Méta-analyses d'essais randomisés sur données individuelles dans le traitement des cancers ORL non métastatiques : principes, résultats, perspectives [Individual patient data meta-analyses of randomized trials for the treatment of non-metastatic head and neck squamous cell carcinomas: Principles, results and perspectives].

Meta-analyses are considered as an important pillar of evidence-based medicine. The aim of this review is to describe the main principles of a meta-analysis and to use examples of head and neck oncology to demonstrate their clinical impact and methodological interest. The major role of individual patient data is outlined, as well as the superiority of individual patient data over meta-analyses based on published summary data. The major clinical breakthrough of head and neck meta-analyses are summarized, regarding concomitant chemotherapy, altered fractionated chemotherapy, new regimens of induction chemotherapy or the use of radioprotectants. Recent methodological developments are described, including network meta-analyses, the validation of surrogate markers. Lastly, the future of meta-analyses is discussed in the context of personalized medicine.

Identification of potential HIV restriction factors by combining evolutionary genomic signatures with functional analyses.

BACKGROUND: Known antiretroviral restriction factors are encoded by genes that are under positive selection pressure, induced during HIV-1 infection, up-regulated by interferons, and/or interact with viral proteins. To identify potential novel restriction factors, we performed genome-wide scans for human genes sharing molecular and evolutionary signatures of known restriction factors and tested the anti-HIV-1 activity of the most promising candidates. RESULTS: Our analyses identified 30 human genes that share characteristics of known restriction factors. Functional analyses of 27 of these candidates showed that over-expression of a strikingly high proportion of them significantly inhibited HIV-1 without causing cytotoxic effects. Five factors (APOL1, APOL6, CD164, TNFRSF10A, TNFRSF10D) suppressed infectious HIV-1 production in transfected 293T cells by >90% and six additional candidates (FCGR3A, CD3E, OAS1, GBP5, SPN, IFI16) achieved this when the virus was lacking intact accessory vpr, vpu and nef genes. Unexpectedly, over-expression of two factors (IL1A, SP110) significantly increased infectious HIV-1 production. Mechanistic studies suggest that the newly identified potential restriction factors act at different steps of the viral replication cycle, including proviral transcription and production of viral proteins. Finally, we confirmed that mRNA expression of most of these candidate restriction factors in primary CD4+ T cells is significantly increased by type I interferons. CONCLUSIONS: A limited number of human genes share multiple characteristics of genes encoding for known restriction factors. Most of them display anti-retroviral activity in transient transfection assays and are expressed in primary CD4+ T cells.

Les codes de l'obligations : méta-analyses pragmatologiques de l'application de méthodes en sciences sociales

Cette thèse rassemble une série de méta-analyses, c'est-à-dire d'analyses ayant pour objet des analyses produites par des sociologues (notamment celles résultant de l'application de méthodes de traitement des entretiens). Il s'agit d'une démarche réflexive visant les pratiques concrètes des sociologues. Celles-ci sont envisagées comme des activités gouvernées par des règles. Une part importante de cette thèse sera donc consacrée au développement d'un outil d'analyse « pragmatologique » (E. Durkheim), c'est-à-dire permettant l'étude des pratiques et des règles en rapport avec elles. Pour aborder les règles, la philosophie analytique d'inspiration wittgensteinienne apporte plusieurs propositions importantes. Les règles sont ainsi considérées comme des concepts d'air de famille : il n'y a pas de définitions communes recouvrant l'ensemble des règles. Pour étudier les règles, il convient alors de faire des distinctions à partir de leurs usages. Une de ces distinctions concerne la différence entre règles constitutives et règles régulatives : une règle constitutive crée une pratique (e.g. le mariage), alors qu'une règle régulative s'applique à des activités qui peuvent exister sans elle (e.g. les règles du savoir-vivre). L'activité méthodologique des sociologues repose et est contrainte par ces types de règles, qui sont pour l'essentiel implicites. Cette thèse vise donc à rendre compte, par la description et la codification des règles, du caractère normatif des méthodes dans les pratiques d'analyse de la sociologie. Elle insiste en particulier sur les limites logiques qu'instituent les règles constitutives, celles-ci rendant impossibles (et non pas interdites) certaines actions des sociologues. This thesis brings together a series of meta-analyzes, that is, analyzes that tackle analyzes produced by sociologists (notably those resulting from the application of methods in treating interviews). The approach is reflexive and aimed at the concrete practices of sociologists, considered as activities governed by rules. An important part of this thesis is therefore devoted to the development of a "pragmatological" analytical tool (Durkheim) to conduct a study of such practices and of the rules that govern them. To approach these rules, Wittgenstein-inspired analytic philosophy offers several important proposals. The rules are, at first, seen as concepts of family resemblance, assuming that there is no common definition accounting for all rules. In order to conduct the study of such rules, it is therefore necessary to discern how they are respectively used. One of these distinctions concerns the difference between constitutive rules and regulative rules: a constitutive rule creates a practice (for example marriage), while a regulative rule applies to activities that can exist outside of the rule (for example, the rules of etiquette). The methodological activity of sociologists relies on, and is constrained by these types of rules, which are essentially implicit. Through the description and codification of rules, this thesis aims to account for the normative character of methods governing analytical practices in sociology. Particular emphasis is on the logical limits established by constitutive rules, limits that render several of the sociologist's actions impossible (rather than forbidden).

Nicolas Collins, Analyses

Nicolas Collins est un musicien né en 1954 à New York, dont l'oeuvre compose notamment avec le feedback pour interroger en profondeur l'expérience musicale. Héritier de la culture punk et de la musique expérimentale américaine, il détourne l'usage de technologies existantes pour en réinventer les ressources sonores. Ses textes racontent l'histoire des musiciens avec lesquels il a dialogué (John Cage, Alvin Lucier, David Tudor), des oeuvres qu'il a créées et des instruments qu'il a fabriqués, incitant chacun à transformer à son tour les objets mêmes (micros, réseaux, synthétiseurs, etc.) de la transmission sonore. Avec un dvd inédit composé par Nicolas Collins, Salvaged.

An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules.

OBJECTIVES: To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING: We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS: Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION: Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Erreurs innées du métabolisme: transition enfant-adulte [Inborn errors of metabolism: transition from childhood to adulthood].

Les erreurs innées du métabolisme (EIM) sont dues à des mutations de gènes codant pour des enzymes du métabolisme et sont classées selon trois grands groupes de maladies: 1) intoxications; 2) déficit énergétique et 3) déficit de synthèse ou catabolisme des maladies complexes. Le progrès thérapeutique des vingt dernières années a permis d'améliorer le pronostic des enfants atteints d'EIM. Ces enfants grandissent et doivent être pris en charge à l'adolescence et à l'âge adulte par des équipes spécialisées. Cette médecine métabolique pour adultes est une discipline relativement nouvelle avec une information limitée chez l'adulte. Les recommandations pédiatriques sont extrapolées à la prise en charge des adultes tout en intégrant les différentes étapes de vie (indépendance sociale, grossesse, vieillissement et éventuelles complications tardives). Inborn errors of metabolism (IEM) are due to mutations of genes coding for enzymes of intermediary metabolism and are classified into 3 broad categories: 1) intoxication, 2) energy defect and 3) cellular organelles synthesis or catabolism defect. Improvements of therapy over these last 20 years has improved prognosis of children with IEM. These children grow up and should have their transition to specialized adult care. Adult patients with IEM are a relatively new phenomenon with currently only limited knowledge. Extrapolated pediatric guidelines are applied to the adult population taking into account adult life stages (social independence, pregnancy, aging process and potential long-term complications).

Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder.

BACKGROUND: Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD. METHODS: In this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset. RESULTS: We found an enrichment of Turner's syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79-33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002). CONCLUSIONS: After statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.

Neural synchrony indexes impaired motor slowing after errors and novelty following white matter damage.

In humans, action errors and perceptual novelty elicit activity in a shared frontostriatal brain network, allowing them to adapt their ongoing behavior to such unexpected action outcomes. Healthy and pathologic aging reduces the integrity of white matter pathways that connect individual hubs of such networks and can impair the associated cognitive functions. Here, we investigated whether structural disconnection within this network because of small-vessel disease impairs the neural processes that subserve motor slowing after errors and novelty (post-error slowing, PES; post-novel slowing, PNS). Participants with intact frontostriatal circuitry showed increased right-lateralized beta-band (12-24 Hz) synchrony between frontocentral and frontolateral electrode sites in the electroencephalogram after errors and novelty, indexing increased neural communication. Importantly, this synchrony correlated with PES and PNS across participants. Furthermore, such synchrony was reduced in participants with frontostriatal white matter damage, in line with reduced PES and PNS. The results demonstrate that behavioral change after errors and novelty result from coordinated neural activity across a frontostriatal brain network and that such cognitive control is impaired by reduced white matter integrity.

Hybridization Capture Using RAD Probes (hyRAD), a New Tool for Performing Genomic Analyses on Collection Specimens.

In the recent years, many protocols aimed at reproducibly sequencing reduced-genome subsets in non-model organisms have been published. Among them, RAD-sequencing is one of the most widely used. It relies on digesting DNA with specific restriction enzymes and performing size selection on the resulting fragments. Despite its acknowledged utility, this method is of limited use with degraded DNA samples, such as those isolated from museum specimens, as these samples are less likely to harbor fragments long enough to comprise two restriction sites making possible ligation of the adapter sequences (in the case of double-digest RAD) or performing size selection of the resulting fragments (in the case of single-digest RAD). Here, we address these limitations by presenting a novel method called hybridization RAD (hyRAD). In this approach, biotinylated RAD fragments, covering a random fraction of the genome, are used as baits for capturing homologous fragments from genomic shotgun sequencing libraries. This simple and cost-effective approach allows sequencing of orthologous loci even from highly degraded DNA samples, opening new avenues of research in the field of museum genomics. Not relying on the restriction site presence, it improves among-sample loci coverage. In a trial study, hyRAD allowed us to obtain a large set of orthologous loci from fresh and museum samples from a non-model butterfly species, with a high proportion of single nucleotide polymorphisms present in all eight analyzed specimens, including 58-year-old museum samples. The utility of the method was further validated using 49 museum and fresh samples of a Palearctic grasshopper species for which the spatial genetic structure was previously assessed using mtDNA amplicons. The application of the method is eventually discussed in a wider context. As it does not rely on the restriction site presence, it is therefore not sensitive to among-sample loci polymorphisms in the restriction sites that usually causes loci dropout. This should enable the application of hyRAD to analyses at broader evolutionary scales.

On-line life history calendar and sensitive topics : A pilot study

The use of the life history calendar (LHC) or the event history calendar as tools for collecting retrospective data has received increasing attention in many fields of social science and medicine. However, little research has examined the use of this method with web-based surveys. In this study, we adapted this method to an on-line setting to collect information about young adults' life histories, sexual behaviors, and substance use. We hypothesized that the LHC method would help respondents to date sensitive and non-sensitive events more precisely than when using a conventional questionnaire. We conducted an experimental design study comparing university students' responses to an on-line LHC and a conventional on-line question list. A test-retest design in which the respondents completed the survey again two weeks later was also applied to test the precision and reliability of the participants' dating of events. The results showed that whereas the numbers of sensitive and non-sensitive events were generally similar for the two on-line questionnaires, the responses obtained with the LHC were more consistent across the two administrations. Analyses of the respondents' on-line behavior while completing the LHC confirmed that respondents used the LHC's graphic interface to correct and reedit previous answers, thus decreasing data errors. (C) 2015 Elsevier Ltd. All rights reserved.