Da Volterra (France)

BackgroundAntibiotics (ATB) induce intestinal dysbiosis and decrease the efficacy of immune checkpoint inhibitors (ICI).1,2 DAV132 is an orally administered colon-targeted ATB adsorbent designed to prevent ATB-induced dysbiosis.3 We investigated whether DAV132 co-administered with ATB could protect gut microbiota diversity and composition. Moreover, in murine avatar tumor model, we assessed anti-PD-1 efficacy through fecal microbiota transplantation (FMT) in germ-free (GF) or antibiotic-treated specific pathogen-free (SPF) mice.MethodsTwenty-four human healthy volunteers (HV) were randomized to receive either ceftazidime-avibactam (CZA, 2g/0.5g q8h IV for 5 days) or CZA+DAV132 (12g PO tid for 7 days). CZA plasmatic and fecal pharmacodynamic levels were measured using HPLC-MS/MS. Microbiome was profiled with 16S and shotgun metagenomics at different timepoints. FMT in GF or ATB-treated SPF mice was performed using fecal samples from 3 HV and 2 HV respectively, in each group before (D1) or after 6 days (D6) of CZA+/-DAV132; subsequently mice were inoculated with MCA-205 tumor and treated intraperitoneally with anti-PD-1, 4 times every 3 days. Immunological population of tumor infiltrating lymphocytes were analyzed by flow cytometry.ResultsDAV132 did not impact plasmatic CZA concentrations, but significantly reduced ceftazidime concentration in feces compared to HV treated with CZA alone (p<0.001). DAV132 significantly prevented the reduction in microbiota alpha-diversity at D6 (p=0.0019) and was associated with a more rapid return to baseline microbiota composition (figure 1). Significantly more bacteria associated with better response to ICI were preserved in the DAV group compared to CZA, among which Faecalibacterium praunistzii and several Alistipes spp. FMT in GF mice transplanted with feces collected at D1 exhibited a significant anti-PD-1 activity. This anti-tumor response was inhibited in mice transplanted with D6 feces from any of the 3 CZA-treated HV. Conversely, the anti-tumor response was maintained in mice transplanted with D6 feces from any of the 3 HV treated with CZA + DAV132 (figure 2). Similar results were observed upon FMT using samples from HVs into ATB-treated SPF mice. Flow cytometry on tumor T cell infiltrates demonstrated that CZA decreased CD8+T cell infiltration and CD8+/Tregulatory ratio, compared to CZA + DAV132 treated HVs (figure 3).ConclusionsDAV132 strongly prevented CZA-induced dysbiosis in HV without influencing plasmatic concentrations. In avatar mice FMT from HV treated with CZA+DAV132 was able to preserve anti-PD-1 cancer efficacy. These results provide rationale to launch clinical trials combining DAV132 in patients on ATB amenable to ICI.AcknowledgementsThis work was funded by Da Volterra, a French biotech company, through the sharing of fecal samples and a collaboration agreement with Pr. Routy’s lab.ReferencesDerosa L, Routy B, Desilets A, Daillère R, Terrisse S, Kroemer G, Zitvogel L. Microbiota-centered interventions: the next breakthrough in Immuno-Oncology? Cancer Discov. 2021;11(10):2396–2412.Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G, Clémenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–97.Vehreschild MJGT, Ducher A, Louie T, Cornely OA, Feger C, Dane A, Varastet M, Vitry F, de Gunzburg J, Andremont A, Mentré F, Wilcox MH. An open randomized multicenter Phase 2 trial to assess the safety of DAV132 and its efficacy to protect gut microbiota diversity in hospitalized patients treated with fluoroquinolones. J Antimicrob Chemother. 2022;77(4):1155–1165.Ethics ApprovalAll animal studies were approved by the Institutional Animal Care Committee (CIPA) and carried out in compliance with the Canadian Council on Animal Care guidelines (Ethics numbers: C18029BRs). 1306 Figure 1Intestinal microbiota composition in CZA ± DAV132 groupsHeatmap of hierarchical clustering of microbiota composition represented by 16SrRNA profiling in 24 healthy volunteers treated with ceftazidime-avibactam ± DAV132 1306 Figure 2Anti-tumor response preserved by DAV132DAV132 prevents antibiotic-induced loss of anti-tumor response in murine germ-free cancer model transplanted with healthy volunteers treated with ceftazidime-avibactam ± DAV132.*** p < 0.001, Mann-Whitney U Tests. Stools from 3 healthy volunteers selected from each group of treatment (CZA ± DAV132) were transplanted in 10 germ-free mice, 5 being treated with ISO-PD-1 and 5 with aPD-1. Statistics at sacrifice were performed on n=15 mice except for the groups CZA+DAV132/ISO-PD-1 (n=14) and CZA+DAV132/aPD-1 (n=11) before treatment and the group CZA+DAV132/ISO-PD-1 (n=14) at D6. 1306 Figure 3DAV132 preserves local immune responseAntibiotic-depressed anti-tumor CD8+ response and CD8+/Treg ratio are preserved by DAV132.* p < 0.05, Mann-Whitney U Tests. Statistics were performed on n = 10 mice (from 2 healthy volunteers) per group.

N. Enkelaar interroge M. Stora, spécialiste des mondes virtuels, sur le rôle des réseaux sociaux dans la construction identitaire des adolescents à partir du livre Réseaux (a)sociaux , publié en 2021. Un dialogue naît autour des idéaux véhiculés par ces réseaux, de leurs paradoxes et de la manière dont ils rencontrent les problématiques adolescentes. Tantôt support, tantôt prison pour l’adolescent en devenir, ce sont ces multiples facettes des réseaux sociaux qui sont ici explorées.

Document processing is a foundational pre-processing task in natural language application applied in the financial domain. In this paper, we present the result of FinSBD-3, the 3rd shared task on Structure Boundary Detection in unstructured text in the financial domain. The shared task is organized as part of the 1st Workshop on Financial Technology on the Web. Participants were asked to create system detecting the boundaries of elements in unstructured text extracted from financial PDF. This edition extends the previous shared tasks by adding boundaries of visual elements such as tables, figures, page headers and page footers; on top of sentences, lists and list items which were already present in previous edition of the shared tasks.

This study aimed to determine if concurrent endurance and strength training that matches the global running pattern would be more effective in increasing running economy (RE) than non-matched training. The global running pattern of 37 recreational runners was determined using the Volodalen® method as being aerial (AER) or terrestrial (TER). Strength training consisted of endurance running training and either plyometric (PLY) or dynamic weight training (DWT). Runners were randomly assigned to a matched (n = 18; DWT for TER, PLY for AER) or non-matched (n = 19; DWT for AER, PLY for TER) 8 weeks concurrent training program. RE, maximal oxygen uptake V̇O2max) and peak treadmill speed at V̇O2max (PTS) were measured before and after the training intervention. None of the tested performance related variables depicted a significant group effect or interaction effect between training and grouping (p ≥ 0.436). However, a significant increase in RE, V̇O2max, and PTS (p ≤ 0.003) was found after the training intervention. No difference in number of responders between matched and non-matched groups was observed for any of the performance related variables (p ≥ 0.248). In recreational runners, prescribing PLT or DWT according to the global running pattern of individuals, in addition to endurance training, did not lead to greater improvements in RE.

Chronic overexposure of populations to Cd in vegetal foods must be reduced. Phytoextraction is currently the only solution to decontaminate huge areas of farmland that are contaminated by this metal. To implement it, we have a plant with an exceptional bioconcentration capacity, the hyperaccumulator Noccaea caerulescens, for which the improvement of useful traits, particularly its biomass production, has been shown. Reasonable simulations indicated the efficiency of phytoextraction as an intermediate fall crop. The study allowed a first definition of the necessary ideotypes. Existing or proposed processes suggest that with adaptations, the biomass of the hyperaccumulator could be used to produce energy or materials, which would reduce the cost of soil remediation. However, there are still many scientific and technological obstacles to overcome to reach this solution: Creation of cultivars with high biomass production, the seeds of which could be produced at an acceptable cost; Development of a treatment sector that would use the biomass from phytoextraction cultures; Designing of agricultural practices allowing the insertion of phytoextraction in field cropping.

BackgroundAlthough the incidence, severity and mortality of Clostridioides (Clostridium) difficile infection (CDI) have been increasing, patients’ quality of life changes resulting from CDI have not been studied thoroughly. This study aimed at exploring the consequences of CDI on quality of life through patients’ perspective.MethodsAn observational, cross-sectional study involving 350 participants with a self-reported CDI diagnosis was conducted through an online self-administered survey. Participants were grouped into those who had active disease (“Current CDI”) and those who had a history of CDI (“Past CDI”).ResultsOne hundred fifteen participants (33%) reported Current CDI and 235 (67%) reported Past CDI. A large majority of participants admitted that their daily activities were impacted by the infection (93.9% and 64.7% of Current and Past CDI respondents respectively, p < 0.05). Physical and psychological consequences of CDI were experienced by 63.5% and 66.1% of participants with active CDI. Despite the infection being cleared, these consequences were still frequently experienced in Past CDI cohort with similar rates (reported by 73.2% of respondents for both, physical consequences p = 0.08; psychological consequences p = 0.21). After the infection, 56.6% of respondents noted that post-CDI symptoms remained; 40.9% believed they would never get rid of them.ConclusionsWhile the societal burden of CDI is well described in the literature, our study is one of the first aimed at understanding the major burden of CDI on quality of life. Our results highlight the long-lasting nature of CDI and further reinforce the need for enhanced therapeutics in the prevention and treatment of this devastating infection.

Quantitative data on fecal shedding of antimicrobial-resistant bacteria are crucial to assess the risk of transmission from dogs to humans. Our first objective was to investigate the prevalence of quinolone/fluoroquinolone-resistant and beta-lactam-resistant Enterobacteriaceae in dogs in France and Spain. Due to the particular concern about possible transmission of extended-spectrum cephalosporin (ESC)-resistant isolates from dogs to their owners, we characterized the ESBL/pAmpC producers collected from dogs. Rectal swabs from 188 dogs, without signs of diarrhea and that had not received antimicrobials for 4 weeks before the study, were quantified for total and resistant Enterobacteriaceae on selective media alone or containing relevant antibiotic concentrations. Information that might explain antibiotic resistance was collected for each dog. Extended-spectrum cephalosporin-resistant isolates were subjected to bacterial species identification (API20E), genetic lineage characterization (MLST), ESBL/pAmpC genes identification (sequencing), and plasmid characterization (pMLST). Regarding beta-lactam resistance, amoxicillin- (AMX) and cefotaxime- (CTX) resistant Enterobacteriaceae were detected in 70 and 18% of the dogs, respectively, whereas for quinolone/fluoroquinolone-resistance, Nalidixic acid- (NAL) and ciprofloxacin- (CIP) resistant Enterobacteriaceae were detected in 36 and 18% of the dogs, respectively. Medical rather than preventive consultation was a risk marker for the presence of NAL and CIP resistance. CTX resistance was mainly due to a combination of specific ESBL/pAmpC genes and particular conjugative plasmids already identified in human patients: blaCTX−M−1/IncI1/ST3 (n = 4), blaCMY−2/IncI1/ST12 (n = 2), and blaCTX−M−15/IncI1/ST31 (n = 1). blaSHV−12 (n = 3) was detected in various plasmid lineages (InI1/ST3, IncI1/ST26, and IncFII). ESBL/pAmpC plasmids were located in different genetic lineages of E. coli, with the exception of two strains in France (ST6998) and two in Spain (ST602). Our study highlights dogs as a potential source of Q/FQ-resistant and ESBL/pAmpC-producing bacteria that might further disseminate to humans, and notably a serious risk of future acquisition of CTX-M-1 and CMY-2 plasmids by the owners of dogs.

Antibiotic disruption of the intestinal microbiota favors colonization by Clostridium difficile Using a charcoal-based adsorbent to decrease intestinal antibiotic concentrations, we studied the relationship between antibiotic concentrations in feces and the intensity of dysbiosis and quantified the link between this intensity and mortality. We administered either moxifloxacin (n = 70) or clindamycin (n = 60) to hamsters by subcutaneous injection from day 1 (D1) to D5 and challenged them with a C. difficile toxigenic strain at D3 Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0 and D3 using diversity indices determined from 16S rRNA gene profiling. Survival was monitored until D16 We analyzed the relationship between fecal antibiotic concentrations and dysbiosis at the time of C. difficile challenge and studied their capacity to predict subsequent death of the animals. Increasing doses of DAV131A reduced fecal concentrations of both antibiotics, lowered dysbiosis, and increased survival from 0% to 100%. Mortality was related to the level of dysbiosis (P < 10-5 for the change of Shannon index in moxifloxacin-treated animals and P < 10-9 in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the receiver operating curve (ROC) of 0.89 (95% confidence interval [CI], 0.82, 0.95) and 0.95 (0.90, 0.98), respectively. Altogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency on the DAV131A dose; mortality after C. difficile challenge was related to the intensity of dysbiosis in similar manners with the two antibiotics.