53 research outputs found
Etude de faisabilitĂ© d'une vĂ©tithĂšque (bibliothĂšque de vĂȘtements) Ă GenĂšve
Ce projet est parti de mon dĂ©sir inassouvi de pouvoir porter tous les jours des habits diffĂ©rents, tendances et de bonne qualitĂ©. Mon budget ne me le permettant pas, jâai dĂ» me restreindre Ă aller chez H&M comme tout le reste de la ville et jâai donc pris lâhabitude de croiser dans les rues des personnes avec les mĂȘmes vĂȘtements que moi, mĂȘme si cela ne mâenchante pas. Passer devant les vitrines des marques prestigieuses reste une torture car avec un budget dâĂ©tudiante il est impossible dâimaginer ne serait-ce que de pousser la porte de lâun de ces magasin. Câest pourquoi quand jâai entendu parler du concept de vĂȘtithĂšque (comprenez bibliothĂšque de vĂȘtements) jâai tout de suite adhĂ©rĂ© ! Jâai pensĂ© quâil fallait absolument quâune VĂȘtithĂšque ouvre Ă GenĂšve ! Ce concept venu de SuĂšde est en rĂ©alitĂ© une boutique de location de prĂȘt-Ă -porter oĂč lâon peut venir emprunter une tenue parmi un grand choix de vĂȘtements et accessoires tendances, grĂące Ă des formules avec ou sans abonnements. Lâobjectif de ce travail est donc de dĂ©montrer la faisabilitĂ© du concept de location de vĂȘtements pour pallier au fait que la mode passe de plus en plus vite et pour remĂ©dier Ă lâuniformitĂ© vestimentaire et Ă la surconsommation de vĂȘtements. Nous verrons au travers de ce travail les diffĂ©rents aspects de la mise en place dâune telle entreprise, Ă travers notamment une analyse de la concurrence et des prĂ©fĂ©rences des consommatrices mais aussi une analyse de lâenvironnement de la sociĂ©tĂ©. Nous Ă©tudierons quels sont les besoins de lâentreprise en ressources humaines et quels sont les partenaires qui lâentoureront. Nous verrons les diffĂ©rents moyens de communication auxquels la VĂȘtithĂšque fera appel pour dĂ©velopper sa notoriĂ©tĂ© ainsi que les risques qui sont susceptibles de survenir. Pour finir, une analyse financiĂšre ainsi quâune estimation des ventes nous montreront que la VĂȘtithĂšque sera en perte la premiĂšre annĂ©e mais quâelle fera ensuite des bĂ©nĂ©fices dĂšs sa deuxiĂšme annĂ©e dâactivitĂ© et que le concept est donc viable sur la base de mes prĂ©visions
BCL-XL inhibition by BH3-mimetic drugs induces apoptosis in models of Epstein-Barr virus-associated T/NK cell lymphoma
Scientific and human errors in a snow model intercomparison
International audienceTwenty-seven models participated in the Earth System Model - Snow Model Intercomparison Project (ESM-SnowMIP), the most data-rich MIP dedicated to snow modelling. Our findings do not support the hypothesis advanced by previous snow MIPs: evaluating models against more variables, and providing evaluation datasets extended temporally and spatially does not facilitate identification of key new processes requiring improvement to model snow mass and energy budgets, even at point scales. In fact, the same modelling issues identified by previous snow MIPs arose: albedo is a major source of uncertainty, surface exchange parametrizations are problematic and individual model performance is inconsistent. This lack of progress is attributed partly to the large number of human errors that led to anomalous model behaviour and to numerous resubmissions. It is unclear how widespread such errors are in our field and others; dedicated time and resources will be needed to tackle this issue to prevent highly sophisticated models and their research outputs from being vulnerable because of avoidable human mistakes. The design of and the data available to successive snow MIPs were also questioned. Evaluation of models against bulk snow properties was found to be sufficient for15 some but inappropriate for more complex snow models whose skills at simulating internal snow properties remained untested. Discussions between the authors of this paper on the purpose of MIPs revealed varied, and sometimes contradictory, motivations behind their participation. These findings started a collaborative effort to adapt future snow MIPs to respond to the diverse needs of the communit
Evolution of Plant-Made Pharmaceuticals
The science and policy of pharmaceuticals produced and/or delivered by plants has evolved over the past twenty-one years from a backyard remedy to regulated, purified products. After seemingly frozen at Phase I human clinical trials with six orally delivered plant-made vaccines not progressing past this stage over seven years, plant-made pharmaceuticals have made a breakthrough with several purified plant-based products advancing to Phase II trials and beyond. Though fraught with the usual difficulties of pharmaceutical development, pharmaceuticals made by plants have achieved pertinent milestones albeit slowly compared to other pharmaceutical production systems and are now at the cusp of reaching the consumer. Though the current economic climate begs for cautious investment as opposed to trail blazing, it is perhaps a good time to look to the future of plant-made pharmaceutical technology to assist in planning for future developments in order not to slow this technologyâs momentum. To encourage continued progress, we highlight the advances made so far by this technology, particularly the change in paradigms, comparing developmental timelines, and summarizing the current status and future possibilities of plant-made pharmaceuticals
Inflammatory chemokine receptors regulate CD8+ T cell contraction and memory generation following infection
CD8+ T cells lacking CXCR3 and CCR5 expression have impaired contraction and generate an increased number of memory cells after virus infection
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Cannabigerol is a novel, well-tolerated appetite stimulant in pre-satiated rats
Rationale
The appetite-stimulating properties of cannabis are well documented and have been predominantly attributed to the hyperphagic activity of the psychoactive phytocannabinoid, â9-tetrahydrocannabinol (â9-THC). However, we have previously shown that a cannabis extract devoid of â9-THC still stimulates appetite, indicating that other phytocannabinoids also elicit hyperphagia. One possible candidate is the non-psychoactive phytocannabinoid cannabigerol (CBG), which has affinity for several molecular targets with known involvement in the regulation of feeding behaviour.
Objectives
The objective of the study was to assess the effects of CBG on food intake and feeding pattern microstructure.
Methods
Male Lister hooded rats were administered CBG (30â120 mg/kg, per ora (p.o.)) or placebo and assessed in open field, static beam and grip strength tests to determine a neuromotor tolerability profile for this cannabinoid. Subsequently, CBG (at 30â240 mg/kg, p.o.) or placebo was administered to a further group of pre-satiated rats, and hourly intake and meal pattern data were recorded over 2 h.
Results
CBG produced no adverse effects on any parameter in the neuromotor tolerability test battery. In the feeding assay, 120â240 mg/kg CBG more than doubled total food intake and increased the number of meals consumed, and at 240 mg/kg reduced latency to feed. However, the sizes or durations of individual meals were not significantly increased.
Conclusions
Here, we demonstrate for the first time that CBG elicits hyperphagia, by reducing latency to feed and increasing meal frequency, without producing negative neuromotor side effects. Investigation of the therapeutic potential of CBG for conditions such as cachexia and other disorders of eating and body weight regulation is thus warranted
Identification of Functional Networks of Estrogen- and c-Myc-Responsive Genes and Their Relationship to Response to Tamoxifen Therapy in Breast Cancer
BACKGROUND: Estrogen is a pivotal regulator of cell proliferation in the normal breast and breast cancer. Endocrine therapies targeting the estrogen receptor are effective in breast cancer, but their success is limited by intrinsic and acquired resistance. METHODOLOGY/PRINCIPAL FINDINGS: With the goal of gaining mechanistic insights into estrogen action and endocrine resistance, we classified estrogen-regulated genes by function, and determined the relationship between functionally-related genesets and the response to tamoxifen in breast cancer patients. Estrogen-responsive genes were identified by transcript profiling of MCF-7 breast cancer cells. Pathway analysis based on functional annotation of these estrogen-regulated genes identified gene signatures with known or predicted roles in cell cycle control, cell growth (i.e. ribosome biogenesis and protein synthesis), cell death/survival signaling and transcriptional regulation. Since inducible expression of c-Myc in antiestrogen-arrested cells can recapitulate many of the effects of estrogen on molecular endpoints related to cell cycle progression, the estrogen-regulated genes that were also targets of c-Myc were identified using cells inducibly expressing c-Myc. Selected genes classified as estrogen and c-Myc targets displayed similar levels of regulation by estrogen and c-Myc and were not estrogen-regulated in the presence of siMyc. Genes regulated by c-Myc accounted for 50% of all acutely estrogen-regulated genes but comprised 85% (110/129 genes) in the cell growth signature. siRNA-mediated inhibition of c-Myc induction impaired estrogen regulation of ribosome biogenesis and protein synthesis, consistent with the prediction that estrogen regulates cell growth principally via c-Myc. The 'cell cycle', 'cell growth' and 'cell death' gene signatures each identified patients with an attenuated response in a cohort of 246 tamoxifen-treated patients. In multivariate analysis the cell death signature was predictive independent of the cell cycle and cell growth signatures. CONCLUSIONS/SIGNIFICANCE: These functionally-based gene signatures can stratify patients treated with tamoxifen into groups with differing outcome, and potentially identify distinct mechanisms of tamoxifen resistance
Twenty-three unsolved problems in hydrology (UPH) â a community perspective
This paper is the outcome of a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts. The procedure involved a public consultation through on-line media, followed by two workshops through which a large number of potential science questions were collated, prioritised, and synthesised. In spite of the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work. Questions remain focussed on process-based understanding of hydrological variability and causality at all space and time scales.
Increased attention to environmental change drives a new emphasis on understanding how change propagates across interfaces within the hydrological system and across disciplinary boundaries. In particular, the expansion of the human footprint raises a new set of questions related to human interactions with nature and water cycle feedbacks in the context of complex water management problems. We hope that this reflection and synthesis of the 23 unsolved problems in hydrology will help guide research efforts for some years to come
Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial
Background:
Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB.
Methods:
We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0â24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014â002632-14), and the ISRCTN registry (ISRCTN91737921).
Findings:
Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4â17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08â2·11) for Ctrough, 1·23 (0·99â1·53) for AUC0â24 h, and 0·94 (0·76â1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30â40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir.
Interpretation:
Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB
Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial
BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124â159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with â„1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir
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