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Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts
No full textInternational audienceAbstract Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leukocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesized the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms at genome-wide significance (P < 5 × 10−8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD-mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses
Mycoplasma pneumoniae infection in adult inpatients during the 2023–24 outbreak in France (MYCADO): a national, retrospective, observational study
No full textInternational audienc
Multifunctional dietary approach reduces intestinal inflammation in relation with changes in gut microbiota composition in subjects at cardiometabolic risk: the SINFONI project
No full textInternational audienceThe development of cardiometabolic (CM) diseases is associated with chronic low-grade inflammation, partly linked to alterations of the gut microbiota (GM) and reduced intestinal integrity. The SINFONI project investigates a multifunctional (MF) nutritional strategy's impact combining different bioactive compounds on inflammation, GM modulation and CM profile. In this randomized crossover-controlled study, 30 subjects at CM-risk consumed MF cereal-products, enriched with polyphenols, fibers, slowly-digestible starch, omega-3 fatty acids or Control cereal-products (without bioactive compounds) for 2 months. Metabolic endotoxemia (lipopolysaccharide (LPS), lipopolysaccharide-binding protein over soluble cluster of differentiation-14 (LBP/sCD14), systemic inflammation and cardiovascular risk markers, intestinal inflammation, CM profile and response to a one-week fructose supplementation, were assessed at fasting and post mixed-meal. GM composition and metabolomic analysis were conducted. Mixed linear models were employed, integrating time (pre/post), treatment (MF/control), and sequence/period. Compared to control, MF intervention reduced intestinal inflammation (fecal calprotectin, p = 0.007) and endotoxemia (fasting LPS, p < 0.05), without alteration of systemic inflammation. MF decreased serum branched-chain amino acids compared to control (p < 0.05) and increased B.ovatus, B.uniformis, A.butyriciproducens and unclassified Christensenellaceae.CAG-74 (p < 0.05). CM markers were unchanged. A 2-month dietary intervention combining multiple bioactive compounds improved intestinal inflammation and induced GM modulation. Such strategy appears as an effective strategy to target low-grade inflammation through multi-target approach
ICU mortality of post-myocardial infarction ventricular septal defect complicated by cardiogenic shock: a retrospective multicentric cohort.
No full textInternational audiencePurpose: Post myocardial infarction ventricular septal defect (PMI-VSD) complicated by refractory cardiogenic shock is associated with an extremely high mortality rate. We sought to evaluate the factors associated with in-ICU mortality in patients with PMI-VSD-related cardiogenic shock.Methods: Patients with PMI-VSD complicated by cardiogenic shock, admitted in 10 French tertiary centers between 2008 and 2022, were retrospectively included. The primary outcome was in-ICU mortality. The timing of surgery was classified as early (≤ 7 days) or late (> 7 days). Multivariable analysis was performed to identify the variables associated with in-ICU mortality.Results: A total of 138 patients were included (mean age 70 (± 10) years, female sex 54%). Of these, 116 patients (84%) received MCS, including 43 patients (31%) with VA-ECMO. VSD surgical closure was performed in 93 patients (67%, 60 early, 33 late). Only 2 patients had percutaneous closure without surgical repair. A total of 84 patients (61%) died. The type of surgical management strategy was significantly associated with in-ICU mortality (no surgery, 100%; early surgery, 45%; late surgery, 27%; ptrend < 0.001). In all patients, the variables independently associated with in-ICU mortality were: old age (adjusted OR = 1.1, 95%CI [1.02-1.12.], p = 0.004), SOFA score (adjusted OR = 1.2, 95%CI [1.07.-1.37], p = 0.003), and VA-ECMO (adjusted OR = 2.9, 95%CI [1.2-7.7], p = 0.02). In patients with VSD surgical closure, a longer delay between ICU admission and VSD surgical closure was independently associated with decreased in-ICU mortality (adjusted OR = 0.9, 95%CI [0.79-0.96], p = 0.003).Conclusion: Delayed VSD closure is associated with improved outcomes in PMI-VSD complicated by cardiogenic shock
Therapeutic plasma exchange accelerates immune cell recovery in severe COVID-19
No full textInternational audienceBackground: Immunological disturbances (anti-type I IFN auto-antibody production, cytokine storm, lymphopenia, T-cell hyperactivation and exhaustion) are responsible for disease exacerbation during severe COVID-19 infections.Methods: In this study, we set up a prospective, randomised clinical trial (ClinicalTrials.gov ID: NCT04751643) and performed therapeutic plasma exchange (TPE) in severe COVID-19 patients in order to decrease excess cytokines and auto-antibodies and to assess whether adding TPE to the standard treatment (ST, including corticosteroids plus high-flow rate oxygen) could help restore immune parameters and limit the progression of acute respiratory distress syndrome (ARDS).Results: As expected, performing TPE decreased the amount of anti-type I IFN auto-antibodies and improved the elimination or limited the production of certain inflammatory mediators (IL-18, IL-7, CCL2, CCL3, etc.) circulating in the blood of COVID-19 patients, compared to ST controls. Interestingly, while TPE did not influence changes in ARDS parameters throughout the protocol, it proved more effective than ST in reversing lymphopenia, preventing T-cell hyperactivation and reducing T-cell exhaustion, notably in a fraction of TPE patients who had an early favourable respiratory outcome. TPE also restored appropriate numbers of CD4+ and CD8+ T–cell memory populations and increased the number of circulating virus-specific T cells in these patients.Conclusion: Our results therefore indicate that the addition of TPE sessions to the standard treatment accelerates immune cell recovery and contributes to the development of appropriate antiviral T-cell responses in some patients with severe COVID-19 disease
Methotrexate versus conventional disease-modifying antirheumatic drugs in the treatment of non-anterior sarcoidosis-associated uveitis.
No full textInternational audienceAims To compare the safety and efficacy of methotrexate (MTX), mycophenolate mofetil (MMF) and azathioprine (AZA) in non-anterior sarcoidosis-associated uveitis. Methods Retrospective study including non-anterior sarcoidosis-associated uveitis according to the revised International Workshop on Ocular Sarcoidosis criteria. The primary outcome was defined as the median time to relapse or occurrence of serious adverse events leading to treatment discontinuation. Results 58 patients with non-anterior sarcoidosis-associated uveitis (MTX (n=33), MMF (n=16) and AZA (n=9)) were included. The time to treatment failure (ie, primary outcome) after adjustment for corticosteroids dose and the presence of vasculitis was significantly higher with MTX (median time of 34.5 months with MTX (IQR: 11.8 –not reached) vs 8.4 months (3.1–22.9) with MMF and 16.8 months (8.0–90.1) with AZA (p=0.020)). The risk of relapse at 12 months was more than twice lower in MTX as compared with MMF (p=0.046). Low visual acuity at the last visit was significantly lower with MTX (4% vs 9% in MMF vs 57% in AZA group (p=0.008)). Regarding all 75 lines of treatment (MTX (n=39), MMF (n=24) and AZA (n=12)), MTX was more effective than MMF and AZA to obtain treatment response at 3 months (OR 10.85; 95% CI 1.13 to 104.6; p=0.039). Significant corticosteroid-sparing effect at 12 months (p=0.035) was only observed under MTX. Serious adverse events were observed in 6/39 (15%), 5/24 (21%) and 2/12 (17%) with MTX, MMF and AZA, respectively. Conclusion In non-anterior sarcoidosis-associated uveitis, MTX seems to be more efficient compared with AZA and MMF and with an acceptable safety profile
A Randomized clinical trial evaluating the impact on survival and quality of life of 177Lutetium[Lu]-edotreotide versus everolimus in patients with neuroendocrine tumors of the lung and thymus: the LEVEL study (GETNE T-2217)
No full textInternational audienceBackground: Everolimus is the only approved therapy for patients with advanced neuroendocrine tumors (NET) of lung and thymus and new treatment options are urgently needed. Expression of somatostatin receptor 2 (SSTR2) is frequently seen in functional imaging in lung-NETs opening the opportunity to treat SSTR2 positive patients with radioligand therapies (RLT). Retrospective data suggest a potential meaningful benefit of RLT directed to SSTR2 in lung-NET patients.Methods: The LEVEL trial is a randomized, open-label, phase III international trial of 177Lu-edotreotide versus everolimus in patients with progressive, locally advanced or metastatic, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment-naïve or have progressed (PD) on somatostatin analogues or ≤ 2 additional systemic treatments. Prior RLT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177Lu-edotreotide (total administered activity 7.5 ± 0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Only patients with positivity in somatostatin receptor imaging will be included. CT or MRI scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is progression-free survival (PFS) according to RECIST v1.1 based on local investigator assessment. Secondary endpoints include overall survival, overall response rate, safety, and quality of life (EORTC QLQ-C30). The expected sample size is 120 patients to demonstrate statistical significant risk reduction of 46.4% (HR = 0.536) in PFS with the experimental treatment using an overall 5% two-sided alpha error with 80% power. An interim PFS analysis was included using the Lan-DeMets with O'Brian-Fleming-like boundaries.Discussion: The LEVEL trial will investigate if 177Lu-edotreotide has the potential to be incorporated as a standard treatment option for patients with NETs from the lung and Thymus
Mice lacking the fructose transporter Glut5 exhibit excessive androgens and reduced sperm motility
No full textInternational audienceOverconsumption of fructose is linked to metabolic diseases, which are often associated with reduced fertility. GLUT5 is the most specific fructose transporter. To investigate its role in the testes, we analyzed the male reproductive phenotype of transgenic male mice deficient in GLUT5 (GLUT5−/− or GLUT5 knockout [KO] mice). Glut5 expression was shown in Leydig cells and germ cells, from primary spermatocytes to spermatozoa. We found reduced intratesticular fructose and pyruvate concentrations in GLUT5−/− mice. These mice exhibited 30% lower litter sizes compared with control mice. Histological analysis of the testes revealed some seminiferous tubules with a “Sertoli cell-only” phenotype, although spermatogenesis occurred normally in most tubules. Reduced fertility in GLUT5 KO mice was linked to lower sperm production and impaired sperm quality. Spermatozoa from these mice displayed reduced motility, head abnormalities, and a diminished acrosome reaction, which was associated with reduced cyclic adenosine monophosphate content and impaired phosphorylation of protein kinase A substrates in the acrosome. Unexpectedly, androgen production in GLUT5 KO mice was 3-fold higher than in controls, despite unchanged luteinizing hormone levels. Electron microscopy of Leydig cells revealed a highly developed smooth endoplasmic reticulum, increased lipid droplets, and abnormal mitochondrial structures, suggesting disrupted mitochondrial dynamics. Proteomic analysis identified 155 deregulated proteins in the testicular tissue of GLUT5 KO mice, nearly half of which were associated with sperm motility, germ cell morphology, glycolysis, mitochondrial dynamics, and oxidative stress. In conclusion, the absence of the specific fructose transporter GLUT5 reduced testicular fructose content and led to an asthenozoospermia phenotype accompanied by hyperandrogenism
Chapter 10: What parathyroid imaging is required for hyperparathyroidism?
No full textInternational audienceIn over 80% of cases, primary hyperparathyroidism results from hypersecretion of PTH by a single parathyroid adenoma. Multi-glandular involvement, combining adenoma and/or hyperplasia in varying proportions, is also possible, although less frequent. When the diagnosis of hyperparathyroidism is certain and surgery is envisaged, imaging is useful for locating the hyperfunctioning gland or glands. First-line exploration is based on a parathyroid ultrasound and a nuclear medicine examination, which may be parathyroid scintigraphy, preferably double isotope I/12399m Tc-sestamibi, with planar and tomoscintigraphic acquisitions, or a PET-CT scan with 18F-choline. In the event of negative results, it is advisable to perform a choline PET scan if the initial examination was scintigraphy. In difficult situations, additional investigations using 4D parathyroid CT or parathyroid MRI, fine-needle aspiration cytology and determination of PTH in the flushing fluid are possible after multidisciplinary discussion in an expert center
Pharmacological effects of osimertinib on a chicken chorioallantoic membrane xenograft model with the EGFR exon‐19‐deleted advanced NSCLC mutation
No full textInternational audienceNon‐small cell lung cancer (NSCLC) affects 10–50% of patients with epidermal growth factor receptor ( EGFR ) mutations. Osimertinib is a third‐generation EGFR tyrosine kinase inhibitor (TKI) that radically changes the outcome of patients with tumors bearing EGFR sensitizing or EGFR T790M resistance mutations. However, resistance usually occurs, and new therapeutic combinations need to be explored. The chorioallantoic membrane (CAM) xenograft model is ideal for studying aggressive tumor growth and the responses to complex therapeutic combinations due to its vascularization and complex microenvironment. This study aims to demonstrate the relevance of analyzing a complex therapeutic response to osimertinib treatment, especially through advanced transcriptomic analysis with the CAM model, which has been limited thus far. We engrafted HCC827 cells ( EGFR p.E746_A750del) into the CAM model and treated them with various osimertinib doses for 7 days. The study involved supervised multivariate discrimination and ontology analysis of human transcriptional data. We found that CDX tumor growth inversely correlated with osimertinib dosage, with a notable 35% tumor weight reduction at 10 μ m . Transcriptomic analysis revealed that osimertinib reduces EGFR pathway activity and its effectors, and dampens chemotaxis, immune recruitment and angiogenesis, indicating that effectiveness extends beyond cellular mechanisms to the tissue level. This was supported by a 15% reduction in blood vessels around the xenograft in osimertinib‐treated cases. This study is the first to demonstrate that ontological analysis of transcriptomic data in the CAM model aligns with clinical observations, highlighting the relevance of this methodology for understanding and ameliorating the efficacy of targeted therapy in NSCLC