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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.

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.

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.

Background The severity and course of sepsis-associated acute kidney injury (SA-AKI) are correlated with the mortality rate. Early detection of SA-AKI subphenotypes might facilitate the rapid provision of individualized care.Patients and methods In this post-hoc analysis of a multicenter prospective study, we combined conventional kidney function variables with serial measurements of urine (tissue inhibitor of metalloproteinase-2 [TIMP-2])* (insulin-like growth factor-binding protein [IGFBP7]) at 0, 6, 12, and 24 h) and then using an unsupervised hierarchical clustering of principal components (HCPC) approach to identify different phenotypes of SA-AKI. We then compared the subphenotypes with regard to a composite outcome of in-hospital death or the initiation of renal replacement therapy (RRT).Results We included 184 patients presenting SA-AKI within 6 h of the initiation of catecholamines. Three distinct subphenotypes were identified: subphenotype A (99 patients) was characterized by a normal urine output (UO), a low SCr and a low [TIMP-2]*[IGFBP7] level; subphenotype B (74 patients) was characterized by existing chronic kidney disease (CKD), a higher SCr, a low UO, and an intermediate [TIMP-2]*[IGFBP7] level; and subphenotype C was characterized by very low UO, a very high [TIMP-2]*[IGFBP7] level, and an intermediate SCr level. With subphenotype A as the reference, the adjusted hazard ratio (aHR) [95%CI] for the composite outcome was 3.77 [1.92–7.42] (p

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).

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.

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.

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.

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.

Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high-resolution manometry (HRM). Fifty-two diverse international experts separated into seven working subgroups utilized formal validated methodologies over two-years to develop CCv4.0. Key updates in CCv.4.0 consist of a more rigorous and expansive HRM protocol that incorporates supine and upright test positions as well as provocative testing, a refined definition of esophagogastric junction (EGJ) outflow obstruction (EGJOO), more stringent diagnostic criteria for ineffective esophageal motility and description of baseline EGJ metrics. Further, the CCv4.0 sought to define motility disorder diagnoses as conclusive and inconclusive based on associated symptoms, and findings on provocative testing as well as supportive testing with barium esophagram with tablet and/or functional lumen imaging probe. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification and provide more standardized and rigorous criteria for patterns of disorders of peristalsis and obstruction at the EGJ.

The N6-methyladenosine (m6A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay and splicing. It plays a major role during normal development, differentiation, and disease progression. The modification is regulated by a set of writer, eraser, and reader proteins. The YTH domain family of proteins consists of three homologous m6A-binding proteins, Ythdf1, Ythdf2, and Ythdf3, which were suggested to have different cellular functions. However, their sequence similarity and their tendency to bind the same targets suggest that they may have overlapping roles. We systematically knocked out (KO) the Mettl3 writer, each of the Ythdf readers, and the three readers together (triple-KO). We then estimated the effect in vivo in mouse gametogenesis, postnatal viability, and in vitro in mouse embryonic stem cells (mESCs). In gametogenesis, Mettl3-KO severity is increased as the deletion occurs earlier in the process, and Ythdf2 has a dominant role that cannot be compensated by Ythdf1 or Ythdf3, due to differences in readers' expression pattern across different cell types, both in quantity and in spatial location. Knocking out the three readers together and systematically testing viable offspring genotypes revealed a redundancy in the readers' role during early development that is Ythdf1/2/3 gene dosage-dependent. Finally, in mESCs there is compensation between the three Ythdf reader proteins, since the resistance to differentiate and the significant effect on mRNA decay occur only in the triple-KO cells and not in the single KOs. Thus, we suggest a new model for the Ythdf readers function, in which there is profound dosage-dependent redundancy when all three readers are equivalently coexpressed in the same cell types.