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Abstract For high rate water electrolysers, minimising Ohmic losses through efficient gas bubble evacuation away from the active electrode is as important as minimising activation losses by improving the electrode’s electrocatalytic properties. In this work, by a combined experimental and computational fluid dynamics (CFD) approach, we identify the topological parameters of flow-engineered 3-D electrodes that direct their performance towards enhanced bubble evacuation. In particular, we show that integrating Ni-based foam electrodes into a laterally-graded bi-layer zero-gap cell configuration allows for alkaline water electrolysis to become Proton Exchange Membrane (PEM)-like, even when keeping a state-of-the-art Zirfon diaphragm. Detailed CFD simulations, explicitly taking into account the entire 3-D electrode and cell topology, show that under a forced uniform upstream electrolyte flow, such a graded structure induces a high lateral velocity component in the direction normal to and away from the diaphragm. This work is therefore an invitation to start considering PEM-like cell designs for alkaline water electrolysis as well, in particular the use of square or rectangular electrodes in flow-through type electrochemical cells.

Abstract Reliable automatic diagnosis of Diabetic Retinopathy (DR) and Macular Edema (ME) is an invaluable asset in improving the rate of monitored patients among at-risk populations and in enabling earlier treatments before the pathology progresses and threatens vision. However, the explainability of screening models is still an open question, and specifically designed datasets are required to support the research. We present MAPLES-DR (MESSIDOR Anatomical and Pathological Labels for Explainable Screening of Diabetic Retinopathy), which contains, for 198 images of the MESSIDOR public fundus dataset, new diagnoses for DR and ME as well as new pixel-wise segmentation maps for 10 anatomical and pathological biomarkers related to DR. This paper documents the design choices and the annotation procedure that produced MAPLES-DR, discusses the interobserver variability and the overall quality of the annotations, and provides guidelines on using the dataset in a machine learning context.

Abstract Encephalitis is a rare and potentially fatal manifestation of herpes simplex type 1 infection. Following genome-wide genetic analyses, we identified a previously uncharacterized and very rare heterozygous variant in the E3 ubiquitin ligase WWP2, in a 14-month-old girl with herpes simplex encephalitis. The p.R841H variant (NM_007014.4:c.2522G > A) impaired TLR3 mediated signaling in inducible pluripotent stem cells-derived neural precursor cells and neurons; cells bearing this mutation were also more susceptible to HSV-1 infection compared to control cells. The p.R841H variant increased TRIF ubiquitination in vitro. Antiviral immunity was rescued following the correction of p.R841H by CRISPR-Cas9 technology. Moreover, the introduction of p.R841H in wild type cells reduced such immunity, suggesting that this mutation is linked to the observed phenotypes.

Abstract Background Code-free deep learning (CFDL) is a novel tool in artificial intelligence (AI). This study directly compared the discriminative performance of CFDL models designed by ophthalmologists without coding experience against bespoke models designed by AI experts in detecting retinal pathologies from optical coherence tomography (OCT) videos and fovea-centered images. Methods Using the same internal dataset of 1,173 OCT macular videos and fovea-centered images, model development was performed simultaneously but independently by an ophthalmology resident (CFDL models) and a postdoctoral researcher with expertise in AI (bespoke models). We designed a multi-class model to categorize video and fovea-centered images into five labels: normal retina, macular hole, epiretinal membrane, wet age-related macular degeneration and diabetic macular edema. We qualitatively compared point estimates of the performance metrics of the CFDL and bespoke models. Results For videos, the CFDL model demonstrated excellent discriminative performance, even outperforming the bespoke models for some metrics: area under the precision-recall curve was 0.984 (vs. 0.901), precision and sensitivity were both 94.1% (vs. 94.2%) and accuracy was 94.1% (vs. 96.7%). The fovea-centered CFDL model overall performed better than video-based model and was as accurate as the best bespoke model. Conclusion This comparative study demonstrated that code-free models created by clinicians without coding expertise perform as accurately as expert-designed bespoke models at classifying various retinal pathologies from OCT videos and images. CFDL represents a step forward towards the democratization of AI in medicine, although its numerous limitations must be carefully addressed to ensure its effective application in healthcare.

Abstract Background We designed this study based on both a physician practice survey and real-world patient data to: (1) evaluate clinical management practices in extensive-stage small cell lung cancer (ES-SCLC) among medical centers located across France; and (2) describe first-line treatment patterns among patients with ES-SCLC following the introduction of immunotherapy into clinical practice. Methods A 50-item questionnaire was completed by physicians from 45 medical centers specialized in SCLC management. Responses were collected from June 2022 to January 2023. The survey questions addressed diagnostic workup of ES-SCLC, chemoimmunotherapy in first-line and second-line settings, and use of prophylactic cranial irradiation (PCI) and radiotherapy. In parallel, using a chart review approach, we retrospectively analyzed aggregated information from 548 adults with confirmed ES-SCLC receiving first-line treatment in the same centers. Results In ES-SCLC, treatment planning is based on chest computed tomography (CT) (as declared by 100% of surveyed centers). Mean time between diagnosis and treatment initiation was 2–7 days, as declared by 82% of centers. For detection of brain metastases, the most common imaging test was brain CT (84%). The main exclusion criteria for first-line immunotherapy in the centers were autoimmune disease (87%), corticosteroid therapy (69%), interstitial lung disease (69%), and performance status ≥ 2 (69%). Overall, 53% and 36% of centers considered that patients are chemotherapy-sensitive if they relapse within ≥ 3 months or ≥ 6 months after first-line chemoimmunotherapy, respectively. Among the 548 analyzed patients, 409 (75%) received chemoimmunotherapy as a first-line treatment, 374 (91%) of whom received carboplatin plus etoposide and 35 (9%) cisplatin plus etoposide. Overall, 340/548 patients (62%) received maintenance immunotherapy. Most patients (68%) did not receive radiotherapy or PCI. Conclusions There is an overall alignment of practices reflecting recent clinical guidelines among medical centers managing ES-SCLC across France, and a high prescription rate of immunotherapy in the first-line setting.

Background and purpose: Magnetic resonance imaging (MRI)-to-computed tomography (CT) synthesis is essential in MRI-only radiotherapy workflows, particularly through deep learning techniques known for their accuracy. However, current supervised methods are limited to specific center’s learnings and depend on registration precision. The aim of this study was to evaluate the accuracy of unsupervised and supervised approaches in the context of prostate MRI-to-CT generation for radiotherapy dose calculation. Methods: CT/MRI image pairs from 99 prostate cancer patients across three different centers were used. A comparison between supervised and unsupervised conditional Generative Adversarial Networks (cGAN) was conducted. Unsupervised training incorporates a style transfer method with. Content and Style Representation for Enhanced Perceptual synthesis (CREPs) loss. For dose evaluation, the photon prescription dose was 60 Gy delivered in volumetric modulated arc therapy (VMAT). Imaging endpoint for sCT evaluation was Mean Absolute Error (MAE). Dosimetric endpoints included absolute dose differences and gamma analysis between CT and sCT dose calculations. Results: The unsupervised paired network exhibited the highest accuracy for the body with a MAE at 33.6 HU, the highest MAE was 45.5 HU obtained with unsupervised unpaired learning. All architectures provided clinically acceptable results for dose calculation with gamma pass rates above 94 % (1 % 1 mm 10 %). Conclusions: This study shows that multicenter data can produce accurate sCTs via unsupervised learning, eliminating CT-MRI registration. The sCTs not only matched HU values but also enabled precise dose calculations, suggesting their potential for wider use in MRI-only radiotherapy workflows.

Background and objectivesUp to 46% of patients with presumed autoimmune limbic encephalitis are seronegative for all currently known central nervous system (CNS) antigens. We developed a cell-based assay (CBA) to screen for novel neural antibodies in serum and cerebrospinal fluid (CSF) using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs).MethodsHuman iPSC-derived astrocytes or neurons were incubated with serum/CSF from 99 patients [42 with inflammatory neurological diseases (IND) and 57 with non-IND (NIND)]. The IND group included 11 patients with previously established neural antibodies, six with seronegative neuromyelitis optica spectrum disorder (NMOSD), 12 with suspected autoimmune encephalitis/paraneoplastic syndrome (AIE/PNS), and 13 with other IND (OIND). IgG binding to fixed CNS cells was detected using fluorescently-labeled antibodies and analyzed through automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were used as CNS-irrelevant control target cells. Reactivity profile was defined as positive using a Robust regression and Outlier removal test with a false discovery rate at 10% following each individual readout.ResultsUsing our CBA, we detected antibodies recognizing hiPSC-derived neural cells in 19/99 subjects. Antibodies bound specifically to astrocytes in nine cases, to neurons in eight cases, and to both cell types in two cases, as confirmed by microscopy single-cell analyses. Highlighting the significance of our comprehensive 96-well CBA assay, neural-specific antibody binding was more frequent in IND (15 of 42) than in NIND patients (4 of 57) (Fisher’s exact test, p = 0.0005). Two of four AQP4+ NMO and four of seven definite AIE/PNS with intracellular-reactive antibodies [1 GFAP astrocytopathy, 2 Hu+, 1 Ri+ AIE/PNS)], as identified in diagnostic laboratories, were also positive with our CBA. Most interestingly, we showed antibody-reactivity in two of six seronegative NMOSD, six of 12 probable AIE/PNS, and one of 13 OIND. Flow cytometry using hiPSC-derived CNS cells or PBMC-detected antibody binding in 13 versus zero patients, respectively, establishing the specificity of the detected antibodies for neural tissue.ConclusionOur unique hiPSC-based CBA allows for the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in established routine laboratories, opening new perspectives in establishing a diagnosis of such complex diseases.

Abstract Background Pelvic organ prolapse is a common debilitating condition worldwide. Despite surgical treatment, its recurrence can reach up to 30%. It has multiple risk factors, some of which are particular for a low-resource settings. The identification these factors would help to devise risk models allowing the development of prevention policies. The objective of this study was to explore risk factors for pelvic organ prolapse in a population in eastern Democratic Republic of Congo (DRC). Methods This was an unmatched case-control study conducted between January 2021 and January 2022. The sample size was estimated to be a total of 434 women (217 with prolapse as cases and 217 without prolapse as controls). Data comparisons were made using the Chi-Square and Student T tests. Binary and multivariate logistic regressions were used to determine associated factors. A p

Abstract Cancer cells integrate multiple biosynthetic demands to drive unrestricted proliferation. How these cellular processes crosstalk to fuel cancer cell growth is still not fully understood. Here, we uncover the mechanisms by which the transcription factor Carbohydrate responsive element binding protein (ChREBP) functions as an oncogene during hepatocellular carcinoma (HCC) development. Mechanistically, ChREBP triggers the expression of the PI3K regulatory subunit p85α, to sustain the activity of the pro-oncogenic PI3K/AKT signaling pathway in HCC. In parallel, increased ChREBP activity reroutes glucose and glutamine metabolic fluxes into fatty acid and nucleic acid synthesis to support PI3K/AKT-mediated HCC growth. Thus, HCC cells have a ChREBP-driven circuitry that ensures balanced coordination between PI3K/AKT signaling and appropriate cell anabolism to support HCC development. Finally, pharmacological inhibition of ChREBP by SBI-993 significantly suppresses in vivo HCC tumor growth. Overall, we show that targeting ChREBP with specific inhibitors provides an attractive therapeutic window for HCC treatment.

Extracellular vesicles (EVs) are membrane-bound vesicles secreted by all cell types that play a central role in cell-to-cell communication. Since these vesicles serve as vehicles of cellular content (nucleic acids, proteins and lipids) with the potential to cross biological barriers, they represent a novel attractive window into an otherwise inaccessible organ, such as the brain. The composition of EVs is cell-type specific and mirrors the physiological condition of the cell-of-origin. Consequently, during viral infection, EVs undergo significant changes in their content and morphology, thereby reflecting alterations in the cellular state. Here, we briefly summarize the potential of brain-derived EVs as a lens into viral infection in the central nervous system, thereby: 1) uncovering underlying pathophysiological processes at play and 2) serving as liquid biopsies of the brain, representing a non-invasive source of biomarkers for monitoring disease activity. Although translating the potential of EVs from research to diagnosis poses complexities, characterizing brain-derived EVs in the context of viral infections holds promise to enhance diagnostic and therapeutic strategies, offering new avenues for managing infectious neurological diseases.

Background: MET exon 14 (METex14) skipping mutations are oncogenic drivers observed in approximately 3–4% of non-small cell lung cancers (NSCLC). Several distinct genetic alterations leading to METex14 have been reported but clinical significances of rare mutations are not well defined as well as outcomes of patients upon MET inhibitors (METi). Case presentation: This report presents the case of a patient with metastatic NSCLC harboring an uncommon MET mutational landscape including notably a novel METex14 mutation (R1022L). Dramatic but transient efficacy was observed under crizotinib, due to early occurrence of acquired both on- and off-target mechanisms of resistance such as MET D1246H mutation and wild-type KRAS amplification. Conclusion: Our case provides additional data on MET rare oncogenic variants and their sensitivity to METi. Systematic assessment of post-tyrosine kinase inhibitor tumor sample remains critical to identify on- and off-target mechanisms that may represent therapeutically targetable drivers in resistant patients.

Abstract Background Endometriosis is a chronic disease characterized by growth of endometrial tissue outside the uterine cavity which could affect 200 million women (The term “woman” is used for convenience. Individuals gendered as man or as nonbinary can also suffer from this disease) worldwide. One of the most common symptoms of endometriosis is pelvic chronic pain associated with fatigue. This pain can cause psychological distress and interpersonal difficulties. As for several chronic diseases, adapted physical activity could help to manage the physical and psychological symptoms. The present study will investigate the effects of a videoconference-based adapted physical activity combined with endometriosis-based education program on quality of life, pain, fatigue, and other psychological symptoms and on physical activity. Methods This multicentric randomized-controlled trial will propose to 200 patients with endometriosis to be part of a trial which includes a 6-month program with 45 min to more than 120 min a week of adapted physical activity and/or 12 sessions of endometriosis-based education program. Effects of the program will be compared to a control group in which patients will be placed on a waiting list. All participants will be followed up 3 and 6 months after the intervention. None of the participants will be blind to the allocated trial arm. The primary outcome measure will be quality of life. Secondary outcomes will include endometriosis-related perceived pain, fatigue, physical activity, and also self-image, stereotypes, motivational variables, perceived support, kinesiophobia, basic psychological need related to physical activity, and physical activity barriers. General linear models and multilevel models will be performed. Predictor, moderator, and mediator variables will be investigated. Discussion This study is one of the first trials to test the effects of a combined adapted physical activity and education program for improving endometriosis symptoms and physical activity. The results will help to improve care for patients with endometriosis. Trial registration ClinicalTrials.gov, NCT05831735 . Date of registration: April 25, 2023

Abstract Background The use of naso‐esophageal feeding tubes (NFT) at home could represent an alternative way to reduce the costs for owners and facilitate enteral feeding until recovery of a spontaneous appetite. Objective To describe the use of NFT at home in dogs and cats and evaluate the satisfaction of owners and their capacity to handle the device. Animals One hundred nineteen client‐owned animals (90 cats and 29 dogs) which remained anorexic during hospitalization and were discharged with NFT for at least 24 hours after placement. Methods Medical records were reviewed retrospectively, and owners were contacted by telephone calls. Complications were reported according to their relative severity (minor and major). Owners were asked to report their experience and comfort with NFT management. Results Naso‐esophageal feeding tubes were kept in place at home for a median of 6 days (range, 1‐17) and 62.2% (95% confidence interval [CI]: 53.3‐70.7) of animals recovered a spontaneous appetite while wearing NFT, 60% (95% CI: 44.4‐75.6) of the remaining animals recovered a spontaneous appetite after removal. Overall complication rate was 65.5% (95% CI: 57.0‐74.0), but only 18.5% (95% CI: 11.5‐25.5) required a consultation and no life‐threatening complication occurred. Owners were satisfied in 94.1% (95% CI: 89.9‐98.3) of cases. Conclusion and Clinical Importance Although most animals discharged with NFT at home presented complications, no major adverse effects were reported and NFT were easily handled by owners. This study provides evidence that NFT can be well tolerated at home.

Abstract Noncardiogenic pulmonary edema (NCPE) in hunting dogs is an uncommon and poorly described condition for which no preventive treatment is available. Two dogs were presented for recurrent respiratory distress strictly associated with hunting activities. Diagnosis was based on bilateral, symmetrical, interstitial‐to‐alveolar pattern in the caudodorsal lung fields on thoracic radiographs, exclusion of other causes, and spontaneous clinical and radiographic improvement. Considering that the pathogenesis of exercise‐induced NCPE likely involves α‐ and β‐adrenergic overstimulation, treatment with sympathetic blockers was used in both dogs. The first dog no longer showed respiratory signs during hunting activities. However, treatment failed to prevent respiratory distress in the other dog. Based on the large number of red blood cells in the bronchoalveolar lavage fluid of the second dog, exercise‐induced pulmonary hemorrhage was suspected, as described in racing horses. The loop diuretic furosemide successfully prevented further hunting‐associated respiratory distress episodes in this dog.

Abstract Background As a consequence of SARS-CoV-2 infection various neurocognitive and neuropsychiatric symptoms can appear, which may persist for several months post infection. However, cell type-specific routes of brain infection and underlying mechanisms resulting in neuroglial dysfunction are not well understood. Methods Here, we investigated the susceptibility of cells constituting the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP) to SARS-CoV-2 infection using human induced pluripotent stem cell (hiPSC)-derived cellular models and a ChP papilloma-derived epithelial cell line as well as ChP tissue from COVID-19 patients, respectively. Results We noted a differential infectibility of hiPSC-derived brain microvascular endothelial cells (BMECs) depending on the differentiation method. Extended endothelial culture method (EECM)-BMECs characterized by a complete set of endothelial markers, good barrier properties and a mature immune phenotype were refractory to SARS-CoV-2 infection and did not exhibit an activated phenotype after prolonged SARS-CoV-2 inoculation. In contrast, defined medium method (DMM)-BMECs, characterized by a mixed endothelial and epithelial phenotype and excellent barrier properties were productively infected by SARS-CoV-2 in an ACE2-dependent manner. hiPSC-derived brain pericyte-like cells (BPLCs) lacking ACE2 expression were not susceptible to SARS-CoV-2 infection. Furthermore, the human choroid plexus papilloma-derived epithelial cell line HIBCPP, modeling the BCSFB was productively infected by SARS-CoV-2 preferentially from the basolateral side, facing the blood compartment. Assessment of ChP tissue from COVID-19 patients by RNA in situ hybridization revealed SARS-CoV-2 transcripts in ChP epithelial and ChP stromal cells. Conclusions Our study shows that the BCSFB of the ChP rather than the BBB is susceptible to direct SARS-CoV-2 infection. Thus, neuropsychiatric symptoms because of COVID-19 may rather be associated with dysfunction of the BCSFB than the BBB. Future studies should consider a role of the ChP in underlying neuropsychiatric symptoms following SARS-CoV-2 infection.

The noise reduction effect of noise barriers has been extensively studied, but the effect on pollutant dispersion remains unclear. A computational fluid dynamics (CFD) simulation is conducted to investigate the effects of different heights, lengths, and types of noise barriers and different wind speeds on pollutant dispersion in street canyons with viaducts. The field synergy theory of the convective mass transfer process is used for quantitative analysis of pollutant dispersion in street canyons. The results show that as the height and length of the noise barrier increase, the pollutant dispersion capacity decreases. As the wind speed increases, the rate of decrease in the average CO concentration declines. The effect of the wind speed on the synergistic improvement of the speed and concentration gradient vectors differs for different types of noise barriers. The performance follows the order: fully-closed noise barrier > left noise barrier > right noise barrier > semi-closed noise barrier. The different noise barrier types significantly impact the flow field and pollutant dispersion and reduce the CO concentration to varying degrees, except for the fully-closed type. The average CO concentration in the pedestrian breathing zone is reduced by a maximum of 55.85% on the leeward side and by 53% on the windward side, indicating that an appropriate noise barrier on the viaduct reduces noise pollution and improves the air quality in street canyons, especially in the pedestrian breathing zone.

The detection of contrast-enhancing lesions (CELs) is fundamental for the diagnosis and monitoring of patients with multiple sclerosis (MS). This task is time-consuming and suffers from high intra- and inter-rater variability in clinical practice. However, only a few studies proposed automatic approaches for CEL detection. This study aimed to develop a deep learning model that automatically detects and segments CELs in clinical Magnetic Resonance Imaging (MRI) scans. A 3D UNet-based network was trained with clinical MRI from the Swiss Multiple Sclerosis Cohort. The dataset comprised 372 scans from 280 MS patients: 162 showed at least one CEL, while 118 showed no CELs. The input dataset consisted of T1-weighted before and after gadolinium injection, and FLuid Attenuated Inversion Recovery images. The sampling strategy was based on a white matter lesion mask to confirm the existence of real contrast-enhancing lesions. To overcome the dataset imbalance, a weighted loss function was implemented. The Dice Score Coefficient and True Positive and False Positive Rates were 0.76, 0.93, and 0.02, respectively. Based on these results, the model developed in this study might well be considered for clinical decision support.

Synchrotron Microbeam Radiation Therapy (MRT) has repeatedly proven its superiority compared with conventional radiotherapy for glioma control in preclinical research. The clinical transfer phase of MRT has recently gained momentum; seven dogs with suspected glioma were treated under clinical conditions to determine the feasibility and safety of MRT. We administered a single fraction of 3D-conformal, image-guided MRT. Ultra-high-dose rate synchrotron X-ray microbeams (50 µm-wide, 400 µm-spaced) were delivered through five conformal irradiation ports. The PTV received ~25 Gy peak dose (within microbeams) per port, corresponding to a minimal cumulated valley dose (diffusing between microbeams) of 2.8 Gy. The dogs underwent clinical and MRI follow-up, and owner evaluations. One dog was lost to follow-up. Clinical exams of the remaining six dogs during the first 3 months did not indicate radiotoxicity induced by MRT. Quality of life improved from 7.3/10 [±0.7] to 8.9/10 [±0.3]. Tumor-induced seizure activity decreased significantly. A significant tumor volume reduction of 69% [±6%] was reached 3 months after MRT. Our study is the first neuro-oncologic veterinary trial of 3D-conformal Synchrotron MRT and reveals that MRT does not induce acute to subacute radiotoxicity in normal brain tissues. MRT improves quality of life and leads to remarkable tumor volume reduction despite low valley dose delivery. This trial is an essential step towards the forthcoming clinical application of MRT against deep-seated human brain tumors.

This paper describes the objectives and results of a joint European project named FLYING WAFER. The goal of the project was to provide a methodology for interlinking European R&D centers in micro and nano technologies to a distributed 300-mm CMOS R&D line. The project was carried out as a feasibility study. Therefore, the results provide a model and concept which has the potential of guaranteeing a safe and fast exchange of wafers and data between European R&D nodes to allow multisite processing. An implementation phase is planned as a second step. Index Terms--Multisite processing, nanotechnology, semiconductor manufacturing, 300 mm.

BackgroundVenous thromboembolism (VTE) is a serious complication in non-small cell lung cancer (NSCLC) patients. The use of thromboprophylactic therapy is subject to an accurate assessment of the VTE risk depending on patients, tumor characteristics and type of systemic antineoplastic treatments. However, little is known concerning the risk of VTE in patients suffering from an advanced NSCLC treated with first-line chemo-immunotherapy and the impact of tumor biomarkers such as PD-L1 expression.MethodsWe performed a retrospective, observational, single-centre study in a cohort of advanced NSCLC patients treated with first-line chemo-immunotherapy. The primary endpoint was the incidence of VTE. Secondary endpoints were the cumulative incidence of VTE, the impact of PD-L1 on VTE occurrence, overall survival, the rate of VTE recurrence under anticoagulant treatment and the rate of bleeding complications.Results109 patients were included, of whom 21 (19.3%) presented a VTE event during a median follow-up of 13 months. VTE incidence at 3, 6 and 12 months was 12.1%, 15.1% and 17.5% respectively. 61% were pulmonary embolisms, 9.5% were isolated deep vein thrombosis and 14.3% were central venous catheter-related thrombosis. Our study did not show a significant impact of PD-L1 on VTE occurrence. Overall survival at 6, 12 and 24 months was 81.9%, 74.4% and 70.3% respectively. Four patients developed a recurrent VTE under anticoagulation therapy 3 to 5 months after the first VTE event. One patient suffered from a major bleeding complication while under anticoagulation therapy, leading to death.ConclusionVTE is a common complication in advanced NSCLC patients treated with concomitant chemo-immunotherapy. In our study, 19.3% of patients developed a VTE during a median follow-up of 13 months. PD-L1 did not appear to be associated with VTE occurrence. We recorded high VTE recurrence rates despite anticoagulant treatment. Further investigations are needed to determine if high PD-L1 expression is associated with VTE.

The importance of construction automation has grown worldwide, aiming to deliver new machineries for the automation of roads, tunnels, bridges, buildings and earth-work construction. This need is mainly driven by (i) the shortage and rising costs of skilled workers, (ii) the tremendous increased needs for new infrastructures to serve the daily activities and (iii) the immense demand for maintenance of ageing infrastructure. Shotcrete (sprayed concrete) is increasingly becoming popular technology among contractors and builders, as its application is extremely economical and flexible as the growth in construction repairs in developed countries demand excessive automation of concrete placement. Even if shotcrete technology is heavily mechanized, the actual application is still performed manually at a large extend. RoBétArméEuropean project targets the Construction 4.0 transformation of the construction with shotcrete with the adoption of breakthrough technologies such as sensors, augmented reality systems, high-performance computing, additive manufacturing, advanced materials, autonomous robots and simulation systems, technologies that have already been studied and applied so far in Industry 4.0. The paper at hand showcases the development of a novel robotic system with advanced perception, cognition and digitization capabilities for the automation of all phases of shotcrete application. In particular, the challenges and barriers in shotcrete automation are presented and the RoBétArmésuggested solutions are outlined. We introduce a basic conceptual architecture of the system to be developed and we demonstrate the four application scenarios on which the system is designated to operate.

Abstract Tooth classes are an innovation that has contributed to the evolutionary success of mammals. However, our understanding of the mechanisms by which tooth classes diversified remain limited. We use the evolutionary radiation of noctilionoid bats to show how the tooth developmental program evolved during the adaptation to new diet types. Combining morphological, developmental and mathematical modeling approaches, we demonstrate that tooth classes develop through independent developmental cascades that deviate from classical models. We show that the diversification of tooth number and size is driven by jaw growth rate modulation, explaining the rapid gain/loss of teeth in this clade. Finally, we mathematically model the successive appearance of tooth buds, supporting the hypothesis that growth acts as a key driver of the evolution of tooth number and size. Our work reveal how growth, by tinkering with reaction/diffusion processes, drives the diversification of tooth classes and other repeated structure during adaptive radiations.

Abstract Background In a previous study, telmisartan suppressed aldosterone secretion in healthy cats but not in cats with primary hyperaldosteronism (PHA). Hypotheses Telmisartan suppresses aldosterone secretion in middle‐aged healthy cat and cats with diseases that may result in secondary hyperaldosteronism, but not in those with PHA. Animals Thirty‐eight cats: 5 with PHA; 16 with chronic kidney disease (CKD), subclassified as hypertensive (CKD‐H) or non‐hypertensive (CKD‐NH); 9 with hyperthyroidism (HTH); 2 with idiopathic systemic arterial hypertension (ISH); and 6 healthy middle‐aged cats. Methods Prospective, cross‐sectional study. Serum aldosterone concentration, potassium concentration, and systolic blood pressure were measured before and 1 and 1.5 hours after PO administration of 2 mg/kg of telmisartan. The aldosterone variation rate (AVR) was calculated for each cat. Results No significant difference in the minimum AVR was observed among groups (median [quartile 1 (Q1); quartile 3 (Q3)]: 25 [0; 30]; 5 [−27; −75]; 10 [−6; −95]; 53 [19; 86]; 29 [5; 78]) for PHA, CKD, HTH, ISH, and healthy cats, respectively (P = .05). Basal serum aldosterone concentration (pmol/L) was significantly higher in PHA cats (median [Q1; Q3]: 2914 [2789; 4600]) than in CKD‐H cats (median [Q1; Q3]: 239 [189; 577], corrected P value = .003) and CKD‐NH cats (median [Q1; Q3]: 353 [136; 1371], corrected P value = .004). Conclusions and Clinical Importance The oral telmisartan suppression test using a single dose of 2 mg/kg telmisartan did not discriminate cats with PHA from healthy middle‐aged cats or cats with diseases that may result in secondary hyperaldosteronism.

Abstract Background Development of a telmisartan‐based suppression test may facilitate the diagnosis of primary hyperaldosteronism (PHA) in cats, which remains difficult today. Objectives To develop a telmisartan suppression test (TST) that is safe, and able to suppress aldosterone secretion in healthy cats but not in cats with PHA. Animals Ten healthy cats and 6 cats with PHA. Methods Prospective study using a placebo‐controlled crossover design to investigate a TST in healthy cats, and evaluation of TST in cats with PHA. Plasma aldosterone concentration, potassium concentration, and systolic blood pressure (SBP) were measured before (T0), and 1 hour (T1) and 1.5 hours after (T1.5) PO administration of 1 mg/kg of telmisartan, 2 mg/kg of telmisartan or placebo. Results Median age in healthy cats was 3 years old (range, 1‐7). In healthy cats, a telmisartan dose of 2 mg/kg significantly decreased aldosterone concentration at T1 and T1.5 compared with T0. Placebo had no significant effect on aldosterone concentration. In cats diagnosed with PHA, a 2‐mg/kg dose of telmisartan did not induce any significant change in aldosterone concentration at T1 or T1.5 compared with T0. No adverse effects of telmisartan (e.g., hyperkalemia, systemic hypotension) were observed in any cats. Conclusions and Clinical Importance The oral TST shows promise as a diagnostic test for the diagnosis of PHA in cats.

Abstract Introduction Obstetric anal sphincter injuries (OASIs) at the time of childbirth can lead to serious consequences including anal incontinence, dyspareunia, pain and rectovaginal fistula. These types of lesions and their incidence have been well studied after cephalic presentation deliveries, but no publications have specifically addressed this issue in the context of vaginal breech delivery. The goal of our study was to evaluate the incidence of OASIs following breech deliveries and compare it with cephalic presentation births. Methods This was a retrospective cohort study involving 670 women. Of these, 224 and 446 had a vaginal birth of a fetus in the breech (breech group) and cephalic (cephalic group) presentations respectively. Both groups were matched for birthweight (± 200 g), date of delivery (± 2 years) and vaginal parity. Main outcome of interest was to evaluate the incidence of OASIs following breech vaginal birth compared to cephalic vaginal births. Secondary endpoints were the incidence of intact perineum or first-degree tear, second-degree perineal tear and rates of episiotomies in each group. Results There was no statistically significant difference in OASIs incidence between the breech and cephalic groups (0.9% vs. 1.1%; RR 0.802 (0.157; 4.101); p = 0.31). There were more episiotomies in the breech group (12.5% vs. 5.4%, p = 0.0012) and the rate of intact or first-degree perineum was similar in both groups (74.1% vs. 75.3%, p = 0.7291). A sub-analysis excluding patients with episiotomy and history of OASIs did not show any statistically significant difference either. Conclusion We did not demonstrate a significant difference in the incidence of obstetric anal sphincter injuries between women who had a breech vaginal birth compared to cephalic.

Abstract Solidification of the cores of small planets and moons is thought to occur in the “iron snow” regime, in which iron crystals form near the core‐mantle boundary and fall until re‐melting at greater depth. The resulting buoyancy flux may sustain convection and dynamo action. This regime of crystallization is poorly understood. Here we present the first laboratory experiments designed to model iron snow. We find that solidification happens in a cyclic pattern, with intense solidification bursts separated by crystal‐free periods. This is explained by the necessity of reaching a finite amount of supercooling to re‐initiate crystallization once the crystals formed earlier have migrated away. When scaled to planetary cores, our results suggest that crystallization and the associated buoyancy flux would be strongly heterogeneous in time and space, which eventually impacts the time variability and geometry of the magnetic field.

The conservation of wildlife is one of the most pressing issues in the current times, but wildlife conservation economic values have often been largely ignored due to an absence of market prices, as setting an economic value on biodiversity or whole ecosystems can be challenging. Nevertheless, valuing wildlife can be of great significance to improve decision-making in the conservation field, as it can provide a complementary perspective based on economic principles. Whale-watching provides an opportunity for the economic valuation of wildlife. Specifically, it offers a framework in which the economic revenue allows the economic valuation of the targeted cetaceans to be estimated through the direct and indirect expenditure of the tourists who purchase whale-watching tours. Here, we performed an economic analysis based on population abundances of the three main species targeted by the whale-watching companies in the Strait of Gibraltar (Spain): long-finned pilot whales (Globicephala melas), common dolphins (Delphinus delphis) and killer whales (Orcinus orca). These species generated a total annual income of €4,089,056, €1,876,833, and €505,389, respectively, and each individual would generate an average of €14,048, €951, and €36,099 each year, respectively. Incorporating life expectancy, this corresponded to a total population value of €112,426,185, €16,685,147, and €19,171,107, respectively, over their lifetime. These values provide an idea of the potential contribution of cetaceans to the local economy but only represent their non-consumptive value based on tourism. Our results reinforce the idea that a sustainable, high-quality whale-watching culture, under ACCOBAMS High-Quality Whale-Watching requirements, should be promoted to ensure a sustainable industry, stable economic income and the viability of cetacean populations in the Strait of Gibraltar.

ABSTRACT JC polyomavirus (JCPyV) is an opportunistic virus that remains in a latent state in the kidneys and lymphoid organs of more than half of the human adult population. In rare cases of severe immune suppression, the virus is able to establish a lytic infection of glial cells in the brain, resulting in a debilitating, demyelinating disease known as progressive multifocal leukoencephalopathy (PML). Because of the exceptional species and tissue specificity of the virus, appropriate models of JCPyV infection in the brain are lacking, thus hampering progress toward the development of novel antiviral strategies and biomarkers of disease activity. While PML has traditionally been characterized as a lytic infection of oligodendrocytes, more recent findings suggest an important role for astrocytes during the initial stages of disease. Here, using human-induced pluripotent stem cell (hiPSC)-derived astrocytes coupled with a multiparametric approach, we show that (i) JCPyV readily infects and replicates in astrocytes, (ii) JCPyV strongly dysregulates the cell biology, and (iii) these results adequately reflect ex vivo findings. We perform an in-depth characterization of the effect of JCPyV on the cell proteome over time, demonstrating a strong dysregulation of the cell cycle and activation of the DNA damage response. Furthermore, we show that the proteomic signature observed for infected astrocytes is extended to extracellular vesicles, underlining their potential as a resource to gain valuable insights into JCPyV infection in the brain. IMPORTANCE Progressive multifocal leukoencephalopathy is a crimpling demyelinating disease of the central nervous system caused by JC polyomavirus (JCPyV). Much about JCPyV propagation in the brain remains obscure because of a lack of proper animal models to study the virus in the context of the disease, thus hampering efforts toward the development of new antiviral strategies. Here, having established a robust and representative model of JCPyV infection in human-induced pluripotent stem cell-derived astrocytes, we are able to fully characterize the effect of JCPyV on the biology of the cells and show that the proteomic signature observed for JCPyV-infected astrocytes is extended to extracellular vesicles (EVs). These data suggest that astrocyte-derived EVs found in body fluids might serve as a rich source of information relevant to JCPyV infection in the brain, opening avenues toward better understanding the pathogenesis of the virus and, ultimately, the identification of new antiviral targets.

Herein, the synthesis and optoelectronic properties of a novel push–pull organic dye, pRK1, specifically designed for use in dye‐sensitized photocathodes for hydrogen generation, are reported. The chemical structure of this dye, which incorporates a benzothiadiazole moiety, is inspired by RK1, a dye previously reported as a photosensitizer in n‐type dye‐sensitized solar cells (DSSCs) with power conversion efficiencies above 10% and high stability. The photoelectrochemical activity for hydrogen evolution of pRK1 after grafting onto NiO photocathodes in combination with a cobalt tetrapyridyl catalyst [Co(bapbpy)(OH2)2](BF4)2 in aqueous solution is evaluated and compared with two reference dyes from the literature, RuP2‐bpy and P1. It is shown that among the three photocathodes studied in this work, NiO|pRK1 is the most efficient, producing up to 1.9 μmol cm−2 of hydrogen with a faradaic efficiency of 66%, under visible light irradiation in aqueous electrolyte at pH 4.5. pRK1 shows a turnover number (TONdye) of up to 145 during the 6 h chronoamperometric test, almost twice that of P1. This study demonstrates that the chemical structure of high performance dyes commonly used in DSSCs can be successfully modified to meet the requirements for light‐driven water splitting in dye‐sensitized photoelectrochemical cells.

Plasma-facing materials in tokamak nuclear reactors are subject to intense heat and radiation. The design of liquid metal (LM) divertor walls has several advantages over the solid counterparts. It is important to understand the migration and re-deposition of LMs such as lithium (Li), lead (Pb) or even tin (Sn). This work presents CF LIBS depth profile analysis of the deposited layer on Ni–Cr based screws situated at different places in the COMPASS tokamak vessel during the Capillary Porous System (CPS) LM (LiSn) divertor testing campaign. The experiment was carried out at low Ar pressure (100 mbar) using ns Nd:YAG laser operating at 532 nm. The spectra were recorded using echelle spectrometer (M5000, Andor Tech.) equipped with an iCCD camera (iStar DH743, Andor Tech.). The quantification was based on observed C I, B I, Li I and (weak) Sn I lines, in addition to trace elements (Ca, Na, K) and main matrix elements (Cr, Ni, Fe). The evaluation of electron temperature and density was based on Cr I-II, Ni-II and Fe I-II lines. The LM based content is estimated to be Li (0.3-0.81 at.%) and Sn (0.1-0.23 at.%) with Li/Sn at.% ratio ranging from 3 to 3.5 (wt.% ratio of 0.17-0.20). In practise, the limit of detection of Sn by CF LIBS for this type of Cr-Ni-Fe based matrix is observed to be ∼0.1 at.%.

Purpose: Foundation models are a novel type of artificial intelligence algorithms, in which models are pretrained at scale on unannotated data and fine-tuned for a myriad of downstream tasks, such as generating text. This study assessed the accuracy of ChatGPT, a large language model (LLM), in the ophthalmology question-answering space. Design: Evaluation of diagnostic test or technology. Participants: ChatGPT is a publicly available LLM. Methods: We tested 2 versions of ChatGPT (January 9 “legacy” and ChatGPT Plus) on 2 popular multiple choice question banks commonly used to prepare for the high-stakes Ophthalmic Knowledge Assessment Program (OKAP) examination. We generated two 260-question simulated exams from the Basic and Clinical Science Course (BCSC) Self-Assessment Program and the OphthoQuestions online question bank. We carried out logistic regression to determine the effect of the examination section, cognitive level, and difficulty index on answer accuracy. We also performed a post hoc analysis using Tukey’s test to decide if there were meaningful differences between the tested subspecialties. Main Outcome Measures: We reported the accuracy of ChatGPT for each examination section in percentage correct by comparing ChatGPT’s outputs with the answer key provided by the question banks. We presented logistic regression results with a likelihood ratio (LR) chi-square. We considered differences between examination sections statistically significant at a P value of < 0.05. Results: The legacy model achieved 55.8% accuracy on the BCSC set and 42.7% on the OphthoQuestions set. With ChatGPT Plus, accuracy increased to 59.4% ± 0.6% and 49.2% ± 1.0%, respectively. Accuracy improved with easier questions when controlling for the examination section and cognitive level. Logistic regression analysis of the legacy model showed that the examination section (LR, 27.57; P = 0.006) followed by question difficulty (LR, 24.05; P < 0.001) were most predictive of ChatGPT’s answer accuracy. Although the legacy model performed best in general medicine and worst in neuro-ophthalmology (P < 0.001) and ocular pathology (P = 0.029), similar post hoc findings were not seen with ChatGPT Plus, suggesting more consistent results across examination sections. Conclusion: ChatGPT has encouraging performance on a simulated OKAP examination. Specializing LLMs through domain-specific pretraining may be necessary to improve their performance in ophthalmic subspecialties. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

IntroductionFor radiotherapy based solely on magnetic resonance imaging (MRI), generating synthetic computed tomography scans (sCT) from MRI is essential for dose calculation. The use of deep learning (DL) methods to generate sCT from MRI has shown encouraging results if the MRI images used for training the deep learning network and the MRI images for sCT generation come from the same MRI device. The objective of this study was to create and evaluate a generic DL model capable of generating sCTs from various MRI devices for prostate radiotherapyMaterials and methodsIn total, 90 patients from three centers (30 CT-MR prostate pairs/center) underwent treatment using volumetric modulated arc therapy for prostate cancer (PCa) (60 Gy in 20 fractions). T2 MRI images were acquired in addition to computed tomography (CT) images for treatment planning. The DL model was a 2D supervised conditional generative adversarial network (Pix2Pix). Patient images underwent preprocessing steps, including nonrigid registration. Seven different supervised models were trained, incorporating patients from one, two, or three centers. Each model was trained on 24 CT-MR prostate pairs. A generic model was trained using patients from all three centers. To compare sCT and CT, the mean absolute error in Hounsfield units was calculated for the entire pelvis, prostate, bladder, rectum, and bones. For dose analysis, mean dose differences of D99% for CTV, V95% for PTV, Dmax for rectum and bladder, and 3D gamma analysis (local, 1%/1 mm) were calculated from CT and sCT. Furthermore, Wilcoxon tests were performed to compare the image and dose results obtained with the generic model to those with the other trained models.ResultsConsidering the image results for the entire pelvis, when the data used for the test comes from the same center as the data used for training, the results were not significantly different from the generic model. Absolute dose differences were less than 1 Gy for the CTV D99% for every trained model and center. The gamma analysis results showed nonsignificant differences between the generic and monocentric models.ConclusionThe accuracy of sCT, in terms of image and dose, is equivalent to whether MRI images are generated using the generic model or the monocentric model. The generic model, using only eight MRI-CT pairs per center, offers robust sCT generation, facilitating PCa MRI-only radiotherapy for routine clinical use.

Coronary fistulas are rare, having been described for the first time by Krauss in 1865 in postmortem. They are commonly asymptomatic and can be caused by congenital or acquired malformations. We present the case of a 65-year-old patient who was treated for squamous cell lung cancer with chemoimmunotherapy and presented with angina. The coronary angiography showed a coronaro-bronchial fistula that arises from a branch of the right coronary artery and is associated with lung cancer.