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Context: Many hematology laboratories have adopted semi-automated digital platforms for routine use and the evidence supporting their use is increasing. Aims: The CellaVision platforms are among the most thoroughly studied digital hematology platforms; we wished to determine the accuracy of CellaVision for reticulocyte counting. Design, Materials and Methods: We compared reticulocyte counts performed manually, using the Beckman Coulter LH750 automated analyzer and with the CellaVision DM96 platform. We analyzed the results for pair-wise correlation and bias, and precision. Statistical Analyses Used: Analyses were performed using Statistical Package for the Social Sciences software (SPSS), including Spearman′s rho correlation coefficient, Friedman′s two-way Analysis Of Variance (ANOVA) for comparison of distributions; bias was compared by way of mean and standard deviation. Results: The CellaVision reticulocyte counts correlated most strongly with those of the analyzer (often considered the benchmark test); the reticulocyte count distributions were noted not to be significantly different from each other across all three methods. The mean and standard deviation of bias were lowest in the comparison of CellaVision and LH750 counts. Conclusions: Our data provide additional support for the accuracy of digital hematology applications using the CellaVision DM96 platform.

Abstract Background Deadwood decomposition is an essential ecological process in forest ecosystems, playing a key role in nutrient cycling and carbon sequestration by enriching soils with organic matter. This process is driven by diverse microbial communities encompassing specialized functions in breaking down organic matter, but the specific roles of individual microorganisms in this process are still not fully understood. Results Here, we characterized the deadwood microbiome in a natural mixed temperate forest in Central Europe using PacBio HiFi long-read sequencing and a genome-resolved transcriptomics approach in order to uncover key microbial contributors to wood decomposition. We obtained high quality assemblies, which allowed attribution of complex microbial functions such as nitrogen fixation to individual microbial taxa and enabled the recovery of metagenome-assembled genomes (MAGs) from both abundant and rare deadwood bacteria. We successfully assembled 69 MAGs (including 14 high-quality and 7 single-contig genomes) from 4 samples, representing most of the abundant bacterial phyla in deadwood. The MAGs exhibited a rich diversity of carbohydrate-active enzymes (CAZymes), with Myxococcota encoding the highest number of CAZymes and the full complement of enzymes required for cellulose decomposition. For the first time we observed active nitrogen fixation by Steroidobacteraceae, as well as hemicellulose degradation and chitin recycling by Patescibacteria. Furthermore, PacBio HiFi sequencing identified over 1000 biosynthetic gene clusters, highlighting a vast potential for secondary metabolite production in deadwood, particularly in Pseudomonadota and Myxococcota. Conclusions PacBio HiFi long-read sequencing offers comprehensive insights into deadwood decomposition processes by advancing the identification of functional features involving multiple genes. It represents a robust tool for unraveling novel microbial genomes in complex ecosystems and allows the identification of key microorganisms contributing to deadwood decomposition.

Abstract Selecting patients for phase I cancer trials is crucial to ensure a sufficient life expectancy. Frail patients, better suited for palliative care, should not be exposed to new drugs with minimal benefit. Enrolling patients at high risk of early death can jeopardize the study. Our analysis of two large precision medicine studies used tumor fraction from ctDNA to develop a predictive model, demonstrating notable predictive accuracy and aiding in patient selection.

Abstract Metastatic carcinoma of presumed renal origin (rCUP) has recently emerged as a new entity within the heterogeneous entity of Cancers of Unknown Primary (CUP) but their biological features and optimal therapeutic management remain unknown. We report the molecular characteristics and clinical outcome of a series of 25 rCUP prospectively identified within the French National Multidisciplinary Tumor Board for CUP. This cohort strongly suggests that rCUP share similarities with common RCC subtypes and benefit from renal-tailored systemic treatment. This study highlights the importance of integrating clinical and molecular data for optimal diagnosis and management of CUP.

Background Simulation-based education in healthcare encompasses a wide array of modalities aimed at providing realistic clinical experiences supported by meticulously designed scenarios. The French-speaking Society for Simulation in Healthcare (SoFraSimS) has developed guidelines to assist educators in the design of scenarios for manikin- or simulated participant- based immersive simulation and procedural simulation, the three mainly used modalities.Methods After establishing a French-speaking group of experts within the SoFraSimS network, we performed an extensive literature review with theory-informed practices and personal experiences. We used this approach identify the essential criteria for practice-based scenario design within the three simulation modalities.Results We present three comprehensive templates for creating innovative scenarios and simulation sessions, each tailored to the specific characteristics of a simulation modality. The SoFraSimS templates include five sections distributed between the three modalities. The first section contextualizes the scenario by describing the practicalities of the setting, the instructors and learners, and its connection to the educational program. The second section outlines the learning objectives. The third lists all the elements necessary during the preparation phase, describing the educational method used for procedural simulation (such as demonstration, discovery, mastery learning, and deliberate practice). The fourth section addresses the simulation phase, detailing the behaviors the instructor aims to analyze, the embedded triggers, and the anticipated impact on simulation proceedings (natural feedback). This ensures maximum control over the learning experience. Finally, the fifth section compiles elements for post-simulation modifications to enhance future iterations.Conclusion We trust that these guidelines will prove valuable to educators seeking to implement simulation-based education and contribute to the standardization of scenarios for healthcare students and professionals. This standardization aims to facilitate communication, comparison of practices and collaboration across different learning and healthcare institutions.

Abstract Acoustic cavitation bubbles drive chemical processes through their dynamic lifecycle in liquids. These bubbles are abundant within sonoreactors, where their behavior becomes complex within clusters. This study quantifies their chemical effects within well-defined clusters using a new laser-based method. We focus a laser beam into water, inducing a breakdown that generates a single cavitation bubble. This bubble undergoes multiple collapses, releasing several shockwaves. These shockwaves propagate into the surrounding medium, leading to the formation of secondary bubbles near a reflector, separated from the input laser beam. We evaluate the chemical activity of these bubble clusters of various sizes by KI dosimetry, and to gain insights into their dynamics, we employ high-speed imaging. Hydrophone measurements show that conversion from focused shockwave energy to chemical reactions increases to a maximum of 16.5%. Additional increases in shockwave energy result in denser bubble clusters and a slightly decreased conversion rate, falling to 14.9%, highlighting the key role of bubble dynamics in the transformation of mechanical to chemical energy and as a result in the efficiency of the sonoreactors. The size and frequency of bubble collapses influence the cluster’s chemical reactivity. We introduce a correlation for predicting the conversion rate of cluster energy to chemical energy, based on the cluster’s energy density. The maximum conversion rate occurs at a cluster energy density of 2500 J/L, linked to a cluster with an average bubble diameter of 91 $$\upmu$$ μ m, a bubble density of 3500 bubbles/ml, and a bubble-to-bubble distance ratio of 8.

This study aimed to analyze the ethnobotanical knowledge of ornamental plant producers in Benin for better valorization. An ethnobotanical survey was conducted through semi-structured and individual interviews with 80 individuals. In total, 78 species of ornamental plants belonging to 25 botanical families were identified. The families Euphorbiaceae (15.38%), Apocynaceae (12.82%), Araceae (11.54%), and Verbenaceae (6.41%) were the most dominant. Five categories of uses were identified for ornamental plants in Benin, including aesthetic or decorative, psycho-magical, therapeutic, cosmetic, and food uses. Among these, aesthetic or decorative use of ornamental plants was widely recognized by producers (100% of surveyed producers), followed by use for psycho-magical purposes (45.7% of respondents). The frequency of citation of different categories of use varied according to the gender, age, ethnic group, and educational level of the interviewed producers. Ethnic group and educational level significantly influenced the ethnobotanical knowledge of ornamental plant producers. The first species showing a strong potential for ethnobotanical use were Citrus aurantiifolia (UVI = 10.78), Lippia multiflora (UVI = 9.70), Ocimum basilicum (UVI = 9.03), Verbena bonariensis (UVI = 8.14), Dracaena braunii (UVI = 8.08). These results can be considered as an important source of information for the management of the ornamental plant sector in Benin.

Introduction: Blood flow produces fluid shear stress (SS), a frictional force parallel to the blood flow, on the endothelial cell (EC) layer of the lumen of the vessels. ECs themselves are sensitive to this frictional force in terms of directionality and intensity. The aim of this study was to determine the physiological shear stress value during the cardiac cycle and EC polarity and orientation from blood flow in healthy male and female mouse carotid artery.Methods: Experimentation is done on anesthetized male and female 8-week-old C5BL/6J mice. In vivo measurements of maximum blood velocity and vessel diameter in diastole and systole were performed on the right common carotid artery by Doppler ultrasound imaging. Blood viscosity (total and plasmatic) and hematocrit were determined on blood samples. For SS calculation, we developed a new method assuming heterogenous blood flow, i.e., a red cell central plug flow surrounded by a peripheral plasma sheath flow, and computing SS from vessel diameter and hemodynamical measurements (maximal blood velocity, hematocrit and plasmatic viscosity).Results: Results were compared with the classical method assuming a homogenous blood flow with constant apparent total blood viscosity. EC polarity and orientation were determined ex vivo on the carotid endothelium by confocal imaging after labeling of the EC nucleus and Golgi apparatus. Diastolic and systolic SS were 6 ± 2.5 Pa and 30 ± 6.5 Pa, respectively. Total blood and plasmatic viscosity was 4 ± 0.5 cP and 1.27 cP, respectively. ECs were polarized and significantly oriented against blood flow. No sex difference was identified.

Background Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking.Methods We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis.Results Overall, NRs exhibited drastically lower CD8+, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3).Conclusions These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.

Abstract Background High prostate eicosapentaenoic fatty acid (EPA) levels were associated with a significant reduction of upgrading to grade group (GG) ≥ 2 prostate cancer in men under active surveillance. We aimed to evaluate the effect of MAG-EPA long-chain omega-3 fatty acid dietary supplement on prostate cancer proliferation. Methods A phase II double-blind randomized placebo-controlled trial was conducted in 130 men diagnosed with GG ≥ 2 prostate cancer and undergoing radical prostatectomy between 2015–2017 (Clinicaltrials.gov: NCT02333435). Participants were randomized to receive 3 g daily of either MAG-EPA (n = 65) or placebo (n = 65) for 7 weeks (range 4–10) prior to radical prostatectomy. The primary outcome was the cancer proliferation index quantified by automated image analysis of tumor nuclear Ki-67 expression using standardized prostatectomy tissue microarrays. Additional planned outcomes at surgery are reported including plasma levels of 27 inflammatory cytokines and fatty acid profiles in circulating red blood cells membranes and prostate tissue. Results Cancer proliferation index measured by Ki-67 expression was not statistically different between the intervention (3.10%) and placebo (2.85%) groups (p = 0.64). In the per protocol analyses, the adjusted estimated effect of MAG-EPA was greater but remained non-significant. Secondary outcome was the changes in plasma levels of 27 cytokines, of which only IL-7 was higher in MAG-EPA group compared to placebo (p = 0.026). Men randomized to MAG-EPA prior to surgery had four-fold higher EPA levels in prostate tissue compared to those on placebo. Conclusions This MAG-EPA intervention did not affect the primary outcome of prostate cancer proliferation according to nuclear Ki-67 expression. More studies are needed to decipher the effects of long-chain omega-3 fatty acid dietary supplementation in men with prostate cancer.

Abstract Background Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the β-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience. Results While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the structure of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The observed richness of the antibiotic resistance genes repertoire was significantly reduced up to day 30, while a significant increase in the relative abundance of β-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the β-lactamase activity of the microbiota. The level of β-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools. Conclusions In healthy adults, antibiotics perturb many components of the microbiota, which return close to the baseline state within 30 days. These data suggest an important role of endogenous β-lactamase-producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon. Video Abstract

Abstract Background Infliximab is currently recommended as a third-line treatment for refractory sarcoidosis. Data in function of clinical phenotype are currently lacking. We evaluated patients’ characteristics and responses to infliximab according to their GenPhenReSa cluster. Methods We evaluated clinical and biological characteristics of patients diagnosed with sarcoidosis who received infliximab between September 2008 and April 2019 at our centre. Results Fifty-five patients (median disease duration, 87 months) received infliximab: 48 (87%) as a second- or third-line treatment, and 7 (13%) as a first-line treatment. After a median duration of 12 months, 24 (45%) and 14 (25%) patients achieved complete and partial responses, respectively, together with a significant decrease in the number of affected organs and tapering of steroid doses. All patients with neurosarcoidosis (OR 17), 90% in group 2 (ocular-cardiac-cutaneous-CNS, OR 7.4), and approximately two-thirds of those in groups 1 (abdominal organs), 4 (pulmonary-lympho-nodal), and 5 (extrapulmonary), achieved a response, whereas patients in group 3 (musculoskeletal-cutaneous) had a treatment-failure OR of 9. Infliximab could be stopped after complete remission was achieved in 7 patients: 4 relapsed after a median of 6 months. Overall, 36% of patients experienced serious adverse events, mainly infections, which led to treatment cessation in 29% of patients and caused two deaths. Conclusions Other than patients with musculoskeletal-cutaneous involvement (group 3), infliximab led to a good response for patients with CNS (group 2) and liver (group 1) organ-predominant sarcoidosis. However, it led to serious infections and merely suspended sarcoidosis, so further research on factors predictive of relapse is needed.

Abstract Next-generation sequencing (NGS) assays based on plasma cell-free DNA (cfDNA) are increasingly used for clinical trials inclusion. Their optimized limit of detection applied to a large number of genes leads to the identification of mutations not confirmed in tissue. It becomes essential to describe the characteristics and consequences of these liquid biopsy-only mutations. In the STING protocol (Gustave Roussy, NCT04932525), 542 patients with advanced solid cancer had cfDNA-based and tissue-based NGS analysis (performed by FoundationOne® Liquid CDx and FoundationOne CDx™, respectively). Mutations identified in the liquid biopsy but not in the paired tissue were considered as liquid biopsy-only mutations irrespective of their variant allelic frequency (VAF). Out of 542 patients, 281 (51.8%) harbored at least one liquid biopsy-only mutation. These patients were significantly older, and more heavily pretreated. Liquid biopsy-only mutations occurring in TP53, and in DDR genes (ATM, CHEK2, ATR, BRCA2, and BRCA1) accounted for 90.8% of all the mutations. The median VAF of these mutations was generally low (0.37% and 0.40% for TP53 and DDR genes respectively). The variant type repartition depended on the gene. Liquid biopsy-only mutations affected hotspot in TP53 codon 273, 125, 195, 176, 237 or 280 and ATM codon 2891 and 3008. In a subset of 37 patients, 75.0%, 53.5% and 83.3% of the liquid biopsy-only mutations occurring respectively in ATM, TP53, and CHEK2 were confirmed in the matching whole blood sample. Although liquid biopsy-only mutations makes the interpretation of liquid biopsy results more complex, they have distinct characteristics making them more easily identifiable.

Precision Medicine is being increasingly used in the developed world to improve health care. While several Precision Medicine (PM) initiatives have been launched worldwide, their implementations have proven to be more challenging particularly in low- and middle-income countries. To address this issue, the “Personalized Medicine in North Africa” initiative (PerMediNA) was launched in three North African countries namely Tunisia, Algeria and Morocco. PerMediNA is coordinated by Institut Pasteur de Tunis together with the French Ministry for Europe and Foreign Affairs, with the support of Institut Pasteur in France. The project is carried out along with Institut Pasteur d’Algérie and Institut Pasteur du Maroc in collaboration with national and international leading institutions in the field of PM including Institut Gustave Roussy in Paris. PerMediNA aims to assess the readiness level of PM implementation in North Africa, to strengthen PM infrastructure, to provide workforce training, to generate genomic data on North African populations, to implement cost effective, affordable and sustainable genetic testing for cancer patients and to inform policy makers on how to translate research knowledge into health products and services. Gender equity and involvement of young scientists in this implementation process are other key goals of the PerMediNA project.In this paper, we are describing PerMediNA as the first PM implementation initiative in North Africa. Such initiatives contribute significantly in shortening existing health disparities and inequities between developed and developing countries and accelerate access to innovative treatments for global health.

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