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Call for preserving specialized knowledge and contributions of the CAT to advancing ATMPs in Europe
No full textInternational audienceWith the proposal for major reform of the pharmaceutical legislation (Regulation (EU) 2023/0131, Directive (EU) 2023/0132) in April 2023, the foundations of Europe's regulatory architecture are being reshaped. The revised legislation proposes the removal of specialized committee functions (e.g., Committee for Advanced Therapies-CAT) by integrating their remit into other regulatory bodies, such as the Pharmacovigilance Risk Assessment Committee (PRAC) and Committee for Medicinal Products for Human Use (CHMP) and expert working groups. This decision may further challenge innovation in Europe, particularly in the field of advanced therapy medicinal products (ATMPs), which has already experienced a notable decline in global clinical trial activity over the past decade. This article emphasizes the importance of involving multistakeholder consortia such as T2EVOLVE in shaping pharmaceutical legislation to prevent the loss of specialized knowledge and the need for robust mechanisms that preserve developers' access to ATMP regulatory expertise
ASSOCIATION BETWEEN TYPE AND LOCATION OF GERMLINE BRCA1/2 PATHOGENIC OR LIKELY PATHOGENIC VARIANTS WITH PHENOTYPE AND PROGNOSIS IN YOUNG PATIENTS WITH BREAST CANCER: RESULTS FROM AN INTERNATIONAL COHORT STUDY
No full textInternational audienceBackground: Clinical implications of specific pathogenic and likely pathogenic variant (LP/PV) types and locations in the BRCA1 or BRCA2 tumor-suppressor genes remain to be elucidated.Patients and methods: The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study that included BRCA mutation carriers diagnosed with invasive breast cancer at the age of ≤40 years between January 2000 and December 2020. In this analysis, only patients with detailed available information on LP/PVs in the BRCA genes were included. Clinicopathologic features and survival outcomes (disease-free survival [DFS] and overall survival [OS]) were investigated according to LP/PV type (insertion-deletion mutations [INDEL] vs single nucleotide variants [SNV] vs copy number variations [CNV]; truncating vs non-truncating LP/PVs; frameshift vs nonsense vs splicing vs missense LP/PVs) and location (exon involved and protein domain).Results: Out of 5660 patients from 109 centers worldwide, 3294 were eligible for the present analysis (2080 BRCA1 and 1214 BRCA2). The distribution of LP/PV types showed no meaningful associations with baseline clinicopathologic features. BRCA1 protein truncating variants were associated with worse OS compared to non-truncating variants (HR 2.00 [1.17-3.41]). A similar, though non-significant, trend was observed for BRCA2. Missense variants were linked to better OS for both BRCA1 (HR 0.48 [0.28-0.84]) and BRCA2 mutation carriers (HR 0.17 [0.03-0.96]). Regarding variant location, BRCA1 LP/PVs outside exons 2, 10, and 19 were associated with improved OS. In BRCA2, LP/PVs located in exons 15-26 and other regions were linked to worse DFS compared to those in exon 10, with no significant differences in OS.Conclusions: This study advances our understanding of the influence of specific types of BRCA LP/PVs on breast cancer characteristics and outcomes. A deeper understanding of these mutation-specific features will drive future research and support the development of tailored clinical strategies based on individual BRCA variant
High risk, low rest: a new framework for monitoring sleep vulnerability in emergency medicine
No full textInternational audienceBackground Shift work in emergency care settings disrupts circadian rhythms and sleep, increasing health risks and performance. A key aspect of addressing these challenges lies in predicting the burden of shift work to develop safer schedules. This study introduces the Shift Load Index (SLI) as an advanced and sensitive metric for quantifying recovery constraints and examined its association with objective sleep outcomes in emergency healthcare professionals. Methods A two-phase observational field study was conducted with 72 nurses and physicians from two French emergency departments. In the theoretical validation phase, 140 work shifts were analyzed using the SLI and compared to validated FAID Quantum fatigue scores. In the behavioral validation phase, weekly actigraphy data from 35 participants were analysed to assess time in bed, total sleep time, and Sleep Regularity Index (SRI). We employed generalized linear mixed-effects models to assess the association of SLI with sleep outcomes. Results SLI scores significantly predicted FAID Quantum scores (all p < 0.001). Emergency healthcare professionals obtained on average 6h 09 min of sleep for 8h09min in bed, with irregular sleep patterns (mean SRI = 52%). Higher SLI scores were associated with reduced time in bed ( β = −33.19, p < 0.001), shorter sleep ( β = −18.30, p < 0.001), and lower SRI ( β = −1.06, p < 0.001). SRI and total sleep time, as independent factors, together explained 48% of SLI variance (including random effects, 18% by fixed effects only). Discussion Higher shift load is associated with both reduced sleep quantity and regularity. The SLI provides a useful tool to assess recovery burden, with potential applications in optimizing shift schedules and informing fatigue risk management strategies for emergency healthcare professionals
Targeting ACE2 with a camelid antibody inhibits SARS-CoV-2 binding and has protective effects in vivo
No full textInternational audienceThe continuous emergence of antibody-escape variants of SARS-CoV-2 demands the identification of alternative methods of protection against infection that do not directly target viral proteins. Here, we generated heavy-chain-only antibody (VHHs) from an alpaca immunized with the human angiotensin-converting enzyme 2 (hACE2), the major entry receptor for SARS-CoV-2. The VHHs bind hACE2 without affecting its enzymatic activity, and two of them (B07 and B09) inhibit all SARS-CoV-2 isolates tested, including the most recent circulating variants. Their X-ray structure in complex with hACE2 showed that their epitope overlaps with the footprint of the receptor binding domain (RBD) of the SARS-CoV-2 spike on hACE2. A dimeric B07-Fc fusion construct avidly bound hACE2 with an apparent dissociation constant of 0.1 nM and inhibited infection in vitro with an IC50 ~ 1 nM. In vivo experiments using K18-hACE2 mice showed that intranasal prophylactic administration of B07-Fc conferred a dose-dependent protection against SARS-CoV-2 D614G and Omicron variants. These VHHs targeting hACE2 represent potential broad-spectrum therapeutic candidates against potential new emerging coronaviruses using hACE2 as a receptor
Machine-learning enhanced predictors for accelerated convergence of partitioned fluid-structure interaction simulations
No full textInternational audienceStable partitioned techniques for simulating unsteady fluid-structure interaction (FSI) are known to be computationally expensive when high added-mass is involved. Multiple coupling strategies have been developed to accelerate these simulations, but often use predictors in the form of simple finite-difference extrapolations. In this work, we propose a non-intrusive data-driven predictor that couples reduced-order models of both the solid and fluid subproblems, providing an initial guess for the nonlinear problem of the next time step calculation. Each reduced order model is composed of a nonlinear encoder-regressor-decoder architecture and is equipped with an adaptive update strategy that adds robustness for extrapolation. In doing so, the proposed methodology leverages physics-based insights from high-fidelity solvers, thus establishing a physics-aware machine learning predictor. Using three strongly coupled FSI examples, this study demonstrates the improved convergence obtained with the new predictor and the overall computational speedup realized compared to classical approaches
Impact of Aryl Extension on the Proton-Triggered Transition Switch in Azaheterocycle-Functionalized ESIPT Fluorophores
No full textInternational audienceThis article describes the synthesis along with full photophysical characterization in both solution and solid-state of a series of 2-(2'-hydroxyphenyl)benzazole linked to an aza-heterocycle (pyridine or isoquinoline) by one or two aryl rings. The impact of the length of the spacer is investigated in the light of emission wavelength, quantum yield, sensitivity to protons and possibility of transition switch upon protonation. Correlation of first-principle calculations and experimental results help decipher the excited-state dynamics, allowing to draw and discuss hypotheses concerning the nature of the excited species
Threatened or thriving? Q methodology reveals stakeholder discourses of bats in an insular context
No full textInternational audienceBats are the only indigenous mammals on Reunion Island, with one of the three species, Mormopterus francoismoutoui, being endemic, and another, Pteropus niger, endangered. The endemic bat is highly adapted to urban areas and coexists in proximity to humans, living in large colonies in rooftops of houses, schools, and churches, and also under bridges. These bats hold considerable importance for Reunion Island’s natural heritage, but at the same time, they carry diseases and leave dejections that can cause olfactory discomfort and respiratory problems. As conservation and management measures hold profound implications on both human and bat populations, we need to foster a proper understanding of stakeholder perspectives and find common ground. We applied Q methodology to explore stakeholder discourses of bats on Reunion Island, focusing on aspects of conservation, management, and public health. Our combined quantitative and qualitative analyses revealed three principal discourses. The human-oriented discourse advocates public education and addressing myths and misconceptions to protect bats. The nature-oriented discourse prioritizes the protection of natural habitats to conserve bats. The public health and policy-oriented discourse seeks to adapt bat conservation and management policies to ensure public health safety. All stakeholders agreed that there is a lack of awareness among local media, which at times diffuses sensational and erroneous information, and that as well there is a need to integrate research output into public outreach efforts to garner interest in bats. These results can aid in contextualizing conservation actions and policies and could potentially provide sustainable management solutions to human-bat coexistence on Reunion Island
Counteracting the Mechanisms of Heart Failure is the Most Effective Way to Decongest Patients while Improving Outcomes
No full textInternational audienceDiuretic therapy is not associated with improved outcomes in heart failure and may cause significant side effects. Counteracting the core pathophysiological mechanisms of heart failure through neurohormonal blockade while reducing reliance on diuretics is potentially the most effective method of decongestion
Creatine monohydrate supplementation for older adults and clinical populations
No full textInternational audienceBackground: The biological process of aging is typically associated with a decrease in muscle quantity, muscle performance (primarily strength), bone mass and architecture, functionality and neurological/cognitive function. From a healthy aging perspective, interventions that have the potential to overcome or attenuate these decrements are clinically relevant.Methods: We conducted a narrative review on the efficacy of creatine monohydrate supplementation (CrM) in older adults.Results: Accumulating research shows that CrM, primarily when combined with exercise training, is safe and has beneficial effects on measures of whole-body lean body mass, regional muscle size, muscle strength, bone area and thickness, functional ability, glucose kinetics, cognition and memory.Conclusion: CrM has multiple benefits in older adults and may have application for treating age-related sarcopenia, osteoporosis, frailty, and those with metabolic and neuromuscular disorders
Targeting high circulating dipeptidyl peptidase 3 in circulatory failure
No full textInternational audienceCirculating dipeptidyl peptidase 3 is a new biomarker linked to circulatory failure prognosis and pathophysiology and is a potential actionable therapeutic target. In this short review intended for the clinician, a question-and-answer format provides key insights on the nature of this biomarker and the therapeutical potential of its targeted inhibition in critically ill patients