23 research outputs found
Development and validation of a knowledge-based score to predict Fried's frailty phenotype across multiple settings using one-year hospital discharge data: The electronic frailty score
Background: Most claims-based frailty instruments have been designed for group stratification of older populations according to the risk of adverse health outcomes and not frailty itself. We aimed to develop and validate a tool based on one-year hospital discharge data for stratification on Fried's frailty phenotype (FP). Methods: We used a three-stage development/validation approach. First, we created a clinical knowledge-driven electronic frailty score (eFS) calculated as the number of deficient organs/systems among 18 critical ones identified from the International Statistical Classification of Diseases and Related Problems, 10th Revision (ICD-10) diagnoses coded in the year before FP assessment. Second, for eFS development and internal validation, we linked individual records from the Lc65+ cohort database to inpatient discharge data from Lausanne University Hospital (CHUV) for the period 2004-2015. The development/internal validation sample included community-dwelling, non-institutionalised residents of Lausanne (Switzerland) recruited in the Lc65+ cohort in three waves (2004, 2009, and 2014), aged 65-70 years at enrolment, and hospitalised at the CHUV at least once in the year preceding the FP assessment. Using this sample, we selected the best performing model for predicting the dichotomised FP, with the eFS or ICD-10-based variables as predictors. Third, we conducted an external validation using 2016 Swiss nationwide hospital discharge data and compared the performance of the eFS model in predicting 13 adverse outcomes to three models relying on well-designed and validated claims-based scores (Claims-based Frailty Index, Hospital Frailty Risk Score, Dr Foster Global Frailty Score). Findings: In the development/internal validation sample (n = 469), 14·3% of participants (n = 67) were frail. Among 34 models tested, the best-subsets logistic regression model with four predictors (age and sex at FP assessment, time since last hospital discharge, eFS) performed best in predicting the dichotomised FP (area under the curve=0·71; F1 score=0·39) and one-year adverse health outcomes. On the external validation sample (n = 54,815; 153 acute care hospitals), the eFS model demonstrated a similar performance to the three other claims-based scoring models. According to the eFS model, the external validation sample showed an estimated prevalence of 56·8% (n = 31,135) of frail older inpatients at admission. Interpretation: The eFS model is an inexpensive, transportable and valid tool allowing reliable group stratification and individual prioritisation for comprehensive frailty assessment and may be applied to both hospitalised and community-dwelling older adults. Funding: The study received no external funding
Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.
International audienceSHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice
Analyse comparative du profil développemental de jeunes enfants dépistés "à risque autistique" (valeur prédictive de l'indice d'hétérogénéité du développement global, socio-émotionnel et cognitif sur le diagnostic à 5 ans)
Objectif : cette étude vise à analyser le profil développemental de jeunes enfants avec troubles envahissants du développement (TED) et à étudier la valeur prédictive du degré d hétérogénéité du développement global, socio-émotionnel et cognitif mesuré à la batterie d évaluation cognitive et socio-émotionnelle (BECS) à 3 ans, sur le diagnostic à 5 ans. Méthode : dans cette étude de type rétrospectif, 16 enfants dépistés à risque autistique ont été évalués grâce à la BECS à et ont bénéficié d une seconde évaluation à l aide de l Autism Diagnostic Interview-Revised et de l Autism Diagnostic Observation Schedule-Generic : 11 ont un diagnostic d autisme typique et 5 un diagnostic de troubles envahissants du développement non spécifiés (TED-NOS). Résultats : l hétérogénéité du développement avant 3 ans, dans le sens d une hétérogénéité cognitive plus marquée, est une caractéristique de la population des enfants TED au sens large. Cependant, les trois indices d hétérogénéité du développement ne différent pas significativement entre les enfants AT et les TED-NOS. Conclusion et perspectives : le degré d hétérogénéité du développement global à 3 ans, bien que non prédictif du diagnostic d AT à 5 ans, peut néanmoins être considéré comme un signal d alerte . En outre, le niveau de développement cognitif, significativement supérieur à celui du développement socio-émotionnel dans les deux groupes, vient renforcer l idée d urgence à la mise en place de prises en charge précoces, à un âge où le retard n est pas encore fixé.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF
UTILISATION D'UN ANTICORPS CONTRE LE GANGLIOSIDE GD2 O-ACÉTYLÉ DANS LE BUT D'AMÉLIORER LE POTENTIEL THÉRAPEUTIQUE DE MÉDICAMENTS
Type de la demande A1 N° et date de dépôt EP1782959
Interleukin-7 treatment counteracts IFN-α therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques
International audienceInterferon-α (IFN-α)-based therapy is presently the standard treatment for hepatitis C virus (HCV)-infected patients. Despite good effectiveness, this cytokine is associated with major side effects, including significant lymphopenia, that limits its use for HIV/HCV-coinfected patients. Interleukin-7 (IL-7) has recently shown therapeutic potential and safety in several clinical trials designed to demonstrate T-cell restoration in immunodeficient patients. The purpose of this study was to evaluate, in simian immunodeficiency virus-infected rhesus macaques, the relevance of IL-7 therapy as a means to overcoming IFN-α-induced lymphopenia. We showed that low-dose IFN-α treatment induced strong lymphopenia in chronically infected monkeys. In contrast, high-dose IFN-α treatment stimulated IL-7 production, leading to increased circulating T-cell counts. Moreover, IL-7 therapy more than abrogated the lymphopenic effect of low-dose IFN-α. Indeed, the association of both cytokines resulted in increased circulating T-cell counts, in particular in the naive compartments, as a consequence of central and peripheral homeostatic functions of the IL-7. Finally, reduced PD-1 expression by memory CD8(+) T cells and transient T-cell repertoire diversification were observed under IL-7 therapy. Our data strongly suggest that IL-7 immunotherapy will be of substantial benefit in the treatment of HIV/HCV coinfection and should enhance the likelihood of HCV eradication in poorly responding patients
Recombinant Interleukin-7 Induces Proliferation of Naive Macaque CD4(+) and CD8(+) T Cells In Vivo
Interleukin-7 (IL-7) regulates T-cell homeostasis, and its availability is augmented in lymphopenic hosts. Naive CD8(+) T cells transferred to lymphopenic mice acquire a memory-like phenotype, raising the possibility that IL-7 is the biological mediator of this effect. Here, we provide direct evidence that IL-7 induces the acquisition of memory-cell markers not only in CD8(+) T cells but also in CD4(+) T-cell subsets in immune-competent Indian rhesus macaques. The increase of these memory-like populations was dependent on the dose of the cytokine, and these cells were found in the blood as well as secondary lymphoid organs. Memory-like CD4(+) and CD8(+) T cells acquired the ability to secrete tumor necrosis factor alpha and, to a lesser extent, gamma interferon following stimulation with a cognate antigen. The phenotypic change observed in naive T cells was promptly reversed after discontinuation of IL-7. Importantly, IL-7 induced cycling of both CD4(+) and CD8(+) central memory and effector memory T cells, demonstrating its contribution to the maintenance of the entire T-cell pool. Thus, IL-7 may be of benefit in the treatment of iatrogenic or virus-induced T-cell depletion