On the parametric maximum likelihood estimator for independent but non-identically distributed observations with application to truncated data

International audienceWe investigate the parametric maximum likelihood estimator for truncated data when the truncation value is different according to the observed individual or item. We extend Lehmann's proof (1983) of the asymptotic properties of the parametric maximum likelihood estimator in the case of independent non-identically distributed observations. Two cases are considered: either the number of distinct probability distribution functions that can be observed in the population from which the sample comes from is finite or this number is infinite. Sufficient conditions for consistency and asymptotic normality are provided for both cases

Premiers Pointages chez L'enfant entendant et L'enfant sourd-signeur : deux suivis longitudinaux entre 7 mois et 1 an 7 mois

International audienceLe pointage émerge grâce à la maîtrise des pré-requis moteurs et cognitifs et facilite les processus de symbolisation. Ce geste représente une condition nécessaire à la construction du langage car il donne à l'enfant la possibilité de désigner un objet en tant que lieu d'attention partagée et d'échange avec l'adulte. Par la comparaison entre les suivis longitudinaux de deux petites filles, dont l'une est entendante et élevée en milieu francophone et l'autre sourde et élevée dans un environnement signeur, nous essaierons de détermi- ner si les éléments qui accompagnent les gestes de pointage (regards, vocali- sations) et les paramètres qui caractérisent « l'événement pointage » (situation de la cible du pointage, situation de l'interlocuteur, statut de l'objet dans le discours et attention partagée ou non) permettent de distinguer les fonctions proto-déclarative et proto-impérative décrites dans la littérature

LA GOUVERNANCE D’UNE ONG DE CONSERVATION DE LA NATURE. PERSPECTIVE STRATÉGIQUE

International audienceno abstractLa gouvernance des ONG d'environnement-acteurs privés intervenant dans le champ de l'action publique-constitue un objet de recherche relativement nouveau en sciences de gestion. Au moment où la singularité de ces organisations est parfois controversée, nous montrons que c'est par une approche stratégique de la gouvernance que nous pouvons mettre en lumière les spécificités managériales de telles organisations. Les théories contractuelles de la gouvernance, aujourd'hui dominantes, centrées sur la création de valeur économique ne peuvent en rendre compte. A partir d'une étude de cas, et par un travail de recherche au sein de l'organisation, nous montrons en effet comment une ONG d'environnement, la Tour du Valat, met sa gouvernance au service d'un objectif d'efficacité environnementale, et comment cette gouvernance s'adapte pour remplir cette mission, en lui octroyant des ressources stratégiques majeures : l'information, les réseaux, la légitimation. Mots clés ONG environnementale, gouvernance interne, efficacité environnementale, management stratégique. Abstract The governance of Environmental NGO-entities which intervene in the field of the public sector-is a relatively new object for management research. At a time when the singularity of those organizations is subject to controversy, the present document shows that the managerial specificities of those organizations can be enlighten by a strategic approach of governance. Contractual theories of governance on the contrary, which are dominant today and all focus on economic value and profit making, cannot explain it. Based on a case study and research work in the organization, this study shows how the governance of the environmental NGO "la Tour du Valat" focuses on its environmental efficacy objective and how it adapts to meet success in this specific mission by granting strategic resources, such as information, network and legitimacy

Premiers pointages chez l’enfant entendant et l’enfant sourd-signeur : deux suivis longitudinaux entre 7 mois et 1 an 7 mois

Le pointage émerge grâce à la maîtrise des pré-requis moteurs et cognitifs et facilite les processus de symbolisation. Ce geste représente une condition nécessaire à la construction du langage car il donne à l’enfant la possibilité de désigner un objet en tant que lieu d’attention partagée et d’échange avec l’adulte. Par la comparaison entre les suivis longitudinaux de deux petites filles, dont l’une est entendante et élevée en milieu francophone et l’autre sourde et élevée dans un environnement signeur, nous essaierons de déterminer si les éléments qui accompagnent les gestes de pointage (regards, vocalisations) et les paramètres qui caractérisent ‘l’événement pointage’ (situation de la cible du pointage, situation de l’interlocuteur, statut de l’objet dans le discours et attention partagée ou non) permettent de distinguer les fonctions proto-déclarative et proto-impérative décrites dans la littérature.Pointing emerges thanks to the mastery of motor and cognitive prerequisites and it facilitates symbolization processes. It enables children to designate an object as a focus for joint attention thus paving the way to early language acquisition. In this paper, we compare the data taken from two longitudinal follow-ups of a French-speaking child and a deaf child acquiring French Sign Language (LSF), aged 7 months to 1 year and 7 months, filmed at home with their parents once a month. Traditionally, researchers have attributed two functions to pointing gestures: they could be proto-imperative or proto-declarative. We closely examine each pointing gesture used by the hearing and deaf children in order to determine whether there are significant differences according to these two functions. Thanks to a multimodal approach, we try to determine whether the combination of different features in the pointing-event, such as gaze, the prosody of the vocal productions, the status of the object in the interaction, the focus of attention or the location of the interlocutor could be significant

Premiers pointages chez l’enfant entendant et l’enfant sourd-signeur : deux suivis longitudinaux entre 7 mois et 1 an 7 mois

Le pointage émerge grâce à la maîtrise des pré-requis moteurs et cognitifs et facilite les processus de symbolisation. Ce geste représente une condition nécessaire à la construction du langage car il donne à l’enfant la possibilité de désigner un objet en tant que lieu d’attention partagée et d’échange avec l’adulte. Par la comparaison entre les suivis longitudinaux de deux petites filles, dont l’une est entendante et élevée en milieu francophone et l’autre sourde et élevée dans un environnement signeur, nous essaierons de déterminer si les éléments qui accompagnent les gestes de pointage (regards, vocalisations) et les paramètres qui caractérisent ‘l’événement pointage’ (situation de la cible du pointage, situation de l’interlocuteur, statut de l’objet dans le discours et attention partagée ou non) permettent de distinguer les fonctions proto-déclarative et proto-impérative décrites dans la littérature.Pointing emerges thanks to the mastery of motor and cognitive prerequisites and it facilitates symbolization processes. It enables children to designate an object as a focus for joint attention thus paving the way to early language acquisition. In this paper, we compare the data taken from two longitudinal follow-ups of a French-speaking child and a deaf child acquiring French Sign Language (LSF), aged 7 months to 1 year and 7 months, filmed at home with their parents once a month. Traditionally, researchers have attributed two functions to pointing gestures: they could be proto-imperative or proto-declarative. We closely examine each pointing gesture used by the hearing and deaf children in order to determine whether there are significant differences according to these two functions. Thanks to a multimodal approach, we try to determine whether the combination of different features in the pointing-event, such as gaze, the prosody of the vocal productions, the status of the object in the interaction, the focus of attention or the location of the interlocutor could be significant

Mutations in splicing factor genes are a major cause of autosomal dominant retinitis pigmentosa in Belgian families

Purpose : Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. Methods : Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. Results : Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5-30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). Conclusions : Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular spectrum of PRPH2, PRPF8, RHO, RP1, SNRNP200, and TOPORS-associated adRP by the identification of 17 novel mutations

Investigation of caliciviruses and astroviruses in Gabonese rodents: A possible influence of national and international trade on the spread of enteric viruses.

Caliciviruses (Caliciviridae) and astroviruses (Astroviridae) are among the leading cause of non-bacterial foodborne disease and gastroenteritis in human. These non-enveloped RNA viruses infect a wide range of vertebrate species including rodents. Rodents are among the most important hosts of infectious diseases globally and are responsible for over 80 zoonotic pathogens that affect humans. Therefore, screening pathogens in rodents will be is necessary to prevent cross-species transmission to prevent zoonotic outbreaks. In the present study, we screened caliciviruses and astroviruses in order to describe their diversity and whether they harbor strains that can infect humans. RNA was then extracted from intestine samples of 245 rodents and retrotranscribed in cDNA to screen caliciviruses and astroviruses by PCRs. All the samples tested negative for caliciviruses and while astroviruses were detected in 18 (7.3%) samples of Rattus rattus species. Phylogenetic analyses based on the RdRp gene showed that all the sequences belonged to Mamastrovirus genus in which they were genetically related to R. rattus related AstVs previously detected in Gabon or in Rattus spp. AstV from Kenya and Asia. These findings suggested that transportation such as land and railway, as well national and international trade, are likely to facilitate spread of AstVs by the dissemination of rodents

Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development

Estimating time-to-onset of adverse drug reactions from spontaneous reporting databases.

International audienceBACKGROUND: Analyzing time-to-onset of adverse drug reactions from treatment exposure contributes to meeting pharmacovigilance objectives, i.e. identification and prevention. Post-marketing data are available from reporting systems. Times-to-onset from such databases are right-truncated because some patients who were exposed to the drug and who will eventually develop the adverse drug reaction may do it after the time of analysis and thus are not included in the data. Acknowledgment of the developments adapted to right-truncated data is not widespread and these methods have never been used in pharmacovigilance. We assess the use of appropriate methods as well as the consequences of not taking right truncation into account (naïve approach) on parametric maximum likelihood estimation of time-to-onset distribution. METHODS: Both approaches, naïve or taking right truncation into account, were compared with a simulation study. We used twelve scenarios for the exponential distribution and twenty-four for the Weibull and log-logistic distributions. These scenarios are defined by a set of parameters: the parameters of the time-to-onset distribution, the probability of this distribution falling within an observable values interval and the sample size. An application to reported lymphoma after anti TNF-¿ treatment from the French pharmacovigilance is presented. RESULTS: The simulation study shows that the bias and the mean squared error might in some instances be unacceptably large when right truncation is not considered while the truncation-based estimator shows always better and often satisfactory performances and the gap may be large. For the real dataset, the estimated expected time-to-onset leads to a minimum difference of 58 weeks between both approaches, which is not negligible. This difference is obtained for the Weibull model, under which the estimated probability of this distribution falling within an observable values interval is not far from 1. CONCLUSIONS: It is necessary to take right truncation into account for estimating time-to-onset of adverse drug reactions from spontaneous reporting databases

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria