Polytech Clermont-Ferrand

Although pulmonary vein isolation (PVI) has become the cornerstone ablation procedure for atrial fibrillation (AF), the optimal ablation procedure for persistent and long-standing persistent AF remains elusive. Targeting spatio-temporal electrogram dispersion in a tailored procedure has been suggested as a potentially beneficial alternative to a conventional PVI-only procedure. In this multicenter, randomized, controlled, double-blind, superiority trial, patients with drug-refractory persistent AF were randomly assigned to a tailored ablation procedure targeting areas of spatio-temporal dispersion, as detected by an artificial intelligence (AI) algorithm, in addition to PVI (tailored arm, n = 187, 23% women) or to a conventional PVI-only procedure (anatomical arm, n = 183, 19% women). The primary efficacy endpoint was freedom from documented AF with or without antiarrhythmic drugs at 12 months after a single ablation procedure. Secondary endpoints included freedom from any atrial arrhythmic events, and the secondary composite safety endpoint consisted of death, cerebrovascular events, or treatment-related serious adverse events. One year post-procedure, the trial met its primary efficacy endpoint, which was achieved in 88% of patients in the tailored arm compared with 70% of patients in the anatomical arm (log-rank P < 0.0001 for superiority). However, no significant difference between arms was observed for the freedom from any atrial arrhythmia endpoint after one ablation. The safety endpoint did not differ between arms, with procedure and ablation times being twice as long in the tailored arm. These results show that AI-guided ablation of spatio-temporal dispersion areas in addition to PVI is superior to PVI alone in eliminating AF at 1-year follow-up in patients with persistent and long-standing persistent AF. Ablation of subsequent organized atrial tachycardias may be needed to maintain sinus rhythm long term. ClinicalTrials.gov identifier: NCT04702451.

Introduction In addition to its direct cytotoxic effects, ablative therapies as electrochemotherapy (ECT) can elicit indirect antitumor effects by triggering immune system responses. Here, we comprehensively analyzed this dual effectiveness of intratumoral ECT with chemotherapeutic drugs bleomycin (BLM), oxaliplatin (OXA), and cisplatin (CDDP). Our aim was to determine if ECT can act as in situ vaccination and thereby induce an abscopal effect. By evaluating ECT’s potential for in situ vaccination, our goal was to pave the way for future advancements for its combination with emerging (immuno)therapies, leading to enhanced responses and outcomes. Methods We employed two mouse tumor models, the immunologically cold B16F10 melanoma and 4T1 mammary carcinoma, to explore both local and systemic (i.e., abscopal) antitumor effects following equieffective intratumoral ECT with BLM, OXA, and CDDP. Through histological analyses and the use of immunodeficient and metastatic (for abscopal effect) mouse models, we identified and compared both the cytotoxic and immunological components of ECT’s antitumor efficiency, such as immunologically recognizable cell deaths (immunogenic cell death and necrosis) and immune infiltrate (CD11⁺, CD4⁺, CD8⁺, GrB⁺). Results Differences in immunological involvement after equieffective intratumoral ECT were highlighted by variable kinetics of immunologically recognizable cell deaths and immune infiltrate across the studied tumor models. Particularly, the 4T1 tumor model exhibited a more pronounced involvement of the immune component compared to the B16F10 tumor model. Variances in the antitumor (immune) response were also detected based on the chemotherapeutic drug used in ECT. Collectively, ECT demonstrated effectiveness in inducing in situ vaccination in both tumor models; however, an abscopal effect was observed in the 4T1 tumor model only. Conclusions This is the first preclinical study systematically comparing the immune involvement in intratumoral ECT’s efficiency using three distinct chemotherapeutic drugs in mouse tumor models. The demonstrated variability in immune response to ECT across different tumor models and chemotherapeutic drugs provides a basis for future investigations aimed at enhancing the effectiveness of combined treatments.

Background The GNRI (Geriatric Nutritional Risk Index1) is an index used in geriatrics to predict the risk of complications and mortality associated with malnutrition. It considers serum albumin levels and the ratio of current weight or BMI to the ideal theoretical weight/BMI. Aim The aim of this study was to evaluate this index in a population of metabolically stable chronic hemodialysis patients aged > 60 years and associate it with other nutritional markers. Methods The studied patient cohort was divided into two groups based on their Geriatric Nutritional Risk Index (GNRI) scores: Gr 1 with GNRI score < 97 and Gr 2 with GNRI ≥ 97. We registered the anthropometric, clinical, and biological data of the study population. Results One hundred seventy‐seven patients (102 M‐75F) undergoing chronic hemodialysis were included. There were no differences in age, muscle mass estimated by bioimpedance analysis, potassium levels, phosphorus levels, and nPCR between the groups. However, there were significant differences between the two groups concerning the primary disease. Gr 1 presented with a higher prevalence of diabetes and cardiovascular comorbidities. Additionally, Gr 1 presented with lower handgrip strength (Mean ± standard deviation in kg, 19.79 ± 9.37 vs. 26.83 ± 11.63, p = 0.05), lower fat mass index estimated by bioimpedance analysis (Mean ± standard deviation in kg/m2, 7.31 ± 4.55 vs. 15.24 ± 6.47, p < 0.001), and higher CRP levels (Mean ± standard deviation in mg/l, 22.27 ± 23.49 vs. 8.13 ± 10.14, p < 0.001). Conclusion In conclusion, the GNRI, an easy calculation tool for nutrition assessment, is associated with important nutritional status parameters in chronic hemodialysis patients.

BACKGROUND: Understanding the dietary intake of elite adolescent athletes and its adequacy with sport nutrition recommendation is a key issue for health and player development, as well as performance and recovery. Energy availability needs to be considered to ensure optimal health and performance in young athletes. The present study aimed to quantify energy availability, energy expenditure and macronutrient intake in young male rugby union players competing at national level. METHODS: Twelve male adolescent players (15.6±0.6 years) completed a 7-days prospective observational study (5 days of training and 2 days of full recovery). Total energy expenditure was estimated using indirect calorimetry and heart rate measurement. Energy intake was assessed using weighed food by a dietitian in cafeteria (training days) and image-based dietary (recovery days). Energy availability was calculated using (energy intake-exercise energy expenditure)/fat-free mass. RESULTS: Mean energy availability was 38.5±7.5, 40.2±5.4 and 47.8±5.1 kcal/kgFFM/d on heavy training, moderate training and recovery days, respectively. Players consumed a low carbohydrate (~5.0 g/kg/d), high protein (~2.0 g/kg/d) and high fat (~1.8 g/kg/d) diet on training and recovery days in relation to current international nutritional recommendations for young athletes. CONCLUSIONS: Athletes showed sub-optimal energy availability on training days, high energy availability on recovery days and did not comply with carbohydrate intake recommendations on training nor recovery days. These results highlight the short-term inadequacy of energy availability as a result of low carbohydrate intake, warning about the possible adverse short-term metabolic effects on health and performance of young athletes.

Little is known about the influence of fatigue in repeated overground sprinting on force-velocity properties in children and adolescents, while this ability to repeat sprints is important for future progress in rugby union. Sprint time decline is commonly used to assess fatigability. However, it does not provide data on biomechanical aspects of sprint performance such as maximal power, force, and velocity production. As sprint time performance and force-velocity properties do not linearly change during adolescence, considering maturity status is important. This study aimed to assess the effect of fatigue on sprint time performance fatigability, force-velocity parameters, and mechanical effectiveness according to maturity status. A group of fifteen boys (12.5 ± 0.5 years) children and a group of seventeen boys (15.1 ± 0.6 years) adolescent rugby players completed seven blocks, consisting of a 30-meter sprint followed by five minutes of high-intensity exercise with one minute of passive recovery. The force-velocity parameters were calculated at each sprint, and performance decrement was assessed using a fatigue index. A main effect of block repetition was found for maximal power output, maximal force, maximal velocity, 30-meter sprint time, fatigue index and mechanical effectiveness parameters with large effect sizes (p <0.001; ηp2 = 0.19 to 0.47) and without a main effect of maturity status (p = 0.37 to 0.99; ηp2 = 0.00 to 0.05). This could be explained by the modalities (duration, intensity, recovery) of the protocol and the training level of the adolescent group. For both groups, the decrease in maximal power output was due more to a reduction in maximal velocity than force, and mechanical effectiveness was negatively impacted. Coaches could prioritize the training of horizontal force at high velocity under fatigue conditions, as this ability tends to be the most affected. They could also incorporate training on mechanical effectiveness as this is a determinant in team sports.

We study the role of undervaluation of currency exchange rates in triggering African product export surges. Over the period 1995–2017, 96 episodes are identified for 41 African countries from a basket of their primary and manufactured exported goods (149 products, 4‐digit HS code). We compute country‐product specific real exchange rate misalignments, that allow testing the hypothesis that undervaluation drives competitiveness and thus export surges. The complementary log–log model confirms that product‐specific undervaluation promotes the occurrence of surge episodes. This effect proves robust to the way we define export episodes, the introduction of covariates in the model and the use of the Relogit as an alternative estimator for rare events.

To determine the prevalence of functional, respiratory and renal impairments and of post-intensive-care-syndrome (PICS) among patients who had attended a post-ICU multidisciplinary consultation (post-ICU-MC) around 3 months after ICU discharge, we performed a retrospective, monocentric observational study, at Clermont Ferrand University hospital, France. We included patients who had attended a post-ICU-MC. Their characteristics during ICU stay and at the post-ICU-MC were collected. Functional status was assessed by the 6-min-walking test, handgrip test and peak inspiratory pressure, respiratory function by exploratory functional outcomes, mental status by SF-36 score, and quality of life by SF-36 score and European Quality of Life 5 Dimensions questionnaire. Overall, we enrolled 67 patients, of whom 70%, 74%, and 68% had functional, respiratory, and renal impairments, respectively, at the post-ICU-MC. Additionally, 40%, 28%, 19%, and 2.5% had three, two, one, and none of these impairments, respectively. All patients experienced mental disorders and a decline in quality of life. Functional impairment correlated with frailty score and sex, and respiratory function with age. To conclude, the prevalence of PICS in our cohort was high, as was that of functional, respiratory and renal failure.

Introduction The COVID-19 pandemic has been associated with significant variability in acute kidney injury (AKI) incidence, leading to concerns regarding patient heterogeneity. The study’s primary objective was a cluster analysis, to identify homogeneous subgroups of patients (clusters) using baseline characteristics, including inflammatory biomarkers. The secondary objectives were the comparisons of MAKE-90 and mortality between the different clusters at three months. Methods This retrospective single-center study was conducted in the Medical Intensive Care Unit of the University Hospital of Clermont-Ferrand, France. Baseline data, clinical and biological characteristics on ICU admission, and outcomes at day 90 were recorded. The primary outcome was the risk of major adverse kidney events at 90 days (MAKE-90). Clusters were determined using hierarchical clustering on principal components approach based on admission characteristics, biomarkers and serum values of immune dysfunction and kidney function. Results It included consecutive adult patients admitted between March 20, 2020 and February 28, 2021 for severe COVID-19. A total of 149 patients were included in the study. Three clusters were identified of which two were fully described (cluster 3 comprising 2 patients). Cluster 1 comprised 122 patients with fewer organ dysfunctions, moderate immune dysfunction, and was associated with reduced mortality and a lower incidence of MAKE-90. Cluster 2 comprised 25 patients with greater disease severity, immune dysfunction, higher levels of suPAR and L-FABP/U Creat, and greater organ support requirement, incidence of AKI, day-90 mortality and MAKE-90. Conclusions This study identified two clusters of severe COVID-19 patients with distinct biological characteristics and renal event risks. Such clusters may help facilitate the identification of targeted populations for future clinical trials. Also, it may help to understand the significant variability in AKI incidence observed in COVID-19 patients.

Introduction Cachexia is strongly associated with digestive cancers, particularly oesogastric cancer. Mitochondria in adipose tissue are involved in the regulation of metabolism and physiopathology of cancer cachexia in animal studies. Chemotherapeutic regimens used to control tumour development could also alter mitochondrial function in adipose tissue. We hypothesise that cachexia induces an increase in adipose tissue mitochondrial energy metabolism and that chemotherapy can mitigate this. The purpose of the ChiFMeOE study is to identify adipocyte factors involved in the energy imbalance associated with the cachectic process and their response to chemotherapeutic treatments in patients with oesogastric cancer. Methods and analysis ChiFMeOE is a single-centre observational study that will prospectively include 60 patients referred to chemotherapy and surgery for oesophageal and gastro-oesophageal junction adenocarcinomas at the University Hospital of Clermont-Ferrand, France. Visceral and subcutaneous adipose tissue biopsies will be collected during surgery scheduled before and after neoadjuvant chemotherapy administration, as well as cachexia and nutritional assessment. The primary outcome is the maximum mitochondrial respiration rate (Vmax) measured by high-resolution respirometry. Secondary outcomes are other mitochondrial parameters (ie, enzymatic activities, proteins content and gene expression), tumour characteristics, nutritional status and body composition. Ethics and dissemination The study was approved by an independent institutional review board on June 2023 (Comité de protection des personnes Sud-Méditerranée V; 2023-A00582-43) and declared to the French regulatory authority for research. Written informed consent will be obtained prior to patient inclusion. The principal investigator will be notified of any changes in patient’s health status requiring a modification of his management and/or treatment during the course of the protocol. Results will be published in peer-reviewed journals. Trial registration number ClinicalTrials.gov, NCT05954117 .

To develop effective public health management strategies, it is necessary to account for the viewpoints of all stakeholders. Thus, anthropological approaches can potentially inform strategies for preventing and managing zoonotic diseases. Here, we use Q fever as a starting point for exploring how small ruminant farmers perceive the reality of microbes by disentangling the farmers’ often subtle relationships with their livestock, disease, and the world in general. We found that livestock farmers feel like they exist in the borderlands between two worlds: the non-naturalistic World A, characterised by long timespans and complex relationships with non-humans, and the naturalistic World B, characterised by short timespans and the control of non-humans. The occurrence of diseases leads to tension and shifts between the worlds, depending on how much farmers entrust World B with health risk management and relations with non-humans. Significant or complete delegation of these responsibilities may result in a sense of unease and dispossession, particularly when World B fails to provide productive solutions. Whether farmers view Q fever as mysterious and threatening is also highly dependent on the degree of health risk delegation. Overall, the agent that causes Q fever is perceived in one of two ways: as a fearsome pathogen or a normal denizen in the farm’s ecosystem. These results have implications beyond Q fever and clearly illustrate the concept of the “microbial turn”, which emphasizes the plurality and ambivalence of the relationships between humans and microbes.

PURPOSE The use of inotuzumab ozogamicin (InO), a conjugated anti-CD22 monoclonal antibody, is becoming a promising frontline treatment for older patients with ALL. PATIENTS AND METHODS EWALL-INO is an open-label prospective multicenter phase II trial (ClinicalTrials.gov identifier: NCT03249870 ). Patients age 55 years and older with newly diagnosed CD22 ⁺ Philadelphia chromosome–negative (Ph–) B-cell precursor (BCP) ALL were eligible. After a prephase, a first induction consisting of vincristine, dexamethasone, and three injections of InO (0.8 mg/m ² day 1, 0.5 mg/m ² day 8/day 15) was followed by a second induction combining cyclophosphamide, dexamethasone, and two injections of InO (0.5 mg/m ² day 1/day 8). Responders received up to six cycles of chemotherapy consolidation and 18-month chemotherapy maintenance. Allotransplant was allowed after three consolidations. The primary end point was 1-year overall survival (OS). RESULTS Between December 2017 and March 2022, 131 patients (median age 68 years) were included. Three patients died during induction 1 (n = 130), two from multiple organ failure and one from hemorrhage, and none during induction 2 (n = 120). After induction 2, 90% of the patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 80% had measurable residual disease (MRD2) <10 ⁻⁴ . Among responders (n = 119), 47 relapsed and 14 died in CR/CRp. One-year OS, relapse-free survival (RFS), and cumulative incidence of relapse (CIR) rates were 73.2%, 66%, and 25%, respectively. High-risk cytogenetics and lower CD22 expression (<70%) were associated with worse OS, while both high-risk cytogenetics and MRD2 ≥10 ⁻⁴ were associated with lower RFS and higher CIR. The 10 allotransplanted patients had very favorable outcomes (90% 2-year OS/RFS and no relapse). Only one nonfatal sinusoidal obstructive syndrome was documented during the study. CONCLUSION Our results support InO's use in first-line regimens for older patients with CD22 ⁺ Ph– BCP-ALL.

Background CT-scan and inflammatory and coagulation biomarkers could help in prognostication of COVID-19 in patients on ICU admission. Objective The objectives of this study were to measure the prognostic value of the extent of lung parenchymal lesions on computed tomography (CT) and of several coagulation and inflammatory biomarkers, and to explore the characteristics of the patients depending on the extent of lung parenchymal lesions. Design Retrospective monocentric observational study achieved on a dataset collected prospectively. Setting Medical ICU of the university hospital of Clermont-Ferrand, France. Patients All consecutive adult patients aged ≥18 years admitted between 20 March, 2020 and 31 August, 2021 for COVID-19 pneumonia. Interventions Characteristics at baseline and during ICU stay, and outcomes at day 60 were recorded. The extent of lung parenchyma lesions observed on the chest CT performed on admission was established by artificial intelligence software. Measurements Several clinical characteristics and laboratory features were collected on admission including plasma interleukin-6, HLA-DR monocytic–expression rate (mHLA-DR), and the extent of lung parenchymal lesions. Factors associated with day-60 mortality were investigated by uni- and multivariate survival analyses. Results 270 patients were included. Inflammation biomarkers including the levels of neutrophils, CRP, ferritin and Il10 were the indices the most associated with the severity of the extent of the lung lesions. Patients with more extensive lung parenchymal lesions (≥ 75%) on admission had higher CRP serum levels. The extent of lung parenchymal lesions was associated with a decrease in the PaO2/FiO2 ratio(p<0.01), fewer ventilatory-free days (p = 0.03), and a higher death rate at day 60(p = 0.01). Extent of the lesion of more than 75% was independently associated with day-60 mortality (aHR = 1.72[1.06; 2.78], p = 0.03). The prediction of death at day 60 was improved when considering simultaneously biological and radiological markers obtained on ICU admission (AUC = 0.78). Conclusions The extent of lung parenchyma lesions on CT was associated with inflammation, and the combination of coagulation and inflammatory biomarkers and the extent of the lesions predicted the poorest outcomes.

Heart Rhythm management is a continuously evolving sub-speciality of cardiology. Every year, many physicians and allied professionals start and complete their training in Cardiac Implantable Electronic Devices (CIED) or Electrophysiology (EP) across the EHRA member countries. While this training ideally ends with an EHRA certification, the description of the learning pathway (what, how, when and where) through an EHRA Core Curriculum is also a prerequisite for a successful training. The first EHRA core curriculum for physicians was published in 2009. Due to the huge developments in the field of electrophysiology and device therapy, this document needed updating. In addition, a certification process for allied professionals has been introduced, as well as a recertification process and accreditation of EHRA recognised training centres. Learning pathways are more individualised now, with Objective Structured Assessment of Technical Skills (OSATS) to monitor learning progression of trainees. The 2024 Updated EHRA Core Curriculum for physicians and allied professionals describes, for both CIED and EP, the syllabus, OSATS, training program and certification and recertification for physicians and allied professionals and stresses the importance of continued medical education after certification. In addition, requirements for accreditation of training centres and trainers are given. Finally, suggested reading lists for CIED and EP are attached as online supplements.

Background Glaucoma is a leading cause of blindness, affecting retinal ganglion cells (RGCs) and their axons. By 2040, it is likely to affect 110 million people. Neuroinflammation, specifically through the release of proinflammatory cytokines by M1 microglial cells, plays a crucial role in glaucoma progression. Indeed, in post-mortem human studies, pre-clinical models, and ex-vivo models, RGC degeneration has been consistently shown to be linked to inflammation in response to cell death and tissue damage. Recently, Rho kinase inhibitors (ROCKis) have emerged as potential therapies for neuroinflammatory and neurodegenerative diseases. This study aimed to investigate the potential effects of three ROCKis (Y-27632, Y-33075, and H-1152) on retinal ganglion cell (RGC) loss and retinal neuroinflammation using an ex-vivo retinal explant model. Methods Rat retinal explants underwent optic nerve axotomy and were treated with Y-27632, Y-33075, or H-1152. The neuroprotective effects on RGCs were evaluated using immunofluorescence and Brn3a-specific markers. Reactive glia and microglial activation were studied by GFAP, CD68, and Iba1 staining. Flow cytometry was used to quantify day ex-vivo 4 (DEV 4) microglial proliferation and M1 activation by measuring the number of CD11b⁺, CD68⁺, and CD11b⁺/CD68⁺ cells after treatment with control solvent or Y-33075. The modulation of gene expression was measured by RNA-seq analysis on control and Y-33075-treated explants and glial and pro-inflammatory cytokine gene expression was validated by RT-qPCR. Results Y-27632 and H-1152 did not significantly protect RGCs. By contrast, at DEV 4, 50 µM Y-33075 significantly increased RGC survival. Immunohistology showed a reduced number of Iba1⁺/CD68⁺ cells and limited astrogliosis with Y-33075 treatment. Flow cytometry confirmed lower CD11b⁺, CD68⁺, and CD11b⁺/CD68⁺ cell numbers in the Y-33075 group. RNA-seq showed Y-33075 inhibited the expression of M1 microglial markers (Tnfα, Il-1β, Nos2) and glial markers (Gfap, Itgam, Cd68) and to reduce apoptosis, ferroptosis, inflammasome formation, complement activation, TLR pathway activation, and P2rx7 and Gpr84 gene expression. Conversely, Y-33075 upregulated RGC-specific markers, neurofilament formation, and neurotransmitter regulator expression, consistent with its neuroprotective effects. Conclusion Y-33075 demonstrates marked neuroprotective and anti-inflammatory effects, surpassing the other tested ROCKis (Y-27632 and H-1152) in preventing RGC death and reducing microglial inflammatory responses. These findings highlight its potential as a therapeutic option for glaucoma.

We use the euro area debt crisis experience to study episodes when sovereigns lose access to bond markets. We construct a detailed dataset with potential leading indicators and evaluate their ability to forecast episodes when market access is lost. We show that factors capable of foreseeing market tensions go beyond traditional metrics of the fiscal stance and of global and domestic macroeconomic conditions. Variables that describe conditions in primary and secondary sovereign bond markets are key predictors of market access tensions. We construct simple indices and multivariate models and use them to predict market access tensions. Simple indices capture worsening conditions but yield unsatisfactory out-of-sample results. Multivariate models generate better forecasts highlighting how tools to evaluate risks to sovereign market access trade off communicability and accuracy. Finally, we show the importance of accounting for different policymakers’ preferences.