Benjamin Riche

Retraction: Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus

Nicole Boucheron, Roland Tschismarov, Lisa Goeschl, Mirjam A Moser, Sabine Lagger, Shinya Sakaguchi, Mircea Winter, Florian Lenz, Dijana Vitko, Florian P Breitwieser, Lena Müller, Hammad Hassan, Keiryn L Bennett, Jacques Colinge, Wolfgang Schreiner, Takeshi Egawa, Ichiro Taniuchi, Patrick Matthias, Christian Seiser& Wilfried Ellmeier Nat. Immunol. 15, 439–448 (2014); published online 30 March 2014; corrected after print 6 June 2014

Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a bayesian random-effects model

BackgroundAntibodies directed against haemagglutinin, measured by the haemagglutination inhibition (HI) assay are essential to protective immunity against influenza infection. An HI titre of 1:40 is generally accepted to correspond to a 50% reduction in the risk of contracting influenza in a susceptible population, but limited attempts have been made to further quantify the association between HI titre and protective efficacy.MethodsWe present a model, using a meta-analytical approach, that estimates the level of clinical protection against influenza at any HI titre level. Source data were derived from a systematic literature review that identified 15 studies, representing a total of 5899 adult subjects and 1304 influenza cases with interval-censored information on HI titre. The parameters of the relationship between HI titre and clinical protection were estimated using Bayesian inference with a consideration of random effects and censorship in the available information.ResultsA significant and positive relationship between HI titre and clinical protection against influenza was observed in all tested models. This relationship was found to be similar irrespective of the type of viral strain (A or B) and the vaccination status of the individuals.ConclusionAlthough limitations in the data used should not be overlooked, the relationship derived in this analysis provides a means to predict the efficacy of inactivated influenza vaccines when only immunogenicity data are available. This relationship can also be useful for comparing the efficacy of different influenza vaccines based on their immunological profile.

Spatial distribution of soil contamination by Toxoplasma gondii in relation to cat defecation behaviour in an urban area

In urban areas, there may be a high local risk of zoonosis due to high densities of stray cat populations. In this study, soil contamination by oocysts of Toxoplasma gondii was searched for, and its spatial distribution was analysed in relation to defecation behaviour of cats living in a high-density population present in one area of Lyon (France). Sixteen defecation sites were first identified. Cats were then repeatedly fed with marked food and the marked faeces were searched for in the defecation sites. Of 260 markers, 72 were recovered from 24 different cats. Defecation sites were frequented by up to 15 individuals. Soil samples were also examined in order to detect the presence of T. gondii using real-time PCR. The entire study area was then sampled according to cat density and vegetation cover type. Only three of 55 samples were positive and all came from defecation sites. In a second series of observations, 16 defecation sites were sampled. Eight of 62 samples tested positive, originating in five defecation sites. Laboratory experiments using experimental seeding of soil showed that the inoculated dose that can be detected in 50% of assays equals 100-1000oocysts/g, depending on the strain. This study shows that high concentrations of oocysts can be detected in soil samples using molecular methods and suggests that spatial distribution of contamination areas is highly heterogeneous. Positive samples were only found in some of the defecation sites, signifying that at-risk points for human and animal infection may be very localised.

DNA double-strand breaks induced by mammographic screening procedures in human mammary epithelial cells.

Abstract Purpose: To assess in vitro mammographic radiation-induced DNA damage in mammary epithelial cells from 30 patients with low (LR) or high (HR) family risk of breast cancer. Materials and methods: Spontaneous and radiation-induced DNA double-strand breaks (DSB) were quantified by using immunofluorescence of the phosphorylated H2AX histone (γH2AX) in different conditions of mammography irradiation (2, 4, 2 + 2 mGy). Results: HR patients showed significantly more spontaneous γH2AX foci than LR patients (p = 0.014). A significant dose-effect was observed, with an exacerbation in HR patients (p = 0.01). The dose repetition (2 + 2 mGy) provided more induced and more unrepaired DSB than 2 mGy and 4 mGy, and was exacerbated in HR (p = 0.006). Conclusions: This study highlights the existence of DSB induced by mammography and revealed by γH2AX assay with two major radiobiological effects occurring: A low-dose effect, and a LOw and Repeated Dose (LORD) effect. All these effects were exacerbated in HR patients. These findings may lead us to re-evaluate the number of views performed in screening using a single view (oblique) in women whose mammographic benefit has not properly been proved such as HR patients.

Focal High Intensity Focused Ultrasound of Unilateral Localized Prostate Cancer: A Prospective Multicentric Hemiablation Study of 111 Patients

BACKGROUND Up to a third of patients with localized prostate cancer have unilateral disease that may be suitable for partial treatment with hemiablation. OBJECTIVE To evaluate the ability of high intensity focused ultrasound (HIFU) to achieve local control of the tumor in patients with unilateral localized prostate cancer. DESIGN, SETTING, AND PARTICIPANTS The French Urological Association initiated a prospective IDEAL multi-institutional study (2009-2015), to evaluate HIFU-hemiablation as a primary treatment. INTERVENTION Multiparametric magnetic resonance imaging and biopsy were used for unilateral cancer diagnosis and control, and HIFU-hemiablation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary: absence of clinically significant cancer (CSC) on control biopsy at 1 yr (CSC: Gleason score ≥ 7 or cancer core length>3mm regardless of grade or > 2 positive cores). Secondary: presence of any cancer on biopsy, biochemical response, radical treatment free survival, adverse events, continence (no pad), erectile function (International Index of Erectile Function-5 ≥ 16), and quality of life (European Organization for Research and Treatment of Cancer QLQ-C28) questionnaires. RESULTS AND LIMITATIONS One hundred and eleven patients were treated (mean age: 64.8 yr [standard deviation 6.2]; mean prostate-specific antigen: 6.2 ng/ml [standard deviation 2.6]; 68% low risk, 32% intermediate risk). Of the 101 patients with control biopsy, 96 (95%) and 94 (93%) had no CSC in the treated and contralateral lobes, respectively. Mean prostate-specific antigen at 2 yr was 2.3 ng/ml (standard deviation 1.7). The radical treatment-free survival rate at 2 years was 89% (radical treatments: six radical prostatectomies, three radiotherapies, and two HIFU). Adverse events were Grade 3 in 13%. At 12 mo continence and erectile functions were preserved in 97% and 78%. No significant decrease in quality of life score was observed at 12 mo. One limitation is the number of low-risk patients included in this study. CONCLUSIONS At 1 yr, HIFU-hemiablation was efficient with 95% absence of clinically significant cancer associated with low morbidity and preservation of quality of life. Radical treatment-free survival rate was 89% at 2 yr. PATIENT SUMMARY This report shows that high intensity focused ultrasound half-gland treatment of unilateral prostate cancer provides promising results with high cancer control and low morbidity.

Cascade of HIV care and population viral suppression in a high-burden region of Kenya.

Introduction:Direct measurement of antiretroviral treatment (ART) program indicators essential for evidence-based planning and evaluation – especially HIV incidence, population viral load, and ART eligibility – is rare in sub-Saharan Africa. Design/methods:To measure key indicators in rural western Kenya, an area with high HIV burden, we conducted a population survey in September to November 2012 via multistage cluster sampling, recruiting everyone aged 15–59 years living in 3330 randomly selected households. Consenting individuals were interviewed and tested for HIV at home. Participants testing positive were assessed for CD4+ cell count and viral load, and their infections classified as either recent or long term based on Limiting Antigen Avidity assays. HIV-negative participants were tested by nucleic acid amplification to detect acute infections. Results:Of 6833 household members eligible for the study, 6076 (94.7% of all women and 81.0% of men) agreed to participate. HIV prevalence and incidence were 24.1% [95% confidence interval [CI] 23.0–25.2] and 1.9 new cases/100 person-years (95% CI 1.1–2.7), respectively. Among HIV-positive participants, 59.4% (95% CI 56.8–61.9) were previously diagnosed, 53.1% (95% CI 50.5–55.7) were receiving care, and 39.7% (95% CI 37.1–42.4) had viral load less than 1000 copies/ml. Applying 2013 WHO recommendations for ART initiation increased the proportion of ART-eligible people from 60.0% (based on national guidelines in place during the survey; 95% CI 57.3–62.7) to 82.0% (95% CI 79.5–84.5). Among HIV-positive people not receiving ART, viral load increased with decreasing CD4+ cell count (500–749 vs. ≥750 cells/&mgr;l, adjusted mean difference, 0.40 log10 copies/ml, 95% CI 0.20–0.60, P < 0.01). Conclusion:This study demonstrates how population-level data can help optimize HIV programs. Based on these results, new regional programs are prioritizing diagnosis and expanding ART eligibility, key steps to reach undetectable viral load.

Plasminogen Activator Inhibitor Type 1 is the Most Significant of the Usual Tissue Prognostic Factors in Node-Negative Breast Ductal Adenocarcinoma Independent of Urokinase-Type Plasminogen Activator

PURPOSE The aim of the present investigation was to evaluate the prognostic significance of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) tissue contents in primary breast adenocarcinoma. PATIENTS AND METHODS Patients from 3 medical centers were included between 1994 and 2001. Biologic factors in tumor extracts were all assayed in the same laboratory. PAI-1 and uPA were treated as continuous or dichotomized variables. Metastasis-free survival analyses were performed using the Cox model and the classification algorithm and regression tree (CART) in the whole population and in the subsets of node-negative (pN0) or positive (pN+) cases. Kaplan curves of metastasis-free survival were designed for different groups in relation to uPA/PAI-1 combinations. Urokinase-type plasminogen activator tumor level appears related to the anatomic degree of extension; conversely, PAI-1 tumor content is independent of tumor size and nodal extension. RESULTS In univariate analysis, adjusted on usual prognostic factors, the metastasis risk increased with PAI-1 level in all patients (HR [hazard ratio], 3.1; P < .001), in pN0 (HR, 4.3; P < .001), and pN+ patients (HR, 2.3; P = .019). It increased also with uPA in all patients (HR, 2.6; P = 0.006). In multivariate analysis, when both variables were included, PAI-1 remained significant in all patients (HR, 2.4; P = .002) and pN0 patients (HR, 3.2; P = .003) but not uPA. CART analyses confirmed that the best partitioning factor was PAI-1. CONCLUSION There was no evidence for any additional impact of uPA. PAI-1 is an independent prognostic factor in particular in pN0 breast ductal carcinoma.

Predictive and discriminating three-risk-group prognostic scoring system for staging Hodgkin lymphomas.

Several 3‐stage Ann Arbor classification‐derived prognostic systems were constructed since 1980 to identify the prognosis of Hodgkin lymphoma (HL). Modern statistical tools were applied to 955 patients treated between 1981 and 1996 to build a 3‐stage prognostic scoring system (PSS).

Methodology of the sensitivity analysis used for modeling an infectious disease

Mathematical models may be used to help clarify dynamics of several infectious diseases. Because of the complexity of some models and the high degree of uncertainty in estimating many parameters, the present study proposes a rigorous framework for sensitivity analyses of mathematical models using as example a model to assess varicella and herpes zoster incidence. Its main steps are to assess the uncertainty of the factors to be studied, to evaluate qualitatively and quantitatively the impacts of these factors on model results, and to conduct an univariate and multivariate sensitivity analysis. The application of this technique may have considerable utility in the analysis of a wide variety of complex biological and epidemiological models.

Effect of Cyclosporine in Nonshockable Out-of-Hospital Cardiac Arrest: The CYRUS Randomized Clinical Trial.

IMPORTANCE Experimental evidence suggests that cyclosporine prevents postcardiac arrest syndrome by attenuating the systemic ischemia reperfusion response. OBJECTIVE To determine whether early administration of cyclosporine at the time of resuscitation in patients with out-of-hospital cardiac arrest (OHCA) would prevent multiple organ failure. DESIGN, SETTING, AND PARTICIPANTS A multicenter, single-blind, randomized clinical trial was conducted from June 22, 2010, to March 13, 2013 (Cyclosporine A in Out-of-Hospital Cardiac Arrest Resuscitation [CYRUS]). Sixteen intensive care units in 7 university-affiliated hospitals and 9 general hospitals in France participated. A total of 6758 patients who experienced nonshockable OHCA (ie, asystole or pulseless electrical activity) were assessed for eligibility. Analyses were performed according to the intention-to-treat analysis. INTERVENTIONS Patients received an intravenous bolus injection of cyclosporine, 2.5 mg/kg, at the onset of advanced cardiovascular life support (cyclosporine group) or no additional intervention (control group). MAIN OUTCOMES AND MEASURES The primary end point was the Sequential Organ Failure Assessment (SOFA) score, assessed 24 hours after hospital admission, which ranges from 0 to 24 (with higher scores indicating more severe organ failure). Secondary end points included survival at 24 hours, hospital discharge, and favorable neurologic outcome at discharge. RESULTS Of the 6758 patients screened, 794 were included in intention-to-treat analysis (cyclosporine, 400; control, 394). The median (interquartile range [IQR]) ages were 63.0 (54.0-71.8) years for the cyclosporine group and 66.0 (57.0-74.0) years for the control group. The cohorts included 293 men (73.3%) in the treatment group and 288 men (73.1%) in the control group. At 24 hours after hospital admission, the SOFA score was not significantly different between the cyclosporine (median, 10.0; IQR, 7.0-13.0) and the control (median, 11.0; IQR, 7.0-15.0) groups. Survival was not significantly different between the 98 (24.5%) cyclosporine vs 101 (25.6%) control patients at hospital admission (adjusted odds ratio [aOR], 0.94; 95% CI, 0.66-1.34), at 24 hours for 67 (16.8%) vs 62 (15.7%) patients (aOR, 1.08; 95% CI, 0.71-1.63), and at hospital discharge for 10 (2.5%) vs 5 (1.3%) patients (aOR, 2.00; 95% CI, 0.61-6.52). Favorable neurologic outcome at discharge was comparable between the cyclosporine and control groups: 7 (1.8%) vs 5 (1.3%) patients (aOR, 1.39; 95% CI, 0.39-4.91). CONCLUSION AND RELEVANCE In patients presenting with nonshockable cardiac rhythm after OHCA, cyclosporine does not prevent early multiple organ failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01595958; EudraCT Identifier: 2009-015725-37.