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Abstract Background Acute respiratory distress syndrome (ARDS) occurring in patients with hematological malignancies (HM) is a life-threatening condition with specific features. Mortality rate remains high but improvement has been described over the past several years. We aimed to describe characteristics and outcomes of ARDS in HM patients admitted in French ICUs (Intensive Care Units) during a one year-period. Data for this nationwide cohort study were collected from the French national hospital database (Programme de Médicalisation des Systèmes d’Information (PMSI)). All patients (18 years or older) admitted to French ICUs in 2017 and with a diagnosis of ARDS were included. Three groups were compared according to the presence of an HM, a solid cancer or no cancer. The primary endpoint was 90-day mortality. Secondary endpoints were the description of ICU management, etiologies of ARDS and mortality risk factors. Results A total of 12 846 patients with ARDS were included. Among them, 990 had HM and 2744 had a solid cancer. The main malignancies were non-Hodgkin lymphoma (NHL) (28.5%), acute myeloid leukemia (AML) (20.4%) and multiple myeloma (19.7%). Day-90 mortality in patients with HM was higher than in patients with no cancer (64.4% vs. 46.6% p = 0.01) but was not different from that of patients with solid cancer (64.4% vs. 61.4%,p = 0.09). Intubation rate was lower in patients with HM in comparison with both groups (87.7% vs. 90.4% p = 0.02 for patients with solid cancer and 87.7% vs. 91.3%; p

Abstract Background Further research is still needed to fully understand the potential of prostate-specific membrane antigen (PSMA) in breast cancer (BC) and to develop and optimize targeted therapies and imaging modalities. The objective of this study was to present a comprehensive analysis of immunohistochemistry data on PSMA staining in BC and to discuss its potential value in a theranostic approach. Methods Fifty-eight male and female patients were randomly selected from a retrospective database of patients who underwent surgery for breast cancer between January 2012 and December 2017 and for whom a specimen is available in our tumour library. Immunodetection of PSMA and CD31 was performed on serial slides. The digitized slides were reviewed and analysed by an experienced pathologist. Additionally, the corresponding TIFF images were processed to calculate the percentage of positive neovessels. Results Eighteen patients (31.6%) had no expression, 29 (50.9%) had PSMA neovascular expression scored as “1”, and 10 (17.5%) had neovascular expression scored as “2”. Digital immunohistochemistry analysis for this last specific group of patients showed a median proportion of positive neovessels equal to 5% (range: 3–19). A multivariable logistic regression demonstrated that the odds of PSMA positivity were 4.55 times higher in non-luminal tumours and decreased by a factor of 0.12 in lobular subtypes. There was no association between sex or the presence of a germline BRCA1/2 mutation and PSMA expression in tumours. Conclusions Our study highlights generally low neovascular expression of PSMA in specific histopathological subtypes of breast cancer, which will likely hamper the development of an adequate theranostic strategy. Trial registration The procedure has been retrospectively registered to the French National Institute for Health Data (N° F20220615153900).

Abstract Background Understanding of mosquito spatiotemporal dynamics is central to characterize candidate field sites for the sterile insect technique (SIT) testing, and is critical to the effective implementation and evaluation of pilot sterile male release programs. Here, we present a detailed description of Aedes albopictus (Skuse) egg-laying activity over a 6-year period in urban areas identified as potential SIT testing sites on Reunion Island. Method Weekly entomological collections using ovitraps were carried out in residential and adjacent uninhabited habitats in two urban areas, Duparc and Bois Rouge, in the municipality of Sainte Marie, Reunion Island. Time-series data incorporating the frequency of positive ovitraps and the total number of eggs/ovitrap recorded each time at each locality during the study period from May 2013 to December 2018 were analyzed with multifaceted statistical approaches including descriptive statistics and spatiotemporal analyses incorporating the role of climatic factors on overall ovitrap productivity. Results During the ovitrap survey, the proportion of egg-positive ovitraps differed among study sites (χ 2 = 50.21, df = 2, P

Abstract Subarachnoid hemorrhage (SAH) can be associated with neurological deficits and has profound consequences for mortality and morbidity. Cerebral vasospasm (CVS) and delayed cerebral ischemia affect neurological outcomes in SAH patients, but their mechanisms are not fully understood, and effective treatments are limited. Here, we report that urotensin II receptor UT plays a pivotal role in both early events and delayed mechanisms following SAH in male mice. Few days post-SAH, UT expression is triggered by blood or hemoglobin in the leptomeningeal compartment. UT contributes to perimeningeal glia limitans astrocyte reactivity, microvascular alterations and neuroinflammation independent of CNS-associated macrophages (CAMs). Later, CAM-dependent vascular inflammation and subsequent CVS develop, leading to cognitive dysfunction. In an SAH model using humanized UTh+/h+ male mice, we show that post-SAH CVS and behavioral deficits, mediated by UT through Gq/PLC/Ca2+ signaling, are prevented by UT antagonists. These results highlight the potential of targeting UT pathways to reduce early meningeal response and delayed cerebral ischemia in SAH patients.

Background: Several bacterial species belonging to the Gammaproteobacteria possess intrinsic class A β-lactamase genes that may represent a source of further dissemination and acquisition to other Gram-negative species. Here we characterised KSA-1 class A β-lactamase, the gene of which was identified within the chromosome of an environmental Enterobacterales species, namely Kosakonia sacchari, which was also recently identified as the progenitor of an MCR-like colistin-resistance determinant. Methods: In silico analysis using the GenBank database identified a class A β-lactamase gene within the chromosome of K. sacchari SP1 (GenBank accession no. WP_017456759). The corresponding protein KSA-1 shared 63% amino acid identity with the intrinsic CKO-1 from Citrobacter koseri and 53% with TEM-1. Using the K. sacchari DSM 100203 reference strain as a template, blaKSA-1 was amplified, cloned into the plasmid pUCp24 and expressed in Escherchia coli TOP10. Minimal inhibitory concentrations and kinetic parameters were obtained from the purified enzyme. Results: K. sacchari strain SP1 conferred resistance to amino-, carboxy- and ureido-penicillins only. Once produced within E. coli, KSA-1 showed a typical clavulanic acid-inhibited extended spectrum β-lactamase associated with a peculiar temocillin resistance profile. Kinetic assays were performed using a purified extract of KSA-1 and demonstrated a high hydrolysis rate for benzylpenicillin and piperacillin, as well as weakly extended spectrum cephalosporins. Determination of inhibitory constants showed 50% inhibitory concentration values of 2.2, 3 and 1.8 nM for clavulanic acid, tazobactam and avibactam, respectively. Analysis of sequences surrounding the blaKSA-1 gene did not reveal any mobile element that could have been involved in the acquisition of this β-lactamase gene in that species. Conclusion: KSA-1 is a class A extended spectrum β-lactamase distantly related to known extended spectrum or broad-spectrum Ambler class A β-lactamases, which is highly resistant to temocillin. The blaKSA-1 gene could be considered as intrinsic within the species.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to

Abstract Exposure to ionizing radiation can induce genetic aberrations via unrepaired DNA strand breaks. To investigate quantitatively the dose–effect relationship at the molecular level, we irradiated dry pBR322 plasmid DNA with 3 MeV protons and assessed fragmentation yields at different radiation doses using long-read sequencing from Oxford Nanopore Technologies. This technology applied to a reference DNA model revealed dose-dependent fragmentation, as evidenced by read length distributions, showing no discernible radiation sensitivity in specific genetic sequences. In addition, we propose a method for directly measuring the single-strand break (SSB) yield. Furthermore, through a comparative study with a collection of previous works on dry DNA irradiation, we show that the irradiation protocol leads to biases in the definition of ionizing sources. We support this scenario by discussing the size distributions of nanopore sequencing reads in the light of Geant4 and Geant4-DNA simulation toolkit predictions. We show that integrating long-read sequencing technologies with advanced Monte Carlo simulations paves a promising path toward advancing our comprehension and prediction of radiation-induced DNA fragmentation.

Abstract SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool that would maintain its efficacy despite the ongoing emergence of new variants. Here, we challenge male rhesus macaques with SARS-CoV-2 Delta—the most pathogenic variant in a highly susceptible animal model. At the time of challenge, we also treat the macaques with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment equivalently suppresses virus replication in both upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 does not block the development of virus-specific T- and B-cell responses and does not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Crop disease often leads to field epidemics with serious threats to yield. Early symptoms are sometimes difficult to identify, so the origin of primary inoculum is a critical focal point in the study of plant diseases, as it can help design management strategies to reduce crop losses. Here, we investigated whether anthracnose of water yams (Dioscorea alata L.) caused by the species complex Colletotrichum gloeosporioides can start from infected seed tubers from the previous harvest. Over two years, we collected tubers with varying pathogen prevalence in the field directly from producers and conducted fungal isolations in the lab to sample C. gloeosporioides. We also proceeded to artificially inoculate tubers before planting and monitored disease development. Finally, we genotyped isolates from leaves in the fields and assessed fixation indices between plots based on plot ownership (plots with a common seed tuber origin from a single farmer) vs. samples in plots from unrelated producers in Guadeloupe, Martinique, and Barbados. We were unable to isolate the fungus from harvested tubers in either sampling survey nor did any plants grown from inoculated tubers develop any disease symptoms during growth. Also, the genetic structure of samples within each plot was independent of plot ownership, though this occurred with varying levels in the different islands. These results suggest that contaminated planting material from seed tubers is not the primary source of the disease, which is in contrast to the common perception of yam anthracnose prevalence in the Antilles.

Abstract Over the past decade, the emergence of patient-derived tumor organoids (PDTOs) has broadened the repertoire of preclinical models and progressively revolutionized three-dimensional cell culture in oncology. PDTO can be grown from patient tumor samples with high efficiency and faithfully recapitulates the histological and molecular characteristics of the original tumor. Therefore, PDTOs can serve as invaluable tools in oncology research, and their translation to clinical practice is exciting for the future of precision medicine in oncology. In this review, we provide an overview of methods for establishing PDTOs and their various applications in cancer research, starting with basic research and ending with the identification of new targets and preclinical validation of new anticancer compounds and precision medicine. Finally, we highlight the challenges associated with the clinical implementation of PDTO, such as its representativeness, success rate, assay speed, and lack of a tumor microenvironment. Technological developments and autologous cocultures of PDTOs and stromal cells are currently ongoing to meet these challenges and optimally exploit the full potential of these models. The use of PDTOs as standard tools in clinical oncology could lead to a new era of precision oncology in the coming decade.

Abstract Broadly neutralizing antibodies (bNAbs) are promising candidates for the treatment and prevention of HIV-1 infections. Despite their critical importance, automatic detection of HIV-1 bNAbs from immune repertoires is still lacking. Here, we develop a straightforward computational method for the Rapid Automatic Identification of bNAbs (RAIN) based on machine learning methods. In contrast to other approaches, which use one-hot encoding amino acid sequences or structural alignment for prediction, RAIN uses a combination of selected sequence-based features for the accurate prediction of HIV-1 bNAbs. We demonstrate the performance of our approach on non-biased, experimentally obtained and sequenced BCR repertoires from HIV-1 immune donors. RAIN processing leads to the successful identification of distinct HIV-1 bNAbs targeting the CD4-binding site of the envelope glycoprotein. In addition, we validate the identified bNAbs using an in vitro neutralization assay and we solve the structure of one of them in complex with the soluble native-like heterotrimeric envelope glycoprotein by single-particle cryo-electron microscopy (cryo-EM). Overall, we propose a method to facilitate and accelerate HIV-1 bNAbs discovery from non-selected immune repertoires.

Abstract Background Ovarian cancer is the first cause of death from gynecological malignancies mainly due to development of chemoresistance. Despite the emergence of PARP inhibitors, which have revolutionized the therapeutic management of some of these ovarian cancers, the 5-year overall survival rate remains around 45%. Therefore, it is crucial to develop new therapeutic strategies, to identify predictive biomarkers and to predict the response to treatments. In this context, functional assays based on patient-derived tumor models could constitute helpful and relevant tools for identifying efficient therapies or to guide clinical decision making. Method The OVAREX study is a single-center non-interventional study which aims at investigating the feasibility of establishing in vivo and ex vivo models and testing ex vivo models to predict clinical response of ovarian cancer patients. Patient-Derived Xenografts (PDX) will be established from tumor fragments engrafted subcutaneously into immunocompromised mice. Explants will be generated by slicing tumor tissues and Ascites-Derived Spheroids (ADS) will be isolated following filtration of ascites. Patient-derived tumor organoids (PDTO) will be established after dissociation of tumor tissues or ADS, cell embedding into extracellular matrix and culture in specific medium. Molecular and histological characterizations will be performed to compare tumor of origin and paired models. Response of ex vivo tumor-derived models to conventional chemotherapy and PARP inhibitors will be assessed and compared to results of companion diagnostic test and/or to the patient’s response to evaluate their predictive value. Discussion This clinical study aims at generating PDX and ex vivo models (PDTO, ADS, and explants) from tumors or ascites of ovarian cancer patients who will undergo surgical procedure or paracentesis. We aim at demonstrating the predictive value of ex vivo models for their potential use in routine clinical practice as part of precision medicine, as well as establishing a collection of relevant ovarian cancer models that will be useful for the evaluation of future innovative therapies. Trial registration The clinical trial has been validated by local research ethic committee on January 25th 2019 and registered at ClinicalTrials.gov with the identifier NCT03831230 on January 28th 2019, last amendment v4 accepted on July 18, 2023.

Summary: Background: We apply endoscopic ultrasound-guided fine needle aspiration biopsy to cytopathologically diagnose and sample nucleic acids from primary tumours regardless of the disease stage. Methods: 397 patients with proven pancreatic adenocarcinoma were included and followed up in a multicentre prospective study. DNA and mRNA were extracted from materials of primary tumours obtained by endoscopic ultrasound-guided fine needle aspiration biopsy and analysed using targeted deep sequencing and RNAseq respectively. Findings: The variant allele frequency of the KRAS mutation was used to evaluate the tumour cellularity, ranging from 15 to 20% in all cells, regardless of the tumour stage. The molecular profile of metastatic primary tumours significantly differed from other types of tumours, more frequently having TP53 mutations (p = 0.0002), less frequently having RNF43 mutations, and possessing more basal-like mRNA component (p = 0.001). Molecular markers associated with improved overall survival were: mutations in homologous recombination deficiency genes in patients who received first-line platinum-based chemotherapy (p = 0.025) and wild-type TP53 gene in patients with locally advanced tumours who received radio-chemotherapy (p = 0.01). The GemPred transcriptomic profile was associated with a significantly better overall survival in patients with locally advanced or metastatic pancreatic cancer who received a gemcitabine-based first-line treatment (p = 0.019). Interpretation: The combination of genomic and transcriptomic analyses of primary pancreatic tumours enables us to distinguish metastatic tumours from other tumour types. Our molecular strategy may assist in predicting overall survival outcomes for platinum or gemcitabine-based chemotherapies, as well as radio-chemotherapy. Funding: Institut National Du Cancer (BCB INCa_7294), CHU of Toulouse, Inserm and Ligue Nationale Contre le Cancer (CIT program).

Abstract Ultra‐wideband (UWB) microwave sources driven by specialised pulsed power generators have experienced a considerable development in the last decade due to their wide domain of new applications such as defence or counter‐terrorism activity. The authors present the main findings of a research dedicated to the development of a pulsed power‐driven electromagnetic field source for disabling improvised explosive devices (IED). The pulsed power generator driving the source is a 13‐stage compact Marx producing voltage pulses reaching an amplitude of 0.5 MV, with a pulse repetition frequency (PRF) of up to 100 Hz. The generator is coupled to a bipolar pulse forming line, providing bipolar pulses with a dV/dt of around 1.6 MV/ns. This pulsed power system feeds an array composed of 16 Koshelev‐type UWB antennas through an impedance matching transformer. The resulting electromagnetic source is capable to produce pulsed electric fields (PEFs) having a figure‐of‐merit (FOM) of 1 MV. First, practical experiments were carried out to study the effects of the PEFs on targets. The targets used in the present study are M2B type flashbulbs, known to have the same susceptibility as the US army M6 detonator. Different configurations of wires (shielded, twisted, etc) with different lengths were used in connecting items inside these targets. The tests were performed by placing the flashbulbs at different distances to determine the essential parameters (i.e., amplitude, duration, and frequency range) of the PEFs required to trigger them. An overview of the experimental campaign and the main findings are also presented followed by conclusions.

Abstract Background Vaccines play a crucial role in eradicating and containing disease outbreaks. Therefore, understanding the reasons behind vaccine refusal and associated factors is essential for improving vaccine acceptance rates. Our objective was to examine the determinants of COVID-19 vaccine non-uptake and explore the reasons for non-uptake among healthcare workers (HCWs) in Uganda. Methods Between July and August 2021, we conducted a cross-sectional study among healthcare workers in primary healthcare facilities (private and government) in Entebbe Municipality, Uganda. Participants were recruited using convenience sampling, and consenting individuals received credentials to access an electronic database and complete a structured questionnaire. There were no established HCWs contact registers in the municipality, and the study was conducted during a national lock down, therefore, the HCWs who were on duty at the time of the study were approached. The survey questions were based on the ‘3Cs’ model of vaccine hesitancy and focused on confidence, convenience, and complacency factors. Non-uptake of vaccines was defined as not having received any of the available vaccines in the country. We employed counts, percentages, and simple logit models to summarize the reasons for non-uptake of COVID-19 vaccines and to identify associated factors. Results The study recruited 360 HCWs, 61.7% of whom were female, with an average age of 31 years (SD = 7.9). Among them, 124 (34.4%) healthcare workers did not receive any COVID-19 vaccine. Non-uptake of COVID-19 vaccines was independently associated with several factors, including age [35 + years adjusted odds ratio (aOR) = 0.30, 95% CI: 0.13–0.66 compared with 18–24 years], facility ownership [government, aOR = 0.22 (0.10–0.49) compared with private not-for-profit], previous testing for coronavirus [yes, aOR = 0.35 (0.19–0.65)], and previous involvement in COVID-19 vaccine activities [yes, aOR = 0.17 (0.10–0.29)]. The primary reasons cited for non-uptake of COVID-19 vaccines were related to a lack of confidence in the vaccines, such as concerns about side effects (79.8%) and the need for more time to understand the vaccines (89.5%), as well as the importance of weighing benefits and risks (84.7%) before being vaccinated. A smaller proportion, approximately 23%, cited reasons related to complacency and lack of convenience in accessing vaccination services. Conclusion The high proportion of non-uptake of COVID-19 vaccines among this population primarily stems from a lack of confidence and trust in the vaccines, coupled with insufficient time allowed for users to make informed decisions. This underscores the urgent need for ongoing monitoring and trend analysis of vaccine non-uptake to guide the development and implementation of strategies aimed at building and sustaining vaccine confidence. Adequate time should be allowed to explain benefits of vaccination to the population to allay fears that might exist before actual vaccination is rolled out.

Abstract Although intratumoral heterogeneity has been established in pediatric central nervous system tumors, epigenomic alterations at the cell type level have largely remained unresolved. To identify cell type-specific alterations to cytosine modifications in pediatric central nervous system tumors, we utilize a multi-omic approach that integrated bulk DNA cytosine modification data (methylation and hydroxymethylation) with both bulk and single-cell RNA-sequencing data. We demonstrate a large reduction in the scope of significantly differentially modified cytosines in tumors when accounting for tumor cell type composition. In the progenitor-like cell types of tumors, we identify a preponderance differential Cytosine-phosphate-Guanine site hydroxymethylation rather than methylation. Genes with differential hydroxymethylation, like histone deacetylase 4 and insulin-like growth factor 1 receptor, are associated with cell type-specific changes in gene expression in tumors. Our results highlight the importance of epigenomic alterations in the progenitor-like cell types and its role in cell type-specific transcriptional regulation in pediatric central nervous system tumors.

The Mediterranean Region represents a biodiversity hotspot with a high rate of endemism. In its western part, Corsica Island is notable in terms of biodiversity due to its large surface and its large range of habitats from seaside to alpine biotopes. Amongst diverse groups, insects, notably the main orders of pollinators composed of Coleoptera, Hymenoptera, Diptera and Lepidoptera, represent a good part of the insular richness.Our sampling effort focused on the insects from these four orders visiting flowers in a characteristic thermo-Mediterranean vegetation. Our database is an insight into the Corsican floral visitor biodiversity from three sites separated by a few kilometres in the region of Ajaccio during 13 months over two successive years. In total, 4012 specimens were sampled and 252 species or morpho-species identified from 133 genera and 47 families. Beetles were by far the most abundant order representing about 54% of the sampled specimens. The most diverse order was the Hymenoptera representing 39% of the species. Our continuous survey showed that these orders are temporally dynamic both between years and between seasons in terms of abundance and diversity.

Abstract Background While indirect comparison of infliximab (IFX) and vedolizumab (VDZ) in adults with Crohn’s disease (CD) or ulcerative colitis (UC) shows that IFX has better effectiveness during induction, and comparable efficacy during maintenance treatment, comparative data specific to subcutaneous (SC) IFX (i.e., CT-P13 SC) versus VDZ are limited. Aim Pooled analysis of randomised studies to compare efficacy and safety with IFX SC and VDZ in moderate-to-severe inflammatory bowel disease. Methods Parallel-group, randomised studies evaluating IFX SC and VDZ in patients with moderate-to-severe CD or UC were identified. Eligible studies reported ≥ 1 prespecified outcome of interest at Week 6 (reflecting treatment during the induction phase) and/or at 1 year (Weeks 50-54; reflecting treatment during the maintenance phase). Prespecified efficacy and safety outcomes considered in this pooled analysis included the proportions of patients achieving disease-specific clinical responses, clinical remission, or discontinuing due to lack of efficacy, and the proportions of patients experiencing adverse events (AEs), serious AEs, infections, serious infections, or discontinuing due to AEs. Data from multiple studies or study arms were extracted and pooled using a random-effect model; comparative analyses were performed separately for patients with CD and UC. Results We identified three eligible CD trials and four eligible UC trials that assigned over 1200 participants per disease cohort to either IFX SC or VDZ. In patients with CD, intravenous induction therapy with IFX demonstrated better efficacy (non-overlapping 95% confidence intervals [CIs]) compared with VDZ; during the maintenance phase, IFX SC showed numerically better efficacy (overlapping 95% CIs) than VDZ. A lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In patients with UC, efficacy profiles were similar with IFX SC and VDZ during the induction and maintenance phases, and a lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In both cohorts, safety profiles for IFX SC and VDZ were generally comparable during 1 year. Conclusion IFX SC demonstrated better efficacy than VDZ in patients with CD, and similar efficacy to VDZ in patients with UC; 1-year safety was comparable with IFX SC and VDZ.

Abstract Background Microbial communities are of tremendous importance for ecosystem functioning and yet we know little about the ecological processes driving the assembly of these communities in the environment. Here, we used an unprecedented experimental approach based on the manipulation of physical distance between neighboring cells during soil colonization to determine the role of bacterial interactions in soil community assembly. We hypothesized that experimentally manipulating the physical distance between bacterial cells will modify the interaction strengths leading to differences in microbial community composition, with increasing distance between neighbors favoring poor competitors. Results We found significant differences in both bacterial community diversity, composition and co-occurrence networks after soil colonization that were related to physical distancing. We show that reducing distances between cells resulted in a loss of bacterial diversity, with at least 41% of the dominant OTUs being significantly affected by physical distancing. Our results suggest that physical distancing may differentially modulate competitiveness between neighboring species depending on the taxa present in the community. The mixing of communities that assembled at high and low cell densities did not reveal any “home field advantage” during coalescence. This confirms that the observed differences in competitiveness were due to biotic rather than abiotic filtering. Conclusions Our study demonstrates that the competitiveness of bacteria strongly depends on cell density and community membership, therefore highlighting the fundamental role of microbial interactions in the assembly of soil communities.

La production porcine française en AB est très diversifiée de par ses élevages, notamment en termes de taille avec de nombreux ateliers à faibles effectifs ; de par la commercialisation des produits, avec une filière longue bien implantée dans le grand ouest de la France, et des filières courtes plus territorialisées ; et de par la multiplicité de ses acteurs spécifiques à l’AB ou mixtes. Bien que le nombre de truies certifiées en AB ait doublé entre 2016 et 2021, il ne représente que 1,9 % du cheptel français. Face à ce constat, une étude a été réalisée par le consortium ORIGAMI (INRAE-Métabio) pour comprendre les freins et leviers au développement de cette production. Des entretiens de 21 porteurs de projets ont permis d’identifier 164 freins et 231 leviers. Des analyses en composantes multiples suivies d’une classification ont mis en évidence sept types de freins et six types de leviers en fonction de leur niveau d’organisation (de l’animal au territoire) et du maillon de la filière qu’ils concernent (de l’agrofourniture à la consommation). L’interprétation de ces typologies permet d’identifier des thèmes de recherche pour relever les principaux défis identifiés. Ces thèmes concernent l’acquisition de références techniques spécifiques pour l’AB, la meilleure articulation entre filières et territoires, la promotion des débouchés des produits, mais aussi la formation des acteurs actuels et futurs et la communication auprès du grand public. Ces sujets sont des pistes de réflexion pour la construction de projets transdisciplinaires de recherche ou recherche-action avec les acteurs des filières.

Mo2Ti2C3Tx MXene materials, bare or loaded with strongly anchored single Pt atoms, were investigated using various methods, including STEM, XPS, XAS and DFT calculations. Upon Pt impregnation, the delaminated Mo-rich MXene surface undergoes partial oxidation, which is reversed by an H2 thermal treatment at 400 °C. The optimized MXene shows high catalytic activity for CO2 hydrogenation to CO and smaller amounts of methane and methanol. Around and above the pretreatment temperature of 400 °C, the MXene is gradually defunctionalized from O- and F-containing groups and depleted in carbidic carbon, leading to deactivation. Single Pt atoms are cationic after impregnation, and reduce upon H2 treatment, filling surface Mo vacancies. Pt addition increases the MXene activity, in particular by facilitating H2 dissociation, but has little effect on the single-atom catalyst selectivity and on the rate dependence upon reactant partial pressures. The lowest Pt loading leads to the highest turnover frequency, indicating that the MXene surface sites are key to CO2 activation.

Botulinum neurotoxin A (BoNT/A) is a highly potent proteolytic toxin specific for neurons with numerous clinical and cosmetic uses. After uptake at the synapse, the protein is proposed to translocate from synaptic vesicles to the cytosol through a self-formed channel. Surprisingly, we found that after intoxication proteolysis of a fluorescent reporter occurs in the neuron soma first and then centrifugally in neurites. To investigate the molecular mechanisms at play, we use a genome-wide siRNA screen in genetically engineered neurons and identify over three hundred genes. An organelle-specific split-mNG complementation indicates BoNT/A traffic from the synapse to the soma-localized Golgi in a retromer-dependent fashion. The toxin then moves to the ER and appears to require the Sec61 complex for retro-translocation to the cytosol. Our study identifies genes and trafficking processes hijacked by the toxin, revealing a new pathway mediating BoNT/A cellular toxicity.

Background: Several adalimumab preparations are now available for patients with inflammatory bowel disease (IBD). Comparative satisfaction and tolerability are unknown. Objectives: This study investigated IBD patient satisfaction with approved adalimumab biosimilars and their originator. Design: In this cross-sectional study, we included 941 consecutive adalimumab-treated patients with IBD across 45 centres affiliated with the Groupe d’Etude Therapeutique des Affections Inflammatoires du tube Digestif who completed a satisfaction questionnaire comprising four items each rated by a 10-point scale. Methods: The differences in responses were performed using a one-way analysis of variance followed by Tukey’s honest significant difference test. Results: The most commonly used drugs at inclusion were Humira ® (436/941, 46.3%), Amgevita ® (177/941, 18.8%) and Hulio ® (105/941, 11.2%). The mean overall satisfaction rate with adalimumab was 8.5 (standard deviation 1.8). Overall satisfaction was significantly higher in patients treated with Humira (8.6 (1.5)), Hulio (8.6 (1.8)) or Amgevita (8.5 (1.4)) ( p

Abstract The performance and operational stability of perovskite‐based devices heavily rely on the interfacial properties between the photoactive perovskite layer and charge transport layers. Understanding the theoretical relationship between surface/interface dipoles and surface energetics is crucial for scientific understanding and practical applications. In this study, a method is applied that bridges classical electromagnetism and modern atomistic approaches. The impact of dipolar ligand molecules functionalizing the FASnI3 perovskite surface is investigated, with inspection of the interplay between surface dipole, charge transfer, and local strain effect, and corresponding shifts in the valence level. The results reveal that the contribution of individual molecular entities to surface dipoles and electric susceptibilities follows an essentially additive behavior. The influence of F doping usually used to mitigate Sn oxidation in Sn‐based layer for photovoltaic applications, is also discussed. Furthermore, the findings are compared with predictions from classical approaches employing a capacitor model that links the induced vacuum level shift and the molecular dipole moment. The insights gained from the study provide theoretical guidelines for fine‐tuning the work functions of materials, thus enabling effective interfacial engineering in this class of semiconductors.

Summary: Background: An increasing number of countries have or are considering legalizing cannabis. One concern is that legalization of cannabis will result in increased cannabis use and in turn a higher prevalence of anxiety disorders. We examined changes in emergency department (ED) visits for anxiety disorders with cannabis involvement in Ontario, over a period that involved medical and non-medical cannabis legalization. Methods: This repeated cross-sectional population-based study identified all ED visits for anxiety disorders from residents of Ontario, Canada aged 10–105 between 2008 and 2022 (n = 15.7 million individuals). We used interrupted time series analyses to examine immediate and gradual changes in cannabis-involvement and alcohol-involvement (control condition) over four policy periods: medical cannabis legalization (January 2008–November 2015), expanded medical access (December 2015–September 2018), non-medical cannabis legalization with restrictions (October 2018–February 2020), and commercialization which overlapped with the COVID-19 pandemic (March 2020–December 2022). Poisson models were used to generate incidence rate ratios with 95% confidence intervals. Findings: Over the 14-year study, there were 438,700 individuals with one or more ED visits for anxiety disorders of which 3880 (0.89%) individuals had cannabis involvement and 6329 (1.45%) individuals had alcohol involvement. During the commercialization/COVID-19 period monthly rates of anxiety disorders with cannabis-involvement were 156% higher (0.11 vs 0.29 per 100,000 individuals) relative to the pre-legalization period, compared to a 27% increase for alcohol-involvement (0.27 vs 0.35 per 1100,000 individuals). Rates of anxiety ED visits with cannabis involvement per 100,000 individuals increased gradually over the study period with no immediate or gradual changes after expanded medical access, legalization with restrictions or commercialization/COVID-19. However, during the commercialization/COVID-19 period there were large declines in total anxiety disorder ED visits and anxiety disorder ED visits with alcohol-involvement. Consequently, during this period there was an immediate 31.4% relative increase in the proportion of anxiety visits with cannabis-involvement (incidence rate ratio [IRR], 1.31; 95% CI 1.05–1.65). Interpretation: We found large relative increases in anxiety disorder ED visits with cannabis involvement over a 14-year period involving medical and non-medical cannabis legalization. These findings may reflect increasing anxiety disorder problems from cannabis use, increasing self-medication of anxiety disorders with cannabis use, or both. The proportion of anxiety ED visits with cannabis involvement increased during the final period of the study but could have been the results of the market commercialization, COVID-19 or both and ongoing monitoring is indicated. Funding: Canadian Institutes of Health Research (grant #452360).

ABSTRACT Inflammatory bowel diseases (IBD) currently impose an immense social and economic burden on society in terms of both direct and indirect healthcare costs. Their incurable and progressive nature results in an unavoidable lifetime expense. The introduction of infliximab more than two decades ago had revolutionized IBD treatment. Nowadays, while biologic drugs comprise various vital therapeutic options for patients, they can be associated to significant costs to healthcare systems. The most crucial benefit of biosimilars is that they bring more significant cost reduction and increase access to advanced therapies. They also allow the treatment of newly diagnosed patients and dose optimization for those who need it. There is an inverse relationship between price and demand for treatment with biologics. For a more significant reduction in cost to be possible, greater use of biosimilars is necessary. For this to occur, it is imperative not only to use biosimilars in naïve patients but also to switch to biosimilars in those patients who have started therapy with reference biologics. At present, randomized and observational studies have demonstrated effectiveness and safety results in recommending a single switch between a reference product and a biosimilar, and vice versa. The purpose of this manuscript is to review the literature and discuss whether scientific evidence is enough to support multiple switches of biologics and biosimilars in IBD patients.

ABSTRACT The impact of chromosomally encoded wild-type or extended-spectrum (ESAC) AmpC β-lactamases of Escherichia coli on susceptibility to ceftazidime, cefepime, and cefiderocol was evaluated in different genetic backgrounds, including wild-type, PBP3-modified, and porin-deficient E. coli strains. Recombinant E. coli strains possessing the different backgrounds and producing variable ESACs were evaluated. Although ESAC enzymes conferred resistance to ceftazidime and decreased susceptibility to cefepime as expected, we showed here that cefiderocol was also a substrate of ESAC enzymes.IMPORTANCEWe showed here that chromosomally encoded intrinsic extended-spectrum cephalosporinases of Escherichia coli may impact susceptibility not only to ceftazidime and cefepime but also to cefiderocol.

Introduction Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC.Methods and analysis In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score

Recombinant adeno-associated virus (AAV) vectors have emerged as the preferred platform for gene therapy of rare human diseases. Despite the clinical promise, host immune responses to AAV vectors and transgene remain a major barrier to the development of successful AAV-based human gene therapies. Here, we assessed the human innate immune response to AAV9, the preferred serotype for AAV-mediated gene therapy of the CNS. We showed that AAV9 induced type I interferon (IFN) and IL-6 responses in human blood from healthy donors. This innate response was replicated with AAV6, required full viral particles, but was not observed in every donor. Depleting CpG motifs from the AAV transgene or inhibiting TLR9 signaling reduced type I IFN response to AAV9 in responding donors, highlighting the importance of TLR9-mediated DNA sensing for the innate response to AAV9. Remarkably, we further demonstrated that only seropositive donors with preexisting antibodies to AAV9 capsid mounted an innate immune response to AAV9 in human whole blood and that anti-AAV9 antibodies were necessary and sufficient to promote type I IFN release and plasmacytoid dendritic (pDC) cell activation in response to AAV9. Thus, our study reveals a previously unidentified requirement for AAV preexisting antibodies for TLR9-mediated type I IFN response to AAV9 in human blood.

This study evaluates the techno-economic feasibility and the embodied carbon dioxide intensity (eCI) of a novel process for producing nominally pure (>95 mass %) calcium hydroxide without the need for the thermal calcination of limestone. The process relies on the aqueous extraction of calcium from alkaline industrial wastes following which portlandite (Ca(OH)2: CH, a.k.a. slaked lime or hydrated lime) is precipitated by application of a waste-heat based thermal swing. This approach takes advantage of the temperature dependent solubility of CH at ambient pressure. We evaluated the feasibility of implementing this process in the U.S. based on the geospatial availability of waste heat and slags as a Ca-source. For the base case, the cost of production of “Low-Temperature Portlandite (LTP)” is 2-to-3 times that of traditional portlandite (∼$180/tonne). The main driver of cost is the electricity demand for reverse osmosis (RO) which is used to concentrate Ca-ions in solution, and the costs of membrane replacement. Our sensitivity analysis showed that parity with the cost of production of traditional portlandite is readily achievable by selecting membranes with better durability (i.e., better pH resistance) and flux (i.e., higher permeability) without sacrificing selectivity. Significantly, LTP features an eCI that is between 40%- and - 80 % lower than its traditional counterpart when electricity is sourced from natural gas combustion or wind power, respectively. Finally, our geospatial analysis reveals that there are three areas in the U.S. with the potential for implementation of industrial-scale facilities that could produce at least 50 tonnes of pure Ca(OH)2 per day, while achieving a production cost of ∼$270 per tonne of Ca(OH)2, owing to the proximity between slag feedstocks and waste heat sources.

Summary: Metabotropic glutamate receptors (mGlu) regulate multiple functions in the nervous systems and are involved in several neurological disorders. However, selectively targeting individual mGlu subtypes with spatiotemporal precision is still an unmet need. Photopharmacology can address this concern through the utilization of photoswitchable compounds such as optogluram, which is a positive allosteric modulator (PAM) of mGlu4 that enables the precise control of physiological responses using light but does not have an optimal selectivity profile. Optogluram analogs were developed to obtain photoswitchable PAMs of mGlu4 receptor with an improved selectivity. Among them, optogluram-2 emerged as a photoswitchable ligand for mGlu4 receptor with activity as both PAM and allosteric agonists. It presents a higher selectivity and offers improved photoswitching of mGlu4 activity. These improved properties make optogluram-2 an excellent candidate to study the role of mGlu4 with a high spatiotemporal precision in systems where mGlu4 can be co-expressed with other mGlu receptors.

L’agriculture biologique (AB) représentait 10,3 % de la surface agricole française en 2021. Ce mode de production est régi par un cahier des charges européen et des principes qui, combinés à une relation privilégiée aux consommateurs, conduisent à développer des systèmes de production se distinguant généralement de ceux de l’agriculture conventionnelle. L’Agence Bio, structure de coordination nationale en charge du développement, de la promotion et de la structuration de l’AB française, gère une base de données recensant tous les opérateurs français certifiés en AB et qui alimente l’observatoire national de l’agriculture biologique (ONAB). Grâce à cette base, nous avons pu affiner la connaissance des fermes françaises entièrement engagées en AB et ayant une activité d’élevage. Après une présentation globale permettant d’identifier des grands types de fermes en fonction de leur degré de spécialisation animale et du type de production végétale associée, nous analysons huit filières de production majeures : bovins et ovins lait et viande, caprins, poules pondeuses, poulets de chair et porcs. Pour chacune, nous précisons la localisation géographique des fermes tout en tenant compte de leur dimension et de leur gradient de diversification en élevage. Cette première analyse met en évidence la forte incidence de la présence locale de filières d’élevage conventionnelles historiques ayant développé un segment AB, avec a priori des répercussions sur la dimension des ateliers et sur le niveau et le type de diversification des élevages. Ces derniers éléments semblent ainsi être en interaction avec les modes de commercialisation, en particulier de type circuit court ou circuit long.

Abstract This study aimed to explore the potential of metal oxides such as Titanate Scrolled Nanosheets (TNs) in improving the radiosensitivity of sarcoma cell lines. Enhancing the response of cancer cells to radiation therapy is crucial, and one promising approach involves utilizing metal oxide nanoparticles. We focused on the impact of exposing two human sarcoma cell lines to both TNs and ionizing radiation (IR). Our research was prompted by previous in vitro toxicity assessments, revealing a correlation between TNs' toxicity and alterations in intracellular calcium homeostasis. A hydrothermal process using titanium dioxide powder in an alkaline solution produced the TNs. Our study quantified the intracellular content of TNs and analyzed their impact on radiation-induced responses. This assessment encompassed PIXE analysis, cell proliferation, and transcriptomic analysis. We observed that sarcoma cells internalized TNs, causing alterations in intracellular calcium homeostasis. We also found that irradiation influence intracellular calcium levels. Transcriptomic analysis revealed marked disparities in the gene expression patterns between the two sarcoma cell lines, suggesting a potential cell-line-dependent nano-sensitization to IR. These results significantly advance our comprehension of the interplay between TNs, IR, and cancer cells, promising potential enhancement of radiation therapy efficiency.

Abstract This study is the first systematic survey of a large corpus of zinc white (ZnO) artists’ materials. Zinc white is a white pigment developed within the wave of 19th-century technological developments in the paint industry. The composition, particle morphology and size, and luminescence of 49 zinc white samples from artists’ materials were characterized, including three references of known synthesis methods (indirect and direct) and synthesized by the authors (ZnO nanosmoke). The corpus included historical and modern zinc white pigment powders and paint materials from the leading European and American color manufacturers. The study aims to characterize and evaluate the variability of the properties of zinc white and its paint formulations. The reference materials presented properties in agreement with the literature: indirect ZnO exhibited submicron prismoidal blue-luminescent particles of higher purity than direct ZnO, which had larger acicular green-luminescent particles. ZnO nanosmoke presented acicular (tetrapod-like) blue/green-luminescent nanoparticles. Composition, particle morphology, size, and documentary sources suggested a production via the indirect method for the analyzed corpus. However, the luminescence behavior was more complex to interpret. The fundamental emission of ZnO was not always detected, even in pure ZnO powders. Three trends were identified: smaller ZnO particles for the most recent samples; green luminescence connected to larger particle size; fewer trace elements, and of the same type (i.e., lead, sulfur) for historical materials. Another interesting finding was the detection of hydrozincite in some powders, likely a degradation product of ZnO. In terms of methodology, cathodoluminescence proved a valuable tool for pigment identification. The study provides a database of zinc white references for pigment and artwork analysis.

Air pollution is a growing threat to human health. Airborne pollution effects on respiratory, cardiovascular and skin health are well-established. The main mechanisms of air-pollution-induced health effects involve oxidative stress and inflammation. The present study evaluates the potential of a polyphenol-enriched food supplement ingredient comprising Lippia citriodora, Olea europaea, Rosmarinus officinalis, and Sophora japonica extracts in mitigating the adverse effects of environmental pollution on skin and cardiopulmonary systems. Both in vitro and ex vivo studies were used to assess the blend’s effects against pollution-induced damage. In these studies, the botanical blend was found to reduce lipid peroxidation, inflammation (by reducing IL-1α), and metabolic alterations (by regulating MT-1H, AhR, and Nrf2 expression) in human skin explants exposed to a mixture of pollutants. Similar results were also observed in keratinocytes exposed to urban dust. Moreover, the ingredient significantly reduced pollutant-induced ROS production in human endothelial cells and lung fibroblasts, while downregulating the expression of apoptotic genes (bcl-2 and bax) in lung fibroblasts. Additionally, the blend counteracted the effect of urban dust on the heart rate in zebrafish embryos. These results support the potential use of this supplement as an adjuvant method to reduce the impact of environmental pollution on the skin, lungs, and cardiovascular tissues.

We developed a novel culture-based test, the Rapid CAZ/AVI NP test, for rapid identification of ceftazidime/avibactam susceptibility/resistance in Enterobacterales. This test is based on glucose metabolization upon bacterial growth in the presence of a defined concentration of ceftazidime/avibactam (128/53 μg/mL). Bacterial growth is visually detectable by a red to yellow color change of red phenol, a pH indicator. A total of 101 well characterized enterobacterial isolates were used to evaluate the test performance. This test showed positive percent agreement of 100% and negative percent agreement of 98.5% with overall percent agreement of 99%, by comparison with the MIC gradient strip test (Etest) taken as the reference standard method. The Rapid CAZ/AVI NP test had only 1.5% major errors and 0% extremely major errors. This test is rapid (result within 2 hours 45 minutes), reliable, affordable, easily interpretable, and easy to implement in clinical microbiology laboratories without requiring any specific equipment.

Background and Aims: While the occurrence of colonic stricture in Crohn’s disease (CD) always raises concerns about the risk of cancer, the neoplastic risk associated with its stricture remains poorly known. Methods: All consecutive patients with colorectal stricture complicating CD in 3 academic centers between 1993 and 2022 were included in a retrospective cohort. We collected clinical, endoscopic, surgical, and pathology data and information on outcomes. Factors associated with neoplastic stricture were investigated by logistic regression. Results: A total of 88 patients (median age, 25 [interquartile range {IQR}, 19–37] years and median disease duration 12 [4–19] years) with 96 colorectal strictures were included. Strictures were nonpassable by the scope in 61.4% (n = 54) of cases, 70.5% (n = 62) were ulcerated, and 62.5% (n = 55) were symptomatic. Colonic resection and endoscopic balloon dilatation were needed in 47.7% (n = 42) and 28.6% (n = 12) of patients, respectively. After a median follow-up of 21.5 months (IQR [5.5–46.5]), 7 (8%) patients were diagnosed with neoplasia at the colonic stricture site (colonic adenocarcinoma, n = 5; neuroendocrine carcinoma, n = 1; and B-cell lymphoproliferative neoplasia, n = 1), with a median stricture duration at colorectal neoplasia diagnosis of 0 month (IQR [0.0–5.5]). While neoplastic strictures were diagnosed in older patients (58 vs 39 years), with longer disease duration (18 vs 11 years) and frequent obstructive symptoms (57.1% vs 11.1%), no patient-related or stricture-related factor was associated with neoplastic stricture in multivariate analysis. Conclusion: Eight percent of patients with colonic stricture complicating CD developed colorectal cancer. Colorectal cancer and stricture were often diagnosed at the same time and we did not report malignant stricture after 1 year of follow-up.

Abstract Soil fungi are a key constituent of global biodiversity and play a pivotal role in agroecosystems. How arable farming affects soil fungal biogeography and whether it has a disproportional impact on rare taxa is poorly understood. Here, we used the high-resolution PacBio Sequel targeting the entire ITS region to investigate the distribution of soil fungi in 217 sites across a 3000 km gradient in Europe. We found a consistently lower diversity of fungi in arable lands than grasslands, with geographic locations significantly impacting fungal community structures. Prevalent fungal groups became even more abundant, whereas rare groups became fewer or absent in arable lands, suggesting a biotic homogenization due to arable farming. The rare fungal groups were narrowly distributed and more common in grasslands. Our findings suggest that rare soil fungi are disproportionally affected by arable farming, and sustainable farming practices should protect rare taxa and the ecosystem services they support.

Address Resolution Protocol (ARP) spoofing has been a long-standing problem with no clear remedy until now. The attacks can be launched easily utilizing an enormous number of publicly available tools on the web; however, they are extremely tough to counterattack due to ARP’s stateless nature for not authenticating ARP replies for a subsequent request. Previous studies have demonstrated significant efforts to counterattack these assaults in Software-Defined Networks (SDN); however, much effort has been focused solely on detecting the assaults, with little effort being made to address performance bottlenecks, scalability, and Single Point of Failure (SPOF) issues in large-scale networks. In this study, we focus on developing ARP spoofing attacks detection mechanism in large-scale SDN that is immune to SPOF and provides enhanced network performance and scalability. The main purpose is to enable controllers to intercept and analyze all incoming ARP packets, learn address mappings, and store them in the application’s memory to be used as a basis for ongoing ARP cache comparisons while maintaining a global cache in a controller. To achieve the goal of this study, a simulation experiment in a closed network environment was undertaken to precisely monitor network traffic and result patterns. Mininet and the Open Network Operating System were used to implement the data plane and OpenFlow controllers. The results show that, the proposed solution is resistant to ARP spoofing attacks, with an average detection and mitigation time of 4.3 and 26.19 milliseconds, respectively. Further significant improvements have been observed in alleviating SPOF and performance bottlenecks.

Background and Aims: Early biologic therapy treatment has demonstrated better outcomes in Crohn’s disease (CD). We evaluated the impact of CD duration in patients with moderately to severely active CD treated with risankizumab therapy. Methods: This post hoc analysis evaluated clinical, endoscopic, and safety outcomes by baseline CD duration (5–10, and >10 years) in patients from ADVANCE, MOTIVATE, and FORTIFY. Pooled induction analyses included patients who received intravenous 600-mg dose of risankizumab or placebo for 12 weeks. Maintenance analyses included patients who responded to induction risankizumab and received subcutaneous 180-mg or 360-mg dose of risankizumab for 52 weeks. Duration subgroups were compared using Cochrane-Armitage trend tests with nominal P values. Results: Among 527 patients who received risankizumab 600-mg induction therapy, higher outcome rates were observed at week 12 among patients with shorter vs longer baseline disease duration (for 5–10, and >10 years, clinical remission: 42.7%, 46.9%, 43.5%, and 33.2% [P = .046]; endoscopic response: 48.3%, 36.3%, 32.0%, and 33.4% [P = .025]). Among 298 patients receiving risankizumab (180 mg or 360 mg) maintenance therapy, shorter vs longer baseline disease duration was generally associated with numerically higher endoscopic outcome rates at week 52. Higher clinical remission and endoscopic outcome rates were generally observed with shorter disease duration with 180-mg risankizumab dose only. Adverse event rates were generally similar across duration subgroups. Conclusion: Clinical benefits of risankizumab are observed across disease duration subgroups; clinical and endoscopic outcome rates are higher with risankizumab initiation earlier in the disease course (ClinicalTrials.gov numbers: NCT03105128, NCT03104413, and NCT03105102).

ABSTRACT: Objectives: To evaluate the occurrence of plasmid-mediated fos genes among fosfomycin-resistant Escherichia coli isolates collected from patients in Lisbon, Portugal, and characterize the fos-positive strains. Methods: A total of 19 186 E. coli isolates were prospectively collected between April 2022 and January 2023 from inpatients and outpatients at a private laboratory in Lisbon. Fosfomycin resistance was initially assessed by semi-automated systems and further confirmed by the disc diffusion method. Resistant isolates were investigated for plasmid-mediated fos genes (fosA1-fosA10, fosC and fosL1-fosL2) and extended-spectrum beta-lactamases (ESBLs) by PCR and sequencing. Multilocus sequence typing was performed to evaluate the clonal relationship among fos-carrying isolates. Results: Out of the 19 186 E. coli isolates, 100 were fosfomycin-resistant (0.5%), out of which 15 carried a fosA-like gene (15%). The most prevalent fosfomycin-resistant determinant was fosA3 (n = 11), followed by fosA4 (n = 4). Among the 15 FosA-producing isolates, 10 co-produced an ESBL (67%), being either of CTX-M-15 (n = 8) or CTX-M-14 (n = 2) types. The fosA3 gene was carried on IncFIIA-, IncFIB-, and IncY-type plasmids, whereas fosA4 was always located on IncFIB-type plasmids. Most FosA4-producing isolates belonged to a single sequence type ST2161, whereas isolates carrying the fosA3 gene were distributed into nine distinct genetic backgrounds. Conclusion: The prevalence of fosfomycin-resistant E. coli isolates is still low in Portugal. Notably, 15% of fosfomycin-resistant isolates harbour a transferable fosA gene, among which there is a high rate of ESBL producers, turning traditional empirical therapeutical options used in Portugal (fosfomycin and amoxicillin-clavulanic acid) ineffective.

Radiation impacting astronauts in their spacecraft come from a “bath” of high-energy rays (0.1–0.5 mGy per mission day) that reaches deep tissues like the heart and bones and a “stochastic rain” of low-energy particles from the shielding and impacting surface tissues like skin and lenses. However, these two components cannot be reproduced on Earth together. The MarsSimulator facility (Toulouse University, France) emits, thanks to a bag containing thorium salts, a continuous exposure of 120 mSv/y, corresponding to that prevailing in the International Space Station (ISS). By using immunofluorescence, we assessed DNA double-strand breaks (DSB) induced by 1–5 weeks exposure in ISS of human tissues evoked above, identified at risk for space exploration. All the tissues tested elicited DSBs that accumulated proportionally to the dose at a tissue-dependent rate (about 40 DSB/Gy for skin, 3 times more for lens). For the lens, bones, and radiosensitive skin cells tested, perinuclear localization of phosphorylated forms of ataxia telangiectasia mutated protein (pATM) was observed during the 1st to 3rd week of exposure. Since pATM crowns were shown to reflect accelerated aging, these findings suggest that a low dose rate of 120 mSv/y may accelerate the senescence process of the tested tissues. A mathematical model of pATM crown formation and disappearance has been proposed. Further investigations are needed to document these results in order to better evaluate the risks related to space exploration.

This work presents an algorithm for calculating high temperature series expansions (HTSE) of Heisenberg spin models with spin $S=1/2$ in the thermodynamic limit. This algorithm accounts for the presence of a magnetic field. The paper begins with a comprehensive introduction to HTSE and then focuses on identifying the bottlenecks that limit the computation of higher order coefficients. HTSE calculations involve two key steps: graph enumeration on the lattice and trace calculations for each graph. The introduction of a non-zero magnetic field adds complexity to the expansion because previously irrelevant graphs must now be considered: bridged graphs. We present an efficient method to deduce the contribution of these graphs from the contribution of sub-graphs, that drastically reduces the time of calculation for the last order coefficient (in practice increasing by one the order of the series at almost no cost). Previous articles of the authors have utilized HTSE calculations based on this algorithm, but without providing detailed explanations. The complete algorithm is publicly available, as well as the series on many lattice and for various interactions.

Background: Open abdomen with vacuum-assisted wound closure therapy (OA/VAC) is frequently used in critically ill patients although the impact of OA/VAC on antibiotics pharmacokinetics (PK) remains unknown. We thus aimed to characterize the PK of piperacillin–tazobactam (PTZ) in critically ill patients with OA/VAC and assess the optimal dosing regimens based on pharmacodynamics (PD) target attainment. Methods: Over a 15-month study period, 45 patients with OA/VAC treated with PTZ administered continuously and adapted to 24 h creatinine clearance (CLCR) underwent measurements of free concentrations in their plasma, urine, VAC exudate, and peritoneal fluid. Population PK modeling was performed considering the effect of covariates, and Monte Carlo simulations were employed to determine the probability of target attainment (PTA) for the PK/PD targets (100% fT > 16 mg/L) in the plasma and at the peritoneal site at steady state. Results: Piperacillin concentrations were described using a two-compartment model, with age and total body weight as significant covariates for central volume of distribution (V1) and estimated renal function for clearance (CL). Tazobactam concentrations were described using a two-compartment model with estimated renal function as a significant covariate. The central volume of distributions V1 of piperacillin and tazobactam were 21.2 and 23.2 L, respectively. The VAC-induced peritoneal clearance was negligible compared to renal clearance. Most patients achieved the desirable PK/PD target when using a CLCR-pondered PTZ dosing regimen from 12 g/1.5 g/day to 20 g/2.5 g/day. Conclusions: Despite a wide inter-individual variability, the influence of OA/VAC on piperacillin and tazobactam PK parameters is not straightforward. The use of a CLCR-pondered PTZ dosing regimen from 12 g/1.5 g/day to 20 g/2.5 g/day is needed to reach a PTA > 85%.

Anthocyanins, a class of flavonoid compounds responsible for the vibrant colors of many fruits and vegetables, have received considerable attention in recent years due to their potential health benefits. This review, focusing on evidence from both in vitro and in vivo studies, provides a comprehensive overview of the current state of knowledge regarding the health-promoting properties of anthocyanins. The chemical structure and diversity of anthocyanins, their bioavailability, and their mechanisms of action at the cellular and molecular level are examined. Research on the antioxidant, anti-inflammatory, anticancer, and neuroprotective effects of anthocyanins is critically reviewed. Special emphasis is placed on the role of anthocyanins in the prevention and treatment of chronic diseases such as cardiovascular diseases, diabetes, and neurodegenerative diseases. This review also discusses the challenges of translating in vitro findings to in vivo and highlights the importance of considering dose, bioavailability, and metabolism when assessing the therapeutic potential of anthocyanins. This review concludes with the identification of gaps in current research and suggestions for future directions for anthocyanin studies, including the need for more long-term clinical trials and investigations into potential synergistic effects with other phytochemicals. This comprehensive analysis highlights the promising role of anthocyanins in promoting human health and provides valuable insights for researchers, health professionals, and the nutraceutical industry. This study provides new insights, as it comprehensively investigates the dual anti-inflammatory and anticancer effects of anthocyanins in both in vitro and in vivo models. By uncovering the biological properties of anthocyanins from a variety of natural sources, this research not only expands our knowledge of the action of these compounds at the cellular level, but also enhances their clinical relevance through in vivo validation. Furthermore, the innovative use of anthocyanins may lead to important advances in their therapeutic application in the future.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Abstract Background Before the Coronavirus Disease 2019 (COVID-19) pandemic in France, undocumented migrants had a higher risk than general population for being admitted to the intensive care unit (ICU) because of acute respiratory failure or severe infection. Specific data concerning the impact of COVID-19 on undocumented migrants in France are lacking. We aimed to analyze the mortality and respiratory severity of COVID-19 in this specific population. We retrospectively included all undocumented adult migrants admitted in French ICUs from March 2020 through April 2021 using the French nationwide hospital information system (Programme de Médicalisation des Systèmes d’Information). We focused on admissions related to COVID-19. Undocumented migrants were compared to the general population, first in crude analysis, then after matching on age, severity and main comorbidities. The primary outcome was the ICU mortality from COVID-19. Secondary objectives were the incidence of acute respiratory distress syndrome (ARDS), the need for mechanical ventilation (MV), the duration of MV, ICU and hospital stay. Results During the study period, the rate of ICU admission among patients hospitalized for COVID-19 was higher for undocumented migrants than for general population (463/1627 (28.5%) vs. 81 813/344 001 (23.8%); p