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A prospective observational study of plasma concentrations and safety of combined intravenous lidocaine and epidural ropivacaine in laparotomy surgery
No full textInternational audienceIntravenous lidocaine (IVL), an alternative to epidural analgesia (EA) for laparotomies, has demonstrated anti-inflammatory and anti-hyperalgesic effects. However, its combination with EA raises concerns about systemic toxicity. This study aimed to assess the safety of this combination in patients undergoing laparotomy. We conducted a prospective observational study at Amiens University Hospital in France, involving adult patients scheduled for laparotomies. Intravenous lidocaine was administered at induction as a 1.5 mg/kg bolus (ideal body weight), followed by a continuous infusion of 2 mg/kg/h maintained until the end of surgery. An epidural catheter was inserted before surgery, prior to induction of general anesthesia, no local anesthetic was administered intraoperatively. Epidural analgesia was initiated at the end of surgery with a 5 mg bolus of ropivacaine, followed by a continuous infusion. The primary outcome was the occurrence of lidocaine and ropivacaine plasma concentrations outside established safety ranges. Lidocaine plasma concentrations were measured 30 minutes after bolus (LP1), at the end of surgery (LP2), and two hours after discontinuation of the infusion (LP3). Ropivacaine concentrations were measured two hours (RP1) and 24 hours after initiation of epidural infusion (RP2). The secondary endpoint the assessment of cardiac and neurological toxicity within 48 hours post-surgery. Fifty patients were included from March 2022 to March 2024. One patient exceeded the lidocaine threshold (LP2), and another exceeded the ropivacaine threshold (RP2). LP1 was 1.8 [1.5–2.4] µg/ml, LP2 was 2.1 [1.6–2.4] µg/ml, and LP3 was 1.2 [0.8–1.7] µg/ml. Ropivacaine plasma concentration was 126 [87–211] µg/L at RP1, and 785 [524–1318] µg/L at RP2. No cardiac or neurological adverse events were observed. The combination of EA and IVL appeared to be safe for major abdominal surgery. Clinical trials Number NCT05368753. EudraCT Number: 2021-005508-37
Stratégies de Stabilisation pour les EDP linéarisées par des méthodes d'optimisation
No full textWe adapt an optimization technique, originally developed for quadratic matrix model updating problems, to construct optimal stabilizers for linearized partial differential equations (PDEs). The proposed approach is flexible, allowing the optimization of mass, damping, and stiffness operators either individually or simultaneously. It is also straightforward to implement within standard numerical frameworks. We analyze the numerical and practical properties of the method, highlighting its robustness even with loworder discretizations and its capacity to produce interpretable stabilization operators. The effectiveness and versatility of the approach are demonstrated through numerical experiments on several representative linearized PDEs, including the Klein-Gordon, Boussinesq, Benjamin-Bona-Mahony, and Korteweg-de Vries equations. Our results indicate that the method provides a unified, efficient, and modular tool for PDE stabilization.Nous adaptons une technique d'optimisation, initialement développée pour les problèmes de mise à jour de modèles matriciels quadratiques, afin de construire des stabilisateurs optimaux pour les équations aux dérivées partielles (EDP) linéarisées. L'approche proposée est flexible, elle permet l'optimisation des opérateurs de masse, d'amortissement et de rigidité individuellement ou simultanément. Elle est également facile à implémenter dans les environnements numériques standards. Nous analysons les propriétés numériques et pratiques de la méthode, en soulignant sa robustesse même avec des discrétisations d'ordre faible et sa capacité à produire des opérateurs de stabilisation interprétables. L'efficacité et la polyvalence de l'approche sont démontrées par des expériences numériques sur plusieurs EDP linéarisées représentatives, notamment les équations de Klein-Gordon, de Boussinesq, de Benjamin-Bona-Mahony et de Korteweg-de Vries. Nos résultats indiquent que la méthode constitue un outil unifié, efficace et modulaire pour la stabilisation des EDP
Cancer treatment-related ischemic arterial events: Focus on peripheral arterial disease and cerebrovascular events
No full textInternational audienceCancer therapies, including VEGF inhibitors, BCR-ABL tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), multiple myeloma and hormonal therapies, are associated with an increased risk of arterial thrombotic events (ATEs). While most studies have focused on myocardial and cerebral ischemia, this review highlights the underreported peripheral arterial complications, peripheral arterial disease (PAD) and cerebrovascular events. VEGF inhibitors, such as bevacizumab and VEGFR-TKIs (e.g., sorafenib, sunitinib), significantly elevate the risk of ATEs, with hypertension and proteinuria as common comorbidities. BCR-ABL-TKIs, especially nilotinib and ponatinib, are linked to rapid-onset PAD, even in patients without prior cardiovascular risk factors. ICIs triple the progression of aortic plaque volume, increasing the risk of ischemic stroke and myocardial infarction. Hormonal therapies, including tamoxifen and androgen deprivation therapy, also contribute to ATEs through metabolic and vascular mechanisms. Radiotherapy further exacerbates arterial disease, particularly carotid stenosis and iliofemoral atherosclerosis, in head, neck, and pelvic cancer survivors. Monitoring and prevention strategies, such as regular cardiovascular risk assessments, lipid management, and arterial ultrasound surveillance, are critical for high risk patients. Multidisciplinary onco-vascular teams are essential to mitigate these risks and optimize patient outcomes
Zinc: A metallic shield against cardiac inflammation
No full textInternational audienceZinc (Zn) is a trace element essential for the function of over 10% of the human proteome, yet the average adult body contains only about two grams. Despite its trace status, Zn plays an indispensable role in immune regulation, inflammation control, and redox signalling. Low Zn status is associated with impaired immune function and increased oxidative stress—factors that critically contribute to the pathogenesis of cardiac inflammatory diseases (CIDs), including myocarditis and pericarditis. These conditions are rising in incidence globally, particularly in younger adults, and are linked to viral infections, autoimmune triggers, and post-vaccination inflammatory responses. Zn not only protects cysteine thiol groups from oxidation but also acts as a redox-sensitive secondary messenger via the “Redox Zinc Switch” mechanism—a key process in modulating cellular responses to oxidative stress. In the cardiovascular system, Zn influences antioxidant defence, cytokine regulation, and membrane repair pathways, including cellular responses that are regulated by protein kinase C and metallothioneins. Emerging evidence supports Zn supplementation as a strategy to mitigate myocardial inflammation, reduce cardiac remodelling, and improve outcomes in oxidative stress driven heart diseases. This review synthesizes current knowledge on Zn’s biochemical, immunological, and therapeutic roles in cardiac inflammation. We argue that maintaining optimal Zn levels through diet or supplementation represents a promising, accessible intervention to reduce the burden of CIDs and improve cardiovascular resilience in at-risk populations
A human next generation PBK model for PFOA
No full textInternational audienceThe human toxicological risk assessment of per- and polyfluoroalkyl substances (PFAS) is challenging, due to their sheer number and structural diversity, but also the paucity of the toxicity data required to characterize them. The development of Next Generation Physiologically Based Kinetic (NG-PBK) models may assist in overcoming this challenge. The mechanistic nature of NG-PBK models allows for their extrapolation from data-rich PFAS, such as perfluorooctanoic acid (PFOA), to data-poor ones, facilitating their application in Next Generation Risk Assessment (NGRA). The present study proposes a NG-PBK model for PFOA in humans, parametrized exclusively using in vitro-, and in silico- derived data. The model describes the toxicokinetic processes of 1) partitioning to plasma and tissue proteins, 2) partitioning to cell membrane lipids, 3a) transporter-mediated entero-hepatic circulation and 3b) renal elimination and reabsorption, and 4) elimination via menstruation. Global sensitivity analysis indicated that the model was most sensitive to the fraction unbound in plasma, active-transport parameters, and tissue-plasma partition coefficients. The model was equivalent to already available validated human PFOA-PBK models, while compared to those, it is not calibrated to observed animal, nor human data, illustrating its strength in being mechanistic. The serum concentrations and half-lives predicted by the NG-PBK model were within the ranges of those reported in human volunteer and biomonitoring (HBM) studies, demonstrating the model’s capacity to accurately predict PFOA toxicokinetics on exposure estimates. Extrapolation of the NG-PBK model to other PFAS, in conjunction with its integration with HBM data, will facilitate the NGRA of PFAS. This is particularly relevant given the paucity of in vivo data for most PFAS, ensuring compliance with the 3R principles
Evaluation of a virtual travel therapy device in long-term care facilities: A clinical survey in real-life conditions.
No full textInternational audienceVirtual travel therapy (VTT) devices have yielded encouraging results as a non-drug therapy for improving behavioral disorders in patients with Alzheimer's disease or related conditions. However, no data are available concerning the real-life use of these VTT devices in long-term care facilities (LTCF) and their efficacy in this population. We conducted a survey of all LTCF equipped with VTT devices. A questionnaire was designed and dedicated on the characteristics of the LTCF. A part focused on the last 10 residents to have made use of the VTT device. Efficacy was assessed with the Hamilton Anxiety Scale (HAS), the QUALIDEM quality-of-life score and a subjective assessment before and after the session. Fifteen LTCF responded (62%). Six LTCF provided data for 35 residents using the VTT device. The subjective evaluation and the HAS and QUALIDEM scores revealed a positive effect of the VTT device. This is the first multicentre study to present subjective and objective data demonstrating the efficacy of VTT devices in LTCF residents suffering from Alzheimer's disease and related disorders and presenting behavioral disorders. This device was appreciated by the various health professionals working in these LTCF, who were able to use it routinely, confirming its value in this population
DOP135 Bowel damage and disability in Crohn’s disease in the first year after diagnosis - results from the CROCO study.
No full textDigital oral presentationInternational audienceBackground Crohn’s disease (CD) progression can result in bowel damage (BD) and disability. BD is often believed to occur as a consequence of long-term progression. However, there is limited data about the early occurrence of BD within the first year of disease. Methods The Crohn’s Disease Cohort (CROCO) is a multicentre European study enrolling newly diagnosed CD patients (<12 months since diagnosis) and prospectively following them for 5 years to characterise BD progression and disability. BD is assessed using the Lémann Index (LI) (0 – no damage to 115 – maximal damage) at years 1 (Y1), 3, and 5 after diagnosis. The presence of any degree of BD was defined as a LI > 0, and the presence of significant BD as a LI > 2.1 Disability is evaluated every six months using the IBD-Disability Index (IBD-DI). Here, we report BD at Y1 and its associations with key disease features and with the IBD-DI. Results 539 patients were enrolled across 19 centres, with a median interval between diagnosis and inclusion of 3.7 months (IQR 1.5–7.3). Of these, 415 completed the Y1 visit, and 243 (58%) the LI evaluation [57% male; median age at diagnosis 35yo (IQR 25–50)]. At inclusion, 89% had ileal or ileocolonic disease, 73% had inflammatory phenotype, and 8% had perianal disease. During the first year, 10% underwent surgery (18 intestinal, 5 perianal) and 21% required hospitalisation. During the first year after diagnosis, 18% received 5-ASA, 30% systemic corticosteroids, 36% immunosuppressants, and 61% advanced therapy. The median time from diagnosis to advanced therapy was 3.5 months (IQR 1.4–5.7), with 48% initiating it within six months. Overall, 64% of patients showed some degree of BD at Y1, although the median LI remained low [0.6 (IQR 0–1)]; 41 patients (17%) had significant BD. In multivariate logistic regression analysis, B2/B3 behaviour (p < 0.001) and perianal disease (p = 0.008) were independently associated with BD at Y1 (Table 1). In a sensitivity analysis restricted to B1 patients without prior surgery, isolated colonic disease (L2) was associated with a decreased likelihood of BD (OR 0.34, 95% CI 0.12–1.00, p = 0.039). Among patients with LI data, 227 completed the IBD-DI at Y1. The median IBD-DI was 16 (IQR 10–29), with 18% showing moderate-to-severe disability (IBD-DI>35). No association was observed between any BD and moderate-to-severe disability (OR 1.06, 95% CI 0.52–2.15, p = 0.88). Conclusion In this cohort of newly diagnosed CD patients, two-thirds showed some degree of BD after one year, which was mostly minimal, with only 17% developing significant BD and 18% experiencing moderate-to-severe disability. No association was observed between BD and disability. These findings support early disease as an important period for disease modification. Reference: 1. Gilletta C, Lewin M, Bourrier A, Nion-Larmurier I, Rajca S, Beaugerie L, Sokol H, Pariente B, Seksik P, Cosnes J. Changes in the Lémann Index Values During the First Years of Crohn’s Disease. Clin Gastroenterol Hepatol. 2015 Sep;13(9):1633-40.e3. Conflict of interest: Revés, Joana: Has received consulting fees from Janssen and Pfizer. Arebi, Naila: Personal Fees: Janssen,Lilly, Pfizer and Takeda Non-financial Support: Janssen (J & J), Novonesis Fadra, Adam: None to declare Madsen, Gorm Roager: None Burisch, Johan: Grant: Johnson & Johnson, MSD, Takeda, Tillots Pharma, BMS, Novo Nordisk Personal Fees: Celgene, MSD, Pfizer, AbbVie, Takeda, Tillots Pharma, Samsung Bioepis, BMS, Pharmacosmos, Galapagos, Zealand Pharma, Orion Pharma, Ferring, Johnson & Johnson Cravo, Marilia: None Bonnet-Dodel, Marie: None Kaimakliotis, John: None Vieujean, Sophie: Speaker fees from Abbvie, Takeda and Janssen. Van Kemseke, Catherine: No conflicts Ellul, Pierre: No Conflicts Conti, Kelly: None. Duricova, Dana: Personal Fees: Lecture fee from Janssen, Takeda, Pfizer, Eli Lilly, AbbVie, Ferring. Horutova, Jana: None. Rodríguez-Lago, Iago: Financial support for traveling and educational activities from or has served as an advisory board member for Abbvie, Adacyte, Alfasigma, Biogen, Chiesi, Faes Farma, Ferring, Fresenius Kabi, Galapagos, Johnson & Johnson, Eli Lilly, Mirum Pharmaceuticals, Merck, Pfizer, Roche, Takeda, and Tillotts Pharma. Research support from AbbVie. Supported by a research grant from Gobierno Vasco-Eusko Jaurlaritza (Grant No 2020111061 and 2023222006). Elorza, Ainara: None. Ordás Jiménez, Ingrid: None. Fernandez Clotet, Agnes: None Sebastian, Shaji: Grant: Takeda, Tillots pharma, Biogen, Pfizer, Abbvie, Johnson & Johnson, Olympus -Odin Vision Personal Fees: Tillots, Johnson & Johnson, Olympus Odin Vision, AbbVie, Takeda, Merck, Pharmacosmos, Amgen, Eli Lilly, BMS, Odin Vision Non-financial Support: Tillots, Takeda, AbbVie, Celltrion, Johnson & Johnson, Eli Lilly, Alphasigma, Ferring Pharma Thut, Jessica: None. Mocanu, Irina: None. Hernández Ramirez, Vicente: Vicent Hernandez has served as consultant, has served as speaker, has received travel support or research funding from MSD, AbbVie, Ferring, Dr. Falk Pharma, Tillotts Pharma, Pfizer, Takeda, Janssen, KernPharma Biologics, Adacyte, Sandoz, FAES Farma, Galapagos, Lilly and Casen-Recordati Fumery, Mathurin: Grant: Pfizer Personal Fees: Abbvie, Janssen, Takeda, MSD, Biogen, Amgen, Sandoz, Fresenius, Gilead, Celgene, Galapagos, Mylan, Tillots, Ferring, Pfizer, Hospira, CTMA, Boehringer, Lilly, Arena Non-financial Support: Abbvie, Janssen, Takeda, MSD, Galapagos, Ferring, Pfizer Nachury, Maria: Abbvie, Alfa Sigma, Biosynex, Celltrion, Galapagos, Janssen, Lilly, MSD, Pfizer, Takeda Pedersen, Natalia: No any Rajão Saraiva, Margarida: None. Goldiș, Adrian Eugen: None. Guedes, Ana: None. Ribeiro, Ana Raquel: None. Ungaro, Ryan: Personal Fees: AbbVie, Bristol Myers Squibb, Genentech, Lilly, Pfizer, Janssen, Takeda Bigot, Noemie: None. Mary, Jean-Yves: none Lambert, Jérome: none Colombel, Jean-Frédéric: Grant: AbbVie, Janssen Pharmaceuticals, Takeda, Prometheus and Bristol Myers Squibb Lectures from: AbbVie, Roche and Takeda Other: AbbVie, Amgen, AnaptysBio, Allergan, Apini, Arena Pharmaceuticals, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, candidrx Celgene, Celltrion, Clearview Curogen, Eli Lilly, Envision Pharma Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Roche, Janssen Pharmaceuticals, Kaleido Biosciences, Immunic, Iterative Scopes, Landos, Microba Life Science, Merck, Mirador, Novartis, Otsuka Pharmaceutical, Owkin, Pfizer, Protagonist Therapeutics, Sanofi, Sun Pharma, Takeda, Teva, TiGenix, and is holding stock options in Intestinal Biotech Development Buisson, Anthony: Grant: Abbvie, Celltrion, Pfizer and Takeda Personal Fees: Abbvie, Amgen, Arena, Biogen, Celltrion, Ferring, Janssen, MSD, Pfizer, Roche, Sanofi-Aventis, Takeda, Tillotts, Vifor Pharma, Tinoco da Silva Torres, Joana: Grant: Abbvie, Janssen Personal Fees: Pfizer, Janssen, Abbvie, Sandoz, Lilly, Sanofi, Takeda Non-financial Support: Janssen, Abbvi
Towards approaches that respect human health and ecosystems in agricultural practices
No full textPlant protection products used in agriculture contain molecules specifically designed to be toxic to target organisms. However, their use can also have unintended effects, posing potential risks to ecosystems and non-target organisms, including humans. Research has deepened our understanding of the links between exposure to these substances and the effects observed in the environment. In particular, studies have highlighted how even low levels of exposure can cause chronic effects on non-target organisms and disrupt ecosystems. These findings underscore the importance of quantifying and characterising these exposures in order to better assess their potential impacts on human health and the environment.International audienceThe roundtable discussion held on 6 February 2025 at ONIRIS in Nantes, co-organised by “Carrefours de l’Innovation INRAE” and “ECOPHYTO recherche & innovation”, revisited and expanded upon the presentation of the effects of plant protection products (PPPs) on human health and ecosystems. PPPs, designed to target pests and diseases, also affect non-target organisms, leading to human illnesses (cancers, neurological and respiratory diseases) and ecological imbalances. Robust research, including an INSERM report, has established the strength of the links between exposure to PPPs and various pathologies, particularly among agricultural workers, but also among children exposed in utero. On the environmental front, an INRAE-Ifremer study highlights widespread contamination, with serious impacts on biodiversity (bees, birds, invertebrates) and even the marine environment. The concept of “symbiotoxicity” underscores the disruption of organisms’ microbiomes, exacerbating their vulnerability. Research still lacks data on PPP degradation products and their combined effects (“cocktail effects”). Training programmes such as the One Health Master’s degree aim to prepare professionals capable of addressing these challenges in a systemic way. Since 2020, a compensation fund has been supporting PPP victims, including children exposed before birth. Specialised paediatric consultations are emerging to provide better support for families. Taken together, this body of work clearly calls for a rapid and widespread agroecological transition, implying far-reaching changes in farming practices. However, current policy orientations appear to favour a gradual approach, based on pragmatic actions that can be implemented without disrupting the foundations of the existing agricultural model
Efficacy, safety, pharmacokinetics, immunogenicity, and serum neutralizing activity of AZD7442 (tixagevimab-cilgavimab) in patients hospitalized with COVID-19: long-term results from the DisCoVeRy trial
No full textInternational audienceObjectives: To report long-term clinical efficacy, safety, pharmacokinetics, immunogenicity and seroneutralization results of AZD7442 (monoclonal antibodies tixagevimab-cilgavimab) in patients hospitalized with COVID-19.Methods: In this phase 3, double-blind, randomized, multicentre trial, hospitalized adults with PCR-confirmed SARS-CoV-2 infection were randomly assigned 1:1 to receive AZD7442 or placebo, and followed-up until day 456, with repeated blood sample collections until day 365. Clinical endpoints included clinical status, mortality, rehospitalization, SARS-CoV-2 reinfection, and adverse events. Antidrug antibodies and serum drug concentrations were measured. Analyses were performed on the modified intention-to-treat (mITT) populations, defined as participants who actually received the intervention.Results: Between April 28, 2021, and June 23, 2022, 237 participants were randomly assigned to AZD7442 (n = 127) or placebo (n = 110), and 123 participants actually received AZD7442. Participants were infected with pre-Omicron variants in 58.8% (133/226) of cases, versus 33.2% (75/226) of Omicron BA1, BA2, or BA5, and 8% (18/226) missing data. There was no significant difference in the distribution of the 7-point ordinal scale between the AZD7442 and placebo groups, either on day 15 (primary endpoint) (OR = 0.93 [0.54-1.61], p 0.81), or any other time point. Significantly more rehospitalizations occurred between discharge and day 456 among participants who received AZD7442 in the global mITT population (OR = 2.04 [1.03-4.05], p 0.04), but not in the antigen-positive mITT population (OR = 1.78 [0.80-3.94], p 0.15). No significant differences were observed in mortality, SARS-CoV-2 reinfection, or adverse events. In the AZD7442 group, 12 of 87 participants (13.8%) had treatment-emergent antidrug antibodies versus 5 of 69 (7.2%) in the placebo group (OR = 2.02 [0.66-6.14], p 0.21). Serum drug concentrations were detectable up to day 365 for all sampled participants (35/35). Neutralizing antibody titres were significantly higher in the AZD7442 group up to day 180.Conclusions: AZD7442 did not demonstrate any clinical benefit and was safe up to 15 months. This study also provides valuable data on the pharmacokinetics, immunogenicity, and neutralizing activity of AZD7442 in patients hospitalized with COVID-19
