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BA.1 breakthrough infection elicits distinct antibody and memory B cell responses in vaccinated-only versus hybrid immunity individuals
No full textInternational audienceImmune memory is influenced by the frequency and type of antigenic challenges. Here, we performed a cross-sectional comparison of immune parameters following a BA.breakthrough infection in individuals with prior hybrid immunity (conferred by infection and vaccination) versus those solely vaccinated in a cohort of health care workers in Lyon, France. The results showed higher levels of serum anti-RBD antibodies and neutralizing antibodies against BA.1 post-infection in the vaccine-only group. Individuals in this group also showed a decrease in memory B cells against the ancestral strain but an increase in those specific and cross-reactive to BA.1, suggesting a more limited immune imprinting. Conversely, hybrid immunity prevents the decrease in ADCC response, possibly by limiting IgG4 class-switching, and enhanced anti-N responses post-infection. This highlights that BA.1 breakthrough infection induces different immune responses depending on prior history of vaccination and infection, which should be considered for further vaccination guidelines
A three‐dimensional scoring system for assessment of individual bony and laxity phenotype restoration (knee SIPR) in personalised TKA as a base for treatment guidance
No full textInternational audienceAbstract Purpose Although personalised alignment has become popular in total knee arthroplasty (TKA), it is unclear which workflow and alignment strategy best restores the bony and laxity phenotype and whether this varies between knee phenotypes. The aim of this study was, therefore, to develop a three‐dimensional (3D) scoring system which assesses bony anatomy, laxity and alignment parameters for TKA. This novel 3D scoring system was tested using a validated TKA simulator on three different knee phenotypes with various alignment workflows. 3D scores were compared between phenotypes and workflows. Methods In this 3D scoring system, analyses of bony resections of all six joint planes were included (maximum score for anatomical resections ± 1 mm) as well as joint laxity/gap analysis (maximum score for balanced extension/flexion gap, medial and lateral side ± 2 mm). Additional alignment parameters (hip–knee–ankle angle, medial proximal tibial angle, lateral distal femoral angle, Tibia slope and coronal plane alignment of the knee) were integrated. All data points were obtained from preoperative long leg x‐rays, intraoperative gap analysis with CAS and intraoperative cartilage measurements. The maximum score for all categories was 27 points (12/10/5). The 3D scores were analysed for nine knees with three knee phenotypes (neutral, varus and valgus) with six different alignment workflows (mechanical alignment—femur first, adjusted mechanical alignment—femur first, unrestricted kinematic alignment, restricted kinematic alignment, inverse kinematic alignment and functional alignment‐tibia first) using the Knee‐computational alignment trainer simulator. Comparison between workflows in all phenotypes was performed for each category. Results In neutral phenotypes, all alignment workflows, including mechanical alignment, showed similar high mean scores. In varus and valgus phenotypes, personalised alignment workflows scored higher than systematic workflows. While in varus phenotypes, scoring of personalised alignment workflows was similarly high to that in straight knees phenotypes, it showed lower means in valgus phenotypes. Measured‐resection workflows restored bony phenotypes in a higher percentage while gap‐balanced workflows performed better in the category of laxity/gap balance. None of the personalised workflows performed best in all knees. Conclusions The new 3D scoring system for individual knee phenotype restoration in TKA allowed a quantitative analysis of the individual reconstruction of the bony and laxity anatomy in different knee phenotypes. First preliminary results show that personalised alignment workflows perform better than systematic mechanical alignment in varus and valgus phenotypes, while in neutral phenotypes, the difference was minimal. None of the personalised workflows scored best in all knees, showing the potential for a 3D phenotype workflow including more bony alignment and laxity parameters. Testing of this 3D scoring system in a larger series of cases is crucial to prove the concept and test correlations between 3D scores and clinical outcomes. Level of Evidence Level IIa
Aarskog-Scott syndrome: a clinical study based on a large series of 111 male patients with a pathogenic variant in FGD1 and management recommendations
No full textInternational audienceBackground: Aarskog-Scott syndrome (AAS) is a rare condition with multiple congenital anomalies, caused by hemizygote variants in the FGD1 gene. Its description was based mostly on old case reports, in whom a molecular diagnosis was not always available, or on small series. The aim of this study was to better delineate the phenotype and the natural history of AAS and to provide clues for the diagnosis and the management of the patients.Methods: Phenotypic characterisation of the largest reported AAS cohort, comprising 111 male patients with proven causative variants in FGD1, through comprehensive analyses of clinical data including congenital anomalies, growth and neurodevelopment. Review of photographs and radiographs by experts in dysmorphology and skeletal disorders.Results: This study refines the phenotypic spectrum of AAS, with the description of new morphological and radiological features, and refines the prevalence of the features. Short stature is less frequent than previously reported and has a prenatal onset in more than half of the patients. The growth has a specific course with a catch-up during the first decade often leading to low-normal stature in adulthood. Whereas intellectual disability is rare, patients with AAS have a high prevalence of specific learning difficulties and attention hyperactivity disorder. In light of this better knowledge of AAS, we provide management recommendations.Conclusion: A better knowledge of the natural history and phenotypic spectrum of AAS will be helpful for the clinical diagnosis and for the interpretation of FGD1 variants using a retrophenotyping strategy, which is becoming the most common way of diagnosis nowadays. Recommendations for care will improve the management of the patients
Serotonin 5-HT1A receptor biased agonists: The challenge of translating an innovative neuropharmacological concept into therapeutics
No full textInternational audienceSerotonin 5-HT 1A receptor agonists are prime candidates for CNS drug discovery due to their involvement physiological and pathological processes relevant to neurology and psychiatry. However, the lack of target specificity of many previously characterized agonists has long been a barrier to pharmacological and therapeutic progress. Some of the obstacles may be overcome through the recent concept of biased agonism, which has attracted considerable attention to the development of novel chemical entities at 5-HT, and particularly 5-HT 1A receptors, by specifically targeting intracellular signalling pathways that may themselves be linked to specific brain regions and therapeutic indications. There is now abundant translational data demonstrating distinct molecular and functional pharmacological signatures between different 5-HT 1A receptor agonists, opening new opportunities for research in neurology and psychiatry. Nevertheless, important limitations need to be overcome, including understanding the precise molecular basis for biased agonism, the need for improved translatable models, and the currently limited clinical data on biased agonists. Here, we review the current limits of our knowledge of 5-HT 1A receptor biased agonists and the limitations of available pharmacological tools, counterbalanced by the translational possibilities and therapeutic perspectives opened by novel, highly selective 5-HT1A receptor drug-candidates
French protocol for the diagnosis and management of giant cell arteritis
No full textInternational audienceGiant cell arteritis (GCA) is a large-vessel vasculitis that mainly affects women over fifty. GCA usually involves branches from the external carotid arteries, causing symptoms such as headaches, scalp tenderness, and jaw claudication. The most severe complication is ophthalmologic involvement, including acute anterior ischemic optic neuropathy and, less frequently, central retinal artery occlusion with a risk of permanent blindness. Approximately 40% of patients may have involvement of the aorta or its branches, which has a poor prognosis, although this is often asymptomatic at diagnosis. Diagnosis is largely based on imaging techniques such as FDG-PET combined with CT, CT angiography, or MRI angiography of the aorta and its branches. Polymyalgia rheumatica is associated with GCA in 30-50% of cases but may also occur independently. Treatment must be initiated urgently in the presence of ophthalmologic signs or when GCA is strongly suspected to prevent vision loss. The gold standard to confirm the diagnosis is temporal artery biopsy. However, Doppler ultrasound and vascular imaging are also reliable diagnostic techniques. Initially, high doses of corticosteroids like prednisone (40-80mg per day) are the mainstay of treatment. Tocilizumab can be discussed in combination with prednisone for corticosteroid sparing. Long-term management is essential, including monitoring for disease recurrence and corticosteroid-related side effects. General practitioners play a crucial role in early diagnosis, directing patients to specialized centres, and in managing ongoing treatment in collaboration with specialists. This collaboration is essential to address potential long-term complications such as cardiovascular events. They can occur five to ten years after the diagnosis of GCA even when the disease is no longer active, meaning that vigilant follow-up is required due to the patients' age and status
Nanopore Sequencing as a Cutting-Edge Technology for Medulloblastoma Classification
No full textInternational audienceBackground: Medulloblastoma (MB) is one of the most prevalent embryonal malignant brain tumors. Current classification organizes these tumors into four molecular subgroups (WNT, SHH, Group 3, and Group 4 MB). Recently, a comprehensive classification has been established, identifying numerous subtypes, some of which exhibit a poor prognosis. It is critical to establish effective subtyping methods for accurate diagnosis and patient's management that strikes a delicate balance between improving outcomes and minimizing the risk of comorbidities.Methods: We evaluated the ability of Nanopore sequencing to provide clinically relevant methylation and copy number profiles of MB. Nanopore sequencing was applied to an EPIC cohort of 44 frozen MB, benchmarked against the gold standard EPIC array, and further evaluated on an integrated diagnosis cohort of 116 MB.Results: Most MB of both cohorts (42/44; 95.5% and 106/116; 91.4% respectively) were accurately subgrouped by Nanopore sequencing. Employing Flongle flow cells for 18 MB allowed a more rapid and cost-effective analysis, with 94.4% (17/18) being correctly classified. Nanopore sequencing enabled us to accurately subtype 28/30 (93.3%) MB.Conclusion: This study, conducted on the largest cohort of MB analyzed with Nanopore sequencing to date, establishes the proof of concept that this modern and innovative technology is well-suited for MB classification. Nanopore sequencing demonstrates a robust capacity for precise subtyping of MB, a critical advancement that holds significant potential for enhancing patient stratification in future clinical trials. Its ability to deliver quick and cost-effective results firmly establishes it as a game-changer in the field of MB classification
Attentes méthodologiques pour la démonstration de l’efficacité des produits de santé par les études observationnelles
No full textAteliers de Giens 2024/Recherche clinique et évaluation des produits de santéInternational audienceLa problématique de l’évaluation de l’efficacité des technologies de santé (médicaments, dispositifs, etc.) par les études observationnelles prend de plus en plus d’importance depuis que les agences d’enregistrement et d’accès au marché envisagent de les considérer dans leur processus d’évaluation. Dans ce contexte, les études observationnelles doivent être capables d’apporter de réelles démonstrations, d’un niveau de fiabilité comparable à celles produites par l’approche classique basée sur l’essai randomisé et contrôlé (RCT). L’objectif de la table ronde a été d’établir les critères d’acceptabilité pour qu’une étude observationnelle (« non-randomized, non-interventional study ») puisse prétendre apporter ces démonstrations, et éventuellement servir d’étude confirmatoire pour les autorités d’enregistrement et d’accès au marché, la construction des stratégies thérapeutiques ou l’élaboration des recommandations. Pour cela, l’étude doit être une véritable étude de confirmation respectant la démarche hypothético-déductive et garantissant l’absence de HARKing et de p-hacking en attestant de l’élaboration d’un protocole et d’un plan d’analyse statistique, enregistrés avant toute analyse inférentielle. Elle doit aussi s’inscrire dans une démarche formalisée d’inférence causale et montrer qu’elle permet d’identifier correctement l’estimand causal recherché. L’étude doit garantir l’absence de biais de confusion résiduelle à l’aide d’une prise en compte de tous les facteurs de confusion affectant la comparaison, ceux-ci devant être déterminés par une approche formelle (de type graphique de causalité, DAGs). Les diagnostics de biais de confusion résiduel par analyse de falsification et de nullification doivent montrer leur absence. L’étude doit être à faible risque de biais, en particulier de biais de sélection, entre autres en utilisant un design d’émulation d’essai cible. Le risque alpha global doit être strictement contrôlé. L’absence de publication sélective de résultat et de biais de sélection doit être garantie
SEMA3A as a biomarker of primary ventricular fibrillation complicating STEMI
No full textInternational audienceNo abstract availabl
Characteristics and outcomes of ECMO cannula-related infections: a European multicenter retrospective study
No full textInternational audienceObjective: Only few data regarding epidemiology and management of ECMO cannula-related infections (ECMO-CRIs) exist. The aim of our study was to describe their epidemiology and prognosis, and to evaluate factors associated with outcome.Methods: We performed a multicenter retrospective study in 12 European ICUs, including patients with ECMO-CRI, defined as a clinical suspicion plus a positive bacterial sample of ECMO-cannulation site. Primary objective was to describe ECMO-CRI characteristics and outcomes. Secondary objectives were to evaluate the rates of infection recurrence, their risk factors, and to evaluate the impact of antimicrobial treatment duration on outcome.Results: During the study period, 109 patients with ECMO-CRI (78 having concomitant positive blood culture with the same pathogen) were included. Pathogens responsible for infections were predominantly Enterobacteriaceae, coagulase-negative Staphylococcus and Enterococcus spp., and 42% of episodes were polymicrobial. Rates of infection recurrence was 13% and ICU-mortality rate was 51%. Risk factors for death were concomitant bloodstream infection with same pathogen and septic shock Patients with antibiotic course ≤ 8 days had similar infection recurrence rate and outcomes (including mortality) than patients with prolonged (> 8 days) antibiotic course.Conclusion: ECMO-CRIs are frequently associated with BSI and frequently polymicrobial. Duration of antimicrobial treatment for ECMO-CRI ≤ 8 days does not seem to be associated with an increased risk of recurrence or death, as compared to longer treatment
