Implementation of raltegravir in routine clinical practice: selection criteria for choosing this drug, virologic response rates, and characteristics of failures.

BACKGROUND: Raltegravir (RAL) achieved remarkable virologic suppression rates in randomized-clinical trials, but today efficacy data and factors for treatment failures in a routine clinical care setting are limited. METHODS: First, factors associated with a switch to RAL were identified with a logistic regression including patients from the Swiss HIV Cohort Study with a history of 3 class failure (n = 423). Second, predictors for virologic outcome were identified in an intent-to-treat analysis including all patients who received RAL. Last observation carried forward imputation was used to determine week 24 response rate (HIV-1 RNA >or= 50 copies/mL). RESULTS: The predominant factor associated with a switch to RAL in patients with suppressed baseline RNA was a regimen containing enfuvirtide [odds ratio 41.9 (95% confidence interval: 11.6-151.6)]. Efficacy analysis showed an overall response rate of 80.9% (152/188), whereas 71.8% (84/117) and 95.8% (68/71) showed viral suppression when stratified for detectable and undetectable RNA at baseline, respectively. Overall CD4 cell counts increased significantly by 42 cells/microL (P < 0.001). Characteristics of failures were a genotypic sensitivity score of the background regimen <or=1, very low RAL plasma concentrations, poor adherence, and high viral load at baseline. CONCLUSIONS: Virologic suppression rates in our routine clinical care setting were promising and comparable with data from previously published randomized-controlled trials.

Conditional manipulation of sex ratios by ant workers: A test of kin selection theory

Variable queen mating frequencies provide a unique opportunity to study the resolution of worker-queen conflict over sex ratio in social Hymenoptera, because the conflict is maximal in colonies headed by a singly mated queen and is weak or nonexistent in colonies headed by a multiply mated queen. In the wood ant Formica exsecta, workers in colonies with a singly mated queen, but not those in colonies with a multiply mated queen, altered the sex ratio of queen-laid eggs by eliminating males to preferentially raise queens. By this conditional response to queen mating frequency, workers enhance their inclusive fitness.

Community-wide plasmid gene mobilization and selection.

Plasmids have long been recognized as an important driver of DNA exchange and genetic innovation in prokaryotes. The success of plasmids has been attributed to their independent replication from the host's chromosome and their frequent self-transfer. It is thought that plasmids accumulate, rearrange and distribute nonessential genes, which may provide an advantage for host proliferation under selective conditions. In order to test this hypothesis independently of biases from culture selection, we study the plasmid metagenome from microbial communities in two activated sludge systems, one of which receives mostly household and the other chemical industry wastewater. We find that plasmids from activated sludge microbial communities carry among the largest proportion of unknown gene pools so far detected in metagenomic DNA, confirming their presumed role of DNA innovators. At a system level both plasmid metagenomes were dominated by functions associated with replication and transposition, and contained a wide variety of antibiotic and heavy metal resistances. Plasmid families were very different in the two metagenomes and grouped in deep-branching new families compared with known plasmid replicons. A number of abundant plasmid replicons could be completely assembled directly from the metagenome, providing insight in plasmid composition without culturing bias. Functionally, the two metagenomes strongly differed in several ways, including a greater abundance of genes for carbohydrate metabolism in the industrial and of general defense factors in the household activated sludge plasmid metagenome. This suggests that plasmids not only contribute to the adaptation of single individual prokaryotic species, but of the prokaryotic community as a whole under local selective conditions.

Sex of College Students Moderates Associations among Bedtime, Time in Bed, and Circadian Phase Angle.

Sex differences in circadian rhythms have been reported with some conflicting results. The timing of sleep and length of time in bed have not been considered, however, in previous such studies. The current study has 3 major aims: (1) replicate previous studies in a large sample of young adults for sex differences in sleep patterns and dim light melatonin onset (DLMO) phase; (2) in a subsample constrained by matching across sex for bedtime and time in bed, confirm sex differences in DLMO and phase angle of DLMO to bedtime; (3) explore sex differences in the influence of sleep timing and length of time in bed on phase angle. A total of 356 first-year Brown University students (207 women) aged 17.7 to 21.4 years (mean = 18.8 years, SD = 0.4 years) were included in these analyses. Wake time was the only sleep variable that showed a sex difference. DLMO phase was earlier in women than men and phase angle wider in women than men. Shorter time in bed was associated with wider phase angle in women and men. In men, however, a 3-way interaction indicated that phase angles were influenced by both bedtime and time in bed; a complex interaction was not found for women. These analyses in a large sample of young adults on self-selected schedules confirm a sex difference in wake time, circadian phase, and the association between circadian phase and reported bedtime. A complex interaction with length of time in bed occurred for men but not women. We propose that these sex differences likely indicate fundamental differences in the biology of the sleep and circadian timing systems as well as in behavioral choices.

Statistical Modeling of the Eye for Multimodal Treatment Planning for External Beam Radiation Therapy of Intraocular Tumors.

PURPOSE: Ocular anatomy and radiation-associated toxicities provide unique challenges for external beam radiation therapy. For treatment planning, precise modeling of organs at risk and tumor volume are crucial. Development of a precise eye model and automatic adaptation of this model to patients' anatomy remain problematic because of organ shape variability. This work introduces the application of a 3-dimensional (3D) statistical shape model as a novel method for precise eye modeling for external beam radiation therapy of intraocular tumors. METHODS AND MATERIALS: Manual and automatic segmentations were compared for 17 patients, based on head computed tomography (CT) volume scans. A 3D statistical shape model of the cornea, lens, and sclera as well as of the optic disc position was developed. Furthermore, an active shape model was built to enable automatic fitting of the eye model to CT slice stacks. Cross-validation was performed based on leave-one-out tests for all training shapes by measuring dice coefficients and mean segmentation errors between automatic segmentation and manual segmentation by an expert. RESULTS: Cross-validation revealed a dice similarity of 95% ± 2% for the sclera and cornea and 91% ± 2% for the lens. Overall, mean segmentation error was found to be 0.3 ± 0.1 mm. Average segmentation time was 14 ± 2 s on a standard personal computer. CONCLUSIONS: Our results show that the solution presented outperforms state-of-the-art methods in terms of accuracy, reliability, and robustness. Moreover, the eye model shape as well as its variability is learned from a training set rather than by making shape assumptions (eg, as with the spherical or elliptical model). Therefore, the model appears to be capable of modeling nonspherically and nonelliptically shaped eyes.

Fast low-specific absorption rate B0 -mapping along projections at high field using two-dimensional radiofrequency pulses.

PURPOSE: At 7 Tesla (T), conventional static field (B0 ) projection mapping techniques, e.g., FASTMAP, FASTESTMAP, lead to elevated specific absorption rates (SAR), requiring longer total acquisition times (TA). In this work, the series of adiabatic pulses needed for slab selection in FASTMAP is replaced by a single two-dimensional radiofrequency (2D-RF) pulse to minimize TA while ensuring equal shimming performance. METHODS: Spiral gradients and 2D-RF pulses were designed to excite thin slabs in the small tip angle regime. The corresponding selection profile was characterized in phantoms and in vivo. After optimization of the shimming protocol, the spectral linewidths obtained after 2D localized shimming were compared with conventional techniques and published values from (Emir et al NMR Biomed 2012;25:152-160) in six different brain regions. RESULTS: Results on healthy volunteers show no significant difference (P > 0.5) between the spectroscopic linewidths obtained with the adiabatic (TA = 4 min) and the new low-SAR and time-efficient FASTMAP sequence (TA = 42 s). The SAR can be reduced by three orders of magnitude and TA accelerated six times without impact on the shimming performances or quality of the resulting spectra. CONCLUSION: Multidimensional pulses can be used to minimize the RF energy and time spent for automated shimming using projection mapping at high field. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

Autoimmunity-Associated LYP-W620 Does Not Impair Thymic Negative Selection of Autoreactive T Cells.

A C1858T (R620W) variation in the PTPN22 gene encoding the tyrosine phosphatase LYP is a major risk factor for human autoimmunity. LYP is a known negative regulator of signaling through the T cell receptor (TCR), and murine Ptpn22 plays a role in thymic selection. However, the mechanism of action of the R620W variant in autoimmunity remains unclear. One model holds that LYP-W620 is a gain-of-function phosphatase that causes alterations in thymic negative selection and/or thymic output of regulatory T cells (Treg) through inhibition of thymic TCR signaling. To test this model, we generated mice in which the human LYP-W620 variant or its phosphatase-inactive mutant are expressed in developing thymocytes under control of the proximal Lck promoter. We found that LYP-W620 expression results in diminished thymocyte TCR signaling, thus modeling a "gain-of-function" of LYP at the signaling level. However, LYP-W620 transgenic mice display no alterations of thymic negative selection and no anomalies in thymic output of CD4(+)Foxp3(+) Treg were detected in these mice. Lck promoter-directed expression of the human transgene also causes no alteration in thymic repertoire or increase in disease severity in a model of rheumatoid arthritis, which depends on skewed thymic selection of CD4(+) T cells. Our data suggest that a gain-of-function of LYP is unlikely to increase risk of autoimmunity through alterations of thymic selection and that LYP likely acts in the periphery perhaps selectively in regulatory T cells or in another cell type to increase risk of autoimmunity.

Etat des lieux et potentiel de l'agriculture urbaine en Suisse : analyse de deux projets d'agriculture urbaine sous l'angle des régimes institutionnels des ressources naturelles

Ce travail de recherche dresse un panorama de l'état du développement des pratiques d'agriculture urbaine en Suisse et analyse le potentiel que celles-ci pourraient y développer, compte tenu des particularités du contexte national. La démarche adoptée suit une logique allant du général au particulier, de la théorie à la pratique, du descriptif vers l'analytique. Dans un premier temps, l'agriculture urbaine est abordée sous un angle conceptuel, comprenant un retour historique sur la relation ville-campagne et sur l'apparition récente du terme d'agriculture urbaine, un tour d'horizon de la littérature sur le sujet, une revue de ses diverses approches scientifiques et la circonscription des enjeux de sa définition. Dans un deuxième temps, l'agriculture urbaine est envisagée sous sa forme pratique, en Suisse comme à l'étranger. En ressort un inventaire étendu de ses différents types de mises en application, auquel correspond un panel d'atouts identifiés selon les trois versants du développement durable : social, écologique et économique. En troisième lieu les spécificités du contexte helvétique sont étudiées afin de comprendre quel est le cadre dans lequel le potentiel de l'agriculture urbaine pourrait se développer. Finalement, ce sont deux cas concrets d'agriculture urbaine qui sont analysés et évalués dans les détails, selon l'approche dite des régimes institutionnels des ressources naturelles (RIRN): le « plantage » lausannois du quartier de la Bourdonnette et le Stadiongarten dans le quartier Kreis 5 à Zurich. Au fil de cette recherche, il apparaît que l'agriculture urbaine révèle toute une série d'avantages en termes de développement durable, alors même que les villes suisses sont unanimement reconnues comme présentant un déficit dans ce domaine. De même, malgré les bienfaits importants que présentent ses diverses pratiques, l'agriculture urbaine reste encore très peu répandue en Suisse, le concept lui-même n'apparaissant que très rarement dans le discours des pouvoirs publics. Le principal frein à l'agriculture en ville est identifié comme étant le manque d'espace disponible dans les agglomérations, contrainte pourtant largement surmontable en y regardant de plus près. De par sa configuration topographique, le territoire suisse est particulièrement sujet à une étroite proximité entre espaces urbains et étendues agricoles, accroissant de ce fait la problématique de l'étalement urbain et du mitage du paysage. Parmi les enjeux de la lutte contre ces phénomènes concomitants, l'agriculture urbaine aurait un rôle important à jouer. En conclusion, une série de recommandations sont proposées afin que les projets d'agriculture urbaine puissent se développer et perdurer en Suisse. Abstract : This research paper provides an overview of the state of development of urban agriculture practices in Switzerland. It analyzes their potential of expansion while taking into account the particularities of the national context. The method follows a general to particular, theory to practice and descriptive to analytical reasoning. Firstly, urban agriculture is approached through a conceptual view, including a historical overview of the relationship between town and country and of the recent appearance of the term "urban agriculture". An outline of the literature on the subject, an examination of its various scientific approaches and riding issues of its definition are elaborated as well. In a second step, urban agriculture is considered in its practical form, both in Switzerland and abroad. From this we created an extensive inventory of various types of implementations which corresponds to a panel of assets identified according to the three aspects of sustainable development: social, ecology and economics. Thirdly the specificities of Swiss context are studied in order to understand the frame in which the potential of urban agriculture could be developed. Finally, two case studies of urban agriculture are analyzed and evaluated in detail, according to the so-called institutional regimes of natural resources (RIRN) approach: the "plantage" of the Bourdonnette neighborhood in Lausanne and the "Stadiongarten" in the Kreis 5 neighborhood in Zurich. Throughout this research, urban agriculture reveals a number of advantages in terms of sustainable development, even though the Swiss cities are unanimously recognized as having a deficit in this area. As well, despite the significant benefits that are its various practices, urban agriculture is still very uncommon in Switzerland, the concept itself appearing only rarely in public debates. The main obstacle to city agriculture is identified as the lack of available space in urban areas, however this constraint can easily be surpassed. By its topographical configuration, Switzerland is particularly prone to a close proximity between urban and agricultural spaces, thereby increasing the problems of urban sprawl. Among the stakes in the struggle against these interrelated phenomena, urban agriculture could play an important role. In conclusion, a series of recommendations are proposed so that urban agriculture projects can grow and persist in Switzerland.

Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilisation of the needle track.

BACKGROUND: The preservation of globe integrity has always been a major concern during the treatment of retinoblastoma for fear of extraocular or metastatic spread. Intravitreal chemotherapy has been attempted as a desperate salvage therapy only for eyes with refractory retinoblastoma. Published data on the safety and efficacy of this route are, however, limited. METHODS: A modified technique of intravitreal injection in eyes with retinoblastoma is described. All children with retinoblastoma who received one or more intravitreal injections using this technique were retrospectively reviewed concerning ocular complications of the injection procedure as well as clinical or histopathological evidence of tumour spread. RESULTS: 30 eyes of 30 children with retinoblastoma received a total of 135 intravitreal injections, with a median follw-up duration of 13.5 months. No extraocular spread was seen on clinical follow-up in any patients and there was no tumour contamination of the retrieved entry sites histopathologically analysed among the five enucleated eyes. No significant ocular side effects were observed except transient localised vitreous haemorrhage (3/135). CONCLUSION: This technique is potentially safe and effective at a low cost and may play a promising role, especially in the treatment of recurrent and/or resistant vitreous disease in retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy. However, this treatment should not replace the primary standard of care of retinoblastoma and should not be considered in group E eyes. Its application should be approved by an ophthalmological-oncological team and it should be performed by an experienced eye surgeon in a tertiary referral centre after careful selection of a tumour-free injection site.

Imaging the ultrasmall-angle x-ray scattering distribution with grating interferometry.

X-ray imaging with grating interferometry has previously been regarded as a technique providing information only in direct space. It delivers absorption, phase, and dark-field contrast, which can be viewed as parameters of the underlying but unresolved scattering distribution. Here, we present a method that provides the ultrasmall-angle x-ray scattering distribution and, thus, allows simultaneous access to direct and reciprocal space information.

Environmental pollution promotes selection of microbial degradation pathways

Astonishing as it may seem, one organism's waste is often ideal food for another. Many waste products generated by human activities are routinely degraded by microorganisms under controlled conditions during waste-water treatment. Toxic pollutants resulting from inadvertent releases, such as oil spills, are also consumed by bacteria, the simplest organisms on Earth. Biodegradation of toxic or particularly persistent compounds, however, remains problematic. What has escaped the attention of many is that bacteria exposed to pollutants can adapt to them by mutating or acquiring degradative genes. These bacteria can proliferate in the environment as a result of the selection pressures created by pollutants. The positive outcome of selection pressure is that harmful compounds may eventually be broken down completely through biodegradation. The downside is that biodegradation may require extremely long periods of time. Although the adaptation process has been shown to be reproducible, it remains very difficult to predict.

Selectome update: quality control and computational improvements to a database of positive selection.

Selectome (http://selectome.unil.ch/) is a database of positive selection, based on a branch-site likelihood test. This model estimates the number of nonsynonymous substitutions (dN) and synonymous substitutions (dS) to evaluate the variation in selective pressure (dN/dS ratio) over branches and over sites. Since the original release of Selectome, we have benchmarked and implemented a thorough quality control procedure on multiple sequence alignments, aiming to provide minimum false-positive results. We have also improved the computational efficiency of the branch-site test implementation, allowing larger data sets and more frequent updates. Release 6 of Selectome includes all gene trees from Ensembl for Primates and Glires, as well as a large set of vertebrate gene trees. A total of 6810 gene trees have some evidence of positive selection. Finally, the web interface has been improved to be more responsive and to facilitate searches and browsing.