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Objective To compare the effect of the biological reference agents (infliximab, etanercept, adalimumab) in RA in pivotal superiority placebo-controlled trials (reference agent vs placebo) vs their effect in equivalence active comparator-controlled trials (reference agent vs biosimilar). Methods The PubMed, EMBASE and Cochrane databases were searched for randomized, double-blind, controlled trials up to March 2020 comparing a biological reference agent vs placebo or biosimilar. The study assessed the ACR 20/50/70 responses of the reference agent in these groups (Reference-pbo and Reference-bs, respectively). The effect of the reference agent in both groups was estimated with 95% CI, pooled using random-effects models and then compared using a meta-regression model. Results We included 31 trials. The main characteristics of the population (disease duration and activity, % seropositivity and methotrexate dose) of the population in both groups were similar. The meta-analysis found a better ACR20 response to the biological originator in the Reference-bs group with a global rate of 70% (95% CI, 66, 74) compared with 59% (95% CI, 55, 62) in the reference-pbo group (P =0.001). A significant difference was also found for ACR 50 [44% (95% CI, 39, 50) vs 35% (95% CI, 31, 39), respectively, P Conclusion The effect of the reference biologic agent was better when compared with an active drug to a placebo. This could be linked to an increased placebo effect in active comparator-controlled studies or a nocebo effect in placebo-controlled studies. This effect can be called the lessebo effect.

International audience; Systemic sclerosis may be complicated by digital ulcers. Nailfold capillaroscopy on one finger might reflect an increased risk of digital ulcer (DU). In the present study we studied the correlations between a history of ulcer and capillary findings on the finger.Method: This study is part of Sclerocap, a multicenter study aiming at validating prospectively the prognostic value of Maricq's and Cutolo's capillaroscopic classifications during a three-year longitudinal follow-up. A history of past or present digital ulcer was recorded at inclusion and nailfold capillaroscopy was performed. Elementary findings as well as Cutolo and Maricq's classifications were assessed.Results: 387 patients were included in Sclerocap (327 females, 60 males) and 3096 fingers were examined by capillaroscopy at inclusion: 316 fingers (10%) belonging to 113 patients had a history of DU. Late Cutolo's stage was statistically correlated with a history of DU, both by univariate: OR 2.08 [1.09-3.96] and multivariate analysis: OR 1.97 [1.06-3.63]. Among the elemental abnormalities, only edema and decreased capillary density were correlated with a history of DU by multivariate analysis: respectively OR 1.92 [1.17-3.16] and 0.65 [0.49-0.85].Conclusion: This cross-sectional study in a large cohort of patients with systemic sclerosis shows a correlation between a history of digital ulcer and edema, a decrease in capillary density and the late stage in Cutolo's classification. The extent of capillary abnormalities on one finger is associated with a history of local digital ulcer. Capillaroscopy might be used to predict the risk of DU but these results need first to be confirmed by prospective studies.

Anorectal infections with Chlamydia trachomatis are commonly found in women. Although the efficacy of doxycycline and azithromycin is comparable in the treatment of urogenital infection, their efficacies toward anorectal infection remain unclear. We therefore aimed to compare a single dose of azithromycin with a 7-day course of doxycycline for the treatment of anorectal C trachomatis infection in women with concurrent vaginal infection.We did a multicentre, open-label, randomised, controlled, superiority trial involving four sexually transmitted infection screening centres and three pregnancy termination centres in France. We included sexually active adult women (≥18 years) with a positive C trachomatis vaginal swab who agreed to provide self-collected anorectal swabs for C trachomatis detection. Participants were randomly assigned (1:1), using block sizes of six and eight and stratification by each investigating centre, to orally receive either azithromycin (a single 1-g dose, with or without food) or doxycycline (100 mg in the morning and evening at mealtimes for 7 days [ie, 100 mg of doxycycline twice per day for 7 days]). All laboratory staff who did the bacteriological analyses, but not the participants and the investigators, were masked to the treatment groups. The primary outcome was the microbiological anorectal cure rate defined as a C trachomatis-negative nucleic acid amplification test (NAAT) result in anorectal specimens 6 weeks after treatment initiation among women who had a baseline C trachomatis-positive anorectal NAAT result. The primary analysis was done in the modified intention-to-treat population, with multiple imputation, which included all women who underwent randomisation and had a C trachomatis-positive vaginal and anorectal NAAT result at baseline. Adverse events were reported in all women who underwent randomisation. This study is registered with ClinicalTrials.gov, number NCT03532464.Between Oct 19, 2018, and April 17, 2020, we randomly assigned a total of 460 participants to either the doxycycline group (n=230) or the azithromycin group (n=230). Four (1%) of 460 participants were excluded because they refused to take doxycycline or were found to be ineligible after randomisation. Among the 456 participants, 357 (78%) had a concurrent C trachomatis-positive anorectal NAAT result at baseline; 184 (52%) of 357 were in the doxycycline group and 173 (48%) were in the azithromycin group (ie, the modified intention-to-treat population). Microbiological anorectal cure occurred in 147 (94%) of 156 participants in the doxycycline group (28 missing values) versus 120 (85%) of 142 in the azithromycin group (31 missing values; adjusted odds ratio with imputation of missing values 0·43 [95% CI 0·21-0·91]; p=0·0274). Reported adverse events possibly related to treatment were notified in 53 (12%) of 456 women: 24 (11%) of 228 in the doxycycline group and 29 (13%) of 228 in the azithromycin group. Gastrointestinal disorders were the most frequently occurring, in 43 (9%) of 456 women: 17 (8%) of 228 in the doxycycline group and 26 (11%) of 228 in the azithromycin group.The microbiological anorectal cure rate was significantly lower among women who received a single dose of azithromycin than among those who received a 1-week course of doxycycline. This finding suggests that doxycycline should be the first-line therapy for C trachomatis infection in women.French Ministry of Health.For the French translation of the abstract see Supplementary Materials section.

International audience; Objectives: To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness.Methods: COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here.Results: The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59-68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3-5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%-18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4-21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms.Discussion: Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19.

The 2011 French Bioethics Law regarding disclosure of genetic information within families enables health professionals to notify any at-risk relatives directly, with the patient’s consent, using a template letter. To assess the impact of this template letter in terms of understanding, personal feelings and intent to contact a health professional, we conducted a study interviewing patients, members of the public and genetic professionals. Although the main response to the letter was anxiety, this was associated with good understanding of the content and most individuals mentioned intention to contact a health professional. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12687-019-00418-7) contains supplementary material, which is available to authorized users.

Objectives To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. Trial design Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. Participants Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate 5.5 mmol/L or The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. Intervention and comparator The four experimental treatments planned in protocol version 1.2 (April 8th, 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. Main outcome The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. Randomisation Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home). Blinding (masking) This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. Numbers to be randomised (sample size) A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. Trial Status This describes the Version 1.2 (April 8th, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15th, 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15th, 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. Trial registration The trial was registered on Clinical Trials.gov on April 22nd, 2020 (Identifier: NCT04356495): and on EudraCT on April 10th, 2020 (Identifier: 2020-001435-27). Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

International audience; Evaluation of immunogenicity is a key step in the clinical development of novel vaccines. T-cell responses to vaccine candidates are typically assessed by intracellular cytokine staining (ICS) using multiparametric flow cytometry. A conventional statistical approach to analyze ICS data is to compare, between vaccine regimens or between baseline and post-vaccination of the same regimen depending on the trial design, the percentages of cells producing a cytokine of interest after ex vivo stimulation of peripheral blood mononuclear cells (PBMC) with vaccineantigens, after subtracting the non-specific response (of unstimulated cells) of each sample. Subtraction of the non-specific response is aimed at capturing the specific response to the antigen, but raises methodological issues related to measurement error and statistical power. We describe here a new statistical approach to analyze ICS data from vaccine trials. We propose a bivariate linear random-effect regression model for estimating the nonspecificand antigen-specific ICS responses. We benchmarked the performance of the model in terms of both bias and control of type-I and -II errors in comparison with conventional approaches, and applied it to simulated data as well as real pre- and post-vaccination data from two recent HIV vaccine trials (ANRS VRI01 in healthy volunteers and therapeutic VRI02 ANRS 149 LIGHT in HIV-infected participants). The model was as good as the conventional approaches (with or without subtraction of the non-specific response) in all simulation scenarios in terms of statistical performance, whereas the conventional approaches did not provide robust results across all scenarios. The proposed model estimated the T-cell responses to the antigens without any effect of the nonspecific response on the specific response, irrespective of the correlation between the nonspecific and specific responses. This novel method of analyzing T-cell immunogenicity data based on bivariate modelling allows consideration of all T-cell data and is more flexible than conventional methods, and so yields more detailed results and enables accurate interpretation of vaccine efficacy.

BACKGROUND: In a previous study of subjects suspected of having ventilator-associated pneumonia, a rapid susceptibility testing approach by using ETEST (BioMerieux) strips directly applied to bronchoalveolar lavage samples provided valuable information at hour 24. The primary objective of this study was to assess a new direct specimen testing by using an even more-rapid E-test approach (at hour 10), which could promote an early de-escalation of the antimicrobial therapy. METHODS: Twenty-eight subjects with ventilator-associated pneumonia admitted to a medical ICU were prospectively included. In parallel with standard routine methods, E-test strips were directly applied onto agar plates seeded with bronchoalveolar lavage samples and were analyzed after 10 h of incubation. E-test results were used to identify potential drug choices by simulating clinical decision making if the microscopy results had been available at the point of care. These choices were analyzed for concordance with the narrowest adequate antimicrobial therapy according to the Minimum Inhibitory Concentrations (MICs) provided by the reference method (ie, the laboratory routine diagnostic). RESULTS: At hour 10, direct specimen testing was readable in 18 of 28 bronchoalveolar lavage samples (64%). Total agreement between the 10-h direct specimen testing approach and the laboratory routine diagnostic approach was 90%, with a sensitivity of 83% and a specificity of 95%, with 8% major errors and 3% very major errors. The concordance between the 2 tests was very good (kappa = 0.79). If the 10-h E-test results were taken into account, then an early de-escalation strategy would have been possible in 10 of 18 cases (55%) at hour 10. CONCLUSIONS: This rapid susceptibility testing approach provided early (10 h) and valuable information that could lead to an early adjustment of empirical antimicrobial treatment in a ventilator-associated pneumonia setting. (ClinicalTrials.gov registration NCT01266863.)

International audience; Background: Chlamydia trachomatis can lead to a persistent infection in the lower gastrointestinal tract, suggesting a potential role of autoinoculation of cervical chlamydial infection from the rectal site, contributing to repeat infections. Moreover, around 75% of women with urogenital C. trachomatis have concurrent anorectal infection. Current treatment guidelines for urogenital C. trachomatis infection recommend either a single 1 g dose of azithromycin or doxycycline 100 mg twice daily for 7 days. Doxycycline appears to be more effective in treating anorectal infections as suggested in a population of men who have sex with men, but no randomized controlled trial (RCT) had directly compared azithromycin with doxycycline for the treatment of rectal infections. We propose an open-label RCT to compare the microbial cure obtained with a single 1 g dose of azithromycin versus 100 mg of doxycycline twice daily for 7 days, for the treatment of anorectal C. trachomatis infection concurrent to urogenital infection in women. Methods and study design: A total of 460 women with C. trachomatis urogenital infection will be enrolled in the study. Women will be asked to provide self-collected anorectal swabs and will be randomized to receive either a 1 g single dose of azithromycin or doxycycline 100 mg twice daily for 7 days. Clinical and biological data will be collected and patients will complete questionnaires about their sexual behavior. The primary outcome is the microbial cure rate, defined as a C. trachomatis negative nucleic acid amplification test (NAAT) result in the anorectal specimens 6 weeks after treatment initiation among women with a C. trachomatis positive urogenital and anorectal NAAT result at the baseline. The secondary outcome is autoinoculation from the rectum to the vagina, which will be evaluated based on the number of women with the same C. trachomatis genotype profile that will be identified in an anorectal-positive specimen obtained 6 weeks after treatment initiation and in a vaginal-positive specimen obtained four months after treatment. Discussion: The results of this trial will establish which treatment is more efficacious against anorectal infection and could affect recommendations for the treatment of urogenital C. trachomatis infection, taking into account concurrent anorectal infection. Trial registration numbers: EudraCT number: 2017-002595-15. ClinicalTrials.gov Identifier: NCT03532464. Date of registration: May 31, 2018. World Health Organisation International Clinical Trials Registry: NTC03532464. Secondary ID: CHUBX 2016/26. Date of registration: May 09, 2018.

Introduction Dans le developpement clinique vaccinal, l’evaluation de la capacite du vaccin candidat a generer des reponses immunitaires est un objectif important. La mesure de l’immunogenicite cellulaire s’effectue en cytometrie de flux multiparametrique permettant la caracterisation de lymphocytes T produisant des cytokines apres stimulation antigenique specifique. L’approche statistique actuellement utilisee pour l’analyse de ces donnees consiste a effectuer une comparaison inter-bras ou intra-bras des pourcentages de cellules produisant une ou des cytokine(s) d’interet, apres soustraction de la reponse observee dans des cellules non-stimulees (NS) de chaque echantillon. Soustraire cette reponse NS vise a analyser la reponse specifique a l’antigene, mais souleve des questions methodologiques liees a l’erreur de mesure, a des biais potentiels et a la puissance statistique. Un modele bivarie modelisant simultanement la reponse NS et la reponse induite par la stimulation specifique (S) permet une evaluation plus valide de l’effet du vaccin dans les essais cliniques vaccinaux. Methodes Nous avons construit un modele lineaire bivarie modelisant simultanement un vecteur de reponse avec deux variables dependantes (reponses NS et S) et l’effet du vaccin comme principale variable explicative. Les performances du modele ont ete evaluees au travers de simulations numeriques avec differents scenarii en termes de biais et de controle des erreurs de type 1 et 2, en comparaison des approches conventionnelles. Nous avons applique ce modele sur les donnees de deux essais vaccinaux contre le VIH (ANRS VRI01 et VRI02 ANRS 149 LIGHT). Les simulations ont ete effectuees sous SAS ; l’implementation du modele sous SAS (proc mixed) et R (package nlme). Resultats Cette nouvelle methode permet de modeliser une relation lineaire entre la reponse NS et les reponses antigeniques, tout en tenant compte de la correlation dans leur erreur de mesure. Le modele garantit un controle de l’erreur de type 1 en toute circonstances et une puissance statistique toujours au moins aussi bonne que l’approche conventionnelle dans tous les scenarii ( Fig. 1 ). Le modele a aussi ete applique sur les essais ANRS VRI01 et VRI02 ANRS 149 LIGHT. Conclusion Cette nouvelle methode permet de prendre en compte toutes les informations disponibles contrairement aux approches conventionnelles, conduisant a des resultats plus robustes et une absence de biais dans l’evaluation de l’immunogenicite vaccinale.

International audience; INTRODUCTION:Initial evaluation of a candidate vaccine against HIV includes an assessment of the vaccine's ability to generate immune responses. However, the dynamics of vaccine-induced immune responses are unclear. We hypothesized that the IFN-γ producing cytotoxic CD8+ (CD8+ IFN-γ+) T cell responses could be predicted by early IL-2 producing CD4+ (CD4+ IL-2+) helper T cell responses, and we evaluated this hypothesis using data from a phase I/II prophylactic HIV vaccine trial. The objective was to assess the dynamics and correlations between CD4+ IL-2+ T cell and CD8+ IFN-γ+ T cell responses after vaccination with a recombinant adenoviral serotype 5 (rAd5) HIV vaccine.METHODS:We analyzed data from the HVTN 068 HIV vaccine trial, which evaluated the immunogenicity of two different strategies for prime and boost vaccination (rAd5-rAd5 vaccine versus DNA-rAd5) in 66 healthy volunteers. Spearman correlations between immunogenicity markers across time-points were calculated. CD8+ IFN-γ+ T cell response in the rAd5-rAd5 arm was modeled as a function of CD4+ IL-2+ T cell response and time using mixed effects regression models.RESULTS:Moderate to high correlations (r = 0.48-0.76) were observed in the rAd5-rAd5 arm between the CD4+ IL-2+ T cell response at week 2 and later CD8+ IFN-γ+ T cell responses (weeks 2-52). Regression models confirmed this relationship with a significant association between the two markers: for a 1.0% increase in CD4+ IL-2+ T cells at week 2 post-prime, a 0.3% increase in CD8+ IFN-γ+ T cell responses across subsequent time points, including post-boost time points, was observed (p

International audience; HIV vaccine strategies are expected to be a crucial component for controlling the HIV epidemic. Despite the large spectrum of potential candidate vaccines for both prophylactic and therapeutic use, the overall development process of an efficacious HIV vaccine strategy is lengthy. The design of clinical trials and the progression of a candidate strategy through the different clinical development stages remain methodologically challenging, mainly due to the lack of validated correlates of protection. In this review, we describe recent advances in clinical trial designs to increase the efficiency of the clinical development of candidate HIV vaccine strategies. The methodological aspects of the designs for early- (phase I and II) and later -stage (phase IIB and III) development are discussed, taking into account the specificities of both prophylactic and therapeutic HIV vaccine development.

Introduction Les epidemies de maladie a virus Ebola (MVE) surviennent de maniere recurrente et imprevisible depuis plusieurs dizaines d’annees, et la derniere epidemie (2013–2015) a ete d’une ampleur exceptionnelle. Dans ce contexte et en l’absence de therapeutiques specifiques, le developpement de vaccins preventifs a ete accelere. Actuellement, en l’absence de correlat de protection identifie, l’evaluation de l’efficacite des candidats vaccins contre la MVE repose principalement sur la mesure de la reponse anticorps apres vaccination. Cependant, les facteurs influencant cette reponse restent encore peu connus. L’objectif etait de determiner si la reponse anticorps apres vaccination contre la MVE pouvait etre influencee par d’autres facteurs que le type de vaccin, notamment par les caracteristiques des methodes de mesure ou de la population vaccinee. Methodes Nous avons realise une revue systematique de la litterature pour selectionner tous les essais vaccinaux contre la MVE menes chez l’humain ou chez le primate non humain (PNH). Pour chaque groupe de vaccination retrouve dans les etudes selectionnees, nous avons extrait des donnees sur la reponse anticorps et sur les facteurs susceptibles de la faire varier. L’unite statistique etait le groupe de vaccination. Une analyse descriptive a ete menee sur l’ensemble des groupes. Les groupes humains d’au moins huit individus ont ensuite ete inclus dans une analyse d’heterogeneite utilisant un modele de meta-regression lineaire multivariable a intercept aleatoire. L’heterogeneite a ete evaluee graphiquement par un diagramme en foret et quantifiee par un test Q, par la proportion de variation totale due a l’heterogeneite (I2) et par la variabilite expliquee par les facteurs inclus dans le modele (R2). Les analyses ont ete effectuees a l’aide du package metafor du logiciel R. Resultats Au total, 45 etudes ont ete selectionnees, ce qui correspondait a 188 groupes de vaccination (68 groupes humains et 120 groupes de PNH). Le titre d’anticorps variait de 0 a 5,79 log10, avec une moyenne de 3,02 (intervalle de confiance a 95 % (IC95) [2,89 ; 3,15]). Il etait plus eleve chez les PNH que chez les humains : titres moyens de 3,16 (IC95 [2,99 ; 3,33]) versus 2,77 (IC95 [2,59 ; 2,95]). Dans le modele multivariable final incluant 55 groupes humains, le type de vaccin (p

To evaluate characteristic features of mammography, ultrasound and magnetic resonance imaging (MRI) of sporadic breast cancer in women40 years and to determine correlations with pathological and biological factors.A retrospective review of radiological, clinicopathological and biological features of sporadic breast cancers for women under 40 years at our institution between 2007-2012 covering 91 patients. Mammography was available for 97 lesions, ultrasound for 94 and MRI for 38.The most common imaging features were masses, nearly all classified BI-RADS 4 or 5. On mammography microcalcifications alone accounted for 31 %, all suspicious. There were 42.6 % luminal B, 24.5 % luminal A, 19.1 % HER2-enriched and 10.6 % triple-negative (TN) tumours by immunohistochemistry. HER2 overexpression was correlated with the presence of calcifications at mammography (P = 0.03). TN cancers more often had an oval shape and abrupt interface at ultrasound and rim enhancement on MRI. MRI features were suspicious for all cancers and rim enhancement of a mass was a significant predictor of triple-negative tumours (P = 0.01).The imaging characteristics of cancers in patients under 40 years without proven gene mutations do not differ from their older counterparts, but appear correlated to phenotypic profiles, which have a different distribution in young women compared to the general population.

Introduction Les evaluations cliniques initiales d’un vaccin candidat contre le VIH se fondent sur sa capacite a generer des reponses immunitaires. Actuellement, la dynamique des marqueurs de reponses immunologiques au vaccin reste mal connue. Une meilleure connaissance de cette dynamique pourrait permettre d’optimiser les mesures dans des futurs essais. Nous faisons l’hypothese que la dynamique de certains marqueurs immunitaires pourrait etre predite a partir de la dynamique d’autres marqueurs. En particulier, une reponse precoce des CD4 auxiliaires (lymphocytes T CD4+ producteurs d’IL-2) pourrait predire la reponse plus tardive des CD8 cytotoxiques (lymphocytes T CD8+ producteurs d’IFN-γ). L’objectif de cette etude etait d’evaluer les dynamiques et correlations entre les CD4 auxiliaires et les CD8 cytotoxiques dans un essai vaccinal prophylactique de phase 2 contre le VIH. Methodes Cette etude etait basee sur les donnees de l’essai clinique vaccinal HVTN protocole 068, qui a evalue deux strategies de primo et revaccination differentes (vaccin rAd5-rAd5 versus ADN-rAd5) chez 66 volontaires sains. Des mesures d’immunogenicite cellulaire (CD4 auxilliaires et CD8 cytotoxiques) ont ete effectuees de facon repetee chez les participants. L’association entre les CD4 auxiliaires et les CD8 cytotoxiques a d’abord ete etudiee aux differents temps de mesure en utilisant des correlations de Spearman. La reponse des CD8 cytotoxiques a ensuite ete modelisee en fonction de la reponse des CD4 auxiliaires afin de tenir compte de la correlation entre ces deux marqueurs dans le bras rAd5-rAd5 en utilisant des modeles a effets mixtes. L’effet du temps a ete introduit dans les modeles sous forme de splines. Un premier modele a inclus comme variable explicative la reponse des CD4 auxiliaires a chaque temps et a ete ajuste sur le temps. Dans un second modele, les CD4 auxiliaires ont ete introduits sous forme de deux variables explicatives, la premiere representant leur evolution de j0 a j7, la seconde la valeur fixe de j14 afin d’etudier plus precisement l’association de la mesure specifique des CD4 auxilliaires a j14 sur l’ensemble de la reponse des CD8 cytotoxiques. Le meilleur modele a ete choisi en fonction du critere d’Akaike. Resultats Des correlations moyennes a fortes (r = 0,50–0,80) etaient observees dans le bras rAd5-rAd5 entre les reponses des CD4 auxiliaires a j14 et des CD8 cytotoxiques au cours de la vaccination. Aucune correlation n’etait retrouvee dans le bras ADN-rAd5. Des modeles de regression ont confirme cette relation dans le bras rAd5-rAd5 en mettant en evidence une association significative entre les CD4 auxiliaires a j14 et la reponse des CD8 cytotoxique consecutive : pour une augmentation de 1,0 % du pourcentage des CD4 auxiliaires a la visite a j14, le pourcentage de CD8 cytotoxiques augmentait de 0,29 % (IC 95 % 0,16–0,42 ; p Conclusion La modelisation des reponses immunitaires au vaccin au cours d’un essai clinique demande des modeles complexes. Dans notre application, la modelisation a souligne le role precoce de la reponse des CD4 auxiliaires dans la reponse cellulaire au vaccin et notamment dans la stimulation et le maintien de la reponse des CD8 cytotoxiques qui permet de lutter contre le virus. Cette approche montre l’interet de la modelisation pour mieux cibler les temps de mesure dans des futurs essais cliniques et predire la reponse vaccinale.