Institut Necker Enfants Malades

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Understanding the causes of the exceptional rate of evolution of the mammalian placenta is likely to aid the understanding of placental development and the etiology of the human-specific pregnancy disorder pre-eclampsia (PE). As retroelements are often lineage-specific and known to be co-opted for placental function, here we consider the binding of the transcription factors GATA3 and DLX5 to retroelements. These factors are dysregulated in pre-eclampsia, as are their downstream consequences. We identify retrovirus-derived LTR8B as a placentally-relevant cis-regulatory element (CRE), not least within the PSG array, a primate-specific genomic region that exhibits high intraspecies variability. LTR8B at PSG9 is particularly influential affecting other PSG family members. Moreover, unique among PSGs, PSG9 produces both secreted and membrane-anchored isoforms. The retroelement MER65-int provides alternative polyA signals that enable the evolution of secreted PSG variants by truncating the ancestral CEACAM protein's transmembrane domain. Functional characterization finds that LTR8B/PSG9 regulates the differentiation of multinucleated trophoblasts (syncytialization) and, like chorionic gonadotropin and syncytin1, determines the identity of syncytiotrophoblasts. Notably, PSG9 is the most upregulated PSG in PE, with levels correlated with GATA3 and DLX5 levels. Retroelements contribute to the structural and expression evolution of PSG genes, facilitating lineage-specific placental evolution. The LTR8B/PSG9 regulatory network plays a central role in syncytiotrophoblast differentiation. Given the association between DLX5/GATA3 dysregulation and elevated PSG9 levels, along with PSG9's expression in the first trimester, PSG9 shows potential as a predictive biomarker for preeclampsia.

There is a significant need for trials that evaluate the treatment of University of Texas (UT) grade 2 and 3 diabetic foot ulcers (bone, joint, or tendon exposed wounds). We undertook a trial looking at the effect of intact fish skin graft (IFSG) on these deep and difficult-to-heal ulcers. 262 patients Intent to Treat (ITT) patients with UT grade 2 and 3 DFUs were randomised to receive intact fish skin graft (IFSG) or a standardised treatment (SOC) that adhered to the International Working Group on the Diabetic Foot (IWGDF) guidelines. The secondary endpoints that were measured included wound area reduction (WAR), healing rates at 20 and 24 weeks; closure rates by UT grade, perfusion, quality of life, pain reduction and IFSG safety. We report ITT (all randomised) (mITT previosly reported) The (WAR) at 12 weeks was 65.53% for IFSG versus 30.82% for SOC (p = 0.007). UT 2 wounds (60% of total) exhibited a closure rate of 47% versus 23% at 16 weeks for IFSG versus SOC (p = 0.0033). Target wound infections were comparable (39 vs. 37) and major outcomes were comparable during the 24 week period (target-limb amputations 8% vs. 7%). Time-to-heal favoured IFSG (restricted mean to 24 weeks 17.31 vs. 19.37 weeks; KM/log-rank significant; Cox HR 1.59). The in the treatment of deep complex diabetic foot wounds the addition of IFSG significantly improved the number of patients with total wound closure as well as the time to wound closure without increased risk of complications. This improvement in total wound closure and time to wound closure was noted across prior amputation status, quality of perfusion, and UT grade.

Tisagenlecleucel (tisa-cel), an autologous anti-CD19 CAR T-cell therapy, has significantly improved outcomes in pediatric, adolescents and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). However, 30-50% experience early failure or relapse. We retrospectively analyzed 52 cases of early failures (n = 13) or relapses (n = 39), evaluating post-tisa-cel outcomes and prognostic factors. CD19 antigen loss was the only factor associated with a lower complete remission rate after salvage therapy (OR = 0.16, 95%CI [0.03-0.90], p = 0.04). Median overall survival (OS) was 14.5 months, with a 2-year OS of 37.4% (95%CI [24.4-50.4]), similar between early failure (38.5%) and relapse (37.0%) groups (p = 0.78). Patients with measurable residual disease only at salvage initiation had significantly improved 2-year OS (61.9%, (95%CI [38.1-78.8])) compared to those with overt disease (20.7%, (95%CI [8.4-36.7], p = 0.008)). Factors associated with inferior OS included high pre-infusion tumor burden (HR = 3.57, p < 0.01), and prior inotuzumab ozogamicin exposure (HR = 3.81, p < 0.01). Although salvage therapies and hematopoietic stem cell transplantation benefit some patients, 5 of 18 transplanted patients died from treatment-related toxicity, underscoring the significant associated risks. These findings highlight the poor prognosis of tisa-cel failures and the urgent need for novel strategies.

Some pediatric tracheal pathologies remain therapeutic dead ends for which current palliative strategies are fraught with serious complications. With the aim of a tracheal replacement, our team has previously developed and patented a clinical grade partially decellularized trachea (PDT) from porcine tracheas. The aim of this work was to study and compare the biointegration mechanisms of this PDT in vivo, in a pig cervical muscle, with or without immunosuppressant. The secondary objective was to evaluate the optimal maturation time of the PDT in this heterotopic position. In total, 11 female Large White/Landrace pigs, weighing between 50 and 70 kg were included in this study. The mean age of the animals at the implantation was 4.8 months. The PDTs were implanted in a cervical muscle of pigs for either 28 days, with or without cyclosporin A treatment, or for 56 days without immunosuppression. Histological evaluation showed very good PDT biointegration, characterized by neovascularization and fibroblast colonization, and no detectabale infection. Additionally, tissue and blood analyses showed no signs of graft rejection or surrounding tissue necrosis. Immunosuppression did not show any superiority in terms of biointegration after 28 days of treatment. After 56 days of implantation, a more significant degradation of the cartilage. Therefore, the optimal condition for PDT maturation proved to be 28 days, without immunosuppression.

Autoimmune blistering diseases (AIBDs) in children and adolescents present a major challenge in diagnosis and management because of their rarity and the presence of other differential diagnoses with blistering. They are potentially serious, and timely diagnosis and optimal management can help prevent morbidity related to both the diseases and their treatments. The Autoimmune Blistering Diseases Task Force of the European Academy of Dermatology and Venereology (EADV) has initiated evidence-based, expert-informed clinical guidelines for the diagnosis, treatment and monitoring of paediatric AIBDs. A writing group conducted a systematic review of the available literature on AIBDs in children and adolescents, and since there is limited strong evidence in the literature, recommendations were formulated by consensus over three rounds of structured feedback and revision by the Core Group and Expert Group of the task force (32 voting experts; >75% agreement threshold). Although all AIBDs-including intra-epidermal and subepidermal blistering disorders-are reported in children, linear IgA dermatosis (LAD) is the most common (42-83%). The diagnostic approach in the paediatric age group does not differ from that in adults. Treatment recommendations are tailored to paediatric patients, taking into account developmental pharmacokinetics, potential adverse effects and the impact of disease and therapy on quality of life. These guidelines provide the first comprehensive, paediatric-focused framework for the diagnosis and management of AIBDs. Implementing the recommendations should harmonize care, reduce treatment-related toxicity and improve quality of life for affected children while steering future research towards critical knowledge gaps.

BackgroundTo develop a 10-year risk score to predict lower-limb amputation (LLA) in individuals with type 1 diabetes, and to assess whether this score also predicts kidney failure, and cardiovascular disease (CVD).MethodsThe LLA risk score was derived from GENEDIAB and GENESIS, two prospective French and Belgian cohorts of 828 individuals with type 1 diabetes. External validation was assessed in SURGENE, an independent cohort of 247 individuals with type 1 diabetes. LLA was defined as a non-traumatic amputation above the metatarsophalangeal joint, kidney failure as the need for renal replacement therapy, transplantation, or an estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m2, CVD as the occurrence of myocardial infarction, heart failure, or stroke, and major adverse cardiac event (MACE) as a composite of myocardial infarction, stroke, heart failure, or all-cause death.ResultsDuring 12 years of follow-up, LLA, kidney failure, CVD and MACE occurred in 71 (9%), 84 (11%), 138 (17%) and 265 (32.0%) of participants, respectively. Sex, diabetes duration, prior LLA, eGFR, and albuminuria were identified as independent determinants of incident LLA and were used to construct the risk score. Compared to participants in the lowest score, those in the highest score had a significantly increased risks of LLA (multivariable-adjusted HR 6.02 [95% CI, 1.92–18.89]), kidney failure (8.97 [3.95–20.37]), CVD (2.50 [1.34–4.64]) and MACE (1.91 [1.24–2.96]). The score demonstrated good discriminative performance for LLA (C-index 0.82 [0.77–0.87]), kidney failure (0.86 [0.82–0.91]), CVD (0.73 [0.68–0.78]), and MACE (0.71 [0.68–0.75]). Similar predictive performance was observed in the validation cohort.ConclusionThis newly developed 10-year LLA risk score achieved excellent ability to identify individuals with type 1 diabetes at high risk for LLA, kidney failure, CVD, and MACE.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s12933-025-03056-1.