Polymorphism of Plasmodium falciparum Na+/H+ exchanger is indicative of a low in vitro quinine susceptibility in isolates from Viet Nam

<p>Abstract</p> <p>Background</p> <p>The <it>Plasmodium falciparum </it>NA+/H+ exchanger (<it>pfnhe1</it>, gene PF13_0019) has recently been proposed to influence quinine (QN) susceptibility. However, its contribution to QN resistance seems to vary geographically depending on the genetic background of the parasites. Here, the role of this gene was investigated in <it>in vitro </it>QN susceptibility of isolates from Viet Nam.</p> <p>Method</p> <p>Ninety-eight isolates were obtained from three different regions of the Binh Phuoc and Dak Nong bordering Cambodia provinces during 2006-2008. Among these, 79 were identified as monoclonal infection and were genotyped at the microsatellite <it>pfnhe1 </it>ms4760 locus and <it>in vitro </it>QN sensitivity data were obtained for 51 isolates. Parasite growth was assessed in the field using the HRP2 immunodetection assay.</p> <p>Results</p> <p>Significant associations were found between polymorphisms at <it>pfnhe1 </it>microsatellite ms4760 and susceptibility to QN. Isolates with two or more DNNND exhibited much lower susceptibility to QN than those harbouring zero or one DNNND repeats (median IC₅₀of 682 nM <it>versus </it>median IC₅₀of 300 nM; <it>p </it>= 0.0146) while isolates with one NHNDNHNNDDD repeat presented significantly reduced QN susceptibility than those who had two (median IC₅₀of 704 nM <it>versus </it>median IC₅₀of 375 nM; p < 0.01). These QNR associated genotype features were mainly due to the over representation of profile 7 among isolates (76.5%). The majority of parasites had <it>pfcrt76T </it>and wild-type <it>pfmdr1 </it>(> 95%) thus preventing analysis of associations with these mutations. Interestingly, area with the highest median QN IC₅₀showed also the highest percentage of isolates carrying the <it>pfnhe1 </it>haplotype 7.</p> <p>Conclusions</p> <p>The haplotype 7 which is the typical Asian profile is likely well-adapted to high drug pressure in this area and may constitute a good genetic marker to evaluate the dissemination of QNR in this part of the world.</p

Cross-Sectional HIV Incidence Surveillance: A Benchmarking of Approaches for Estimating the 'Mean Duration of Recent Infection'.

The application of biomarkers for 'recent' infection in cross-sectional HIV incidence surveillance requires the estimation of critical biomarker characteristics. Various approaches have been employed for using longitudinal data to estimate the Mean Duration of Recent Infection (MDRI) - the average time in the 'recent' state. In this systematic benchmarking of MDRI estimation approaches, a simulation platform was used to measure accuracy and precision of over twenty approaches, in thirty scenarios capturing various study designs, subject behaviors and test dynamics that may be encountered in practice. Results highlight that assuming a single continuous sojourn in the 'recent' state can produce substantial bias. Simple interpolation provides useful MDRI estimates provided subjects are tested at regular intervals. Regression performs the best - while 'random effects' describe the subject-clustering in the data, regression models without random effects proved easy to implement, stable, and of similar accuracy in scenarios considered; robustness to parametric assumptions was improved by regressing 'recent'/'non-recent' classifications rather than continuous biomarker readings. All approaches were vulnerable to incorrect assumptions about subjects' (unobserved) infection times. Results provided show the relationships between MDRI estimation performance and the number of subjects, inter-visit intervals, missed visits, loss to follow-up, and aspects of biomarker signal and noise.MRC Funding: MC_UP_1302/3’ and U10526056

Biomarker-Based HIV Incidence in a Community Sample of Men Who Have Sex with Men in Paris, France

BACKGROUND: Population-based estimates of HIV incidence in France have revealed that men who have sex with men (MSM) are the most affected population and contribute to nearly half of new infections each year. We sought to estimate HIV incidence among sexually active MSM in Paris gay community social venues. METHODOLOGY/ PRINCIPAL FINDINGS: A cross-sectional survey was conducted in 2009 in a sample of commercial venues such as bars, saunas and backrooms. We collected a behavioural questionnaire and blood sample. Specimens were tested for HIV infection and positive specimens then tested for recent infection by the enzyme immunoassay for recent HIV-1 infection (EIA-RI). We assessed the presence of antiretroviral therapy among infected individuals to rule out treated patients in the algorithm that determined recent infection. Biomarker-based cross-sectional incidence estimates were calculated. We enrolled 886 MSM participants among which 157 (18%) tested HIV positive. In positive individuals who knew they were infected, 75% of EIA-RI positive results were due to ART. Of 157 HIV positive specimens, 15 were deemed to be recently infected. The overall HIV incidence was estimated at 3.8% person-years (py) [95%CI: 1.5-6.2]. Although differences were not significant, incidence was estimated to be 3.5% py [0.1-6.1] in men having had a negative HIV test in previous year and 4.8% py [0.1-10.6] in men having had their last HIV test more than one year before the survey, or never tested. Incidence was estimated at 4.1% py [0-8.3] in men under 35 years and 2.5% py [0-5.4] in older men. CONCLUSIONS/ SIGNIFICANCE: This is the first community-based survey to estimate HIV incidence among MSM in France. It includes ART detection and reveals a high level of HIV transmission in sexually active individuals, despite a high uptake of HIV testing. These data call for effective prevention programs targeting MSM engaged in high-risk behaviours

Routine HIV Screening in France: Clinical Impact and Cost-Effectiveness

BACKGROUND. In France, roughly 40,000 HIV-infected persons are unaware of their HIV infection. Although previous studies have evaluated the cost-effectiveness of routine HIV screening in the United States, differences in both the epidemiology of infection and HIV testing behaviors warrant a setting-specific analysis for France. METHODS/PRINCIPAL FINDINGS. We estimated the life expectancy (LE), cost and cost-effectiveness of alternative HIV screening strategies in the French general population and high-risk sub-populations using a computer model of HIV detection and treatment, coupled with French national clinical and economic data. We compared risk-factor-based HIV testing ("current practice") to universal routine, voluntary HIV screening in adults aged 18-69. Screening frequencies ranged from once to annually. Input data included mean age (42 years), undiagnosed HIV prevalence (0.10%), annual HIV incidence (0.01%), test acceptance (79%), linkage to care (75%) and cost/test (€43). We performed sensitivity analyses on HIV prevalence and incidence, cost estimates, and the transmission benefits of ART. "Current practice" produced LEs of 242.82 quality-adjusted life months (QALM) among HIV-infected persons and 268.77 QALM in the general population. Adding a one-time HIV screen increased LE by 0.01 QALM in the general population and increased costs by €50/person, for a cost-effectiveness ratio (CER) of €57,400 per quality-adjusted life year (QALY). More frequent screening in the general population increased survival, costs and CERs. Among injection drug users (prevalence 6.17%; incidence 0.17%/year) and in French Guyana (prevalence 0.41%; incidence 0.35%/year), annual screening compared to every five years produced CERs of €51,200 and €46,500/QALY. CONCLUSIONS/SIGNIFICANCE. One-time routine HIV screening in France improves survival compared to "current practice" and compares favorably to other screening interventions recommended in Western Europe. In higher-risk groups, more frequent screening is economically justifiable.Haute Autorite de Sante; the Institut de Veille Sanitaire; Sidaction; the Agence Nationale de Recherches sur le SIDA et les hepatites virales; the National Institute of Allergy and Infectious Diseases (R01 AI042006, K24 AI062476, P30 AI42851); the National Institute of Mental Health (R01 MH65869); the National Institute on Drug Abuse (R01 DA015612

AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine

International audienceAGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

Estimation de l’incidence de l’infection par le VIH en France à l’aide d’un test biologique d’infection récente

Knowledge of HIV incidence is essential to provide a timely picture of the HIV epidemie, in arder to target and evaluate prevention efforts. However, current methods of HIV incidence estimation can hardly provide data on current transmission patterns. A new approach based on biological procedures that discriminate recent from long-standing HIV infection has been developed since the mid 1990s. Its major advantage is that it can provide incidence estimates from a single population sample without the need for a longitudinal follow-up. The French national HIV/AIDS case reporting system has included aroutine testing for recent infection since its debut in 2003. The objective of this PhD thesis is to estimate population-based HIV incidence in France by using HIV case reporting data and results from recent infection testing. Its first part is a review of laboratory-based methods for HIV incidence estimation. The second part is dedicated to the calibration of the test for recent infection used in France using a reference sample of population. The third partis giving estimates of population-based HIV incidence in France. Based on this new method applied at a national scale, HIV incidence will be tracked over time in arder to monitor the HIV transmission dynamics in the various risk groups of the population and to better target prevention.La connaissance de l'incidence de l'infection par le VIH est cruciale pour appréhender la dynamique de l'épidémie de VIH/sida, afin de mesurer les besoins en termes de prévention ou l'impact des interventions pour contrôler cette maladie. Cependant, les méthodes classiques d'estimation sont difficiles à mettre en oeuvre pour estimer l'incidence de cette infection. Une nouvelle approche d'estimation, reposant sur la caractérisation, par un test biologique, d'individus récemment infectés parmi une population de personnes séropositives a été proposée au milieu des années 1990. Cette approche présente l'avantage de pouvoir fournir une estimation d'incidence à partir d'un échantillon constitué à un moment donné de personnes diagnostiquées, sans suivi longitudinal. En France, la surveillance des diagnostics d'infection par le VIH par l'institut de veille sanitaire a intégré, dès sa mise en place en 2003, l'utilisation d'un test d'infection récente. Cette thèse a pour objectif d'estimer, par cette nouvelle approche, l'incidence de l'infection par le VIH en France à partir des données de surveillance des diagnostics et de la caractérisation de l'infection récente. Une première partie consiste en une revue des méthodes d'estimation basées sur la mise en évidence de marqueurs biologiques de l'infection récente. La deuxième partie est consacrée à la calibration du test d'infection récente utilisé en France à partir d'un échantillon de référence de patients suivis dans le cadre de cohortes. La troisième partie fournie les estimations d 'incidence en population en France. Le développement de cette méthode d'estimation contribue à mieux décrire la dynamique de transmission du virus en France dans les différents groupes de population, afin de mieux cibler la prévention

Les CDAG et la prise en charge de l’infection par le VIH

En France, depuis 1988, des consultations de dépistage anonyme et gratuit (CDAG) du VIH ont été mises en place dans chaque département, pour permettre une démarche individuelle et volontaire de dépistage de l’infection par le VIH. Il existe actuellement plus de 380 CDAG dont les missions ont été régulièrement élargies par les autorités sanitaires. Elles doivent favoriser le dépistage précoce, faciliter l’accès au dépistage des personnes précarisées et des personnes vulnérables aux risques, renforcer la prévention en aidant les consultants à définir une stratégie personnelle de prévention vis-à-vis du VIH, mais aussi du VHC, de la syphilis et des autres maladies sexuellement transmissibles. Elles doivent aussi renforcer le lien entre dépistage et prise en charge. Les CDAG drainent une population jeune, donc plus à risque pour l’infection par le VIH que la population générale. Leur activité augmente régulièrement, et leur taux de positivité du dépistage est double de celui des laboratoires d’analyse médicale. Entre 1 000 et 2 000 diagnostics positifs d’infection par le VIH sont faits dans les CDAG chaque année, ce qui représentait 11 % des sérologies positives à l’échelle nationale en 2002. La connaissance de l’impact réel des CDAG sur la prévention de l’infection par le VIH et leur rôle dans le dépistage sont limités par l’anonymat et le type de recueil d’informations volontairement réduit. Pour mieux connaître la typologie des consultants, le recueil des données d’activité va évoluer à partir de 2004 et sera complété par une enquête épidémiologique transversale et par la mise en place d’un réseau de CDAG assurant un recueil de données épidémiologiques plus complet et continu

Set-membership methods applied to identify high-frequency elements of EMI filters

International audienceIn order to enhance the performance of electromagnetic interference (EMI) filters, it is necessary to identify high-frequency parasitic elements of their passive components, mainly those related to the coupled inductors. motivated by this issue, in this work a realistic high-frequency model is proposed for the coupled inductors. Actually, using interval analysis in particular the forward-backward contractor, a set-membership algorithm has been developed to estimate systematically the parasitic elements linked with the magnetic components. The main advantages of this algorithm compared to the fitting methods are the values of the estimated parameters are always positive and the corrupted data are taken into account. The comparison of the simulation results and the experimental data allows us to validate the proposed method