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.

Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial.

BACKGROUND: The recent large randomized controlled trial of glutamine and antioxidant supplementation suggested that high-dose glutamine is associated with increased mortality in critically ill patients with multiorgan failure. The objectives of the present analyses were to reevaluate the effect of supplementation after controlling for baseline covariates and to identify potentially important subgroup effects. MATERIALS AND METHODS: This study was a post hoc analysis of a prospective factorial 2 × 2 randomized trial conducted in 40 intensive care units in North America and Europe. In total, 1223 mechanically ventilated adult patients with multiorgan failure were randomized to receive glutamine, antioxidants, both glutamine and antioxidants, or placebo administered separate from artificial nutrition. We compared each of the 3 active treatment arms (glutamine alone, antioxidants alone, and glutamine + antioxidants) with placebo on 28-day mortality. Post hoc, treatment effects were examined within subgroups defined by baseline patient characteristics. Logistic regression was used to estimate treatment effects within subgroups after adjustment for baseline covariates and to identify treatment-by-subgroup interactions (effect modification). RESULTS: The 28-day mortality rates in the placebo, glutamine, antioxidant, and combination arms were 25%, 32%, 29%, and 33%, respectively. After adjusting for prespecified baseline covariates, the adjusted odds ratio of 28-day mortality vs placebo was 1.5 (95% confidence interval, 1.0-2.1, P = .05), 1.2 (0.8-1.8, P = .40), and 1.4 (0.9-2.0, P = .09) for glutamine, antioxidant, and glutamine plus antioxidant arms, respectively. In the post hoc subgroup analysis, both glutamine and antioxidants appeared most harmful in patients with baseline renal dysfunction. No subgroups suggested reduced mortality with supplements. CONCLUSIONS: After adjustment for baseline covariates, early provision of high-dose glutamine administered separately from artificial nutrition was not beneficial and may be associated with increased mortality in critically ill patients with multiorgan failure. For both glutamine and antioxidants, the greatest potential for harm was observed in patients with multiorgan failure that included renal dysfunction upon study enrollment.

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).

Labor market experience and well-being after firm closure. Survey evidence on displaced manufacturing workers in Switzerland

This study examines how plant closure affected individuals' careers and lives about two years after they lost their job. We analyze the displaced workers' reemployment prospects and study for reemployed workers the characteristics of their new jobs in terms of reemployment sectors, wages, and job quality. Additionally, we inquire how workers' sociability and subjective well-being were affected by job loss. Our analysis is based on our own survey conducted in Switzerland in 2011. The survey included the workforce of five manufacturing companies that had closed down two years earlier. We addressed the risk of biases typically prevailing with observational data by complementing it with register data from the public unemployment insurance. Moreover, we use a control group based on matched data from the Swiss Household Panel. We find that workers experience strongly diverging outcomes after plant closure: on the one hand, high proportions of the workers experience a smooth transition after plant closure. More than two-thirds of the workers returned to employment, more than half of them within less than six months. With respect to their social lives, we find that positive changes in relationships with their spouse, family and friends are more frequent than negative changes. On the other hand, for a small group of workers plant closure had a detrimental effect. Close to twenty percent remained unemployed. About ten percent of the workers were long-term unemployed and subsequently often were reemployed in jobs of lower quality. Unemployed workers and workers who dropped out of the labor force were particularly prone to find their subjective well-being decreasing. The most vulnerable subgroup in our study were workers over 55. This result stands in striking contrast to a large body of literature that considers labor market institutions to be primarily biased against young workers. Our findings show that older workers not only take longer to find a job but are also less likely to return to employment. Moreover, if they manage to find a job, they experience the severest cuts in wages and job quality of all cohorts. From a life-course perspective this result is remarkable since it shows that workers are not protected from hardship in their late careers. In light of the current demographic changes this finding may have important policy implications. -- Cette étude analyse l'impact des fermetures d'entreprises sur les travailleurs licenciés. Plus précisément, nous examinons les chances de réinsertion des travailleurs dans le marché du travail et - pour ceux qui l'ont fait avec succès - dans quels secteurs, pour quels salaires et avec quelle qualité d'emploi ils sont réengagés. Nous nous intéressons également aux répercussions engendrées par la perte de l'emploi sur la sociabilité et le bien-être subjectif des travailleurs concernés. Notre analyse se base sur les données d'une enquête que nous avons menée en 2011. Cette enquête cible le personnel de cinq entreprises industrielles suisses qui avaient fermé leurs portes deux ans auparavant. Pour dépasser les biais typiques liés aux données d'observation, nous utilisons en complément des données administratives issues de l'assurance chômage publique. De plus, nous utilisons un groupe de contrôle basé sur des données appariées provenant du Panel Suisse de Ménage. Nos analyses montrent des résultats fortement contrastés. D'un côté, la majeure partie des travailleurs ont vécu une transition professionnelle plutôt facile : plus des deux tiers des personnes ont retrouvé un travail et parmi elles plus de la moitié en moins de six mois. Par rapport aux relations sociales, tant avec leur partenaire, qu'avec les membres de leur famille et leurs amis, les changements expérimentés étaient plus fréquemment positifs que négatifs. De l'autre côté, cependant, pour une petite partie de travailleurs la fermeture de leur entreprise a eu des conséquences très négatives sur leur carrière et leur bien-être. Au moment de notre enquête, presque vingt pourcents des travailleurs étaient au chômage. Les personnes au chômage et celles qui avaient quitté le marché du travail ont été particulièrement affectées par une diminution de leur bien-être subjectif. Les plus vulnérables parmi les travailleurs licenciés étaient ceux qui étaient âgés de plus de 55 ans. Notre analyse montre que les travailleurs âgés ont beaucoup moins fréquemment retrouvé un travail. Pour les personnes de plus de 55 ans qui ont tout de même retrouvé un emploi, la réinsertion a durée plus longtemps, les pertes de salaire étaient plus conséquentes et la diminution de la qualité de l'emploi plus grande que pour les autres cohortes. Au vu des changements démographiques actuels, ce résultat interpellant peut avoir des implications politiques importantes.

Prenatal Risk Factors and Outcomes in Gastroschisis: A Meta-Analysis.

BACKGROUND AND OBJECTIVE: Gastroschisis is a congenital anomaly with increasing incidence, easy prenatal diagnosis and extremely variable postnatal outcomes. Our objective was to systematically review the evidence regarding the association between prenatal ultrasound signs (intraabdominal bowel dilatation [IABD], extraabdominal bowel dilatation, gastric dilatation [GD], bowel wall thickness, polyhydramnios, and small for gestational age) and perinatal outcomes in gastroschisis (bowel atresia, intra uterine death, neonatal death, time to full enteral feeding, length of total parenteral nutrition and length of in hospital stay). METHODS: Medline, Embase, and Cochrane databases were searched electronically. Studies exploring the association between antenatal ultrasound signs and outcomes in gastroschisis were considered suitable for inclusion. Two reviewers independently extracted relevant data regarding study characteristics and pregnancy outcome. All meta-analyses were computed using individual data random-effect logistic regression, with single study as the cluster unit. RESULTS: Twenty-six studies, including 2023 fetuses, were included. We found significant positive associations between IABD and bowel atresia (odds ratio [OR]: 5.48, 95% confidence interval [CI] 3.1-9.8), polyhydramnios and bowel atresia (OR: 3.76, 95% CI 1.7-8.3), and GD and neonatal death (OR: 5.58, 95% CI 1.3-24.1). No other ultrasound sign was significantly related to any other outcome. CONCLUSIONS: IABD, polyhydramnios, and GD can be used to an extent to identify a subgroup of neonates with a prenatal diagnosis of gastroschisis at higher risk to develop postnatal complications. Data are still inconclusive on the predictive ability of several signs combined, and large prospective studies are needed to improve the quality of prenatal counseling and the neonatal care for this condition.

The role of adjuvant chemotherapy for lymph node-positive upper tract urothelial carcinoma following radical nephroureterectomy: a retrospective study.

OBJECTIVE: To evaluate the effect of adjuvant chemotherapy (AC) on mortality after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) with positive lymph nodes (LNs) and to identify patient subgroups that are most likely to benefit from AC. PATIENTS AND METHODS: We retrospectively analysed data of 263 patients with LN-positive UTUC, who underwent full surgical resection. In all, 107 patients (41%) received three to six cycles of AC, while 156 (59.3%) were treated with RNU alone. UTUC-related mortality was evaluated using competing-risks regression models. RESULTS: In all patients (Tall N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3-4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019). The absolute difference in mortality was 10% after the first year and increased to 23% after 5 years. On multivariable analysis, administration of AC was associated with significantly reduced UTUC-related mortality (subhazard ratio 0.67, P = 0.022). Limitations of this study are the retrospective non-randomised design, selection bias, absence of a central pathological review and different AC protocols. CONCLUSIONS: AC seems to reduce mortality in patients with pT3-4 LN-positive UTUC after RNU. This subgroup of LN-positive patients could serve as target population for an AC prospective randomised trial.

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.

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.

Cost-minimization analysis of three decision strategies for cardiac revascularization : results of the "suspected CAD"cohort of the european cardiovascular magnetic resonance registry.

BACKGROUND: Coronary artery disease (CAD) continues to be one of the top public health burden. Perfusion cardiovascular magnetic resonance (CMR) is generally accepted to detect CAD, while data on its cost effectiveness are scarce. Therefore, the goal of the study was to compare the costs of a CMR-guided strategy vs two invasive strategies in a large CMR registry. METHODS: In 3'647 patients with suspected CAD of the EuroCMR-registry (59 centers/18 countries) costs were calculated for diagnostic examinations (CMR, X-ray coronary angiography (CXA) with/without FFR), revascularizations, and complications during a 1-year follow-up. Patients with ischemia-positive CMR underwent an invasive CXA and revascularization at the discretion of the treating physician (=CMR + CXA-strategy). In the hypothetical invasive arm, costs were calculated for an initial CXA and a FFR in vessels with ≥50 % stenoses (=CXA + FFR-strategy) and the same proportion of revascularizations and complications were applied as in the CMR + CXA-strategy. In the CXA-only strategy, costs included those for CXA and for revascularizations of all ≥50 % stenoses. To calculate the proportion of patients with ≥50 % stenoses, the stenosis-FFR relationship from the literature was used. Costs of the three strategies were determined based on a third payer perspective in 4 healthcare systems. RESULTS: Revascularizations were performed in 6.2 %, 4.5 %, and 12.9 % of all patients, patients with atypical chest pain (n = 1'786), and typical angina (n = 582), respectively; whereas complications (=all-cause death and non-fatal infarction) occurred in 1.3 %, 1.1 %, and 1.5 %, respectively. The CMR + CXA-strategy reduced costs by 14 %, 34 %, 27 %, and 24 % in the German, UK, Swiss, and US context, respectively, when compared to the CXA + FFR-strategy; and by 59 %, 52 %, 61 % and 71 %, respectively, versus the CXA-only strategy. In patients with typical angina, cost savings by CMR + CXA vs CXA + FFR were minimal in the German (2.3 %), intermediate in the US and Swiss (11.6 % and 12.8 %, respectively), and remained substantial in the UK (18.9 %) systems. Sensitivity analyses proved the robustness of results. CONCLUSIONS: A CMR + CXA-strategy for patients with suspected CAD provides substantial cost reduction compared to a hypothetical CXA + FFR-strategy in patients with low to intermediate disease prevalence. However, in the subgroup of patients with typical angina, cost savings were only minimal to moderate.

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.