to-treat analysis, 142 were assigned to non-invasive ventilation and 171 to high-flow oxygen therapy. Severe hypoxaemia occurred in 33 (23%) of 142 patients after preoxygenation with non-invasive ventilation and 47 (27%) of 171 with high-flow oxygen (absolute difference -4·2%, 95% CI -13·7 to 5·5; p=0·39). In the 242 patients with moderate-to-severe hypoxaemia (PaO/FiO ≤200 mm Hg), severe hypoxaemia occurred less frequently after preoxygenation with non-invasive ventilation than with high-flow oxygen (28 [24%] of 117 patients vs 44 [35%] of 125; adjusted odds ratio 0·56, 0·32 to 0·99, p=0·0459). Serious adverse events did not differ between treatment groups, with the most common immediate complications being systolic arterial hypotension (70 [49%] patients in the non-invasive ventilation group vs 86 [50%] patients in the high-flow oxygen group) and chest infiltrate on x-ray (28 [20%] vs 33 [19%]), and the most common late complications being death at day 28 (53 [37%] vs 58 [34%]) and ventilator-associated pneumonia during ICU stay (31 [22%] vs 35 [20%]).

Interpretation: In patients with acute hypoxaemic respiratory failure, preoxygenation with non-invasive ventilation or high-flow oxygen therapy did not change the risk of severe hypoxaemia. Future research should explore the effect of preoxygenation method in patients with moderate-to-severe hypoxaemia at baseline.

Funding: French Ministry of Health.
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http://dx.doi.org/10.1016/S2213-2600(19)30048-7DOI Listing
April 2019

The antiSMASH database version 2: a comprehensive resource on secondary metabolite biosynthetic gene clusters.

Nucleic Acids Res 2019 01;47(D1):D625-D630

Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet, Building 220, 2800 Kgs. Lyngby, Denmark.

Natural products originating from microorganisms are frequently used in antimicrobial and anticancer drugs, pesticides, herbicides or fungicides. In the last years, the increasing availability of microbial genome data has made it possible to access the wealth of biosynthetic clusters responsible for the production of these compounds by genome mining. antiSMASH is one of the most popular tools in this field. The antiSMASH database provides pre-computed antiSMASH results for many publicly available microbial genomes and allows for advanced cross-genome searches. The current version 2 of the antiSMASH database contains annotations for 6200 full bacterial genomes and 18,576 bacterial draft genomes and is available at https://antismash-db.secondarymetabolites.org/.
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http://dx.doi.org/10.1093/nar/gky1060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324005PMC
January 2019

New-onset atrial fibrillation in ICU: A FROG in the throat.

Int J Cardiol 2018 11;270:189

University Hospital, Intensive Care Unit, Dijon, France; INSERM, CIE 1, Dijon, France.

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http://dx.doi.org/10.1016/j.ijcard.2018.06.101DOI Listing
November 2018

What are the ethical dimensions in the profession of intensive care specialist?

Ann Transl Med 2017 Dec;5(Suppl 4):S47

Department of Intensive Care, Dieppe General Hospital, Dieppe, France.

Two essential components of the profession of a medical doctor are the constant review of the patient's therapeutic project, and collaboration between healthcare professionals. The profession of intensive care unit (ICU) physician goes further in terms of responsibility, vis-à-vis the intensive treatments dispensed to the patients, and the physician's responsibilities towards the patient's family and the caregiving team, also bearing in mind that ICU care is costly in terms of human and financial resources. In this review, we address the profession of ICU physician from the perspective of the ethical questions that arise constantly, focusing on the timeframe of the reflection process. Firstly, admission to the ICU must be anticipated. The concept of advance care planning is a suitable tool for this, and in case of non-admission to the ICU, does not by any means constitute an abandonment of the patient, because palliative care can also be anticipated, with a view to avoiding suffering for the patient and their family. Next, during an ICU stay, while the technical aspects undoubtedly characterise the ICU best at the start of the patient's stay, the process of reflection rapidly becomes preponderant, and involves the analysis of often complex situations with a view to defining the level of therapeutic engagement and optimizing the care dispensed to the patient. Last, a further ethical issue concerns the decision to re-admit (or not) a patient to the ICU. This decision can be made, for example, in the framework of a systematic, formalised, structured, multidisciplinary meeting at the end of an ICU stay, using a similar procedure to that implemented for decisions relating to withholding or withdrawal of life-sustaining therapies. The profession of ICU physician is not simply a question of prolonging or sustaining life, but is also fraught with ethical questions about how best to employ their competences. In this regard, it is essential to foster interdisciplinary collaboration, and emphasise the need for ICU physicians to be involved in the development of therapeutic projects, particularly when the disease in question is likely to be complicated by acute situations that may require admission of the patient to the ICU.
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http://dx.doi.org/10.21037/atm.2017.09.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750243PMC
December 2017

What are the ethical questions raised by the integration of intensive care into advance care planning?

Ann Transl Med 2017 Dec;5(Suppl 4):S46

Department of Intensive Care, Dieppe General Hospital, Dieppe, France.

A major goal of intensive care units (ICUs) is to offer optimal management, but for many patients admitted to the ICU, they are unlikely to yield any lasting benefit. In this context, the ICU physician remains a key intermediary, particularly when a decision regarding possible limitation or withdrawal of life-sustaining therapy becomes necessary. The possibility of admission to the ICU, and the type of care the patient would like to receive there, should be integrated into the healthcare project in agreement with the patient, regardless of the stage of disease that the patient suffers from. These dispositions should be recorded in the patient's file, and should respect the progressive nature of both the disease itself, and the discussions necessary in such complex situations. The ICU physician can serve as a valuable consultant for the treating physician, in particular to guide patient choices when formalizing their healthcare preferences in the form of advance care planning (ACP) or advance directives (AD). Ideally, the best time to address this issue is before the patient's clinical situation deteriorates towards an acute emergency, and providing complete and transparent information to inform the patient's choices.
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http://dx.doi.org/10.21037/atm.2017.08.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750251PMC
December 2017

What are the ethical aspects surrounding the collegial decisional process in limiting and withdrawing treatment in intensive care?

Ann Transl Med 2017 Dec;5(Suppl 4):S43

Department of Intensive Care, Dieppe General Hospital, Dieppe, France.

The decision to limit or withdraw life-support treatment is an integral part of the job of a physician working in the intensive care unit, and of the approach to care. However, this decision is influenced by a number of factors. It is widely accepted that a medical decision that will ultimate lead to end-of-life in the intensive care unit (ICU) must be shared between all those involved in the care process, and should give precedence to the patient's wishes (either directly expressed by the patient or in written form, such as advance directives), and taking into account the opinion of the patient's family, including the surrogate if the patient is no longer capable of expressing themselves. A number of questions still remain unanswered regarding how decisions to limit or withdraw treatment are taken in daily practice, especially when this decision can be anticipated. We discuss here the collegial procedure for decision-making, in particular in the context of recent French legislation on end-of-life issues. We describe how collegial decision-making procedures should be carried out, and what points are covered in shared discussions regarding decisions to limit or withdraw life-sustaining therapies.
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http://dx.doi.org/10.21037/atm.2017.04.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750242PMC
December 2017

What are the ethical issues in relation to the role of the family in intensive care?

Ann Transl Med 2017 Dec;5(Suppl 4):S40

Department of Intensive Care, Dieppe General Hospital, Dieppe, France.

A large proportion of patients admitted to the intensive care unit (ICU) are unable to express themselves, often due to acute illness, shock or trauma, and this precludes any communication and/or consent for care that might reflect their wishes and opinions. In such cases, the only solution for the ICU physician is to include the patient's family in the healthcare decisions. This can represent a significant burden on the family, on top of the psychological distress of the ICU environment and hospitalisation of their relatives, and many family members may suffer from anxiety, depression or symptoms of post-traumatic stress disorder (PTSD) during or after the hospitalisation and/or death of a loved one in the ICU. Good communication remains the cornerstone of family satisfaction in the ICU. Information imparted to the patient and/or family should cover diagnosis, prognosis and treatment. Information should be given orally, in person, using accessible language. Several other measures that can lessen the burden on the families of patients in the ICU and help to reduce anxiety and stress are also detailed in this review. Overall, family-centred care in the ICU requires a systematic communication strategy within the healthcare team, combined with an environment that is as amenable as possible to the family's presence and involvement, in order to maximize family satisfaction with ICU care, and ensure that the patient's values and preferences are respected.
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http://dx.doi.org/10.21037/atm.2017.04.44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750250PMC
December 2017

Intersecting vulnerabilities in professionals and patients in intensive care.

Ann Transl Med 2017 Dec;5(Suppl 4):S39

Department of Intensive Care, François Mitterrand University Hospital, 14 rue Paul Gaffarel, Dijon, France.

In the context of healthcare delivery, the vulnerabilities of patients in the intensive care unit (ICU) are intricately linked with those experienced on a daily basis by caregivers in the ICU in a symbiotic relation, whereby patients who are suffering can in turn engender suffering in the caregivers. In the same way, caregivers who are suffering themselves may be a source of suffering for their patients. The vulnerabilities of both patients and caregivers in the ICU are simultaneously constituted through a process that is influenced on the one hand by the healthcare objectives of the ICU, and on the other hand, by the conformity of the patients who are managed in that ICU. The specific challenges of management in high-technology units such as an ICU may have consequences on the practices and work conditions of healthcare professionals. Constructing the patient, collectively redefining the patient's identity, and ascribing the patient to a specific healthcare trajectory enables professionals to circumscribe, contain and fight against the spectrum of extreme vulnerabilities of their patients. Imposing this normative framework is the sole means of guiding these professionals through their daily practices. In spite of this, situations of suffering remain a constitutive feature of the caregiving relation in the ICU.
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http://dx.doi.org/10.21037/atm.2017.09.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750249PMC
December 2017

Impact of a stay in the intensive care unit on the preparation of Advance Directives: Descriptive, exploratory, qualitative study.

Anaesth Crit Care Pain Med 2018 Apr 4;37(2):113-119. Epub 2017 Aug 4.

Service de réanimation médicale, université de Bourgogne-Franche-Comté, CHU de Dijon, Dijon, France; LipnessTeam, Inserm, UMR866, université de Bourgogne-Franche-Comté, Dijon, France; Inserm CIC 1432, faculté de médecine de Dijon, université de Bourgogne-Franche-Comté, Dijon, France. Electronic address:

Background: Our objective was to assess, through a qualitative, exploratory study, the thought processes of patients regarding the formulation of advance directives (AD) after a stay in the ICU.

Methods: The study was conducted from May to July 2016 using telephone interviews performed by four senior ICU physicians. Inclusion criteria were: patients discharged from ICU to home>3 months earlier. Semi-directive interviews with patients focused on 5 main points surrounding AD.

Results: In total, among 159 eligible patients, data from 94 (59%) were available for analysis. Among all those interviewed, 83.5% had never heard of "advance directives". Only 2% had executed AD before ICU admission, and 7% expressed a desire to prepare AD further to their ICU stay. Among the barriers to preparation of AD, lack of information was the main reason cited for not executing AD. Patients noted the following in their AD: withdrawal of life-support in case of vegetative/minimally conscious state or when there is no longer any hope, in case of uncontrollable pain, and if impossible to wean from mechanical ventilation.

Conclusion: The ideal time to engage patients in these discussions is most likely well before an acute health event occurs, although this warrants further investigation both before and after ICU admissions.
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http://dx.doi.org/10.1016/j.accpm.2017.05.007DOI Listing
April 2018
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