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Abstract Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells and derive multiple stable clones with various degrees of aneuploidy. We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics. Concomitantly, we functionally interrogate their cellular vulnerabilities, using genome-wide CRISPR/Cas9 and large-scale drug screens. Aneuploid clones activate the DNA damage response and are more resistant to further DNA damage induction. Aneuploid cells also exhibit elevated RAF/MEK/ERK pathway activity and are more sensitive to clinically-relevant drugs targeting this pathway, and in particular to CRAF inhibition. Importantly, CRAF and MEK inhibition sensitize aneuploid cells to DNA damage-inducing chemotherapies and to PARP inhibitors. We validate these results in human cancer cell lines. Moreover, resistance of cancer patients to olaparib is associated with high levels of RAF/MEK/ERK signaling, specifically in highly-aneuploid tumors. Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, and reveals a therapeutically-relevant cellular dependency of aneuploid cells.

Abstract Background Nitric oxide (NO) is a strong vasodilator, selectively directed on pulmonary circulation through inhaled administration. In adult intensive care units (ICU), it is mainly used for refractory hypoxemia in mechanically ventilated patients. Several medical delivery devices have been developed to deliver inhaled nitric oxide (iNO). The main purpose of those devices is to guarantee an accurate inspiratory NO concentration, whatever the ventilator used, with NO2 concentrations lower than 0.3 ppm. We hypothesized that the performances of the different available iNO delivery systems could depend on their working principle and could be influenced by the ventilator settings. The objective of this study was to assess the accuracy of seven different iNO-devices combined with different ICU ventilators’ flow-by to reach inspiratory NO concentration targets and to evaluate their potential risk of toxicity. Methods We tested seven iNO-devices on a test-lung connected to distinct ICU ventilators offering four different levels of flow-by. We measured the flow in the inspiratory limb of the patient circuit and the airway pressure. The nitric oxide/nitrogen (NO/N2) flow was measured on the administration line of the iNO-devices. NO and NO2 concentrations were measured in the test-lung using an electrochemical analyzer. Results We identified three iNO-device generations based on the way they deliver NO flow: “Continuous”, “Sequential to inspiratory phase” (I-Sequential) and “Proportional to inspiratory and expiratory ventilator flow” (Proportional). Median accuracy of iNO concentration measured in the test lung was 2% (interquartile range, IQR -19; 36), -23% (IQR -29; -17) and 0% (IQR -2; 0) with Continuous, I-Sequential and Proportional devices, respectively. Increased ventilator flow-by resulted in decreased iNO concentration in the test-lung with Continuous and I-Sequential devices, but not with Proportional ones. NO2 formation measured to assess potential risks of toxicity never exceeded the predefined safety target of 0.5 ppm. However, NO2 concentrations higher than or equal to 0.3 ppm, a concentration that can cause bronchoconstriction, were observed in 19% of the different configurations. Conclusion We identified three different generations of iNO-devices, based on their gas administration modalities, that were associated with highly variable iNO concentrations’ accuracy. Ventilator’s flow by significantly impacted iNO concentration. Only the Proportional devices permitted to accurately deliver iNO whatever the conditions and the ventilators tested.

Abstract Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations’ occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.

Stimulated Brillouin scattering offers a broad range of applications, including lasers, sensors, and microwave photonics, most of which require strong Brillouin gain within a narrow bandwidth. Here, we experimentally report the first measurement of stimulated Brillouin scattering in silica optical nanofibers from both hybrid and surface acoustic waves. Using a pump–probe technique in the radio frequency domain, we measured a Brillouin gain as high as 15 m−1 W−1 and linewidth to 16 MHz for the L03 hybrid acoustic mode near 9 GHz using a 990-nm diameter nanofiber. This gain is 65 times larger than the highest gain obtained in standard single-mode fibers. In addition, we report a Brillouin gain of up to 5 m−1 W−1 from surface acoustic waves around 5 GHz. We further demonstrate a nanofiber-based Brillouin laser with a threshold of 350 mW. Our results create opportunities for advanced Brillouin-based applications utilizing optical nanofibers.

Summary: Activating EGFR (epidermal growth factor receptor) mutations can be inhibited by specific tyrosine kinase inhibitors (TKIs), which have changed the landscape of lung cancer therapy. However, due to secondary mutations and bypass receptors, such as AXL (AXL receptor tyrosine kinase), drug resistance eventually emerges in most patients treated with the first-, second-, or third-generation TKIs (e.g., osimertinib). To inhibit AXL and resistance to osimertinib, we compare two anti-AXL drugs, an antibody (mAb654) and a TKI (bemcentinib). While no pair of osimertinib and an anti-AXL drug is able to prevent relapses, triplets combining osimertinib, cetuximab (an anti-EGFR antibody), and either anti-AXL drug are initially effective. However, longer monitoring uncovers superiority of the mAb654-containing triplet, possibly due to induction of receptor endocytosis, activation of immune mechanisms, or disabling intrinsic mutators. Hence, we constructed a bispecific antibody that engages both AXL and EGFR. When combined with osimertinib, the bispecific antibody consistently inhibits tumor relapses, which warrants clinical trials.

Music reading is the key to literacy for musicians in the Western music tradition. This high-level activity requires an efficient extraction of the visual information from the score to the current needs of the execution. Differences in eye movements between expert and non-expert musicians during music reading have been shown. The present study goes further, using a machine learning approach to classify musicians according to their level of expertise in analyzing their eye movements and performance during sight-reading. We used a support vector machine (SVM) technique to (a) investigate whether the underlying expertise in musical reading could be reliably inferred from eye movements, performance, and subjective measures collected across five levels of expertise and (b) determine the best predictors for classifying expertise from 24 visual measures (e.g., the number of progressive fixations, the number of regressive fixations, pupil size, first-pass fixations, and second-pass fixations), 10 performance measures (e.g., eye–hand span, velocity, latency, play duration, tempo, and false notes), and 4 subjective measures (perceived complexity and cognitive skills). Eye movements from 68 pianists at five different levels of music expertise (according to their level in the conservatory of music—from first cycle to professional) were co-registered with their piano performance via a Musical Instrument Digital Interface, while they sight-read classical and contemporary music scores. Results revealed relevant classifications based on the SVM analysis. The model optimally classified the lower levels of expertise (1 and 2) compared to the higher levels (3, 4, and 5) and the medium level (3) compared to higher levels (4 and 5). Furthermore, across a total of 38 measures, the model identified the four best predictors of the level of expertise: the sum of fixations by note, the number of blinks, the number of fixations, and the average fixation duration. Thus, efficiently classifying musical reading expertise from musicians' eye movements and performance using SVM is possible. The results have important theoretical and practical implications for music cognition and pedagogy, enhancing the specialized eye and performance behaviors required for an expert music reading.

The SunoCaps dataset aims to provide an innovative contribution to music data. Expert description of human-made musical pieces, from the widely used MusicCaps dataset, are used as prompts for generating complete songs for this dataset. This Automatic Music Generation is done with the state-of-the-art Suno generator of audio-based music. A subset of 64 pieces from MusicCaps is currently included, with a total of 256 generated entries. This total stems from generating four different variations for each human piece; two versions based on the original caption and two versions based on the original aspect description.As an AI-generated music dataset, SunoCaps also includes expert-based information on prompt alignment, with the main differences between prompt and final generation annotated. Furthermore, annotations describing the main discrete emotions induced by the piece. This dataset can have an array of implementations, such as creating and improving music generation validation tools, training systems for multi-layered architectures and the optimization of music emotion estimation systems.

We hypothesize that the fundamental difference between expert and learner musicians is the capacity to efficiently integrate cross-modal information. This capacity might be an index of an expert memory using both auditory and visual cues built during many years of learning and extensive practice. Investigating this issue through an eye-tracking experiment, two groups of musicians, experts and non-experts, were required to report whether a fragment of classical music, successively displayed both auditorily and visually on a computer screen (cross-modal presentation) was same or different. An accent mark, associated on a particular note, was located in a congruent or incongruent way according to musical harmony rules, during the auditory and reading phases. The cross-modal competence of experts was demonstrated by shorter fixation durations and less errors. Accent mark appeared for non-experts as interferences and lead to incorrect judgments. Results are discussed in terms of amodal memory for expert musicians that can be supported within the theoretical framework of Long-Term Working Memory (Ericsson and Kintsch, 1995).

Invasive fusariosis can be life-threatening, especially in immunocompromised patients who require intensive care unit (ICU) admission. We conducted a multicenter retrospective study to describe clinical and biologic characteristics, patient outcomes, and factors associated with death and response to antifungal therapy. We identified 55 patients with invasive fusariosis from 16 ICUs in France during 2002­–­­2020. The mortality rate was high (56%). Fusariosis-related pneumonia occurred in 76% of patients, often leading to acute respiratory failure. Factors associated with death included elevated sequential organ failure assessment score at ICU admission or history of allogeneic hematopoietic stem cell transplantation or hematologic malignancies. Neither voriconazole treatment nor disseminated fusariosis were strongly associated with response to therapy. Invasive fusariosis can lead to multiorgan failure and is associated with high mortality rates in ICUs. Clinicians should closely monitor ICU patients with a history of hematologic malignancies or stem cell transplantation because of higher risk for death.

IntroductionThe goal of the present study was to test the effect of signaling associated with feed-back in learning forest ecosystems in the context of realistic living forest simulator, in IVR conditions for students in agriculture. Two signaling modalities, corresponding to two signaling levels, were investigated: visual flashing of forest elements (tree species, plants, flowers, fungi, wet-areas etc.) and marker-stones, both with text in pop-up windows, in a 2x2 experimental plan.MethodsNinety-three pupils of an agricultural technological high school had to explore (including physically), interrogate (search for) and select (using the joysticks) relevant elements of the forest in three living forest areas (visually delimited inside of a broader forest area) in order to choose (and justify) the best area, among the three, in which an equipped public-tourist reception site (picnic, resting, reception site) could be built. The chosen site must have the least possible negative impact on the ecosystem of the forest and its development over time. After their decision (and justification) they were provided a feed-back with a series of VR desktop multimedia slides showing the effect of this choice on the ecosystem of the chosen area. After the feed-back they had to decide and justify again whether they would change or maintain their first decision. Finally, subjective scales were also used in order to investigate presence, cognitive complexity, sickness and overall enjoyment.Results and discussionResults showed significant positive effects of both signaling levels, and of the feed-back on the correct decision answers. Further, the combination, and interaction, between signaling and feedback seemed to enhance, the activation and retrieval from memory, of the task-relevant concepts. In addition, the results indicated a significant positive effect (medium size) of presence on decision performances, a finding which is consistent with the immersion principle.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Hemophagocytic lymphohistiocytosis (HLH) syndrome is an uncontrolled activation of macrophages, causing multiorgan dysfunction. The prognosis depends on the cause and the delay of diagnosis and treatment. Several infections can cause HLH, including rickettsia, a gram-negative bacterium. The diagnosis of rickettsia is based on clinical signs, including fever, headache, rash and sometimes tick bite site. The importance of an early diagnosis of rickettsia is the key. We present a case of rickettsia infection complicated with severe HLH occurring in a 21-year-old woman. The diagnosis was confirmed by serology 4 weeks after admission. She was treated with immunoglobulin, corticosteroids, and doxycycline with a favorable outcome.

This work aims to study the existing results of mild solutions for a semi-linear Atangana-Baleanu-Caputo fractional differential equation with order $ 0 < \theta < 1 $ in an arbitrary Banach space. We rely on some arguments to present the mild solution to our problem in terms of an $ \theta $-resolvent family. Then we study the existence of this mild solution by using Krasnoselskii's fixed point theorem. Finally, we give an example to prove our results.

This study aimed to evaluate the impact of three two-dimensional (2D) mammographic acquisition techniques on image quality and radiation dose in the presence of silicone breast implants (BIs). Then, we propose and validate a new International Atomic Energy Agency (IAEA) phantom to reproduce these techniques. Images were acquired on a single Hologic Selenia Dimensions® unit. The mammography of the left breast of a single clinical case was included. Three methods of image acquisition were identified. They were based on misused, recommended, and reference settings. In the clinical case, image criteria scoring and the signal-to-noise ratio on breast tissue (SNRBT) were determined for two 2D projections and compared between the three techniques. The phantom study first compared the reference and misused settings by varying the AEC sensor position and, second, the recommended settings with a reduced current-time product (mAs) setting that was 13% lower. The signal-difference-to-noise ratio (SDNR) and detectability indexes at 0.1 mm (d’ 0.1 mm) and 0.25 mm (d’ 0.25 mm) were automatically quantified using ATIA software. Average glandular dose (AGD) values were collected for each acquisition. A statistical analysis was performed using Kruskal–Wallis and corrected Dunn tests (p < 0.05). The SNRBT was 2.6 times lower and the AGD was −18% lower with the reference settings compared to the recommended settings. The SNRBT values increased by +98% with the misused compared to the recommended settings. The AGD increased by +79% with the misused settings versus the recommended settings. The median values of the reference settings were 5.8 (IQR 5.7–5.9), 1.2 (IQR 0.0), 7.0 (IQR 6.8–7.2) and 1.2 (IQR 0.0) mGy and were significantly lower than those of the misused settings (p < 0.03): 7.9 (IQR 6.1–9.7), 1.6 (IQR 1.3–1.9), 9.2 (IQR 7.5–10.9) and 2.2 (IQR 1.4–3.0) mGy for the SDNR, d’ 0.1 mm, d’ 0.25 mm and the AGD, respectively. A comparison of the recommended and reduced settings showed a reduction of −6.1 ± 0.6% (p = 0.83), −7.7 ± 0.0% (p = 0.18), −6.4 ± 0.6% (p = 0.19) and −13.3 ± 1.1% (p = 0.53) for the SDNR, d’ 0.1 mm, d’ 0.25 mm and the AGD, respectively. This study showed that the IAEA phantom could be used to reproduce the three techniques for acquiring 2D mammography images in the presence of breast implants for raising awareness and for educational purposes. It could also be used to evaluate and optimize the manufacturer’s recommended settings.

The purpose of the study was to assess the performance of readers in diagnosing thoracic anomalies on standard chest radiographs (CXRs) with and without a deep-learning-based AI tool (Rayvolve) and to evaluate the standalone performance of Rayvolve in detecting thoracic pathologies on CXRs. This retrospective multicentric study was conducted in two phases. In phase 1, nine readers independently reviewed 900 CXRs from imaging group A and identified thoracic abnormalities with and without AI assistance. A consensus from three radiologists served as the ground truth. In phase 2, the standalone performance of Rayvolve was evaluated on 1500 CXRs from imaging group B. The average values of AUC across the readers significantly increased by 15.94%, with AI-assisted reading compared to unaided reading (0.88 ± 0.01 vs. 0.759 ± 0.07, p < 0.001). The time taken to read the CXRs decreased significantly, by 35.81% with AI assistance. The average values of sensitivity and specificity across the readers increased significantly by 11.44% and 2.95% with AI-assisted reading compared to unaided reading (0.857 ± 0.02 vs. 0.769 ± 0.02 and 0.974 ± 0.01 vs. 0.946 ± 0.01, p < 0.001). From the standalone perspective, the AI model achieved an average sensitivity, specificity, PPV, and NPV of 0.964, 0.844, 0.757, and 0.9798. The speed and performance of the readers improved significantly with AI assistance.

Purpose: The aim of this study is to evaluate the influence of explanatory texts characteristics on comprehension performances in children from 2nd to 9th grade. Method: Several metrics have been applied to 40 explanatory texts, accounting for length, complexity and age accuracy. Children were asked to read an age-appropriate text, and answer questions evaluating surface, semantic and inferential dimensions of comprehension. Results: Results revealed that all group age obtained similar performances on surface questions, but younger children performed poorly in semantic and inferential questions in comparison to older ones, suggesting a weaker ability to rely on previous knowledge. Comprehension performances were also modulated by text characteristics. Principal Components Analysis identified metrics accounting for text coherence, namely number of words, word length and word frequency with 75% of variance explained. Multiple Regression Analysis allowed us to identify sentence length and word length as predictors of performances obtained at the surface and inferential questions. Conclusion: this research provides interesting evidence to increase our comprehension of explanatory text comprehension in French language for different grades. The results obtained should also be useful to develop further researches using text characteristics to predict readers' comprehension performances.

Pregnancy-related complications (PRC) impact maternal and fetal morbidity and mortality and place a huge burden on healthcare systems. Thus, effective diagnostic screening strategies are crucial. Currently, national and international guidelines define patients at low risk of PRC exclusively based on their history, thus excluding the possibility of identifying patients with de novo risk (patients without a history of disease), which represents most women. In this setting, previous studies have underlined the potential contribution of non-coding RNAs (ncRNAs) to detect patients at risk of PRC. However, placenta biopsies or cord blood samples are required, which are not simple procedures. Our review explores the potential of ncRNAs in biofluids (fluids that are excreted, secreted, or developed because of a physiological or pathological process) as biomarkers for identifying patients with low-risk pregnancies. Beyond the regulatory roles of ncRNAs in placental development and vascular remodeling, we investigated their specific expressions in biofluids to determine favorable pregnancy outcomes as well as the most frequent pathologies of pregnant women. We report distinct ncRNA panels associated with PRC based on omics technologies and subsequently define patients at low risk. We present a comprehensive analysis of ncRNA expression in biofluids, including those using next-generation sequencing, shedding light on their predictive value in clinical practice. In conclusion, this paper underscores the emerging significance of ncRNAs in biofluids as promising biomarkers for risk stratification in PRC. The investigation of ncRNA expression patterns and their potential clinical applications is of diagnostic, prognostic, and theragnostic value and paves the way for innovative approaches to improve prenatal care and maternal and fetal outcomes.

IntroductionCryoglobulinemic vasculitis is a type of small vessel vasculitis diseases that can cause dysfunction in multiple organs. It is characterized by general symptoms, often accompanied by nonspecific cutaneous, articular, neurological, and renal manifestations. Diagnosing cryoglobulinemia through biological testing can be time-consuming and sometimes yields negative results, making diagnosis challenging. There are also other potentially life-threatening complications that can significantly impact prognosis and delay urgent treatment, including digestive manifestations and heart failure.Case presentationWe report the case of a 60-year-old male patient with a medical history of rheumatoid arthritis. He was admitted to the Nephrology Department for investigation of necrotic vascular purpura, acute kidney injury, and pancytopenia. Laboratory tests revealed consumption of the C3 and C4 complement fractions and the presence of mixed-type III cryoglobulinemia. Despite the initiation of the treatment, the patient rapidly developed multiple severe organ failures, including renal, cardiac, respiratory, and finally digestive complications. Acute colic ischemia led to emergency surgery and the patient was transferred to the Intensive Care Unit. Despite surgical intervention and hemodynamic support, the patient experienced multi-visceral organ failure and died two hours after admission.DiscussionMixed cryoglobulinemia vasculitis may result in rare cases of acute and life-threatening organ damage, such as cardiac or respiratory failure with pulmonary hemorrhage, gastrointestinal ischemia, and neurological disorders. These severe manifestations are associated with a poor prognosis and it is crucial to promptly initiate an aggressive therapeutic strategy.

We report the observation of Brillouin backscattering in a 50-cm long spiral high-index doped silica chip waveguide and measured a Brillouin frequency shift of 16 GHz which is in very good agreement with theoretical predictions and numerical simulations based on the elastodynamics equation. © 2023.

Background: Using easy-to-determine bedside measurements, we developed an echocardiographic algorithm for predicting left ventricular ejection fraction (LVEF) and longitudinal strain (LVLS) in patients with septic shock. Methods: We measured septal and lateral mitral annular plane systolic excursion (MAPSE), septal and lateral mitral S-wave velocity, and the left ventricular longitudinal wall fractional shortening in patients with septic shock. We used a conditional inference tree method to build a stratification algorithm. The left ventricular systolic dysfunction was defined as an LVEF

Abstract Aims This study sought to describe and evaluate the impact of a routine in‐hospital cardiac resynchronization therapy (CRT) programme, including comprehensive heart failure (HF) evaluation and systematic echo‐guided CRT optimization. Methods and results CRT implanted patients were referred for optimization programme at 3 to 12 months from implantation. The program included clinical and biological status, standardized screening for potential cause of CRT non‐response and systematic echo‐guided atrioventricular and interventricular delays (AVd and VVd) optimization. Initial CRT‐response and improvement at 6 months post‐optimization were assessed with a clinical composite score (CCS). Major HF events were tracked during 1 year after optimization. A total of 227 patients were referred for CRT optimization and enrolled (71 ± 11 years old, 77% male, LVEF 30.6 ± 7.9%), of whom 111 (48.9%) were classified as initial non‐responders. Left ventricular lead dislodgement was noted in 4 patients (1.8%), and loss or ≤90% biventricular capture in 22 (9.7%), mostly due to arrhythmias. Of the 196 patients (86%) who could undergo echo‐guided CRT optimization, 71 (36.2%) required VVd modification and 50/144 (34.7%) AVd modification. At 6 months post‐optimization, 34.3% of the initial non‐responders were improved according to the CCS, but neither AVd nor VVd echo‐guided modification was significantly associated with CCS‐improvement. After one‐year follow‐up, initial non‐responders maintained a higher rate of major HF events than initial responders, with no significant difference between AVd/VVd modified or not. Conclusions Our study supports the necessity of a close, comprehensive and multidisciplinary follow‐up of CRT patients, without arguing for routine use of echo‐guided CRT optimization.

ObjectivesTo evaluate extracellular vesicles levels in a cohort of SARS-CoV-2’s patients hospitalized in an intensive care unit with and without COVID-19 associated thromboembolic events.MethodsIn this study, we aim to assess endothelial and platelet membrane-derived extracellular vesicles levels in a cohort of SARS-CoV-2 patients with and without COVID-19-associated thromboembolic events who were hospitalized in an intensive care unit. Annexin-V positive extracellular vesicles levels were prospectively assessed by flow cytometry in one hundred twenty-three critically ill adults diagnosed with acute respiratory distress syndrome associated with a SARS-CoV-2 infection, ten adults diagnosed for moderate SARS-CoV-2 infection and 25 healthy volunteers.ResultsOn our critically ill patients, thirty-four patients (27.6%) had a thromboembolic event, Fifty-three (43%) died. Endothelial and platelet membrane-derived extracellular vesicles were drastically increased in SARS-CoV-2 patients hospitalized in the ICU compared to healthy volunteers. Moreover a slighty higher small/large ratio for platelets membrane-derived extracellular vesicles in patients was linked to thrombo-embolic events.ConclusionA comparison between total annexin-V positive extracellular vesicles levels in severe and moderate SARS-CoV-2 infection and healthy controls showed a significant increase in patients with severe infection and their sizes could be considered as biomarkers of SARS-CoV-2 associated thrombo-embolic events.

The therapeutic management of Crohn’s disease (CD), a chronic relapsing–remitting inflammatory bowel disease (IBD), is highly challenging. Surgical resection is sometimes a necessary procedure even though it is often associated with postoperative recurrences (PORs). Tofacitinib, an orally active small molecule Janus kinase inhibitor, is an anti-inflammatory drug meant to limit PORs in CD. Whereas bidirectional interactions between the gut microbiota and the relevant IBD drug are crucial, little is known about the impact of tofacitinib on the gut microbiota. The HLA-B27 transgenic rat is a good preclinical model used in IBD research, including for PORs after ileocecal resection (ICR). In the present study, we used shotgun metagenomics to first delineate the baseline composition and determinants of the fecal microbiome of HLA-B27 rats and then to evaluate the distinct impact of either tofacitinib treatment, ileocecal resection or the cumulative effect of both interventions on the gut microbiota in these HLA-B27 rats. The results confirmed that the microbiome of the HLA-B27 rats was fairly different from their wild-type littermates. We demonstrated here that oral treatment with tofacitinib does not affect the gut microbial composition of HLA-B27 rats. Of note, we showed that ICR induced an intense loss of bacterial diversity together with dramatic changes in taxa relative abundances. However, the oral treatment with tofacitinib neither modified the alpha-diversity nor exacerbated significant modifications in bacterial taxa induced by ICR. Collectively, these preclinical data are rather favorable for the use of tofacitinib in combination with ICR to address Crohn’s disease management when considering microbiota.

The proximity of obstacles in a ventilation network can result in a significant increase of the noise production. In this paper, a tandem diaphragm inserted in a rigid duct with rectangular cross section is investigated and compared to a single diaphragm obstruction. The disturbed flow which reaches the second obstacle causes an amplification of the radiated noise which goes beyond a simple doubling of the power. Experimental results, carried with various spacing between the two diaphragms and bulk velocity, allows identifying other aeroacoustic source mechanisms which does not appear with a single diaphragm. Depending on the configuration, the broadband level can increase by more than 10 dB and feedback phenomena can appear at low frequency. Explanations and illustrations of those phenomena are given thanks to compressible-fluid simulations.

Abstract One of the major events in animal morphogenesis is the emergence of a polar body axis. Here, we combine classic grafting techniques with live imaging to explore the plasticity of polarity determination during whole body regeneration in Hydra. Composite tissues are made by fusing two rings, excised from separate animals, in different configurations that vary in the polarity and original positions of the rings along the body axes of the parent animals. Under frustrating initial configurations, body axis polarity that is otherwise stably inherited from the parent animal, can become labile and even be reversed. Importantly, the site of head regeneration exhibits a strong bias toward the edges of the tissue, even when this involves polarity reversal. In particular, we observe head formation at an originally aboral tissue edge, which is not compatible with models of Hydra regeneration based only on preexisting morphogen gradients or an injury response. The site of the new head invariably contains an aster-like defect in the organization of the supra-cellular ectodermal actin fibers. While a defect is neither required nor sufficient for head formation, we show that the defect at the new head site can arise via different routes, either appearing directly following excision as the tissue seals at its edge or through de novo defect formation at the fusion site. Altogether, our results show that the emergence of a polar body axis depends on the original polarity and position of the excised tissues as well as structural factors, suggesting that axis determination is an integrated process that arises from the dynamic interplay of multiple biochemical and mechanical processes.

Abstract Background The modulation of perioperative inflammation seems crucial to improve postoperative morbidity and cancer-related outcomes in patients undergoing oncological surgery. Data from the literature suggest that perioperative corticosteroids decrease inflammatory markers and might be associated with fewer complications in esophageal, liver, pancreatic and colorectal surgery. Their benefit on cancer-related outcomes has not been assessed. Methods The CORTIFRENCH trial is a phase III multicenter randomized double-blind placebo-controlled trial to assess the impact of a flash dose of preoperative corticosteroids versus placebo on postoperative morbidity and cancer-related outcomes after elective curative-intent surgery for digestive cancer. The primary endpoint is the frequency of patients with postoperative major complications occurring within 30 days after surgery (defined as all complications with Clavien-Dindo grade > 2). The secondary endpoints are the overall survival at 3 years, the disease-free survival at 3 years, the frequency of patients with intraabdominal infections and postoperative infections within 30 days after surgery and the hospital length of stay. We hypothesize a reduced risk of major complications and a better disease-survival at 3 years in the experimental group. Allowing for 5% of drop-out, 1 200 patients (600 per arm) should be included. Discussion This will be the first trial focusing on the impact of perioperative corticosteroids on cancer related outcomes. If significant, it might be a strong improvement on oncological outcomes for patients undergoing surgery for digestive cancers. Trial registration ClinicalTrials.gov, NCT03875690, Registered on March 15, 2019, URL: https://clinicaltrials.gov/ct2/show/NCT03875690 .