Cécile Chouquet

Correlation between breadth of memory HIV-specific cytotoxic T cells, viral load and disease progression in HIV infection

Background: Memory cytotoxic T lymphocytes (CTL) should play a key role in controlling HIV infection. The correlations between the breadth and specificities of memory CTL and virus production and disease progression are still unknown, but are of major importance for vaccine strategies. Methods and design: One-hundred and forty-eight chronically-infected patients, enrolled before the advent of highly active antiretroviral therapy, were followed-up prospectively over 5 years. Memory CTL were tested in vitro against autologous target cells expressing Env, Gag, Pol, Nef, Vif, Rev or Tat HIV-LAI sequences. Results: At entry, an HIV-specific CTL response was detected against at least one viral protein in 77% cases, with Pol and Gag recognized in 57% each, Env and Nef in 36% and 30%, Vif, Rev and Tat in 14%, 10% and 5% of cases respectively. The same pattern was observed over time with some individual variations in responder status. Multivariate analysis of longitudinal data showed that the average number of recognized proteins of two at entry significantly decreased over time with the average loss of one protein per 7 years. The number of recognized proteins was negatively associated with viral load (P < 0.05), and with occurrence of opportunistic infection (P < 0.01), and significantly correlated with CD8 cell counts (P < 0.05) but not with CD4 cell counts. Conclusion: The breadth of HIV antigens recognized by memory CTL is a major correlate of immune control of HIV-replication and disease progression.

Interleukin-2 accelerates CD4 cell reconstitution in HIV-infected patients with severe immunosuppression despite highly active antiretroviral therapy: the ILSTIM study - ANRS 082

Background: Despite effective highly active antiretroviral therapy (HAART), some patients infected with HIV have persistently low CD4 cell counts with risk of HIV disease progression. The addition of interleukin-2, a cytokine that stimulates CD4 T lymphocyte helper cells, may benefit patients with discordant responses. Methods: A total of 72 HIV-infected patients with CD4 cell counts of 25–200 × 106 cells/l (median 145) and plasma HIV RNA < 1000 copies/ml were randomized in a multicentre study to receive open-label 4.5 × 106 IU interleukin-2 subcutaneously twice daily for 5 days every 6 weeks plus their ongoing HAART or were maintained on HAART alone (control group). After 24 weeks, all patients received interleukin-2 therapy plus HAART up to week 80. Primary end-point was the CD4 T cell area under the curve minus baseline up to week 24. Results: After four cycles of interleukin-2, in an intent-to-treat analysis, the respective median CD4 cell area under the curve minus baseline values were +51 and +11 cells in the interleukin-2 (n = 34) and the control group (n = 36) (P < 0.0001). The percentage of patients in the two groups with CD4 cell counts > 200 × 106 cells/l was 81% and 33%, respectively (P < 0.0001). At week 80, the median CD4 cell counts in the two groups were 380 and 270 × 106 cells/l, respectively. Interleukin-2 treatment was reasonably well tolerated and did not result in sustained increases in plasma HIV RNA levels. Conclusions: Administration of interleukin-2 produces significant and sustained increase in CD4 cell counts in HAART-treated patients with persistent CD4 cell counts < 200 × 106 cells/l.

Prevalence of inherited ichthyosis in France: a study using capture-recapture method

BackgroundInherited ichthyoses represent a group of rare skin disorders characterized by scaling, hyperkeratosis and inconstant erythema, involving most of the tegument. Epidemiology remains poorly described. This study aims to evaluate the prevalence of inherited ichthyosis (excluding very mild forms) and its different clinical forms in France.MethodsCapture – recapture method was used for this study. According to statistical requirements, 3 different lists (reference/competence centres, French association of patients with ichthyosis and internet network) were used to record such patients. The study was conducted in 5 areas during a closed period.ResultsThe prevalence was estimated at 13.3 per million people (/M) (CI95%, [10.9 – 17.6]). With regard to autosomal recessive congenital ichthyosis, the prevalence was estimated at 7/M (CI 95% [5.7 – 9.2]), with a prevalence of lamellar ichthyosis and congenital ichthyosiform erythroderma of 4.5/M (CI 95% [3.7 – 5.9]) and 1.9/M (CI 95% [1.6 – 2.6]), respectively. Prevalence of keratinopathic forms was estimated at 1.1/M (CI 95% [0.9 – 1.5]). Prevalence of syndromic forms (all clinical forms together) was estimated at 1.9/M (CI 95% [1.6 – 2.6]).ConclusionsOur results constitute a crucial basis to properly size the necessary health measures that are required to improve patient care and design further clinical studies.

On the impact of domain expertise on query formulation, relevance assessment and retrieval performance in clinical settings

A crowd-based evaluation on the impact of domain expertise on query formulation, relevance assessment and retrieval performance.Queries issues by experts are significantly longer and more technical than queries issued by novices.There is a low level of relevance assessment agreement among both experts and novices but the reasons of the relevance assessment difficulty significantly differ between them.Traditional information retrieval models which mainly consider the presence or absence of query terms within documents are particularly unsuccessful for experts who rather leverage from their knowledge and past experience to assess a multi-dimensional relevance. The large volumes of medical information available on the web may provide answers for a wide range of users attempting to solve health-related problems. While experts generally utilize reliable resources for diagnosis search and professional development, novices utilize different (social) web resources to obtain information that helps them manage their health or the health of people who they care for. A diverse number of related search topics address clinical diagnosis, advice searching, information sharing, connecting with experts, etc. This paper focuses on the extent to which expertise can impact clinical query formulation, document relevance assessment and retrieval performance in the context of tailoring retrieval models and systems to experts vs. non-experts. The results show that medical domain expertise 1) plays an important role in the lexical representations of information needs; 2) significantly influences the perception of relevance even among users with similar levels of expertise and 3) reinforces the idea that a single ground truth does not exist, thereby leading to the variability of system rankings with respect to the level of users expertise. The findings of this study presents opportunities for the design of personalized health-related IR systems, but also for providing insights about the evaluation of such systems.

Analysis of biomedical and health queries: Lessons learned from TREC and CLEF evaluation benchmarks

A large body of research work examined, from both the query side and the user behavior side, the characteristics of medical‐ and health‐related searches. One of the core issues in medical information retrieval (IR) is diversity of tasks that lead to diversity of categories of information needs and queries. From the evaluation perspective, another related and challenging issue is the limited availability of appropriate test collections allowing the experimental validation of medically task oriented IR techniques and systems. In this paper, we explore the peculiarities of TREC and CLEF medically oriented tasks and queries through the analysis of the differences and the similarities between queries across tasks, with respect to length, specificity, and clarity features and then study their effect on retrieval performance. We show that, even for expert oriented queries, language specificity level varies significantly across tasks as well as search difficulty. Additional findings highlight that query clarity factors are task dependent and that query terms specificity based on domain‐specific terminology resources is not significantly linked to term rareness in the document collection. The lessons learned from our study could serve as starting points for the design of future task‐based medical information retrieval frameworks.

How to take into account exposure to drugs over time in pharmacoepidemiology studies of pregnant women

The aim of this study was to develop a new pharmacoepidemiological method to take into account intensity and evolution of drug exposure, applied to pregnant women.

Interest of the trajectory method for the evaluation of outcomes after in utero drug exposure: example of anxiolytics and hypnotics

The aim of this study was to examine the potential benefit to take into account duration and intensity of drug exposure using the recently published method based on individual drug trajectories. This approach was used to define profiles of exposure to anxiolytics/hypnotics during pregnancy and to evaluate the potential effect on newborn health.

Characterizing Health-Related Information Needs of Domain Experts

In information retrieval literature, understanding the users’ intents behind the queries is critically important to gain a better insight of how to select relevant results. While many studies investigated how users in general carry out exploratory health searches in digital environments, a few focused on how are the queries formulated, specifically by domain expert users. This study intends to fill this gap by studying 173 health expert queries issued from 3 medical information retrieval tasks within 2 different evaluation compaigns. A statistical analysis has been carried out to study both variation and correlation of health-query attributes such as length, clarity and specificity of either clinical or non clinical queries. The knowledge gained from the study has an immediate impact on the design of future health information seeking systems.

Incidence and risk factors of first-line HAART discontinuation: is it worth choosing competing risk or standard survival approaches?

Objectives: To estimate the incidences of first-line HAART discontinuation (for intolerance, treatment failure or treatment simplification) and their risk factors by standard survival (1-KM, Cox model) or competing risk approach (CIF, Fine-Gray model) in HIV infected patients. Methods: We studied 1136 patients receiving first-line Highly Active Antiretroviral Therapies (HAART), aged over 18 years, from the Dat’AIDS cohort, Toulouse, France, between January 2000 and June 2008. Cumulative incidence was estimated with 1-KM and CIF estimators and risk factors with Cox and Fine-Gray models. Results: There were 265 discontinuations for intolerance, 136 simplifications, 101 treatment failure and 274 other reasons. One year incidences were 19.0% versus 16.8%, 8.0% versus 6.0%, 6.3% versus 4.8% and 20.0% versus 17.3%, with the estimators 1-KM and CIF, respectively. For intolerance, both models identified similar risk factors. For risk factors of simplification or treatment failure, results differed by the model. Conclusions: As expected, the 1-KM overestimates the incidence of treatment discontinuation. For early and frequent events such as intolerance, the Cox and the Fine-Gray models appear to give similar results. For late and rare events, potentially exposed to competing risk, results differed. The common or specific nature of a factor may also play a role.