Search

Purpose: In France, radiation oncologists are predominantly men with only 44 % of women. Many studies have highlighted gender disparities in medicine. The main objective of our study was to assess the impact of discriminations on radiation oncologists’ career. Materials and methods: An anonymous online questionnaire, adapted from the one used by the ESMO W4O group, was sent to all radiation oncologists in France between March and June 2022. It included questions related to professional experience, gender, socio-ethnicity, sexual orientation, and personal life. Results: Among the 999 radiation oncologists and 168 residents in France, 225 questionnaires were collected (19.2 %). Among the respondents, 60 % were women and 25 % were residents. The mean age was 39.2 years (range: 25–78). The career satisfaction rate was 92 %, with no gender difference. Gender was considered to have a negative impact on the career development by 65 % of women. Social origin was an obstacle to career development for 37 % of all the respondents, and ethnic origin for 25 %. Sixty two percent of women reported having experienced inappropriate behavior or sexual harassment in their workplace, 38 % felt that having a child had “extremely“ or ”very“ much impacted their career versus 8.5 % of men (p

The SARS-CoV-2 pandemic has highlighted the need for broad-spectrum antiviral drugs to respond promptly to viral emergence. We conducted a preclinical study of molnupiravir (MOV) against SARS-CoV-2 to fully characterise its antiviral properties and mode of action. The antiviral activity of different concentrations of MOV was evaluated ex vivo on human airway epithelium (HAE) and in vivo in a hamster model at three escalating doses (150, 300 and 400 mg/kg/day) according to three different regimens (preventive, pre-emptive and curative). We assessed viral loads and infectious titres at the apical pole of HAE and in hamster lungs, and MOV trough concentration in plasma and lungs. To explore the mode of action of the MOV, the entire genomes of the collected viruses were deep-sequenced. MOV effectively reduced viral titres in HAE and in the lungs of treated animals. Early treatment after infection was a key factor in efficacy, probably associated with high lung concentrations of MOV, suggesting good accumulation in the lung. MOV induced genomic alteration in viral genomes with an increase in the number of minority variants, and predominant G to A transitions. The observed reduction in viral replication and its mechanism of action leading to lethal mutagenesis, supported by clinical trials showing antiviral action in humans, provide a convincing basis for further research as an additional means in the fight against COVID-19 and other RNA viruses.

Objective: As craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our centre over an 11-year period. Methods and materials: Our study included all patients that underwent CSI by HT, between September 2009 and January 2020, in the Department of Radiation Oncology of the Toulouse Cancer Institute. Acute radiotherapy toxicities were reported and medium- to long-term outcomes analysed. Results: Among the 79 patients included, 70.9 % were younger than 18 years at diagnosis, the median age was 13 (range: 1–52) at the time of radiation therapy, 67.1 % of patients had medulloblastoma. Half of them (49.4 %) had a metastatic disease at diagnosis. The median dose of CSI was 36 Gy (range, 18–36). Seventy-seven patients received a radiation boost to the original location of the primary tumour (97.5 %), 32 patients also received a boost to their metastatic sites (40.5 %). Median follow-up was 55.5 months (95 %CI = [41.2; 71.8]). The 3-year event-free survival rate was 66.3 % (95 %CI = [54.2; 75.9]). Most patients presented with acute haematological toxicities during CSI (85.9 %), predominantly severe thrombocytopenia (39.7 %). Among the 64 patients assessed for medium- and long-term outcomes, 52 survived and 47 were alive and disease-free at the latest follow-up visit on record. There were 3.8 % secondary tumours: two meningiomas and one diffuse intrinsic pontine glioma. Adult and paediatric patients respectively presented with secondary cataract (4.3 % vs 22.0 %), persistent hearing disorders (26.1 % vs 29.3 %), pulmonary or cardiac late effects (4.3 % vs 2.4 %), hormonal pituitary gland deficiencies (30.0 % vs 56.8 %) and psycho-cognitive disorders (56.5 % vs 53.7 %). Conclusion: CSI dispensed by HT, did not result in any additional acute or late toxicities when compared to 3D-CSI. There was no increase in the secondary tumour rate compared to that reported in the literature.

Summary: In vivo genome-wide CRISPR screens in primary T cells allow the systematic and unbiased identification of non-redundant regulatory mechanisms shaping immune responses. Here, we present an optimized protocol for efficient generation of a pool of genome-wide inactivated Cas9-expressing T cells using a retroviral library of sgRNA. We detail the process of large-scale viral production and library integration in activated murine T cells as well as the two-step PCR approach for sgRNA recovery and abundance evaluation.For complete details on the use and execution of this protocol, please refer to Sutra Del Galy et al. (2020). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background: Posterior fossa tumors represent two thirds of brain tumors in children. Although progress in treatment has improved survival rates over the past few years, long-term memory impairments in survivors are frequent and have an impact on academic achievement. The hippocampi, cerebellum and cerebellar-cortical networks play a role in several memory systems. They are affected not only by the location of the tumor itself and its surgical removal, but also by the supratentorial effects of complementary treatments, particularly radiotherapy. The IMPALA study will investigate the impact of irradiation doses on brain structures involved in memory, especially the hippocampi and cerebellum. Methods/design: In this single-center prospective behavioral and neuro-imaging study, 90 participants will be enrolled in three groups. The first two groups will include patients who underwent surgery for a posterior fossa brain tumor in childhood, who are considered to be cured, and who completed treatment at least 5 years earlier, either with radiotherapy (aggressive brain tumor; Group 1) or without (low-grade brain tumor; Group 2). Group 3 will include control participants matched with Group 1 for age, sex, and handedness. All participants will perform an extensive battery of neuropsychological tests, including an assessment of the main memory systems, and undergo multimodal 3 T MRI. The irradiation dose to the different brain structures involved in memory will be collected from the initial radiotherapy dosimetry. Discussion: This study will provide long-term neuropsychological data about four different memory systems (working memory, episodic memory, semantic memory, and procedural memory) and the cognitive functions (attention, language, executive functions) that can interfere with them, in order to better characterize memory deficits among the survivors of brain tumors. We will investigate the correlations between neuropsychological and neuroimaging data on the structural (3DT1), microstructural (DTI), functional (rs-fMRI), vascular (ASL) and metabolic (spectroscopy) impact of the tumor and irradiation dose. This study will thus inform the setting of dose constraints to spare regions linked to the development of cognitive and memory functions. Trial registration: ClinicalTrials.gov: NCT04324450, registered March 27, 2020, updated January 25th, 2021. Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT04324450.

The SARS-CoV-2 Alpha variant exhibits similar transmission dynamics to an ancestral D614G variant in a Syrian hamster model, suggesting the limitations of using the hamster as the sole model to assess differences between SARS-CoV-2 strains.

MRI is the gold standard modality for speech imaging. However, it remains relatively slow, which complicates imaging of fast movements. Thus, an MRI of the vocal tract is often performed in 2D. While 3D MRI provides more information, the quality of such images is often insufficient. The goal of this study was to test the applicability of super-resolution algorithms for dynamic vocal tract MRI. In total, 25 sagittal slices of 8 mm with an in-plane resolution of 1.6 × 1.6 mm2 were acquired consecutively using a highly-undersampled radial 2D FLASH sequence. The volunteers were reading a text in French with two different protocols. The slices were aligned using the simultaneously recorded sound. The super-resolution strategy was used to reconstruct 1.6 × 1.6 × 1.6 mm3 isotropic volumes. The resulting images were less sharp than the native 2D images but demonstrated a higher signal-to-noise ratio. It was also shown that the super-resolution allows for eliminating inconsistencies leading to regular transitions between the slices. Additionally, it was demonstrated that using visual stimuli and shorter text fragments improves the inter-slice consistency and the super-resolved image sharpness. Therefore, with a correct speech task choice, the proposed method allows for the reconstruction of high-quality dynamic 3D volumes of the vocal tract during natural speech.

Measurement(s) Vocal tract images • Speech Technology Type(s) Magnetic Resonance Imaging • Microphone Device Sample Characteristic - Organism Homo sapiens Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.16404453

Summary: Background: To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. Methods: In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2. Findings: First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50. Interpretation: These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19. Funding: This work was supported by the Fondation de France “call FLASH COVID-19”, project TAMAC, by “Institut national de la santé et de la recherche médicale” through the REACTing (REsearch and ACTion targeting emerging infectious diseases), by REACTING/ANRS MIE under the agreement No. 21180 (‘Activité des molécules antivirales dans le modèle hamster’), by European Virus Archive Global (EVA 213 GLOBAL) funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 871029 and DNDi under support by the Wellcome Trust Grant ref: 222489/Z/21/Z through the COVID-19 Therapeutics Accelerator”.