Search

Abstract Background Varicella-zoster virus (VZV) is one of the main viruses responsible of acute encephalitis. However, data on the prognosis and neurologic outcome of critically ill patients with VZV encephalitis are limited. We aimed to describe the clinical features of VZV encephalitis in the ICU and to identify factors associated with a favorable neurologic outcome. We performed a multicenter cohort study of patients with VZV encephalitis admitted in 18 ICUs in France between 2000 and 2017. Factors associated with a favorable neurologic outcome, defined by a modified Rankin Score (mRS) of 0–2 1 year after ICU admission, were identified by multivariable regression analysis. Results Fifty-five patients (29 (53%) men, median age 53 (interquartile range 36–66)) were included, of whom 43 (78%) were immunocompromised. ICU admission occurred 1 (0–3) day after the onset of neurological symptoms. Median Glasgow Coma Score at ICU admission was 12 (7–14). Cerebrospinal fluid examination displayed a median leukocyte count of 68 (13–129)/mm3, and a median protein level of 1.37 (0.77–3.67) g/L. CT scan and MRI revealed brain lesions in 30% and 66% of the cases, respectively. Invasive mechanical ventilation was implemented in 46 (84%) patients for a median duration of 13 (3–30) days. Fourteen (25%) patients died in the ICU. One year after ICU admission, 20 (36%) patients had a favorable neurologic outcome (mRS 0–2), 12 (22%) had significant disability (mRS 3–5), and 18 (33%) were deceased (lost to follow-up n = 5, 9%). On multivariable analysis, age (OR 0.92 per year, (0.88–0.97), p = 0.01), and invasive mechanical ventilation (OR 0.09 CI 95% (0.01–0.84), p = 0.03) reduced the likelihood of favorable neurologic outcome. Conclusion One in every three critically ill patients with VZV encephalitis had a favorable neurologic outcome 1 year after ICU admission. Older age and invasive mechanical ventilation were associated with a higher risk of disability and death.

Abstract Background Long-term pulmonary sequelae, including 1-year thoracic computed tomography (CT) sequelae of paediatric acute respiratory distress syndrome (ARDS) remain unknown. The purpose of the study was to determine pulmonary abnormalities in child survivors of pulmonary (p-ARDS) and extra-pulmonary ARDS (ep-ARDS) 1 year after paediatric intensive care unit discharge (PICUD). Methods Prospective multicentre study in four paediatric academic centres between 2005 and 2014. Patients with ARDS were assessed 1 year after PICUD with respiratory symptom questionnaire, thoracic CT and pulmonary function tests (PFT). Results 39 patients (31 p-ARDS) aged 1.1–16.2 years were assessed. Respiratory symptoms at rest or exercise and/or respiratory maintenance treatment were reported in 23 (74%) of children with p-ARDS but in 1 (13%) of those with ep-ARDS. Thoracic CT abnormalities were observed in 18 (60%) of children with p-ARDS and 4 (50%) of those with ep-ARDS. Diffuse and more important CT abnormalities, such as ground glass opacities or mosaic perfusion patterns, were observed in 5 (13%) of children, all with p-ARDS. PFT abnormalities were observed in 30 (86%) of patients: lung hyperinflation and/or obstructive pattern in 12 (34%) children, restrictive abnormalities in 6 (50%), mild decrease in diffusing capacity in 2 (38%) and 6-min walking distance decrease in 11 (73%). Important PFT abnormalities were observed in 7 (20%) children, all with p-ARDS. Increasing driving pressure (max plateau pressure—max positive end-expiratory pressure) was correlated with increasing CT-scan abnormalities and increasing functional residual capacity (more hyperinflation) (p

Cyanobacterial harmful algal blooms are a critical risk for public health since the release of cyanotoxins can reach hazardous levels in drinking water. In this study, a cost-effective monitoring programme has been developed and applied by a Spanish water operator to detect cyanobacteria presence in a drinking water plant reservoir; a total of 65 phytoplankton genera and seven cyanobacterial taxa were identified. Based on these monitoring data, different analysis techniques such as classification trees have been used to identify the potential situations of risk and to forecast cyanobacteria evolution in surface water. As a result, a new operational risk management plan has been developed and applied by the water operator since 2019. The main improvements concern the classification of the situations of risk in six groups (from low to very high, according to chlorophyl-a and cyanobacteria concentrations), the planning of the actions required under each situation (monitoring, management practice and treatment), and the use of the risk forecast to perform some of these actions from 2–3 days in advance. The methodology can be replicated to other case studies to facilitate the management of cyanobacteria risk and comply with the requirements of the revised European Drinking Water Directive adopted in 2020. HIGHLIGHTS A robust forecasting of cyanobacteria risk in reservoir was developed.; An upgrade of the operational cyanotoxin risk management procedure was performed.; The risk control methodology can be replicated to other drinking water treatment plants.;

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 global pandemic. SARS-CoV-2 is an enveloped RNA virus that relies on its trimeric surface glycoprotein spike for entry into host cells. Here we describe the COVID-19 vaccine candidate MV-014-212, a live, attenuated, recombinant human respiratory syncytial virus expressing a chimeric SARS-CoV-2 spike as the only viral envelope protein. MV-014-212 was attenuated and immunogenic in African green monkeys (AGMs). One mucosal administration of MV-014-212 in AGMs protected against SARS-CoV-2 challenge, reducing by more than 200-fold the peak shedding of SARS-CoV-2 in the nose. MV-014-212 elicited mucosal immunoglobulin A in the nose and neutralizing antibodies in serum that exhibited cross-neutralization against virus variants of concern Alpha, Beta, and Delta. Intranasally delivered, live attenuated vaccines such as MV-014-212 entail low-cost manufacturing suitable for global deployment. MV-014-212 is currently in Phase 1 clinical trials as an intranasal COVID-19 vaccine.

Host versus graft reaction is a major impediment to CAR-T cell immune therapy in allogeneic settings. Authors show here that CAR-T cells, engineered to be deficient in MHC I expression but to express the NK inhibitor HLA-E, are resistant to destruction by both T and NK cells of the host.

Abstract From aerial parts of Austroeupatorium inulifolium was isolated the ent-nor-furano triol labdane austroeupatol 1. The compound 1 was treated with IBX showing an unexpected selectivity at the potentially oxidizable sites of the substrate yielding the 2-oxoaustroeupatol (2) and 2,19-dioxoaustroeupatol (3). The treatment of 2 with sodium periodate yields a heterocyclic derivative (ε-caprolactone derivate 4) formed by oxidative cleavage and unexpected intramolecular attack of the hydroxymethylene (C-19) oxygen to the ketonic carbon (C-2). A plausible mechanistic pathway for the obtention of compound 4 is proposed. Graphical Abstract

Abstract Background and aims There are limited comparative data for infliximab and vedolizumab in inflammatory bowel disease patients. Methods We conducted a systematic review and meta-analysis to compare the efficacy and safety of infliximab and vedolizumab in adult patients with moderate-to-severe Crohn’s disease or ulcerative colitis. Results We identified six eligible Crohn’s disease and seven eligible ulcerative colitis trials that randomised over 1900 participants per disease cohort to infliximab or vedolizumab. In the Crohn’s disease and ulcerative colitis cohorts, infliximab yielded better efficacy than vedolizumab for all analysed outcomes (CDAI-70, CDAI-100 responses, and clinical remission for Crohn’s disease and clinical response and clinical remission for ulcerative colitis) during the induction phase, with non-overlapping 95% confidence intervals. In the maintenance phase, similar proportions of infliximab- or vedolizumab-treated patients achieved clinical response, clinical remission, or mucosal healing in both Crohn’s disease and ulcerative colitis. For the safety outcomes, rates of adverse events, serious adverse events, and discontinuations due to adverse events were similar in infliximab- and vedolizumab-treated patients in both diseases. The infection rate was higher in infliximab for Crohn’s disease and higher in vedolizumab when treating patients with ulcerative colitis. There was no difference between the treatments in the proportions of patients who reported serious infections in both indications. Conclusions Indirect comparison of infliximab and vedolizumab trials in adult patients with moderate-to severe Crohn’s disease or ulcerative colitis demonstrated that infliximab has better efficacy in the induction phase and comparable efficacy during the maintenance phase and overall safety profile compared to vedolizumab.

The plant xylem microbiota remains understudied. Here, the authors characterise the xylem microbiota in maize plants finding that some bacteria carried N fixing genes. By using synthetic communities the authors confirm that xylem inhabiting and N fixing bacteria provide the host plant with N.

Adoptive cell therapy based on chimeric antigen receptor (CAR)-engineered T-cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has so far been restricted to only a few malignancies, with solid tumors proving to be especially recalcitrant to efficient therapy. Poor intra-tumor infiltration by T cells and T cell dysfunction due to a desmoplastic, immunosuppressive microenvironment are key barriers for CAR T-cell success against solid tumors. Cancer-associated fibroblasts (CAFs) are critical components of the tumor stroma, evolving specifically within the tumor microenvironment (TME) in response to tumor cell cues. The CAF secretome is a significant contributor to the extracellular matrix and a plethora of cytokines and growth factors that induce immune suppression. Together they form a physical and chemical barrier which induces a T cell-excluding ‘cold’ TME. CAF depletion in stroma rich solid tumors can thus provide an opportunity to convert immune evasive tumors susceptible to tumor-antigen CAR T-cell cytotoxicity. Using our TALEN-based gene editing platform we engineered non-alloreactive, immune evasive CAR T-cells (termed UCAR T-cells) targeting the unique CAF marker Fibroblast Activation Protein, alpha (FAP). In an orthotopic mouse model of triple-negative breast cancer (TNBC) composed of patient derived-CAFs and tumor cells, we demonstrate the efficacy of our engineered FAP UCAR T-cells in CAF depletion, reduction of desmoplasia and successful tumor infiltration. Furthermore, while previously resistant, pre-treatment with FAP UCAR T-cells now sensitized these tumors to Mesothelin (Meso) UCAR T-cell infiltration and anti-tumor cytotoxicity. Combination therapy of FAP UCAR, Meso UCAR T cells and the checkpoint inhibitor anti-PD-1 significantly reduced tumor burden and prolonged mice survival. Our study thus proposes a novel treatment paradigm for successful CAR T-cell immunotherapy against stroma-rich solid tumors.

Cellular senescence is a reprogrammed cell state triggered as an adaptative response to a variety of stresses, most often those affecting the genome integrity. Senescent cells accumulate in most tissues with age and contribute to the development of several pathologies. Studying molecular pathways involved in senescence induction and maintenance, or in senescence escape, can be hindered by the heterogeneity of senescent cell populations. Here, we describe a flow cytometry strategy for sorting senescent cells according to three senescence canonical markers whose thresholds can be independently adapted to be more or less stringent: (i) the senescence-associated-β-galactosidase (SA-β-Gal) activity, detected using 5-dodecanoylaminofluorescein Di-β-D-galactopyranoside (C12FDG), a fluorigenic substrate of β-galactosidase; (ii) cell size, proportional to the forward scatter value, since increased size is one of the major changes observed in senescent cells; and (iii) cell granularity, proportional to the side scatter value, which reflects the accumulation of aggregates, lysosomes, and altered mitochondria in senescent cells. We applied this protocol to the sorting of normal human fibroblasts at the replicative senescence plateau. We highlighted the challenge of sorting these senescent cells because of their large sizes, and established that it requires using sorters equipped with a nozzle of an unusually large diameter: at least 200 µm. We present evidence of the sorting efficiency and sorted cell viability, as well as of the senescent nature of the sorted cells, confirmed by the detection of other senescence markers, including the expression of the CKI p21 and the presence of 53BP1 DNA damage foci. Our protocol makes it possible, for the first time, to sort senescent cells from contaminating proliferating cells and, at the same time, to sort subpopulations of senescent cells featuring senescent markers to different extents.Graphical abstract

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are lifelong diseases characterized by chronic inflammation of the gastrointestinal tract leading to its progressive and irreversible destruction. Whether early initiation of IBD-specific therapy impacts the long-term course of the disease remains unclear and has to be further explored in prospective disease-modification trials. Historically, surgery and hospitalization rates have been the surrogate markers to measure disease progression in IBD, providing an overview of the effectiveness of medical therapies. However, neither surgery nor hospitalization necessarily reflects a fail in therapeutic medical management, and many confounding factors make them biased outcomes. The Selecting Endpoints for Disease-Modification Trials consensus has defined the disease-modification endpoints required for these trials, including the impact of the disease on patient’s life (health-related quality of life, disability, and fecal incontinence), the mid-term disease complications (bowel damage in CD, IBD-related surgery and hospitalizations, disease extension in UC, extra-intestinal manifestations, permanent stoma, short bowel syndrome), and the development of dysplasia/cancer and mortality in the long term. Most available data in the literature regarding the impact of current therapies on disease progression focused on anti-tumor necrosis factor agents and are based on retrospective or post-hoc studies. Thus, prospective disease-modification trials are pressingly required to explore the effectiveness of early intensified treatment in patients with severe disease or at risk for disease progression.

Background: Long-term management of inflammatory bowel diseases (IBD) is challenging and the identification of reliable predictors for treatment outcomes is an unmet need. Neutrophil-related biomarkers have been mainly studied in the feces, but blood analyses have inherent advantages. Objective: To review the recent learnings on the ability of blood-based neutrophil-expressed biomarkers to predict treatment outcomes in IBD. Design: Systematic scoping review. Data sources and methods: We performed a literature search in Pubmed, EMBASE, SCOPUS, Web of Science, ScienceDirect, and Cochrane Central Register of Controlled Trials from inception until May 2022 according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. All human studies associating blood-based neutrophil-related compounds with the prediction of disease progression, complication onset, or treatment outcomes were included. Results: From 1032 retrieved entries, 34 studies were selected, 32 published in 2013 or later. In all, 17 biomarkers from granules, cytoplasm, plasmatic membrane, and plasma were explored. In total, 1850 Crohn’s disease (CD) and 1122 ulcerative colitis non-duplicated patients were included. The most mentioned biomarkers were nCD64, serum calprotectin (SC), oncostatin M (OSM), neutrophil elastase-generated calprotectin fragment (CPa9-HNE), and triggering receptor expressed on myeloid cells 1 (TREM1). Six biomarkers showed promising results: OSM, SC, eNAMPT, nCD64, TREM1, and CPa9-HNE. Variable positive signals were found for human neutrophil peptide 1-3, LL-37, S100A12, and neutrophil gelatinase–associated lipocalin. No predictive ability was found for the remaining markers. Sharing a neutrophil compartment did not indicate similar behavior. Conclusion: Advances in the last decade began to unveil the untapped potential of the readily accessible blood neutrophil-expressed biomarkers, especially nCD64, TREM1, and CPa9-HNE. Current evidence suggests that future research should focus on well-defined subpopulations instead of a one-size-fits-all biomarker. Registration: https://osf.io/kes9a .

Background The goal of this study was to determine whether an awake prone position (aPP) reduces the global inhomogeneity (GI) index of ventilation measured by electrical impedance tomography (EIT) in COVID-19 patients with acute respiratory failure (ARF). Methods This prospective crossover study included COVID-19 patients with COVID-19 and ARF defined by arterial oxygen tension:inspiratory oxygen fraction (PaO2:FIO2) of 100–300 mmHg. After baseline evaluation and 30-min EIT recording in the supine position (SP), patients were randomised into one of two sequences: SP-aPP or aPP-SP. At the end of each 2-h step, oxygenation, respiratory rate, Borg scale and 30-min EIT were recorded. Results 10 patients were randomised in each group. The GI index did not change in the SP-aPP group (baseline 74±20%, end of SP 78±23% and end of aPP 72±20%, p=0.85) or in the aPP-SP group (baseline 59±14%, end of aPP 59±15% and end of SP 54±13%, p=0.67). In the whole cohort, PaO2:FIO2 increased from 133±44 mmHg at baseline to 183±66 mmHg in aPP (p=0.003) and decreased to 129±49 mmHg in SP (p=0.03). Conclusion In spontaneously breathing nonintubated COVID-19 patients with ARF, aPP was not associated with a decrease of lung ventilation inhomogeneity assessed by EIT, despite an improvement in oxygenation.

Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%–10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US.Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel.Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV.Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.

The European Commission's Innovative Medicines Initiative (IMI) has funded many projects focusing on neurodegenerative disorders (ND) that aimed to improve the diagnosis, prevention, treatment and understanding of NDs. To facilitate collaboration across this project portfolio, the IMI funded the “NEURONET” project between March 2019 and August 2022 with the aim of connecting these projects and promoting synergies, enhancing the visibility of their findings, understanding the impact of the IMI funding and identifying research gaps that warrant more/new funding. The IMI ND portfolio currently includes 20 projects consisting of 270 partner organizations across 25 countries. The NEURONET project conducted an impact analysis to assess the scientific and socio-economic impact of the IMI ND portfolio. This was to better understand the perceived areas of impact from those directly involved in the projects. The impact analysis was conducted in two stages: an initial stage developed the scope of the project, defined the impact indicators and measures to be used. A second stage designed and administered the survey amongst partners from European Federation of Pharmaceutical Industries and Associations (EFPIA) organizations and other partners (hereafter, referred to as “non-EFPIA” organizations). Responses were analyzed according to areas of impact: organizational, economic, capacity building, collaborations and networking, individual, scientific, policy, patient, societal and public health impact. Involvement in the IMI ND projects led to organizational impact, and increased networking, collaboration and partnerships. The key perceived disadvantage to project participation was the administrative burden. These results were true for both EFPIA and non-EFPIA respondents. The impact for individual, policy, patients and public health was less clear with people reporting both high and low impact. Overall, there was broad alignment between EFPIA and non-EFPIA participants' responses apart from for awareness of project assets, as part of scientific impact, which appeared to be slightly higher among non-EFPIA respondents. These results identified clear areas of impact and those that require improvement. Areas to focus on include promoting asset awareness, establishing the impact of the IMI ND projects on research and development, ensuring meaningful patient involvement in these public-private partnership projects and reducing the administrative burden associated with participation in them.

Recycled concrete aggregates (RCA) incorporate hydrates that can be carbonated. The FastCarb project aims to mineralize CO2 within RCA, improving the quality of these aggregates by the clogging of the porosity and finally decreasing the CO2 impact of concrete in structures. It has two main objectives: to optimize in laboratory conditions the accelerated carbonation process which can be transposed at an industrial scale at a suitable cost and to show that the process could be used in industrial conditions. This paper presents firstly the results obtained in laboratory conditions: it confirms that it is possible to store between 10 and 50 kg of CO2/t of RCA depending on several factors (natural carbonation, water content, temperature, size of RCA…) and that the treatment allows an improvement of the properties like the water absorption. The feasibility of accelerated carbonation has been also demonstrated by setting up two industrial-scale demonstrators. The first results without optimization showed a CO2 capture rate in the order of 3–4 %, i.e. 30 kg of CO2 per ton of crushed concrete. 80 t of carbonated RCA were produced and used to produce C25/30 and C45/55 concretes. The measurement of the main properties (performance in the fresh state, mechanical performance, and durability) shows that the use of the carbonated RCA doesn’t affect these properties. A variety of precast products (blocks, curbs, stairs) and parts of cast-in-situ structures (construction of walls) were fabricated showing the feasibility of using these aggregates in real situations. Finally, our project considers whether the accelerated carbonation process is environmentally acceptable and economically viable. The first results show that the distance of transport (by trucks) is a major factor and that transportation should be limited to maintain a positive impact of the accelerated carbonation (i.e. local sources of CO2 should be used). The LCA and the economic study confirm that the sand fraction of RCA is the most interesting material for the uptake of CO2. This is also interesting for a circular economy objective because recycled concrete sand is not easily used in concrete made with RCA.

In vitro digestions of dry-cured sausages formulated with four different rates of added sodium nitrite and sodium nitrate (NaNO2 / NaNO3, in ppm: 0/0; 80/80; 120/120; 0/200) were performed with a dynamic gastrointestinal digester (DIDGI®). The chemical reactivity of the potentially toxic nitroso-compounds (NOCs), oxidation reactions products and different iron types were evaluated over time. No nitrite nor nitrate dose effect was observed on NOCs’ chemical reactivity. Nitrosothiols were scarce, and nitrosylheme was destabilized for every conditions, possibly leading to free iron release in the digestive tract. Total noN-volatile N-nitrosamines concentrations increased in the gastric compartment while residual nitrites and nitrates remained stable. The minimal rate of 80/80 ppm nitrite/nitrate was enough to protect against lipid oxidation in the digestive tract. The present results provide new insights into the digestive chemistry of dry sausages, and into new reasonable arguments to reduce the load of additives in formulations.

Due to the potential role of the gut microbiota and bile acids in the pathogenesis of both inflammatory bowel disease (IBD) and sporadic colorectal cancer, we aimed to determine whether these factors were associated with colorectal cancer in IBD patients. 215 IBD patients and 51 non-IBD control subjects were enrolled from 10 French IBD centers between September 2011 and July 2018. Fecal samples were processed for bacterial 16S rRNA gene sequencing and bile acid profiling. Demographic, clinical, endoscopic, and histological outcomes were recorded. Characteristics of IBD patients included: median age: 41.6 (IQR 22); disease duration 13.2 (13.1); 47% female; 21.9% primary sclerosing cholangitis; 109 patients with Crohn’s disease (CD); 106 patients with ulcerative colitis (UC). The prevalence of cancer was 2.8% (6/215: 1 CD; 5 UC), high-grade dysplasia 3.7% (8/215) and low-grade dysplasia 7.9% (17/215). Lachnospira was decreased in IBD patients with cancer, while Agathobacter was decreased and Escherichia-Shigella increased in UC patients with any neoplasia. Bile acids were not associated with cancer or neoplasia. Unsupervised clustering identified three gut microbiota clusters in IBD patients associated with bile acid composition and clinical features, including a higher risk of neoplasia in UC in two clusters when compared to the third (relative risk (RR) 4.07 (95% CI 1.6–10.3, P

Abstract Background Perioperative chemotherapy and surgery are a standard of care for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. However, the prognosis remains poor for this population. The FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) regimen is considered as the new standard chemotherapy regimen for perioperative strategy, despite associated with a 5-year overall survival rate (OS) amounting 45% following radical surgery. Immunotherapy with antibodies that inhibit PD-1/ PD-L1 interaction has recently emerged as a new treatment option with promising and encouraging early trial results for patients with advanced or metastatic gastric or GEJ adenocarcinoma. Currently, no trials have investigated the impact of perioperative immunotherapy in combination with chemotherapy for resectable gastric or GEJ adenocarcinoma. Methods GASPAR trial is a multicenter open-label, nonrandomized, phase II trial to evaluate the efficacy and safety of Spartalizumab in combination with the FLOT regimen as perioperative treatment for resectable gastric or GEJ adenocarcinoma. The main endpoint is the proportion of patients with pathological complete regression (pCR) in the primary tumour after preoperative treatment. Systemic treatment will include a pre-operative neoadjuvant and a post-operative adjuvant treatment, during which FLOT regimen will be administered every two weeks for 4 cycles and Spartalizumab every four weeks for 2 cycles. For patients with confirmed tumor resectability on imaging assessment, surgery will be realized within 4–6 weeks after the last dose of preoperative chemotherapy. Post-operative systemic treatment will then be initiated within 4–10 weeks after surgery. Using a Simon’s two-stage design, up to 67 patients will be enrolled, including 23 in the first stage. Discussion Currently, no trials have investigated the impact of immunotherapy in combination with FLOT chemotherapy as perioperative treatment for resectable gastric or GEJ adenocarcinoma. Some studies have suggested a change in the tumor immune micro-environment following neoadjuvant chemotherapy in this setting, reinforcing the relevance to propose a phase II trial evaluating efficacy and safety of Spartalizumab in combination with perioperative chemotherapy, with the aim of improving treatment efficacy and survival outcomes. Trial registration NCT04736485, registered February, 3, 2021.

Abstract We present a new approach to tuning-fork-based atomic force microscopy for utilizing advanced “tip-on-chip” probes with high sensitivity and broad compatibility. Usually, such chip-like probes with a size reaching 2 × 2 mm2 drastically perturb the oscillation of the tuning fork, resulting in poor performance in its intrinsic force sensing. Therefore, restoring initial oscillatory characteristics is necessary for regaining high sensitivity. To this end, we developed a new approach consisting of three basic steps: tuning-fork rebalancing, revamping holder-sensor fixation, and electrode reconfiguration. Mass rebalancing allows the tuning fork to recover the frequency and regain high Q-factor values up to 104 in air and up to 4 × 104 in ultra-high vacuum conditions. The floating-like holder-fixation using soft wires significantly reduces energy dissipation from the mounting elements. Combined with the soft wires, reconfigured electrodes provide electrical access to the chip-like probe without intervening in the force-sensing signal. Finally, our easy-to-implement approach allows converting the atomic force microscopy tip from a passive tool to a dedicated microdevice with extended functionality.

In France, a ‘natural zone of ecological, faunistic or floristic value’ (Zone Naturelle d'Intérêt Écologique, Faunistique et Floristique - ZNIEFF) is a natural area, regionally known for its remarkable ecological characteristics. The ZNIEFF inventory is a naturalist and scientific survey programme launched in 1982 by the Ecology Ministry, with support from the French National Museum of Natural History (MNHN).This paper describes the ZNIEFF national dataset, which comprises 1,013,725 data for various animal (38%), plant (59%) and fungal (2%) species in terrestrial and marine zones (May 2020). A total of 19,842 sites throughout continental France. as well as in the overseas Departments and territories (Guadeloupe, Martinique, Mayotte, La Réunion, French Guiana, Saint-Martin, Saint-Barthélemy and Saint-Pierre-et-Miquelon), are included in the ZNIEFF dataset (May 2020). This dataset is now available in open access.All data were collected by skilled naturalists using professional protocols over almost 40 years. They consist mainly of observations of rare, threatened or endemic species, all validated by regional experts. Data are updated twice a year after national validation in both national (INPN-OpenObs) and global (GBIF) biodiversity web platforms. Some of the observed species, the so-called ‘trigger species’ or ‘determinant’ species, are of central interest for a site to be designated a ZNIEFF (zone of high ecological value). This concerns more than 35,000 taxa, mainly angiosperms, insects, fungi, birds and fish.

Epithelial ovarian cancers (EOCs) are a heterogeneous collection of malignancies, each with their own developmental origin, clinical behavior and molecular profile. With less than 5% of EOC cases, mucinous ovarian carcinoma is a rare form with a poor prognosis and a 5-year survival of 11% for advanced stages (III/IV). At the early stages, these malignant forms are clinically difficult to distinguish from borderline (15%) and benign (80%) forms with a better prognosis due to the large size and heterogeneity of mucinous tumors. Improving their diagnosis is therefore a challenge with regard to the risk of under-treating a malignant form or of unnecessarily undertaking radical surgical excision. The involvement of microRNAs (miRNAs) in tumor progression and their potential as biomarkers of diagnosis are becoming increasingly recognized. In this study, the comparison of miRNA microarray expression profiles between malignant and borderline tumor FFPE samples identified 10 down-regulated and 5 up-regulated malignant miRNAs, which were validated by individual RT-qPCR. To overcome normalization issues and to improve the accuracy of the results, a ratio analysis combining paired up-regulated and down-regulated miRNAs was performed. Although 21/50 miRNA expression ratios were significantly different between malignant and borderline tumor samples, any ratio could perfectly discriminate the two groups. However, a combination of 14 pairs of miRNA ratios (double ratio) showed high discriminatory potential, with 100% of accuracy in distinguishing malignant and borderline ovarian tumors, which suggests that miRNAs may hold significant clinical potential as a diagnostic tool. In summary, these ratio miRNA-based signatures may help to improve the precision of histological diagnosis, likely to provide a preoperative diagnosis in order to adapt surgical procedures.

We describe the process by which the quarantine whitefly, Aleurocanthus spiniferus (Hemiptera, Aleyrodidae), was detected in France. The initial observation was made by a volunteer who reported a picture of an adult in the Inventaire National du Patrimoine Naturel (INPN Espèces), a citizen science resource developed by l’Office Français de la Biodiversité and the French Muséum National d’Histoire Naturelle. The specimen was suspected to be A. spiniferus from this picture by one of the expert entomologists in charge of the Hemiptera group validation. Once the species was identified, it was mounted on a slide and the information was officially passed on to the ministry in charge of agriculture via a communication channel set up in advance for this type of situation. The ministry then triggered the regulatory actions planned in the event of the suspected detection of quarantine organisms. Sampling was quickly carried out and the specimens collected on this occasion were formally identified as belonging to the species A. spiniferus. This led to the formalization of an outbreak in France. This sequence of decisions took just two months from the first observation to the implementation of a management plan. This case presents how incursion preparedness contributes to a rapid response. Furthermore, this case exemplifies how citizen science can contribute to the early detection of invasive species and highlights the importance of informing both the general public and professionals about major environmental issues.

Heavy metals such as zinc (Zn) and copper (Cu) may be associated with antibiotic resistance dissemination. Our aim was to investigate whether sub-lethal dosage of Zn and Cu may enhance plasmid transfer and subsequently resistance genes dissemination. Plasmid conjugation frequencies (PCF) were performed with Escherichia coli strains bearing IncL-blaOXA-48, IncA/C-blaCMY-2, IncI1-blaCTX-M-1, IncF-blaCTX-M-1, and IncX3-blaNDM-5 as donors. Mating-out assays were performed with sub-dosages of zinc oxide (ZnO) and Cu sulfate (CuSO4). Quantification of the SOS response-associated gene expression levels and of the production of reactive oxygen species were determined. Increased PCF was observed for IncL, IncA/C, and IncX3 when treated with ZnO. PCF was only increased for IncL when treated with CuSO4. The ROS production presented an overall positive correlation with PCF after treatment with ZnO for IncL, IncA/C, and IncX3. For CuSO4 treatment, the same was observed only for IncL. No increase was observed for expression of SOS response-associated genes under CuSO4 treatment, and under ZnO treatment, we observed an increase in SOS response-associated genes only for IncX3. Our data showed that sub-dosages of ZnO and CuSO4 could significantly enhance PCF in E. coli, with a more marked effect observed with IncL, IncA/C, and IncX3 scaffolds. Our study suggested that use of certain heavy metals is not the panacea for avoiding use of antibiotics in order to prevent the dissemination of antibiotic resistance.

The gut microbiota play a pivotal role in human health. Dysbiosis, alterations in microbiota composition and function, is associated with gastrointestinal disorders, including inflammatory bowel disease (IBD). This international survey aimed to assess physicians’ experiences, perceptions, and practices related to microbiome modulation for gastrointestinal conditions, with a focus on IBD. Results from 142 healthcare professionals, predominantly gastroenterologists, confirmed a consensus on the relevance of the gut microbiota in IBD pathogenesis. However, the utilization of microbial composition analysis and probiotics in clinical practice was limited, primarily due to the lack of standardized guidelines and supporting evidence. Physicians held conflicting views on antibiotics, recognizing their potential for inducing remission but also causing flares in IBD. Respondents also had varying opinions on the efficacy of fecal microbiota transplantation (FMT) for different gastrointestinal conditions, with higher confidence in FMT effectiveness for irritable bowel syndrome with diarrhea, pouchitis, and ulcerative colitis. Concerns on FMT included uncertainty about effect duration, administration intervals, and conflicting evidence. Donor selection was believed to be a crucial factor in FMT outcomes. This survey highlights the need for further research and evidence-based guidelines to optimize the use of microbiome-based therapies in clinical practice. As our understanding of the gut microbiome continues to evolve, these insights will contribute to more informed and personalized approaches to managing gastrointestinal disorders.

We describe a methodology to manipulate Caenorhabditis elegans (C. elegans) and irradiate the stem progenitor gonad region using three MeV protons at a specific developmental stage (L1). The consequences of the targeted irradiation were first investigated by considering the organogenesis of the vulva and gonad, two well-defined and characterized developmental systems in C. elegans. In addition, we adapted high-throughput analysis protocols, using cell-sorting assays (COPAS) and whole transcriptome analysis, to the limited number of worms (>300) imposed by the selective irradiation approach. Here, the presented status report validated protocols to (i) deliver a controlled dose in specific regions of the worms; (ii) immobilize synchronized worm populations (>300); (iii) specifically target dedicated cells; (iv) study the radiation-induced developmental alterations and gene induction involved in cellular stress (heat shock protein) and cuticle injury responses that were found.

Two types of alginates, AlgLF and AlgP, were used in this study to produce alginate beads by electro-vibratory extrusion. AlgLF and AlgP exhibited different Mannuronate/Guluronate (M/G) ratios and molecular weights as measured by NMR and SEC-MALS. The calcium chloride concentration was found to have the greatest effect on bead size. Higher concentrations resulted in smaller beads. AlgLF with a higher molecular weight and a lower proportion of G blocks showed smaller beads. For both alginates, the bead size was also influenced by the flow rate and vibration frequency. Alginate solution aging showed a minimal effect. Alginate reticulation was modeled using a mathematical equation. The study provides insights for the optimization of alginate-based materials in different applications by shedding light on the main factors influencing bead size. The importance of the molecular weight, M/G ratio and calcium ion concentration in the gelling process is highlighted, providing opportunities for the tailoring of alginate materials through a phenomenological model.

Continuum mechanics describes compressive failure as a standard bifurcation in the response of a material to an increasing load: Damage, which initially grows uniformly in the material, localizes within a thin band at failure. Yet, experiments recording the acoustic activity preceding localization evidence power-law-distributed failure precursors of increasing size, suggesting that compressive failure is a critical phenomenon. We examine here this apparent contradiction by probing the spatial organization of the damage activity and its evolution until localization during compression experiments of 2D cellular solids. The intermittent damage evolution measured in our experiments is adequately described by a nonstationary depinning equation derived from damage mechanics and reminiscent of critical phenomena. In this description, precursors are damage cascades emerging from the interplay between the material’s disorder and the long-range stress redistributions following individual damage events. Yet, the divergence of their characteristic size close to failure, which we observe in our experiments, is not the signature of a transition toward criticality. Instead, the system remains at a fixed distance to the critical point at all stages of the damage evolution. The divergence results from the progressive loss of stability of the material as it is driven toward localization. Thus, our study shows that compressive failure is a standard bifurcation for which the material disorder plays a marginal role. It also implies that the precursory acoustic activity behaves as a tracer of the evolution of materials toward failure and can therefore be used to assess their residual lifetime.

As a semi-arid Mediterranean country, Tunisia is affected by the impacts of climate change, particularly the coastal regions like the Cap-Bon. Irregular rainfall, rising temperatures and the recurrence of extreme events are all indicators that affect ecosystems and populations and make them more vulnerable to the influence of climatic variables. Therefore, an analysis of the trends of climate variables can contribute to facilitating the development of effective adaptation strategies. In this matter, this study was conducted to assess the homogeneity and trends of minimum and maximum air temperature (Tmin and Tmax) and precipitation (P) in the Cap-Bon region. Daily data were collected from the meteorological station of Nabeul for the period of 1982–2020. Pettitt and SNHT tests for homogeneity were applied to identify the breakpoints in multi-time scales of Tmax, Tmin and P data series. The Mann–Kendall (MK) test was used to detect the change in the time-series trend. A modified Mann–Kendall (mMK) test was used to remove the autocorrelation effect from the data series. Both the MK and mMK tests were used at the 5% significant level. The magnitude of the climatic trend was estimated using the non-parametric Sen’s slope estimator. Contrary to Tmin and P, the results of the homogeneity tests revealed the existence of significant breakpoints in the annual, seasonal and monthly Tmax time series. For most cases, the breakpoint occurred around the year 2000. For Tmin, significant breakpoints were recorded in March and April, while a significant shift in the P time series was detected in December. The Mann–Kendall results show a significant warming trend in annual Tmax, with magnitudes equal to 0.065 and 0.045 °C/year before and after the breakpoint, respectively. Nevertheless, non-significant tendencies were observed in the annual Tmin and P time series. On the monthly time scale, Tmax exhibited a significant upward trend in June and August, before the observed breakpoints, with Sen’s slope values equal to 0.065 and 0.045 °C/year, respectively. Regarding the Tmin data, a significant positive trend was observed in July at a rate of 0.033 °C/year.

Increased life expectancy in industrialized countries is causing an increased incidence of osteoporosis and the need for bioactive bone implants. The integration of implants can be improved physically, but mainly by chemical modifications of the material surface. It was recognized that amino-group-containing coatings improved cell attachment and intracellular signaling. The aim of this study was to determine the role of the amino group density in this positive cell behavior by developing controlled amino-rich nanolayers. This work used covalent grafting of polymer-based nanocoatings with different amino group densities. Titanium coated with the positively-charged trimethoxysilylpropyl modified poly(ethyleneimine) (Ti-TMS-PEI), which mostly improved cell area after 30 min, possessed the highest amino group density with an N/C of 32%. Interestingly, changes in adhesion-related genes on Ti-TMS-PEI could be seen after 4 h. The mRNA microarray data showed a premature transition of the MG-63 cells into the beginning differentiation phase after 24 h indicating Ti-TMS-PEI as a supportive factor for osseointegration. This amino-rich nanolayer also induced higher bovine serum albumin protein adsorption and caused the cells to migrate slower on the surface after a more extended period of cell settlement as an indication of a better surface anchorage. In conclusion, the cell spreading on amine-based nanocoatings correlated well with the amino group density (N/C).

Background It is unclear whether delays in care affect prognosis of patients with lung cancer. The primary objective of this study was to describe the care pathway of patients diagnosed with lung cancer in a French region. Secondary objectives were to identify markers associated with 1) time from imaging to treatment and 2) with 1-year survival. Methods In a retrospective cohort study, clinical data from multidisciplinary team meetings for all incident lung cancer cases discussed in 2018 in one French region were matched with medico-administrative data from the National Health Insurance Database. Care pathway time intervals were estimated for small cell lung cancer (SCLC), resected nonsmall cell lung cancer (NSCLC) and unresected NSCLC. Factors associated with delay in the care pathway were identified using linear regression; 1-year survival was analysed using Cox modelling. Results A total of 685 patients were included. Median time between imaging and treatment was 49 days (interquartile range: 33–73), and was lower in cases of metastatic disease, SCLC and private care. At 1 year, 48% had died (resected NSCLC 12%). In unresected NSCLC, time from diagnostic imaging to first treatment

Deciphering the genetic architecture of human cardiac disorders is of fundamental importance but their underlying complexity is a major hurdle. We investigated the natural variation of cardiac performance in the sequenced inbred lines of the Drosophila Genetic Reference Panel (DGRP). Genome-wide associations studies (GWAS) identified genetic networks associated with natural variation of cardiac traits which were used to gain insights as to the molecular and cellular processes affected. Non-coding variants that we identified were used to map potential regulatory non-coding regions, which in turn were employed to predict transcription factors (TFs) binding sites. Cognate TFs, many of which themselves bear polymorphisms associated with variations of cardiac performance, were also validated by heart-specific knockdown. Additionally, we showed that the natural variations associated with variability in cardiac performance affect a set of genes overlapping those associated with average traits but through different variants in the same genes. Furthermore, we showed that phenotypic variability was also associated with natural variation of gene regulatory networks. More importantly, we documented correlations between genes associated with cardiac phenotypes in both flies and humans, which supports a conserved genetic architecture regulating adult cardiac function from arthropods to mammals. Specifically, roles for PAX9 and EGR2 in the regulation of the cardiac rhythm were established in both models, illustrating that the characteristics of natural variations in cardiac function identified in Drosophila can accelerate discovery in humans.

Summary: Background: Long-term changes in lung cancer (LC) patients are difficult to evaluate. We report results from the French KBP-2020 real-life cohort. Methods: KBP-2020 was a prospective cohort that included all patients diagnosed with LC in 2020, in nonacademic public hospital in France. Patient and tumour characteristics were described and compared with similarly designed cohorts in 2000 and 2010. Findings: In 2020, 82 centers included 8,999 patients diagnosed with LC. The proportion of women increased: 34·6% (3114/8999) compared to, 24·3% (1711/7051) and 16·0% (904/5667) in 2010 and 2000 (p

Background The impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought to investigate differences in paediatric clinical outcomes and identify factors contributing to disparity between countries.Methods The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 database was queried to include children under 19 years of age admitted to hospital from January 2020 to April 2021 with suspected or confirmed COVID-19 diagnosis. Univariate and multivariable analysis of contributing factors for mortality were assessed by country group (HICs vs LMICs) as defined by the World Bank criteria.Results A total of 12 860 children (3819 from 21 HICs and 9041 from 15 LMICs) participated in this study. Of these, 8961 were laboratory-confirmed and 3899 suspected COVID-19 cases. About 52% of LMICs children were black, and more than 40% were infants and adolescent. Overall in-hospital mortality rate (95% CI) was 3.3% [=(3.0% to 3.6%), higher in LMICs than HICs (4.0% (3.6% to 4.4%) and 1.7% (1.3% to 2.1%), respectively). There were significant differences between country income groups in intervention profile, with higher use of antibiotics, antivirals, corticosteroids, prone positioning, high flow nasal cannula, non-invasive and invasive mechanical ventilation in HICs. Out of the 439 mechanically ventilated children, mortality occurred in 106 (24.1%) subjects, which was higher in LMICs than HICs (89 (43.6%) vs 17 (7.2%) respectively). Pre-existing infectious comorbidities (tuberculosis and HIV) and some complications (bacterial pneumonia, acute respiratory distress syndrome and myocarditis) were significantly higher in LMICs compared with HICs. On multivariable analysis, LMIC as country income group was associated with increased risk of mortality (adjusted HR 4.73 (3.16 to 7.10)).Conclusion Mortality and morbidities were higher in LMICs than HICs, and it may be attributable to differences in patient demographics, complications and access to supportive and treatment modalities.

This manuscript reports the first step towards building a robust and efficient model reduction methodology to capture transient dynamics in a transmission level electric power system. Such dynamics is normally modeled on seconds-to-tens-of-seconds time scales by the so-called swing equations, which are ordinary differential equations defined on a spatially discrete model of the power grid. Following Seymlyen (1974) and Thorpe, Seyler, and Phadke (1999), we suggest to map the swing equations onto a linear, inhomogeneous Partial Differential Equation (PDE) of parabolic type in two space and one time dimensions with time-independent coefficients and properly defined boundary conditions. We illustrate our method on the synchronous transmission grid of continental Europe. We show that, when properly coarse-grained, i.e., with the PDE coefficients and source terms extracted from a spatial convolution procedure of the respective discrete coefficients in the swing equations, the resulting PDE reproduces faithfully and efficiently the original swing dynamics. We finally discuss future extensions of this work, where the presented PDE-based modeling will initialize a physics-informed machine learning approach for real-time modeling, $n-1$ feasibility assessment and transient stability analysis of power systems.

The development of gene editing technologies over the past years has allowed the precise and efficient insertion of transgenes into the genome of various cell types. Knock‐in approaches using homology‐directed repair and designer nucleases often rely on viral vectors, which can considerably impact the manufacturing cost and timeline of gene‐edited therapeutic products. An attractive alternative would be to use naked DNA as a repair template. However, such a strategy faces challenges such as cytotoxicity from double‐stranded DNA (dsDNA) to primary cells. Here, we sought to study the kinetics of transcription activator‐like effector nuclease (TALEN)‐mediated gene editing in primary T cells to improve nonviral gene knock‐in. Harnessing this knowledge, we developed a rapid and efficient gene insertion strategy based on either short single‐stranded oligonucleotides or large (2 Kb) linear naked dsDNA sequences. We demonstrated that a time‐controlled two‐step transfection protocol can substantially improve the efficiency of nonviral transgene integration in primary T cells. Using this approach, we achieved modification of up to ˜ 30% of T cells when inserting a chimeric antigen receptor (CAR) at the T‐cell receptor alpha constant region (TRAC) locus to generate ‘off‐the shelf’ CAR‐T cells.

Abstract Background Soil microbial communities are major drivers of cycling of soil nutrients that sustain plant growth and productivity. Yet, a holistic understanding of the impact of land-use intensification on the soil microbiome is still poorly understood. Here, we used a field experiment to investigate the long-term consequences of changes in land-use intensity based on cropping frequency (continuous cropping, alternating cropping with a temporary grassland, perennial grassland) on bacterial, protist and fungal communities as well as on their co-occurrence networks. Results We showed that land use has a major impact on the structure and composition of bacterial, protist and fungal communities. Grassland and arable cropping differed markedly with many taxa differentiating between both land use types. The smallest differences in the microbiome were observed between temporary grassland and continuous cropping, which suggests lasting effects of the cropping system preceding the temporary grasslands. Land-use intensity also affected the bacterial co-occurrence networks with increased complexity in the perennial grassland comparing to the other land-use systems. Similarly, co-occurrence networks within microbial groups showed a higher connectivity in the perennial grasslands. Protists, particularly Rhizaria, dominated in soil microbial associations, as they showed a higher number of connections than bacteria and fungi in all land uses. Conclusions Our findings provide evidence of legacy effects of prior land use on the composition of the soil microbiome. Whatever the land use, network analyses highlighted the importance of protists as a key element of the soil microbiome that should be considered in future work. Altogether, this work provides a holistic perspective of the differential responses of various microbial groups and of their associations to agricultural intensification.

Introduction Powerchair Hockey (PCH) is one of the few team sports available for electric wheelchair users. In Switzerland, the majority of PCH players are living with degenerative diseases (neuromuscular diseases). Their life expectancy is usually no more than 30 years. Nevertheless, although their physical impairments gradually worsen, most players keep on playing sport until they die. Thus, while death is usually a taboo in our society (Elias, 1987), it is an inherent dimension of PCH. Players’ deaths are collectively organized through rituals. Aims In this presentation, I investigate how the social organization of death in PCH shapes the “status passage” (Glaser & Strauss, 1971) that represent the experience of death. More specifically, what does the players' deaths reveal about the value of their sports commitment, and, more broadly, their life? Methods The study is based on a 4 years multi-sited ethnography (Marcus, 1995) of Powerchair Hockey in French- and German-speaking Switzerland. Different tools have been used to collect data: participant observation, life narrative interviews, photo-elicitation interviews, and archival research and consultation. A thematic analysis was performed on the data set (Paillé & Mucchielli, 2012). Results and discussion The analyses show that, in the daily lives of people living with neuromuscular diseases, death is a taboo. PCH proves to be one of the few social arenas where players have the opportunity to talk about it. The collective management of death by those involved in PCH has two main outcomes: (1) the celebration of the live, accomplishments and legacy of the player who died, (2) the preparation of other players to their own death, which may be approaching. For PCH players, carrying on with their sport commitment until the very end of their lives shapes their “transition to death” (Glaser & Strauss, 1971) significantly. Indeed, being part of a sport that outlasts them and being memorialized during and after death, they become part of the history of the community. This contrasts with the fact that, in other areas of their lives (the specialized institutions, the social insurances, the medical world), their lives may be considered to have little value. Thus, the mortuary rituals and the legacy that players leave are performative of the value of their lives. This contributes to their “grievability” (Butler, 2009; i.e., the recognition of the worthiness of their lives). References Butler, J. (2009). Frames of War: When Is Life Grievable? Verso. Elias, N. (1987). La solitude des mourants [The loneliness of the dying].Bourgois. Glaser, B., & Strauss, A. (1971). Status passage: A formal theory. Aldine. Marcus, G. E. (1995). Ethnography in/of the world system: The emergence of multi-sited ethnography. Annual Review of Anthropology, 24(1), 95-117. https://doi.org/10.1146/annurev.an.24.100195.000523 Paillé, P., & Mucchielli, A. (2012). L’analyse qualitative en sciences humaines et sociales [Qualitative analysis in the humanities and social sciences]. Armand Colin.

Understanding children's conversational skills is crucial for understanding their social, cognitive, and linguistic development, with important applications in health and education. To develop theories based on quantitative studies of conversational development, we need (i) data recorded in naturalistic contexts (e.g., child-caregiver dyads talking in their daily environment) where children are more likely to show much of their conversational competencies, as opposed to controlled laboratory contexts which typically involve talking to a stranger (e.g., the experimenter); (ii) data that allows for clear access to children's multimodal behavior in face-to-face conversations; and (iii) data whose acquisition method is cost-effective with the potential of being deployed at a large scale to capture individual and cultural variability. The current work is a first step to achieving this goal. We built a corpus of video chats involving children in middle childhood (6–12 years old) and their caregivers using a weakly structured word-guessing game to prompt spontaneous conversation. The manual annotations of these recordings have shown a similarity in the frequency distribution of multimodal communicative signals from both children and caregivers. As a case study, we capitalize on this rich behavioral data to study how verbal and non-verbal cues contribute to the children's conversational coordination. In particular, we looked at how children learn to engage in coordinated conversations, not only as speakers but also as listeners, by analyzing children's use of backchannel signaling (e.g., verbal “mh” or head nods) during these conversations. Contrary to results from previous in-lab studies, our use of a more spontaneous conversational setting (as well as more adequate controls) revealed that school-age children are strikingly close to adult-level mastery in many measures of backchanneling. Our work demonstrates the usefulness of recent technology in video calling for acquiring quality data that can be used for research on children's conversational development in the wild.

Clouds are prevalent in many of the exoplanet atmospheres that have been observed to date. For transiting exoplanets, we know if clouds are present because they mute spectral features and cause wavelength-dependent scattering. While the exact composition of these clouds is largely unknown, this information is vital to understanding the chemistry and energy budget of planetary atmospheres. In this work, we observe one transit of the hot Jupiter WASP-17b with JWST’s Mid-Infrared Instrument Low Resolution Spectrometer and generate a transmission spectrum from 5 to 12 μ m. These wavelengths allow us to probe absorption due to the vibrational modes of various predicted cloud species. Our transmission spectrum shows additional opacity centered at 8.6 μ m, and detailed atmospheric modeling and retrievals identify this feature as SiO _2 (s) (quartz) clouds. The SiO _2 (s) clouds model is preferred at 3.5–4.2 σ versus a cloud-free model and at 2.6 σ versus a generic aerosol prescription. We find the SiO _2 (s) clouds are composed of small ∼0.01 μ m particles, which extend to high altitudes in the atmosphere. The atmosphere also shows a depletion of H _2 O, a finding consistent with the formation of high-temperature aerosols from oxygen-rich species. This work is part of a series of studies by our JWST Telescope Scientist Team (JWST-TST), in which we will use Guaranteed Time Observations to perform Deep Reconnaissance of Exoplanet Atmospheres through Multi-instrument Spectroscopy (DREAMS).

We present JWST Early Release Science coronagraphic observations of the super-Jupiter exoplanet, HIP 65426b, with the Near-Infrared Camera (NIRCam) from 2 to 5 μ m, and with the Mid-Infrared Instrument (MIRI) from 11 to 16 μ m. At a separation of ∼0.″82 (87 ${}_{-31}^{+108}$ au), HIP 65426b is clearly detected in all seven of our observational filters, representing the first images of an exoplanet to be obtained by JWST, and the first-ever direct detection of an exoplanet beyond 5 μ m. These observations demonstrate that JWST is exceeding its nominal predicted performance by up to a factor of 10, depending on separation and subtraction method, with measured 5 σ contrast limits of ∼1 × 10 ^−5 and ∼2 × 10 ^−4 at 1″ for NIRCam at 4.4 μ m and MIRI at 11.3 μ m, respectively. These contrast limits provide sensitivity to sub-Jupiter companions with masses as low as 0.3 M _Jup beyond separations of ∼100 au. Together with existing ground-based near-infrared data, the JWST photometry are fit well by a BT-SETTL atmospheric model from 1 to 16 μ m, and they span ∼97% of HIP 65426b's luminous range. Independent of the choice of model atmosphere, we measure an empirical bolometric luminosity that is tightly constrained between $\mathrm{log}\left({L}_{\mathrm{bol}}/{L}_{\odot }\right)$ = −4.31 and −4.14, which in turn provides a robust mass constraint of 7.1 ± 1.2 M _Jup . In totality, these observations confirm that JWST presents a powerful and exciting opportunity to characterize the population of exoplanets amenable to high-contrast imaging in greater detail.

We present the highest fidelity spectrum to date of a planetary-mass object. VHS 1256 b is a

Over 150 000 Americans are diagnosed with colorectal cancer (CRC) every year, and annually over 50 000 individuals will die from CRC, necessitating improvements in screening, prognostication, disease management, and therapeutic options. Tumor metastasis is the primary factor related to the risk of recurrence and mortality. Yet, screening for nodal and distant metastasis is costly, and invasive and incomplete resection may hamper adequate assessment. Signatures of the tumor-immune microenvironment (TIME) at the primary site can provide valuable insights into the aggressiveness of the tumor and the effectiveness of various treatment options. Spatially resolved transcriptomics technologies offer an unprecedented characterization of TIME through high multiplexing, yet their scope is constrained by cost. Meanwhile, it has long been suspected that histological, cytological, and macroarchitectural tissue characteristics correlate well with molecular information (e.g., gene expression). Thus, a method for predicting transcriptomics data through inference of RNA patterns from whole slide images (WSI) is a key step in studying metastasis at scale. In this work, we collected tissue from 4 stage-III (pT3) matched colorectal cancer patients for spatial transcriptomics profiling. The Visium spatial transcriptomics (ST) assay was used to measure transcript abundance for 17 943 genes at up to 5000 55-micron (i.e., 1–10 cells) spots per patient sampled in a honeycomb pattern, co-registered with hematoxylin and eosin (H&E) stained WSI. The Visium ST assay can measure expression at these spots through tissue permeabilization of mRNAs, which are captured through spatially (i.e., x–y positional coordinates) barcoded, gene specific oligo probes. WSI subimages were extracted around each co-registered Visium spot and were used to predict the expression at these spots using machine learning models. We prototyped and compared several convolutional, transformer, and graph convolutional neural networks to predict spatial RNA patterns at the Visium spots under the hypothesis that the transformer- and graph-based approaches better capture relevant spatial tissue architecture. We further analyzed the model’s ability to recapitulate spatial autocorrelation statistics using SPARK and SpatialDE. Overall, the results indicate that the transformer- and graph-based approaches were unable to outperform the convolutional neural network architecture, though they exhibited optimal performance for relevant disease-associated genes. Initial findings suggest that different neural networks that operate on different scales are relevant for capturing distinct disease pathways (e.g., epithelial to mesenchymal transition). We add further evidence that deep learning models can accurately predict gene expression in whole slide images and comment on understudied factors which may increase its external applicability (e.g., tissue context). Our preliminary work will motivate further investigation of inference for molecular patterns from whole slide images as metastasis predictors and in other applications.

Informational masking has been investigated using the detection of an auditory target embedded in a random multi-tone masker. The build-up of the target percept is influenced by the masker and target properties. Most studies dealing with discrimination performance neglect the dynamics of perceptual awareness. This study aims at investigating the dynamics of perceptual awareness using multi-level survival models in an informational masking paradigm by manipulating masker uncertainty, masker-target similarity and target repetition rate. Consistent with previous studies, it shows that high target repetition rates, low masker-target similarity and low masker uncertainty facilitate target detection. In the context of evidence accumulation models, these results can be interpreted by changes in the accumulation parameters. The probabilistic description of perceptual awareness provides a benchmark for the choice of target and masker parameters in order to examine the underlying cognitive and neural dynamics of perceptual awareness.

This article describes a pilot French/English contrastive study of some peripheral expressions. A “peripheral expression” is understood as one which occurs at the beginning (“left-peripheral” (LP)) or at the end (“right-peripheral” (RP)) of an utterance which acts as its host and over which it has scope. (The nature of the formal link between the peripheral expression and its host is left open for the purposes of this article.) These peripheral slots are prime sites for the expression of speaker stance towards the idea expressed by the host unit, and for the expression of coherence relations between the idea in the host clause and the previous idea(s). They harbour a wide range of adverbial connectors, discourse particles and comment clauses. The pilot study establishes a basic framework, within a broadly functional approach, for the identification and analysis of peripherals that can serve for contrastive study of French and English. Within the framework, the study has two main goals. One is to test whether and how, for French and/or for English expressions that can occur at either periphery, position correlates with other features of the expressions in context: function, prosodic pattern, information status and syntactic status of the host (and potentially other features of the co-text); in particular, the aim is to discover, if position is not random, what the main motivations appear to be in each case. The other main goal, and the focus of this article, is contrastive: to examine the frequencies and distributions, based on the feature analysis, of comparable peripheral expressions across French and English, to identify what generalizations, if any, can be made across the two languages. Interspeaker variation is also monitored. The primary variables here are position (right vs. left) and language (French vs. English).Recent interest in the peripheries has focused on four main issues: defining the peripheries, including devising a model of syntax that adequately accounts for peripheral expressions; determining the order of expressions, where a periphery contains several; tracing the emergence of peripheral expressions through language change; and identifying potential correlations between position and function. The first two issues have been addressed in formal linguistics, where a cartographic model of the syntactic structure of the periphery has been developed (e.g. Speas & Tenny 2003; Haegeman & Hill 2013; Rizzi & Cinque 2016). Functional and cognitive linguists until recently tended to ignore the syntactic status of peripheral elements like discourse particles and connectors, which were often claimed to be “outside” of syntax (e.g. Kaltenböck et al. 2016; Brinton 2017). Some scholars identify clause-initial pragmatic-marker “slots” (e.g. Aijmer 1996). Others posit a special “discourse grammar” distinct from “sentence grammar” (e.g. Heine et al. 2013, Fernandez Vest 2015). It has also been suggested, for English, that RP particles now constitute a formal paradigm (Haselow 2013). Overall, the third and fourth issues have received greater attention. Diachronically, in European languages investigated so far, RP appears to be a relatively recent development that can be viewed as “further grammaticalization” (almost all forms occurring at RP occur also, and occurred earlier, in other positions). The potentially different synchronic functions linked to LP and RP have mainly been investigated from the pragmatic and discourse-analytic perspectives. One widely-cited hypothesis is that the LP is specialized for subjectivity (speaker stance), while the RP is specialized for intersubjectivity (speaker-hearer relations) (e.g. Degand and Fagard 2011; Beeching and Detges 2014a). Subsequent work across languages has been inconclusive, providing moderate support for this hypothesis along with some counter-evidence (Traugott 2012). Where peripheral expressions are connective, it has been suggested for English that at RP their main function is retrospective connectivity (Haselow 2012), tying the host closely to the previous idea and/or modifying the modal or illocutionary force of the previous idea, while at LP they express interpropositional relations more loosely and can scope over longer stretches of discourse. But little attention has been paid to the role of particles at either periphery in signalling prominence relations and information structure, and relatively few studies have focused on prosodic features (v. Wichmann 2001; Bertrand and Chanet 2005; Dehé and Wichmann 2010; Romero Trillo 2018). Discourse particles, especially at LP, are often assumed to have “comma intonation”, but this assumption rests on insufficient evidence and contradictory claims are found. English final particles, it is claimed, are prosodically integrated (Haselow 2016). Although work in different language varieties has started to clarify some of these issues, few constrastive-linguistic studies have so far been carried out. For this article the peripheral expressions chosen were French alors and English then. Both expressions have developed from their lexical roots into modal adverbs and then discourse particles and/or connectives. Alors and then are both temporal adverbs that have developed very similar non-temporal polysemies. And, relevantly for this study, both now occur as discourse particles of various kinds at both the left and the right peripheries. This corpus-based study first describes a pilot methodology for the contrastive analysis. Data sources are comparable selections of dialogue from spoken-language corpora. Occurrences (and their co-text) are coded for position and on the four parameters listed above (function, prosody, information structure, syntax). The data set is too small for extrapolation, but the study suggests differences in frequency, distribution and usage across the two languages for the comparable genres. It also suggests increased divergence between alors and then for the more abstract and interactional uses. The results of this pilot study can be used to refine the approach in preparation for further work on peripheral expressions"tandis qu’à la PD based on larger corpora.

This chapter deals with the linguistic manifestations of conversation. For a long time, linguists have been interested in the levels of oral language (phonology, lexicon, syntax, discourse) separately, particularly based on prepared and non-interactive speech corpora. Research on conversational speech highlights what modern linguistic theories seek to integrate: the interdependence of these dimensions. Moreover, beyond the description of variants, this work allows us to study in a specific way the processes of language production and comprehension, including by considering them jointly, by relying on the most recent theories of interaction.In this chapter, we propose to first discuss the particularities of conversational language and their impact on the units and phenomena generally studied by linguists: phonemes, morphemes, syntagms, prosodic units, propositions, discourse units. These particularities stem from common parameters to most conversational communication situations: temporal pressure, co-presence of participants, fleeting nature of these conversational productions whose form is forgotten as soon as the message has been transmitted. Temporal pressure provides strong characteristics to conversational language linked to time management (lexical and phonetic reductions, disfluencies, etc.). The transience of productions allows the use of particular strategies (repetitions, redundancies, reformulations) which are generally avoided in other language uses. Finally, co-presence allows the use of all the modalities involved in an interaction, and on which the multiple mechanisms of alignment between participants are based. Moreover, the study of these particularities is profoundly impacted by the notions of context and shared knowledge that underlie an interaction. All these particularities due to conversational language suggest adjustments at all levels of production, but in a specific way for each of them. These adjustments are not always described at each level, but even more so, they are rarely analysed together. An important point is to put into perspective the different types of linguistic modifications linked to conversation.Moreover, understanding these general issues requires a precise description of conversation phenomena (cf. conversational analysis and interactional linguistics). These phenomena include turns of speech, listening signals and conversational feedback, or co-produced utterances.These specific phenomena of conversation must be put into perspective with the question of the interaction existing between units. We know, for example, that phonetic reductions more specifically affect sequences with a low semantic and informational load. It is therefore necessary to describe the conditions under which these interactions are possible. In particular, it is necessary to explain them by putting them in perspective with the question of comprehension.The participants in a conversation seek to achieve goals that are external to the communicative activity, but which involve the achievement of these participants’ communicative goals. In order to achieve these goals, the participants must articulate informative elements through the traditionally studied structures of language which allow the construction and articulation of representations. Conversation is a privileged place to observe these phenomena. Interactions between participants are generally built on an exchange of information. This is not a fixed mechanism as linguistics has long explained. It can be based on very superficial processing during which each participant produces and perceives bits of information. The way in which these are aggregated during a conversation is probably not always based on a compositional process, but rather consists in allowing all participants to construct a shared body of knowledge. In this chapter, we will describe the observable evidence of this mechanism, addressing in particular the question of the alignment of linguistic units that we observe during a conversation. This approach to interaction provides a theoretical framework for explaining the conversational phenomena mentioned above.This chapter will be structured as follows: 1/ conversation will be discussed as the articulation between representation and communication through language as a social action; 2/ a second part will aim at drawing up an inventory of the “traces” of the activity of conversation (communicative goal, temporal pressure, co-presence, cognitive load, social pressure) on the different linguistic units (phonemes, lexicon, syntax, prosody); 3/ we will then address the phenomena specific to conversation which are not identifiable in other types of speech (speech turns, disfluencies, conversational feedback, co-produced utterances, non-phrastic utterances, non-lexical utterances, etc.)); 4/ we will finally develop some perspectives related to all these works.

The EU is faced with a Member State where all of its top courts are now unlawfully composed; where every single judicial appointment procedure since 2018 is inherently defective due to the involvement of an unconstitutional body; and where core EU and ECHR requirements relating to effective judicial protection and the fundamental right to an independent court established by law have been held “unconstitutional” in 2021 and 2022 by the body masquerading as Poland’s Constitutional Tribunal.