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The metabolic capacity, stress response and evolution of uncultured environmental Tenericutes have remained elusive, since previous studies have been largely focused on pathogenic species. In this study, we expanded analyses on Tenericutes lineages that inhabit various environments using a collection of 840 genomes. Several novel environmental lineages were discovered inhabiting the human gut, ground water, bioreactors and hypersaline lake and spanning the Haloplasmatales and Mycoplasmatales orders. A phylogenomics analysis of Bacilli and Tenericutes genomes revealed that some uncultured Tenericutes are affiliated with novel clades in Bacilli, such as RF39, RFN20 and ML615. Erysipelotrichales and two major gut lineages, RF39 and RFN20, were found to be neighboring clades of Mycoplasmatales. We detected habitat-specific functional patterns between the pathogenic, gut and the environmental Tenericutes, where genes involved in carbohydrate storage, carbon fixation, mutation repair, environmental response and amino acid cleavage are overrepresented in the genomes of environmental lineages. We hypothesize that the two major gut lineages, namely RF39 and RFN20, are probably acetate and hydrogen producers. Furthermore, deteriorating capacity of bactoprenol synthesis for cell wall peptidoglycan precursors secretion is a potential adaptive strategy employed by these lineages in response to the gut environment. This study uncovers the characteristic functions of environmental Tenericutes and their relationships with Bacilli, which sheds new light onto the pathogenicity and evolutionary processes of Mycoplasmatales.IMPORTANCEEnvironmental Tenericutes bacteria were recently discovered in numerous environments. However, our current collection of Tenericutes genomes was overrepresented by those for pathogens. Our phylogenomics study displays the relationships between all the available Tenericutes, as well as those between Tenericutes and the clades in Bacilli, which casts lights into the uncertain boundary between the environmental lineages of Tenericutes and Bacilli. By comparing the genomes of the environmental and pathogenic Tenericutes, we revealed the metabolic pathways and adaptive strategies of the Tenericutes in the different environments and hosts. We also predicted the metabolism of the two major gut lineages RF39 and RFN20 of Tenericutes, indicating their potential importance in stabilization of the gut microbiome and contribution to human health.

The brainstem conveys sensory and motor inputs between the spinal cord and the brain, and contains nuclei of the cranial nerves. It controls the sleep-wake cycle and vital functions via the ascending reticular activating system and the autonomic nuclei, respectively. Brainstem dysfunction may lead to sensory and motor deficits, cranial nerve palsies, impairment of consciousness, dysautonomia, and respiratory failure. The brainstem is prone to various primary and secondary insults, resulting in acute or chronic dysfunction. Of particular importance for characterizing brainstem dysfunction and identifying the underlying etiology are a detailed clinical examination, MRI, neurophysiologic tests such as brainstem auditory evoked potentials, and an analysis of the cerebrospinal fluid. Detection of brainstem dysfunction is challenging but of utmost importance in comatose and deeply sedated patients both to guide therapy and to support outcome prediction. In the present review, we summarize the neuroanatomy, clinical syndromes, and diagnostic techniques of critical illness-associated brainstem dysfunction for the critical care setting.

International audience; BACKGROUND:Many effective physical activity (PA) interventions have focused on individual factors or a single theoretical model, limiting our understanding of the determinants of PA practice and their interactions in the cancer trajectory. The present mixed-method study aims to capture social and psychological determinants of PA practice from diagnosis to remission among cancer patients, and to identify key levers for PA practice.METHODS/DESIGN:A nested sequential mixed-method design QUAN (QUAL+QUAL) will be used, with qualitative studies embedded in the quantitative study to broaden our understanding of the determinants of PA practice. The design is sequential, since qualitative data on medical staff will be collected before patient inclusion (Phase 1), followed by quantitative patient data collection lasting one year (Phase 2) and a final qualitative data collection one year after inclusion (Phase 3). Phase 1 will be a case study in the two hospitals involved in the study, exploring knowledge of and support for PA practice among medical staff. Through interviews and documental analyses, the PA support dynamic will be evaluated with regard to PA prescription. Phase 2 will be a one-year observational study among 693 cancer patients. Quantitative medical, social, dispositional and psychological data, PA practices and preferences, will be collected at diagnosis, and six months and one year thereafter. Phase 3 will be a retrospective study, evaluating societal and policy factors, as well as unexpected factors playing a role in PA levels and preferences among cancer patients. For this phase thirty patients will be identified six months after inclusion on the basis of their PA profiles. Quantitative data will provide the main dataset, whilst qualitative data will complete the picture, enabling determinants of PA practice and their interactions to be captured throughout the cancer trajectory.DISCUSSION:The present study aims to identify key levers and typical trajectories for PA practice among cancer patients, adapted to different times in the course of cancer and taking into account "what works", "for whom", "where" and "how". The challenge is the tailoring of PA interventions to patients at different times in their cancer trajectory, and the implication of medical staff support.TRIAL REGISTRATION:Clinical Trial NCT03919149 , 18 April 2019. Prospectively registered.

Background Subjective cognitive decline (SCD) defines a heterogeneous population, part of which having Alzheimer’s disease (AD). We aimed at characterizing SCD populations according to whether or not they referred to a memory clinic, by assessing the factors associated with increased AD risk. Methods Seventy-eight cognitively unimpaired older adults from the IMAP+ study (Caen) were included, amongst which 28 healthy controls (HC) and 50 SCD recruited from the community (SCD-community; n = 23) or from a memory clinic (SCD-clinic; n = 27). Participants underwent cognitive, psychoaffective, structural MRI, FDG-PET, and amyloid-PET assessments. They were followed up over a mean period of 2.4 ± 0.8 years. The groups were compared in terms of baseline and follow-up levels of SCD (self- and informant-reported), cognition, subclinical anxiety and depression, and atrophy progression over time. We also investigated SCD substrates within each SCD group through the correlations between self-reported SCD and other psychometric and brain measures. Results Compared to HC, both SCD groups showed similar cognitive performances but higher informant-reported SCD and anxiety. Compared to SCD-community, SCD-clinic showed higher informant-reported SCD, depression score, and atrophy progression over time but similar brain amyloid load. A significant increase over time was found for depression in the SCD-community and for self-reported praxis-domestic activities SCD factor in the SCD-clinic. Higher self-reported SCD correlated with (i) lower grey matter volume and higher anxiety in SCD-community, (ii) greater informant-reported SCD in SCD-clinic, and (iii) lower glucose metabolism in both SCD groups. Conclusions Higher subclinical depression and informant-reported SCD specifically characterize the SCD group that refers to a memory clinic. The same group appears as a frailer population than SCD-community as they show greater atrophy progression over time. Yet, both the SCD groups were quite similar otherwise including for brain amyloid load and the SCD-community showed increased depression score over time. Altogether, our findings highlight the relevance of assessing psychoaffective factors and informant-reported SCD in SCD populations and point to both differences and similarities in SCD populations referring or not to a memory clinic. Electronic supplementary material The online version of this article (10.1186/s13195-019-0514-z) contains supplementary material, which is available to authorized users.

International audience; BACKGROUND:Kodamaea ohmeri is a yeast is frequently mistaken for Candida, which belongs to the same family. This micro-organism has been reported to cause life-threatening infections in humans.CASE PRESENTATION:A 81-year-old woman developed a severe fungemic pulmonary infection due to Kodamaea ohmeri that was identified from bronchoalveolar fluid and blood cultures, which is unusual in immunocompetent patients. Because K. ohmeri was first wrongly identified as Candida albicans, the patient inadequately received caspofungin, which was clinically ineffective, especially as the strain was resistant to echinocandins. Clinical cure was obtained after treatment was switched to voriconazole.CONCLUSIONS:An increasing number of serious infections due to K. ohmeri has been reported in the literature, but the correct identification of this micro-organism remains difficult.

Background The interplay between metabolic processes and signalling pathways remains poorly understood. Global, detailed and comprehensive reconstructions of human metabolism and signalling pathways exist in the form of molecular maps, but they have never been integrated together. We aim at filling in this gap by integrating of both signalling and metabolic pathways allowing a visual exploration of multi-level omics data and study of cross-regulatory circuits between these processes in health and in disease. Results We combined two comprehensive manually curated network maps. Atlas of Cancer Signalling Network (ACSN), containing mechanisms frequently implicated in cancer; and ReconMap 2.0, a comprehensive reconstruction of human metabolic network. We linked ACSN and ReconMap 2.0 maps via common players and represented the two maps as interconnected layers using the NaviCell platform for maps exploration (https://navicell.curie.fr/pages/maps_ReconMap%202.html). In addition, proteins catalysing metabolic reactions in ReconMap 2.0 were not previously visually represented on the map canvas. This precluded visualisation of omics data in the context of ReconMap 2.0. We suggested a solution for displaying protein nodes on the ReconMap 2.0 map in the vicinity of the corresponding reaction or process nodes. This permits multi-omics data visualisation in the context of both map layers. Exploration and shuttling between the two map layers is possible using Google Maps-like features of NaviCell. The integrated networks ACSN-ReconMap 2.0 are accessible online and allows data visualisation through various modes such as markers, heat maps, bar-plots, glyphs and map staining. The integrated networks were applied for comparison of immunoreactive and proliferative ovarian cancer subtypes using transcriptomic, copy number and mutation multi-omics data. A certain number of metabolic and signalling processes specifically deregulated in each of the ovarian cancer sub-types were identified. Conclusions As knowledge evolves and new omics data becomes more heterogeneous, gathering together existing domains of biology under common platforms is essential. We believe that an integrated ACSN-ReconMap 2.0 networks will help in understanding various disease mechanisms and discovery of new interactions at the intersection of cell signalling and metabolism. In addition, the successful integration of metabolic and signalling networks allows broader systems biology approach application for data interpretation and retrieval of intervention points to tackle simultaneously the key players coordinating signalling and metabolism in human diseases. Electronic supplementary material The online version of this article (10.1186/s12859-019-2682-z) contains supplementary material, which is available to authorized users.

International audience; The cerebrospinal fluid (CSF) biochemical markers (biomarkers) Amyloidβ 42 (Aβ42), total Tau (T-tau) and Tau phosphorylated at threonine 181 (P-tau181) have proven diagnostic accuracy for mild cognitive impairment and dementia due to Alzheimer's Disease (AD). In an effort to improve the accuracy of an AD diagnosis, it is important to be able to distinguish between AD and other types of dementia (non-AD). The concentration ratio of Aβ42 to Aβ40 (Aβ42/40 Ratio) has been suggested to be superior to the concentration of Aβ42 alone when identifying patients with AD. This article reviews the available evidence on the use of the CSF Aβ42/40 ratio in the diagnosis of AD. Based on the body of evidence presented herein, it is the conclusion of the current working group that the CSF Aβ42/40 ratio, rather than the absolute value of CSF Aβ42, should be used when analysing CSF AD biomarkers to improve the percentage of appropriately diagnosed patients.

Background DOPPS reported that thousands of life-years could be gained in the US and Europe over 5 years by correcting six modifiable haemodialysis practices. We estimated potential life-years gained across 10 European countries using MONITOR-CKD5 study data. Methods The DOPPS-based target ranges were used, except for haemoglobin due to label changes, as well as DOPPS-derived relative mortality risks. Percentages of MONITOR-CKD5 patients outside targets were calculated. Consistent with the DOPPS-based analyses, we extrapolated life-years gained for the MONITOR-CKD5 population over 5 years if all patients were within targets. Results Bringing the 10 MONITOR-CKD5 countries’ dialysis populations into compliance on the six practices results in a 5-year gain of 97,428 patient-years. In descending order, survival impact was the highest for albumin levels, followed by phosphate levels, vascular access, haemoglobin, dialysis adequacy, and interdialytic weight gain. Conclusions Optimal management of the six modifiable haemodialysis practices may achieve 6.2% increase in 5-year survival. Trial Registration NCT01121237. Clinicaltrials.gov registration May 12, 2010 (retrospectively registered). Electronic supplementary material The online version of this article (10.1186/s12882-019-1251-z) contains supplementary material, which is available to authorized users.

Background The Cancer of the Prostate Risk Assessment (CAPRA) score was designed and validated several times to predict the biochemical recurrence-free survival after a radical prostatectomy. Our objectives were, first, to study the clinical validity of the CAPRA score, and, second, to assess its clinical utility for stratified medicine from an original patient-centered approach. Methods We proposed a meta-analysis based on a literature search using MEDLINE. Observed and predicted biochemical-recurrence-free survivals were compared to assess the calibration of the CAPRA score. Discriminative capacities were evaluated by estimating the summary time-dependent ROC curve. The clinical utility of the CAPRA score was evaluated according to the following stratified decisions: active monitoring for low-risk patients, prostatectomy for intermediate-risk patients, or radio-hormonal therapy for high risk patients. For this purpose, we assessed CAPRA’s clinical utility in terms of its ability to maximize time-dependent utility functions (i.e. Quality-Adjusted Life-Years – QALYs). Results We identified 683 manuscripts and finally retained 9 studies. We reported good discriminative capacities with an area under the SROCt curve at 0.73 [95%CI from 0.67 to 0.79], while graphical calibration seemed acceptable. Nevertheless, we also described that the CAPRA score was unable to discriminate between the three medical alternatives, i.e. it did not allow an increase in the number of life years in perfect health (QALYs) of patients with prostate cancer. Conclusions We confirmed the prognostic capacities of the CAPRA score. In contrast, we were not able to demonstrate its clinical usefulness for stratified medicine from a patient-centered perspective. Our results also highlighted the confusion between clinical validity and utility. This distinction should be better considered in order to develop predictive tools useful in practice. Electronic supplementary material The online version of this article (10.1186/s12911-018-0727-2) contains supplementary material, which is available to authorized users.

International audience; BACKGROUND: Patients' quality of life has become a major objective of care in oncology. At the same time, it has become the object of increasing interest by researchers, working with both quantitative and qualitative methods. Progress in oncology has enabled more patients to survive longer, so that cancer is increasingly often a chronic disease that requires long-term treatment that can have negative effects on patients' quality of daily life. Nonetheless, no qualitative study has explored what patients report affects their quality of daily life during the treatment period. This study is intended to fill this gap.METHODS: We conducted a multicenter qualitative study based on 30 semi-structured interviews. Participants, purposively selected until data saturation, had diverse types of cancer and had started treatment at least 6 months before interview. Data were examined by thematic analysis.RESULTS: Our analysis found two themes: (1) what negatively affected for patient's quality of daily life during the treatment period, a question to which patients responded by talking only about the side effects of treatment; and (2) what positively affected their quality of daily life during the treatment period with three sub-themes: (i) The interest in having -investing in - a support object that can be defined as an object, a relationship or an activity particularly invested by the patients which makes them feel good and makes the cancer and its treatment bearable, (ii)The subjective perception of the efficacy of the antitumor treatment and (iii) the positive effects of relationships, with friends and family, and also with their physician.CONCLUSIONS: Patients must be involved in their care if they are to be able to bear their course of treatment and find ways to endure the difficult experience of cancer care. The support object represents an important therapeutic lever that can be used by their oncologists. They should be interested in their support objects, in order to support the patients in this investment and to help them to maintain it throughout the health care pathway. Furthermore, showing interest in this topic, important to the patient, could improve the physician-patient relation without using up very much of the physician's time.

Background Helicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. Epidemiological evidence shows that progression to cancer depends upon the host and pathogen factors, but questions remain about why cancer phenotypes develop in a minority of infected people. Here, we use comparative genomics approaches to understand how genetic variation amongst bacterial strains influences disease progression. Results We performed a genome-wide association study (GWAS) on 173 H. pylori isolates from the European population (hpEurope) with known disease aetiology, including 49 from individuals with gastric cancer. We identified SNPs and genes that differed in frequency between isolates from patients with gastric cancer and those with gastritis. The gastric cancer phenotype was associated with the presence of babA and genes in the cag pathogenicity island, one of the major virulence determinants of H. pylori, as well as non-synonymous variations in several less well-studied genes. We devised a simple risk score based on the risk level of associated elements present, which has the potential to identify strains that are likely to cause cancer but will require refinement and validation. Conclusion There are a number of challenges to applying GWAS to bacterial infections, including the difficulty of obtaining matched controls, multiple strain colonization and the possibility that causative strains may not be present when disease is detected. Our results demonstrate that bacterial factors have a sufficiently strong influence on disease progression that even a small-scale GWAS can identify them. Therefore, H. pylori GWAS can elucidate mechanistic pathways to disease and guide clinical treatment options, including for asymptomatic carriers. Electronic supplementary material The online version of this article (10.1186/s12915-018-0550-3) contains supplementary material, which is available to authorized users.

Background Since the 2000s, selective episiotomy has been systematically recommended worldwide. In France, the recommended episiotomy rate in vaginal deliveries is less than 30%. The aims of this study were to describe the evolution of episiotomy rates between 2007 and 2014, especially for vaginal deliveries without instrumental assistance and to assess individual characteristics and birth environment factors associated with episiotomy. Methods This population-based study included all hospital discharge abstracts for all deliveries in France from 2007 to 2014. The use of episiotomy in vaginal deliveries was identified by one code in the French Common Classification of Medical Procedures. The episiotomy rate per department and its evolution is described from 2007 to 2014. A mixed model was used to assess associations with episiotomy for non-operative vaginal deliveries and the risk factors related to the women’s characteristics and the birth environment. Results There were approximately 540,000 non-operative vaginal deliveries per year, in the study period. The national episiotomy rate for vaginal deliveries overall significantly decreased from 26.7% in 2007 to 19.9% in 2014. For non-operative deliveries, this rate fell from 21.1% to 14.1%. For the latter, the use of episiotomy was significantly associated with breech vaginal delivery (aOR = 1.27 [1.23–1.30]), epidural analgesia (aOR = 1.45 [1.43–1.47]), non-reassuring fetal heart rate (aOR = 1.47 [1.47–1.49]), and giving birth for the first time (aOR = 3.85 [3.84–4.00]). Conclusions The episiotomy rate decreased throughout France, for vaginal deliveries overall and for non-operative vaginal deliveries. This decrease is probably due to proactive changes in practices to restrict the number of episiotomies, which should be performed only if beneficial to the mother and the infant. Electronic supplementary material The online version of this article (10.1186/s12884-018-1747-8) contains supplementary material, which is available to authorized users.

Background Colon cancer occurrence is increasing worldwide, making it the third most frequent cancer. Although many therapeutic options are available and quite efficient at the early stages, survival is strongly decreased when the disease has spread to other organs. The identification of molecular markers of colon cancer is likely to help understanding its course and, eventually, to uncover novel genes to be targeted by drugs. In this study, we compared gene expression in a set of 95 human colon cancer samples to that in 19 normal colon mucosae, focusing on 401 genes from 5 selected pathways (Apoptosis, Cancer, Cholesterol metabolism and lipoprotein signaling, Drug metabolism, Wnt/beta-catenin). Deregulation of mRNA levels largely matched that of proteins, leading us to build in silico protein networks, starting from mRNA levels, to identify key proteins central to network activity. Results Among the analyzed genes, 10.5% (42) had no reported link with colon cancer, including the SFRP1, IGF1 and ADH1B (down), and MYC and IL8 (up), whose encoded proteins were most interacting with other proteins from the same or even distinct networks. Analyzing all pathways globally led us to uncover novel functional links between a priori unrelated or rather remotely connected pathways, such as the Drug metabolism and the Cancer pathways or, even more strikingly, between the Cholesterol metabolism and lipoprotein signaling and the Cancer pathways. In addition, we analyzed the responsiveness of some of the deregulated genes essential to network activities, to chemotherapeutic agents used alone or in presence of Lovastatin, a lipid-lowering drug. Some of these treatments could oppose the deregulations occurring in cancer samples, including those of the CHECK2, CYP51A1, HMGCS1, ITGA2, NME1 or VEGFA genes. Conclusions Our network-based approach allowed discovering genes not previously known to play regulatory roles in colon cancer. Our results also showed that selected drug treatments might revert the cancer-specific deregulation of genes playing prominent roles within the networks operating to maintain colon homeostasis. Among those genes, some could constitute novel testable targets to eliminate colon cancer cells, either directly or, potentially, through the use of lipid-lowering drugs such as statins, in association with selected anticancer drugs. Electronic supplementary material The online version of this article (10.1186/s12864-017-4139-y) contains supplementary material, which is available to authorized users.

International audience; BACKGROUND:Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare event occurring mostly during natural pregnancy. Among described etiologies, some activating mutations of FSH receptor (FSHR) have been identified.CASE PRESENTATION:We report hereby the case of a non-pregnant women with three episodes of sOHSS. Hormonal evaluation was normal and no pituitary adenoma was detected. However, genetic analysis identified a novel heterozygous FSHR mutation (c.1901 G > A). This R634H mutation is the first described in the cytoplasmic tail of the receptor. Functional analysis failed to reveal constitutive activity of the mutant but a decreased cAMP production in response to FSH. The weak activity of this mutant is correlated with a markedly reduced cell surface expression.CONCLUSION:Pathophysiology of non gestationnal sOHSS is still ill established. The molecular characterization of this new mutant indicates that it might not be at play. Therefore, further investigations are needed to improve knowledge of the molecular mechanism of this syndrome.

Background The aim of this study was to identify the characteristics of morbidity and mortality conferences (MMCs) associated with the implementation of patient health-care quality and safety improvement initiatives. Methods We conducted an observational study of MMCs and followed up improvement initiatives for 1 year. Data on MMC baseline characteristics were abstracted using document analysis and observation of a meeting in three university hospitals in France (Grenoble, Nice, and Cochin [Paris] hospitals). Fifty-nine MMCs were included in medical (n = 24), surgical (n = 21), and anesthesiology and/or intensive care (n = 14) departments. An effectiveness index was computed by summing a composite score for each initiative pertaining to the MMC. Results Overall, 282 initiatives were identified in 42 MMCs. During the follow-up period, 215 initiatives (76 %) were totally or partially implemented and the impact was evaluated for 73 (26 %). An effectiveness index higher than the median (i.e., ≥10) was associated with a standardized presentation of cases (81 % versus 29 %, p