Search

Objective We report the features and diagnosis of complicated mumps in previously vaccinated young adults. Patients and methods We retrospectively studied 7 cases of complicated mumps managed during 1 year at the Bordeaux University Hospital. The diagnosis was suggested by the clinical presentation and confirmed using specific RT-PCR. Results Five cases of meningitis, 1 of orchitis, and 1 of unilateral hearing impairment were identified. Each of the 7 patients had been previously vaccinated with MMR, 4 had received 2 doses of this vaccine. Blood tests revealed high rates of IgG antibodies, usually considered as sufficient for immunological protection, and every patient had at least 1 positive RT-PCR test for mumps. Conclusion Outbreaks of complicated mumps may still occur despite a broad coverage of MMR vaccination. The clinical presentation suggested mumps but the final diagnosis could only be confirmed by genomic detection of the virus. Unusual viral strains with increased neurovirulence, insufficient population coverage associated with immunity decrease over time may explain outbreaks of complicated mumps. A full vaccine scheme of contact people or a third injection of vaccine for previously vaccinated people who are at risk of developing mumps are required to prevent further spreading of the disease during the outbreak. [ABSTRACT FROM AUTHOR]

We report on laser-driven, strong-shock generation and hot-electron production in planar targets in the presence of a pre-plasma at shock-ignition (SI) relevant laser and pre-plasma conditions. 2-D simulations reproduce the shock dynamics well, indicating ablator shocks of up to 75 Mbar have been generated. We observe hot-electron temperatures of ~70 keV at intensities of 1.4X1015 W/cm² with multiple overlapping beams driving the two-plasmon decay instability. When extrapolated to SI-relevant intensities of ~1016 W/cm², the hot electron temperature will likely exceed 100 keV, suggesting that tightly focused beams without overlap are better suited for launching the ignitor shock. [ABSTRACT FROM AUTHOR]

Shock ignition [R. Betti et al., Phys. Rev. Lett. 98, 155001 (2007)] is being pursued as a viable option to achieve ignition on the National Ignition Facility (NIF). Shock-ignition target designs use a high-intensity laser spike at the end of a low-adiabat assembly pulse to launch a spherically convergent strong shock to ignite the hot spot of an imploding capsule. A shock-ignition target design for the NIF is presented. One-dimensional simulations indicate an ignition threshold factor of 4.1 with a gain of 58. A polar-drive beam-pointing configuration for shock-ignition experiments on the NIF at 750 kJ is proposed. The capsule design is shown to be robust to the various one- and two-dimensional effects and nonuniformities anticipated on the NIF. The target is predicted to ignite with a gain of 38 when including all anticipated levels of nonuniformity and system uncertainty. [ABSTRACT FROM AUTHOR]

Spherical shock-ignition experiments on OMEGA used a novel beam configuration that separates low-intensity compression beams and high-intensity spike beams. Significant improvements in the performance of plastic-shell, D2 implosions were observed with repointed beams. The analysis of the coupling of the high-intensity spike beam energy into the imploding capsule indicates that absorbed hot-electron energy contributes to the coupling. The backscattering of laser energy was measured to reach up to 36% at single-beam intensities of ∼8 × 1015 W/cm2. Hard x-ray measurements revealed a relatively low hot-electron temperature of ∼30 keV independent of intensity and timing. At the highest intensity, stimulated Brillouin scattering occurs near and above the quarter-critical density and the two-plasmon-decay instability is suppressed. [ABSTRACT FROM AUTHOR]

Shock ignition is an inertial confinement fusion scheme where the ignition conditions are achieved in two steps. First, the DT shell is compressed at a low implosion velocity creating a central core at a low temperature and a high density. Then, a strong spherical converging shock is launched before the fuel stagnation time. It increases the central pressure and ignites the core. It is shown in this paper that this latter phase can be described analytically by using a self-similar solution to the equations of ideal hydrodynamics. A high and uniformly distributed pressure in the hot spot can be created thus providing favorable conditions for ignition. Analytic ignition criteria are obtained that relate the areal density of the compressed core with the shock velocity. The conclusions of the analytical model are confirmed in full hydrodynamic simulations. [ABSTRACT FROM AUTHOR]

Abstract: Collapsin Response Mediator Protein (CRMP)-2 is involved in T-cell polarization and migration. To address the role of CRMP2 in neuroinflammation, we analyzed its involvement in lymphocyte recruitment to the central nervous system in mouse infected with neurotropic and non-neurotropic virus strains (RABV, CDV). A sub-population of early-activated CD69+CD3+ T lymphocytes highly expressing CRMP2 (CRMP2hi) peaked in the blood, lymph nodes and brain of mice infected with neurotropic viruses, and correlated with severity of disease. They displayed high migratory properties reduced by CRMP2 blocking antibody. These data point out the potential use of CRMP2 as a peripheral indicator of neuroinflammation. [Copyright &y& Elsevier]

Abstract: Apoptosis is considered to be a way of eliminating unwanted cells without causing major inflammation. Nevertheless, several lines of evidence show that apoptotic cell-derived antigens can be strong immunogens. The rabies virus glycoprotein G-ERA is an apoptotic molecule. We tested the ability of G-ERA to potentiate a B cell response against an exogenous antigen (influenza hemagglutinin, HA). We found that co-expression of G-ERA and HA in apoptotic bodies increased both the primary and memory HA-specific immune responses. The immunopotentiation of G-ERA is apoptosis-mediated but not necrosis-mediated. Our data indicate that G-ERA-mediated apoptosis might be useful to improve the immunogenicity of live vaccines. [Copyright &y& Elsevier]

Abstract: Objective. – To describe efficacy and safety in clinical practice of pegylated interferon plus ribavirin (INFpeg-Riba) in the treatment of hepatitis C viral infection (HCV) in HIV infected patients. Methods. – Monocentric retrospective study with inclusion of all patients who received at least once INFpeg-Riba before April 1st 2003. All patients were followed up to six months after the end of HCV therapy. Results. – Thirty two HIV-positive patients (23 men and 9 women) with chronic hepatitis C treated by INFpeg-Riba were included. The mean age was 43 years. Fourteen patients carried HCV genotype 2 or 3 (43 %) and 18 patients carried genotype 1 or 4 (57%). The Metavir score of fibrosis showed fibrosis F1 (N =3), F2 (N =14), F3 (N =7) and F4 – cirrhosis (N =8). Twenty six patients (81%) were naïve for anti hepatitis C drugs. Thirty one per cent of patients were at AIDS stage and 84% were receiving antiretroviral drugs. The mean CD4 cell count was 469 /ml and the plasma RNA HIV was less than 50 copies /ml in 57% of the cases. Adverse events leading to reduction of dose of drugs occurred in 40% and adverse events leading to discontinuation treatment occurred in 12%. A decline of CD4 cell count <200 CD4/ml was observed in 15%. Clearance of HCV-RNA in end of treatment was seen in 46 % and sustained virological response in 34 %. The main predictors of sustained virological response were HCV genotype 2 or 3 (P =0.04) and plasma HIV RNA less than 50 copies/ml (P =0.001). The predictive value of good virological response of a CD4 cell count >350/ml before treatment was very near the statistical significancy (p =0.07). Conclusions. – The efficacy of pegylated interféron plus ribavirin in HIV-HCV co-infected patients is disappointing mainly due to a poor tolerance. In addition to HCV genotype, plasma HIV RNA level and CD4 cell count were essential to predict INFpeg-Riba response and should be taken into account in the process leading to the initiation of such therapy in HIV-HCV co-infected patients. [Copyright &y& Elsevier]

Presents a study which described the distribution of JC virus genotypes in France, and investigated the correlations between genotypes and progressive multifocal leukoencephalopathy. JC virus genotype distribution in urine and in cerebral samples; Materials and methods; Results.

The aim of this study was to describe the frequency and significance of isolated antibodies against the hepatitis B virus (HBV) core antigen (HBc) in 2185 HIV-infected patients of the Aquitaine Cohort. Antibodies against HBc were found in 372 subjects (17%). Patients with isolated anti-HBc antibodies were more frequently coinfected with hepatitis C virus (HCV) (58.2%) than those who were anti-HB surface (HBs) antibody positive (22.9%, P<0.001) and those who were dually reactive anti-HBs/anti- HBc antibody positive (27.3%, P<0.001). These results suggest interactions between HBV and HCV. As observed in patients not infected with HIV, the ‘anti-HBc-alone’ serological profile could reflect essentially late immunity with undetectable anti-HBs antibodies. However, an occult HBV infection cannot be ruled out. [ABSTRACT FROM AUTHOR]

Objectif de l’étude La radiothérapie stéréotaxique se développe pour les lésions primitives (carcinome hépatocellulaire) ou secondaires (métastase) du foie. Elle est proposée en cas de contre-indication à la chirurgie ou à la radiofréquence et utilisée dans notre centre depuis 2013. Notre objectif était d’évaluer la tolérance et le contrôle local hépatique après radiothérapie stéréotaxique chez les patients pris en charge dans notre institution. Matériel et méthode De janvier 2013 à octobre 2017, 50 patients ont été traités par irradiation stéréotaxique pour 54 lésions (28 métastases et 26 carcinomes hépatocellulaires) dans le centre hospitalier universitaire de Bordeaux. Le traitement a été préparé par une scanographie de centrage après pose de repères fiduciels, compression abdominale (33,3 %) ou scanographie quadridimensionnelle (57,4 %), et réalisé sur accélérateur Elekta versa HD®. La dose totale était de 45 Gy pour les carcinomes hépatocellulaires et 48 à 60 Gy pour les métastases en trois à quatre fractions. Les récidives ont été considérées comme dans le volume en cas de progression dans le volume cible prévisionnel, en bordure de volume en cas de progression à moins de 5 mm du volume cible prévisionnel. Le contrôle local était défini comme l’absence de récidive dans le volume ou en bordure. Les survies ont été calculées en utilisant la méthode de Kaplan–Meier. Résultats Une seule toxicité de grade IV a été observée (ulcère gastrique) alors que 18,5 % des patients ont souffert d’une toxicité de grade I–II. Le suivi médian était de 14,8 mois [1,1–41,6]. Le volume médian traité était de 7,5 cm3 (0,1–286), avec une dose d’au plus 45 Gy pour 83 % des lésions. Huit tumeurs ont récidivé dans le volume, avec une récidive métastatique diffuse intrahépatique ou à distance, une a récidivé uniquement dans le volume et trois en bordure. Les probabilités de contrôle local étaient de 81 % et 67 % respectivement à 1 et 2 ans, celles de survie globale de 90 % et 56 % à 1 et 2 ans, sans différence significative entre les carcinomes hépatocellulaires et les métastases. La dose prescrite, le volume traité et la couverture du volume cible prévisionnel n’avaient pas d’influence sur la récidive. Conclusion La radiothérapie stéréotaxique hépatique a permis un taux de contrôle local à un an de 81 %. Les deux-tiers des récidives dans ou en bordure du volume étaient diffuses dans le foie ou à distance. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to assess whether single-site and multi-site radiomics could improve the prediction of overall survival (OS) of patients with metastatic lung adenocarcinoma compared to clinicopathological model., Materials and Methods: Adults with metastatic lung adenocarcinoma, pretreatment whole-body contrast-enhanced computed tomography examinations, and performance status (WHO-PS) ≤ 2 were included in this retrospective single-center study, and randomly assigned to training and testing cohorts. Radiomics features (RFs) were extracted from all measurable lesions with volume ≥ 1 cm 3 . Radiomics prognostic scores based on the largest tumor (RPS largest ) and the average RF values across all tumors per patient (RPS average ) were developed in the training cohort using 5-fold cross-validated LASSO-penalized Cox regression. Intra-patient inter-tumor heterogeneity (IPITH) metrics were calculated to quantify the radiophenotypic dissimilarities among all tumors within each patient. A clinicopathological model was built in the training cohort using stepwise Cox regression and enriched with combinations of RPS average , RPS largest and IPITH. Models were compared with the concordance index in the independent testing cohort., Results: A total of 300 patients (median age: 63.7 years; 40.7% women; median OS, 16.3 months) with 1359 lesions were included (200 and 100 patients in the training and testing cohorts, respectively). The clinicopathological model included WHO-PS = 2 (hazard ratio [HR] = 3.26; P < 0.0001), EGFR, ALK, ROS1 or RET mutations (HR = 0.57; P = 0.0347), IVB stage (HR = 1.65; P = 0.0211), and liver metastases (HR = 1.47; P = 0.0670). In the testing cohort, RPS average , RPS largest and IPITH were associated with OS (HR = 85.50, P = 0.0038; HR = 18.83, P = 0.0082 and HR = 8.00, P = 0.0327, respectively). The highest concordance index was achieved with the combination of clinicopathological variables and RPS average , significantly better than that of the clinicopathological model (concordance index = 0.7150 vs. 0.695, respectively; P = 0.0049) CONCLUSION: Single-site and multi-site radiomics-based scores are associated with OS in patients with metastatic lung adenocarcinoma. RPS average improves the clinicopathological model., Competing Interests: Declaration of competing interest A.I.: Research grant: AMGEN, AstraZeneca, Bayer, BMS, Merck, MSD, Novartis, CHUGAI, Par-thenon, Roche; Advisory board: Bayer, BMS, Merck, MSD, Novartis, CHUGAI, Parthenon, Roche. S.C.: Advisory board: Amgen, Lilly, Roche, Astrazeneca, Abbvie, BMS The other authors declare no actual or potential conflict of interest related to this study., (Copyright © 2024 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Trans people have diverse life experiences which may include gender-affirming care (GAC). GAC positively impacts the quality of life of trans adults. However, they are often met with barriers to care and are particularly vulnerable within the healthcare system. The needs and expectations surrounding GAC may vary between individual patients. This article aims to analyze trans adults' perceptions, expectations, and recommendations on GAC. Twenty-seven semi-structured interviews were conducted by a team of academic and peer researchers; transcribed interviews were then analyzed using a codebook and thematic analysis. Three main themes were identified; the liberating experience of GAC; the uneven distribution of knowledge and power between patients and providers; and the recommended practices in GAC. Additional training and research are necessary to facilitate high-quality care for trans adults accessing GAC., (© 2024. The Author(s).)

Radiomics has traditionally focused on individual tumors, often neglecting the integration of metastatic disease, particularly in patients with non-small cell lung cancer. This study sought to examine intra-patient inter-tumor lesion heterogeneity indices using radiomics, exploring their relevance in metastatic lung adenocarcinoma. Consecutive adults newly diagnosed with metastatic lung adenocarcinoma underwent contrast-enhanced CT scans for lesion segmentation and radiomic feature extraction. Three methods were devised to measure distances between tumor lesion profiles within the same patient in radiomic space: centroid to lesion, lesion to lesion, and primitive to lesion, with subsequent calculation of mean, range, and standard deviation of these distances. Associations between HIs, disease control rate, objective response rate to first-line treatment, and overall survival were explored. The study included 167 patients (median age 62.3 years) between 2016 and 2019, divided randomly into experimental (N = 117,546 lesions) and validation (N = 50,232 tumor lesions) cohorts. Patients without disease control/objective response and with poorer survival consistently systematically exhibited values of all heterogeneity indices. Multivariable analyses revealed that the range of primitive-to-lesion distances was associated with disease control in both cohorts and with objective response in the validation cohort. This metrics showed univariable associations with overall survival in the experimental. In conclusion, we proposed original methods to estimate the intra-patient inter-tumor lesion heterogeneity using radiomics that demonstrated correlations with patient outcomes, shedding light on the clinical implications of inter-metastases heterogeneity. This underscores the potential of radiomics in understanding and potentially predicting treatment response and prognosis in metastatic lung adenocarcinoma patients., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

This study aimed to evaluate the potential of pre-treatment CT-based radiomics features (RFs) derived from single and multiple tumor sites, and state-of-the-art machine-learning survival algorithms, in predicting progression-free survival (PFS) for patients with metastatic lung adenocarcinoma (MLUAD) receiving first-line treatment including immune checkpoint inhibitors (CPIs). To do so, all adults with newly diagnosed MLUAD, pre-treatment contrast-enhanced CT scan, and performance status ≤ 2 who were treated at our cancer center with first-line CPI between November 2016 and November 2022 were included. RFs were extracted from all measurable lesions with a volume ≥ 1 cm 3 on the CT scan. To capture intra- and inter-tumor heterogeneity, RFs from the largest tumor of each patient, as well as lowest, highest, and average RF values over all lesions per patient were collected. Intra-patient inter-tumor heterogeneity metrics were calculated to measure the similarity between each patient lesions. After filtering predictors with univariable Cox p < 0.100 and analyzing their correlations, five survival machine-learning algorithms (stepwise Cox regression [SCR], LASSO Cox regression, random survival forests, gradient boosted machine [GBM], and deep learning [Deepsurv]) were trained in 100-times repeated 5-fold cross-validation (rCV) to predict PFS on three inputs: (i) clinicopathological variables, (ii) all radiomics-based and clinicopathological (full input), and (iii) uncorrelated radiomics-based and clinicopathological variables (uncorrelated input). The Models' performances were evaluated using the concordance index (c-index). Overall, 140 patients were included (median age: 62.5 years, 36.4% women). In rCV, the highest c-index was reached with Deepsurv (c-index = 0.631, 95%CI = 0.625-0.647), followed by GBM (c-index = 0.603, 95%CI = 0.557-0.646), significantly outperforming standard SCR whatever its input (c-index range: 0.560-0.570, all p < 0.0001). Thus, single- and multi-site pre-treatment radiomics data provide valuable prognostic information for predicting PFS in MLUAD patients undergoing first-line CPI treatment when analyzed with advanced machine-learning survival algorithms.

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G&#95;{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G&#95;{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Introduction: Patients with severe neuromuscular disease (sNMD) are considered at high risk of severe COVID-19. Muscle tissue is often replaced by fibroadipose tissue in these diseases whereas the new mRNA-based vaccines are injected intramuscularly. We aimed at evaluating the efficacy of two injections associated with a booster injection of mRNA vaccine in these patients., Methods: We performed an observational, prospective, single-centre study to investigate the level of anti-S antibodies (Abs) and their neutralization activity at weeks 6 (W6) and 24 (W24) after two injections of mRNA-1273 vaccine and at weeks 12 (BW12) and 29 (BW29) after a booster injection of BNT162b2 vaccine in patients with sNMD., Results: Thirty-three patients with sNMD were included. At W6, 30 patients (90.1%) showed a protective serum level of specific anti-S Abs with a strong neutralization capacity. We observed a decline over time: only 12 patients (36.3%) retained anti-S Abs levels considered as protective at W24. The neutralization activity remained above the cut off in 23 (69.7%). The booster vaccination restored robust neutralization activity for all analysed 22 patients (100%) at BW12, which was maintained without any significant drop at BW29 (16). No severe adverse event was reported in this cohort and none of the 33 patients developed symptomatic COVID-19 over one year., Conclusions: This study provides evidence that most sNMD patients receiving two injections of COVID-19 mRNA-based vaccines develop a strong humoral response after vaccination. A decline over time was observed but a single booster injection restores a long-term immunity. Moreover, no safety issues were observed., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

There has been significant increase in the use of molecular tools for the diagnosis of invasive aspergillosis (IA) and mucormycosis. However, their range of detection may be too limited as species diversity and coinfections are increasing. Here, we aimed to evaluate a molecular workflow based on a new multiplex PCR assay detecting the whole Aspergillus genus and the Mucorales order followed by a species-specific PCR or a DNA-sequencing approach for IA and/or mucormycosis diagnosis and species identification on serum. Performances of the MycoGENIE Aspergillus spp./Mucorales spp. duplex PCR kit were analyzed on a broad range of fungal strains and on sera from high-risk patients prospectively over a 12-month period. The kit allowed the detection of nine Aspergillus species and 10 Mucorales (eight genera) strains assessed. No cross-reactions between the two targets were observed. Sera from 744 patients were prospectively analyzed, including 35 IA, 16 mucormycosis, and four coinfections. Sensitivity varies from 85.7% (18/21) in probable/proven IA to 28.6% (4/14) in COVID-19-associated pulmonary aspergillosis. PCR-positive samples corresponded to 21 A. fumigatus, one A. flavus, and one A. nidulans infections. All the disseminated mucormycosis were positive in serum (14/14), including the four Aspergillus coinfections, but sensitivity fell to 33.3% (2/6) in localized forms. DNA sequencing allowed Mucorales identification in serum in 15 patients. Remarkably, the most frequent species identified was Rhizomucor pusillus (eight cases), whereas it is barely found in fungal culture. This molecular workflow is a promising approach to improve IA and mucormycosis diagnosis and epidemiology.

Purpose: To investigate which acquisition, post-processing, tumor, and patient characteristics contribute the most to the value of radiomics features (RFs) in lung adenocarcinoma in order to better understand and order the potential sources of bias in radiomics studies in a multivariate setting., Methods: This single-center retrospective study included all consecutive patients with newly-diagnosed lung adenocarcinoma treated between December 2016 and September 2018 who had pre-treatment contrast-enhanced CT-scan showing ≥ 2 target lesions per response evaluation criteria in solid tumors (RECIST) v1.1. All measurable lesions were manually segmented; 49 RFs were extracted using LIFEx v7.0.0. Afterwards, we reverted the usual radiomics approach (i.e., predicting a clinical outcome base on multiple RFs). To do so, for each RF, random forests and linear regression algorithms were trained using cross-validation to predict the RF value depending on the following variables: patient, mutational status, phase of CT-scan acquisition, discretization (binsize), lesion location, lesion volume, and best response obtained during the first line of treatment (partial response per RECIST vs other). The most important contributors to the value of reproducible RFs (intra-class correlation coefficient > 0.80) according to the best random forests model (selected via R-squared) were ranked., Results: 101 patients (median age: 62.3) were included, with a median of 5 target lesions per patient (range: 2-10) providing 466 segmented lesions. Twenty-nine RFs were reproducible. The most important predictors of the reproducible RFs values were, in order: tumor volume, binsize, tumor location, CT-scan phase, KRAS mutation, and treatment response (average importance: 61.7%, 57.4%, 8.1%, 3.3%, 3%, and 2.7%, respectively). The treatment response and KRAS and EGFR/ROS1/ALK mutational status remained independently correlated with the RF value for 64.3%, 32.1%, and 50% reproducible RFs, respectively., Conclusion: Tumor volume, location, acquisition and post-processing parameters should systematically be incorporated in radiomics-based modeling; however, most reproducible RFs do have significant relationships with mutational status and treatment response., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.

Rabies is a lethal infectious disease caused by rabies virus (RABV). Fear and anxiety are the distinguished symptoms in rabies patients. Fusion of RABV envelope glycoprotein (RVG) to host cell membrane initiates rabies pathogenesis via interacting with PDZ domain of signaling proteins. We assessed the anxiety-like behaviors, and hypothalamic-pituitary-adrenal axis (HPA) response to RVG infection. Contribution of PDZ binding motif (PBM) of RVG to the observed effects was also examined using a mutant form of RVG, ΔRVG, with deleted last four amino acids at PBM C-terminus. Lentiviral vectors containing RVG and/or ΔRVG genes were injected into the rat brain areas involved in anxiety including hypothalamus, dorsal hippocampus, and amygdala. RVG/ΔRVG neural expression was examined by fluorescent microscopy. Anxiety-like behaviors were assessed by elevated plus maze (EPM) and open field (OF) tasks. HPA response was evaluated via measuring corticosterone serum level by ELISA technique. RVG/ΔRVG were successfully expressed in neurons of the injected areas. RVG, but not ΔRVG, infection of hypothalamus and amygdala increased the time spent in EPM open arms, and OF total distance moved and velocity. RVG, but not ΔRVG, infection of hypothalamus and dorsal hippocampus increased corticosterone level. The anxiety-like behaviors and exploratory/locomotor activities of rats with RVG infection in hypothalamus, and amygdala are mediated by PBM of RVG. The HPA response to RVG infection of hypothalamus and dorsal hippocampus is dependent to PBM of RVG. Triggering anxiety-related signaling by PBM of RVG seems to be one of the mechanisms involved in anxiety behaviors seen in patients with rabies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rabies virus (RABV) is a neurotropic virus exclusively infecting neurons in the central nervous system. RABV encodes five proteins. Among them, the viral glycoprotein (RVG) plays a key role in viral entry into neurons and rabies pathogenesis. It was shown that the nature of the C-terminus of the RABV G protein, which possesses a PDZ-binding motif (PBM), modulates the virulence of the RABV strain. The neuronal protein partners recruited by this PBM may alter host cell function. This study was conducted to investigate the effect of RVG on synaptic function in the hippocampal dentate gyrus (DG) of rat. Two μl (10 8  T.U./ml) of the lentiviral vector containing RVG gene was injected into the DG of rat hippocampus. After 2 weeks, the rat's brain was cross-sectioned and RVG-expressing cells were detected by fluorescent microscopy. Hippocampal synaptic activity of the infected rats was then examined by recording the local field potentials from DG after stimulation of the perforant pathway. Short-term synaptic plasticity was also assessed by double pulse stimulation. Expression of RVG in DG increased long-term potentiation population spikes (LTP-PS), whereas no facilitation of LTP-PS was found in neurons expressing δRVG (deleted PBM). Furthermore, RVG and δRVG strengthened paired-pulse facilitation. Heterosynaptic long-term depression (LTD) in the DG was significantly blocked in RVG-expressing group compared to the control group. This blockade was dependent to PBM motif as rats expressing δRVG in the DG-expressed LTD comparable to the RVG group. Our data demonstrate that RVG expression facilitates both short- and long-term synaptic plasticity in the DG indicating that it may involve both pre- and postsynaptic mechanisms to alter synaptic function. Further studies are needed to elucidate the underlying mechanisms., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in South East Asia. It has been suggested that, as a consequence of the inflammatory process during JEV infection, there is disruption of the blood-brain barrier (BBB) tight junctions that in turn allows the virus access to the central nervous system (CNS). However, what happens at early times of JEV contact with the BBB is poorly understood. In the present work, we evaluated the ability of both a virulent and a vaccine strain of JEV (JEV RP9 and SA14-14-2, respectively) to cross an in vitro human BBB model. Using this system, we demonstrated that both JEV RP9 and SA14-14-2 are able to cross the BBB without disrupting it at early times post viral addition. Furthermore, we find that almost 10 times more RP9 infectious particles than SA14-14 cross the model BBB, indicating this BBB model discriminates between the virulent RP9 and the vaccine SA14-14-2 strains of JEV. Beyond contributing to the understanding of early events in JEV neuroinvasion, we demonstrate this in vitro BBB model can be used as a system to study the viral determinants of JEV neuroinvasiveness and the molecular mechanisms by which this flavivirus crosses the BBB during early times of neuroinvasion., Competing Interests: The authors have declared that no competing interests exist.

Rabies is a life-threatening viral infection of the brain. Rabies virus (RABV) merely infects excitable cells including neurons provoking drastic behaviors including negative emotional memories. RABV glycoprotein (RVG) plays a critical role in RABV pathogenesis. RVG interacts with various cytoplasmic PDZ (PSD-95/Dlg/ZO-1) containing proteins through its PDZ binding motif (PBM). PTZ domains have crucial role in formation and function of signal transduction. Hippocampus is one of the cerebral regions that contain high load of viral antigens. We examined impact of RVG expression in the dorsal hippocampus on aversive as well as spatial learning and memory performance in rats. Two microliter of the lentiviral vector (~10 8  T.U./ml) encoding RVG or ∆RVG (deleted PBM) genomes was microinjected into the hippocampal CA1. After 1 week, rat's brain was cross-sectioned and RVG/∆RVG-expressing neuronal cells were confirmed by fluorescent microscopy. Passive avoidance and spatial learning and memory were assessed in rats by Shuttle box and Morris water maze (MWM). In the shuttle box, both RVG and ∆RVG decreased the time spent in the dark compartment compared to control (p < 0.05). In MWM, RVG and ∆RVG did not affect the acquisition of spatial task. In the probe test, RVG-expressing rats spent more time in the target quadrant, and also reached the platform position sooner than control group (p < 0.05). Rats expressing ∆RVG significantly swam farther from the hidden platform than RVG group (p < 0.05). Our data indicate RVG expression in the hippocampus strengthens aversive and spatial learning and memory performance. The boosting effect on spatial but not avoidance memory is mediated through PBM.

Selecting targets accurately and quickly with eye-gaze input remains an open research question. In this paper, we introduce BayesGaze, a Bayesian approach of determining the selected target given an eye-gaze trajectory. This approach views each sampling point in an eye-gaze trajectory as a signal for selecting a target. It then uses the Bayes' theorem to calculate the posterior probability of selecting a target given a sampling point, and accumulates the posterior probabilities weighted by sampling interval to determine the selected target. The selection results are fed back to update the prior distribution of targets, which is modeled by a categorical distribution. Our investigation shows that BayesGaze improves target selection accuracy and speed over a dwell-based selection method, and the Center of Gravity Mapping (CM) method. Our research shows that both accumulating posterior and incorporating the prior are effective in improving the performance of eye-gaze based target selection.

Mass vaccination with the live attenuated vaccine YF-17D is the current way to prevent infection with Yellow fever virus (YFV). However, 0.000012-0.00002% of vaccinated patients develop post-vaccination neurological syndrome (YEL-AND). Understanding the factors responsible for neuroinvasion, neurotropism, and neurovirulence of the vaccine is critical for improving its biosafety. The YF-FNV vaccine strain, known to be associated with a higher frequency of YEL-AND (0.3-0.4%) than YF-17D, is an excellent model to study vaccine neuroinvasiveness. We determined that neuroinvasiveness of YF-FNV occured both via infection and passage through human brain endothelial cells. Plaque purification and next generation sequencing (NGS) identified several neuroinvasive variants. Their neuroinvasiveness was not higher than that of YF-FNV. However, rebuilding the YF-FNV population diversity from a set of isolated YF-FNV-N variants restored the original neuroinvasive phenotype of YF-FNV. Therefore, we conclude that viral population diversity is a critical factor for YFV vaccine neuroinvasiveness.

The influenza virus and SARS-CoV-2 cause trivial upper and severe lower respiratory infections (Influenza virus 290,000 to 650,000 deaths/year). These viruses come into contact with the airways either by direct projection, by secondary inhalation of airborne droplets, or by handling (fomites). The objective of this article is to clarify the mechanisms of production and penetration of droplets of secretions emitted during all expiratory phenomena likely to transport these viruses and come into contact with the respiratory mucosa. The droplets>5μm follow the laws of ballistics, those<5μm follow Brownian motion and remain suspended in the air. The aerosols of droplets are very heterogeneous whether the subject is healthy or sick. During an infectious period, not all droplets contain viral RNA. If these RNAs are detectable around patients, on surfaces, and in the ambient air at variable distances according to the studies (from 0.5m to beyond the patient's room), this is without prejudice to the infectious nature (viability) of the virus and the minimum infectious dose. There is a time lag between the patient's infectious period and that of RNA detection for both viruses. Subsequently, the inhaled particles must meet the laws of fluid dynamics (filtration) to settle in the respiratory tree. All of this partly explains the contagiousness and the clinical expression of these two viruses from the olfactory cleft to the alveoli., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Introduction: The therapeutic landscape of renal cell cancer has evolved rapidly over the past 2 years with nivolumab and ipilimumab for patients with metastatic disease and an intermediate or poor prognosis, in the first line setting. More recently, data from trials combining antiangiogenic agents and immune checkpoint inhibitors demonstrated a major benefit of this treatment approach for all patients., Areas Covered: One of three recent trials evaluated the combination of atezolizumab, an anti-programmed death ligand 1 antibody, with bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody. In this manuscript, we summarize the preclinical, clinical, and safety data on atezolizumab for treatment of renal cell carcinoma and describe ongoing trials., Expert Opinion: Atezolizumab was evaluated in combination with an antiangiogenic agent. These trials were designed based on the hypothesis that selecting patients according to the expression of programmed death ligand 1 would increase the benefit of the treatment combination. Despite positive effects on the primary endpoints progression-free survival and response rate in this selected population, overall survival in the global population did not meet the criteria for significance at the time of the intermediate analysis. The major information was a proposed tumor gene expression signature. The signature was predictive of the sensitivity to anti-angiogenic and/or immune checkpoint inhibitor therapy.

Protection of neuronal homeostasis is a major goal in the management of neurodegenerative diseases. Microtubule-associated Ser/Thr kinase 2 (MAST2) inhibits neurite outgrowth, and its inhibition therefore represents a potential therapeutic strategy. We previously reported that a viral protein (G-protein from rabies virus) capable of interfering with protein-protein interactions between the PDZ domain of MAST2 and the C-terminal moieties of its cellular partners counteracts MAST2-mediated suppression of neurite outgrowth. Here, we designed peptides derived from the native viral protein to increase the affinity of these peptides for the MAST2-PDZ domain. Our strategy involved modifying the length and flexibility of the noninteracting sequence linking the two subsites anchoring the peptide to the PDZ domain. Three peptides, Neurovita1 (NV1), NV2, and NV3, were selected, and we found that they all had increased affinities for the MAST2-PDZ domain, with K d values decreasing from 1300 to 60 nm, while target selectivity was maintained. A parallel biological assay evaluating neurite extension and branching in cell cultures revealed that the NV peptides gradually improved neural activity, with the efficacies of these peptides for stimulating neurite outgrowth mirroring their affinities for MAST2-PDZ. We also show that NVs can be delivered into the cytoplasm of neurons as a gene or peptide. In summary, our findings indicate that virus-derived peptides targeted to MAST2-PDZ stimulate neurite outgrowth in several neuron types, opening up promising avenues for potentially using NVs in the management of neurodegenerative diseases., (© 2019 Khan et al.)

Rabies causes more than 60,000 human deaths annually in areas where the virus is endemic. Importantly, rabies is one of the few pathogens for which there is no treatment following the onset of clinical disease with the outcome of infection being death in almost 100% of cases. Whilst vaccination, and the combination of vaccine and rabies immunoglobulin treatment for post-exposure administration are available, no tools have been identified that can reduce or prevent rabies virus replication once clinical disease has initiated. The search for effective antiviral molecules to treat those that have already developed clinical disease associated with rabies virus infection is considered one of the most important goals in rabies research. The current study assesses a single chain antibody molecule (ScFv) based on a monoclonal antibody that potently neutralises rabies in vitro as a potential therapeutic candidate. The recombinant ScFv was generated in Nicotiana benthamiana by transient expression, and was chemically conjugated (ScFv/RVG) to a 29 amino acid peptide, specific for nicotinic acetylcholine receptor (nAchR) binding in the CNS. This conjugated molecule was able to bind nAchR in vitro and enter neuronal cells more efficiently than ScFv. The ability of the ScFv/RVG to neutralise virus in vivo was assessed using a staggered administration where the molecule was inoculated either four hours before, two days after or four days after infection. The ScFv/RVG conjugate was evaluated in direct comparison with HRIG and a potential antiviral molecule, Favipiravir (also known as T-705) to indicate whether there was greater bioavailability of the ScFv in the brains of treated mice. The study indicated that the approach taken with the ScFv/RVG conjugate may have utility in the design and implementation of novel tools targetting rabies virus infection in the brain., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The early screening of nervous system medicines on a pertinent and reliable in cellulo BBB model for their penetration and their interaction with the barrier and the brain parenchyma is still an unmet need. To fill this gap, we designed a 2D in cellulo model, the BBB-Minibrain, by combining a polyester porous membrane culture insert human BBB model with a Minibrain formed by a tri-culture of human brain cells (neurons, astrocytes and microglial cells). The BBB-Minibrain allowed us to test the transport of a neuroprotective drug candidate (e.g., Neurovita), through the BBB, to determine the specific targeting of this molecule to neurons and to show that the neuroprotective property of the drug was preserved after the drug had crossed the BBB. We have also demonstrated that BBB-Minibrain constitutes an interesting model to detect the passage of virus particles across the endothelial cells barrier and to monitor the infection of the Minibrain by neuroinvasive virus particles. The BBB-Minibrain is a reliable system, easy to handle for researcher trained in cell culture technology and predictive of the brain cells phenotypes after treatment or insult. The interest of such in cellulo testing would be twofold: introducing derisking steps early in the drug development on the one hand and reducing the use of animal testing on the other hand.

Background: Enterovirus (EV) meningitis is the most common form of meningitis. Clinical and biological manifestations may be non-specific, leading to prolonged and costly investigations., Objectives: To determine the different aspects of EV meningitis and the variables associated with length of stay (LOS) in hospital independently of patients' age., Study Design: Single center retrospective study of all EV PCR positive CSF samples during 3.5 years in Bordeaux University Hospital, France., Results: 172 patients were included. 65 were under 3 years old and 49 over 18 years old. 10% of patients had severe forms of the disease. 47 patients (27.3%) had normal CSF count and in 63 patients (36.6%) polynuclear cells predominated in CSF. Procalcitonin, Hoens' score or PCR in stool samples appeared as good markers for enteroviral diagnosis. Time elapsed before PCR results was associated with LOS (p = .002) and should help in limiting investigations in case of aseptic meningitis., Conclusion: Rapid availability of EV PCR reduces LOS for patients and contributes to diminish unnecessary procedures and further tests., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Live attenuated vaccines have proved to be mostly valuable in the prevention of infectious diseases in humans, especially in developing countries. The safety and potency of vaccine, and the consistency of vaccine batch-to-batch manufacturing, must be proven before being administrated to humans. For now, the tests used to control vaccine safety largely involve animal testing. For live viral vaccines, regulations require suppliers to demonstrate the absence of neurovirulence in animals, principally in non-human primates and mice. In a search to reduce the use of animals and embracing the 3Rs principles (Replacement, Reduction, Refinement in the use of laboratory animals), we developed a new Blood-Brain Barrier Minibrain (BBB-Minibrain) in cellulo device to evaluate the neuroinvasiveness/neurovirulence of live Yellow Fever virus (YFV) vaccines. A pilot study was performed using the features of two distinct YFV strains, with the ultimate goal of proposing a companion test to characterize YFV neurovirulence. Here, we demonstrate that the BBB-Minibrain model is a promising alternative to consider for future replacement of YFV vaccine in vivo neurovirulence testing (see graphical abstract)., (Copyright © 2018. Published by Elsevier Ltd.)

The biomedical applications of antibody engineering are developing rapidly and have been expanded to plant expression platforms. In this study, we have generated a novel antibody molecule in planta for targeted delivery across the blood-brain barrier (BBB). Rabies virus (RABV) is a neurotropic virus for which there is no effective treatment after entry into the central nervous system. This study investigated the use of a RABV glycoprotein peptide sequence to assist delivery of a rabies neutralizing single-chain antibody (ScFv) across an in cellulo model of human BBB. The 29 amino acid rabies virus peptide (RVG) recognizes the nicotinic acetylcholine receptor (nAchR) at neuromuscular junctions and the BBB. ScFv and ScFv-RVG fusion proteins were produced in Nicotiana benthamiana by transient expression. Both molecules were successfully expressed and purified, but the ScFv expression level was significantly higher than that of ScFv-RVG fusion. Both ScFv and ScFv-RVG fusion molecules had potent neutralization activity against RABVin cellulo. The ScFv-RVG fusion demonstrated increased binding to nAchR and entry into neuronal cells, compared to ScFv alone. Additionally, a human brain endothelial cell line BBB model was used to demonstrate that plant-produced ScFv-RVG P fusion could translocate across the cells. This study indicates that the plant-produced ScFv-RVG P fusion protein was able to cross the in celluloBBB and neutralize RABV., (© 2017 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Rabies is a fatal zoonotic disease and infections generally lead to a fatal encephalomyelitis in both humans and animals. In South Africa, domestic (dogs) and the wildlife (yellow mongoose) host species maintain the canid and mongoose rabies variants respectively. In this study, pathogenicity differences of South African canid and mongoose rabies viruses were investigated in a murine model, by assessing the progression of clinical signs and survivorship. Comparison of glycoprotein gene sequences revealed amino acid differences that may underpin the observed pathogenicity differences. Cumulatively, our results suggest that the canid rabies virus may be more neurovirulent in mice than the mongoose rabies variant., (Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

In the field of live viral vaccines production, there is an unmet need for in vitro tests complying a 3R approach (Refine, Replace and Reduce the use of animal experimentation) to replace the post-licensing safety tests currently assayed in animals. Here, we performed a pilot study evaluating whether virulence of rabies virus, RABV, can be forecast by an in vitro test of neurite outgrowth. The rationale to use neurite outgrowth as a read-out for this test is based on the salient property of the cytoplasmic domain of the G-protein (Cyto-G) of virulent RABV strains - not of attenuated RABV strains - to stimulate neurite outgrowth in vitro. We observed that neurite elongation triggered by the Cyto-Gs encoded by different RABV field isolates correlate with the distinct virulence scores obtained in a mouse model of experimental rabies. Our results cast the idea that it could be feasible to predict RABV virulence by testing the in vitro property of a RABV strain to promote neurite outgrowth without the use of animal experimentation., (Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

RNA viruses present an extraordinary threat to human health, given their sudden and unpredictable appearance, the potential for rapid spread among the human population, and their ability to evolve resistance to antiviral therapies. The recent emergence of chikungunya virus, Zika virus, and Ebola virus highlights the struggles to contain outbreaks. A significant hurdle is the availability of antivirals to treat the infected or protect at-risk populations. While several compounds show promise in vitro and in vivo, these outbreaks underscore the need to accelerate drug discovery. The replication of several viruses has been described to rely on host polyamines, small and abundant positively charged molecules found in the cell. Here, we describe the antiviral effects of two molecules that alter polyamine levels: difluoromethylornithine (DFMO; also called eflornithine), which is a suicide inhibitor of ornithine decarboxylase 1 (ODC1), and diethylnorspermine (DENSpm), an activator of spermidine/spermine N 1 -acetyltransferase (SAT1). We show that reducing polyamine levels has a negative effect on diverse RNA viruses, including several viruses involved in recent outbreaks, in vitro and in vivo These findings highlight the importance of the polyamine biosynthetic pathway to viral replication, as well as its potential as a target in the development of further antivirals or currently available molecules, such as DFMO., Importance: RNA viruses present a significant hazard to human health, and combatting these viruses requires the exploration of new avenues for targeting viral replication. Polyamines, small positively charged molecules within the cell, have been demonstrated to facilitate infection for a few different viruses. Our study demonstrates that diverse RNA viruses rely on the polyamine pathway for replication and highlights polyamine biosynthesis as a promising drug target., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)