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BackgroundToday, there are still no DMARDs licensed for primary Sjögren Syndrome (pSS) patients. Among the explanations, are the limitations of current outcome measures used as primary endpoints: e.g; high placebo response rate, evaluation of either symptoms or systemic activity, and important features not being assessed. The NECESSITY consortium (https://www.necessity-h2020.eu/), including pSS experts from academia, pharmaceutical industry and patient groups formed to develop a new composite responder index, the Sjögren’s Tool for Assessing Response (STAR) that solve the issues of current outcome measures in pSS and is intended for use in clinical trials as an efficacy endpoint.ObjectivesTo develop a composite responder index in primary Sjögren’s syndrome (pSS): the STAR.MethodsTo develop the STAR, the NECESSITY consortium used data-driven methods, based on 9 randomized controlled trials (RCTs), and consensus techniques, involving 78 experts and 20 patients. Based on reanalysis of rituximab trials (TRACTISS and TEARS) and literature review, the Delphi panel identified a core set of domains to include in the STAR, with their respective outcome measures. STAR options combining these domains were designed and proposed to the panel to select and improve them. For each STAR option, sensitivity to change was estimated by the C-index (derived from Effect size) in all 9 RCTs. Delphi rounds were run for selecting STAR among these options. The Delphi panel also voted to classify trials as positive, negative or “in between” in regards to primary but also key secondary endpoints. For the options remaining before the final vote, meta-analyses of the RCTs were performed separately for positive and “in between” trials together, and for negative trials.ResultsThe Delphi panel identified 5 core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options, combining these domains, were selected to be tested for sensitivity to change. After two Delphi rounds, meta-analyses of the 20 remaining options were performed. The candidate STAR was selected by a final vote based on metrological properties and clinical relevance. In positive/in between trials, candidate STAR detected a difference between arms (OR 3.29, 95%-CI [2.07;5.22], whereas it did not in negative trials (OR 1.53, 95%-CI [0.81;2.91]).ConclusionThe candidate STAR is a composite responder index, including in a single tool all main disease features, and is designed for use as a primary endpoint in pSS RCTs. Its rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity and specificity to change. The candidate STAR will be prospectively validated in a dedicated three arms RCT of the NECESSITY consortium that will evaluate combination of synthetic DMARDs (hydroxychloroquine + lefunomide or hydroxychloroquine + mycophenolate vs placebo). We encourage the use of STAR in any ongoing and future trials.Table 1.Candidate STARDomainPointDefinition of responseSystemic activity3Decrease of clinESSDAI ≥ 3Patient reported outcome3Decrease of ESSPRI ≥ 1 point or ≥ 15%Lachrymal gland function1Schirmer:If abnormal score at baseline: increase ≥ 5 mm from baselineIf normal score at baseline: no change to abnormalOrOcular Staining Score:If abnormal score at baseline: decrease ≥ 2 points from baselineIf normal score at baseline: no change to abnormalSalivary gland function1Unstimulated Whole Salivary Flow:If score > 0 at baseline: increase ≥ 25% from baselineIf score is 0 at baseline: any increase from baselineorUltrasound:Decrease ≥ 25% in total Hocevar score from baselineBiological1Serum IgG levels: decrease ≥ 10%orRheumatoid Factor levels: decrease ≥ 25%Candidate STAR responder≥ 5 pointsESSDAI: EULAR Sjögren syndrome disease activity index; ESSPRI: EULAR Sjögren syndrome patient reported index; IgG: Immunoglobulin G;AcknowledgementsNECESSITY WP5 STAR development participants: Suzanne Arends (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Francesca Barone (Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK), Albin Björk (Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden), Coralie Bouillot (Association Française du Gougerot Sjögren et des Syndromes Secs, France), Guillermo Carvajal Alegria (University of Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France; Service de Rhumatologie, Centre de Référence Maladies Autoimmunes Rares CERAINO, CHU Cavale Blanche, Brest, France), Wen-Hung Chen (GlaxoSmithKline, Research Triangle Park, North Carolina, USA), Kenneth Clark (GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom), Konstantina Delli (Department of Oral and Maxillofacial Surgery, University Medical Center Groningen (UMCG), University of Groningen, The Netherlands), Salvatore de Vita (Rheumatology Clinic, University Hospital of Udine, Italy), Liseth de Wolff (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Jennifer Evans (Novartis Pharmaceuticals corporation USA), Stéphanie Galtier (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Saviana Gandolfo (Rheumatology Clinic, Department of Medical area, University of Udine, ASUFC, 33100 Udine, Italy), Mickael Guedj (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Dewi Guellec (CHU de Brest, Service de Rhumatologie, Inserm, CIC 1412, Brest, France), Safae Hamkour (Center of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht 3584 GA, Netherlands), Dominik Hartl (Novartis Institutes for BioMedical Research, Basel, Switzerland), Malin Jonsson (Section for Oral and Maxillofacial Radiology, Department of Clinical Dentistry, Faculty of Medicine and Dentistry, University of Bergen, Norway), Roland Jonsson (Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Department of Rheumatology, Haukeland University Hospital, Bergen, Norway), Frans Kroese (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Aike Albert Kruize (University Medical Center Utrecht, Department Rheumatology and Clinical Immunology, Utrecht, Netherlands), Laurence Laigle (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Véronique Le Guern (AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, service de médecine interne, Paris, France), Wen-Lin Luo (Department of Biometrics and Statistical Science, Novartis Pharmaceuticals, East Hanover, New Jersey), Esther Mossel (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Wan-Fai Ng (Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK), Gaëtane Nocturne (Department of Rheumatology, Université Paris-Saclay, INSERM U1184: Centre for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, Paris, France), Marleen Nys (Global Biometric Sciences, Bristol Myers Squibb, Braine L’Alleud, Belgium), Roald Omdal (Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, PO Box 8100, 4068, Stavanger, Norway), Jacques-Olivier Pers (LBAI, UMR1227, University of Brest, Inserm, Brest, France and CHU de Brest, Brest, France), Maggy Pincemin (Association Française du Gougerot Sjögren et des Syndromes Secs, France), Manel Ramos-Casals (Department of Autoimmune Diseases, Hospital Clinic de Barcelona Institut Clinic de Medicinai Dermatologia, Barcelona, Catalunya, Spain), Philippe Ravaud (Centre d’Epidémiologie Clinique, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France), Neelanjana Ray (Global Drug Development - Immunology, Bristol Myers Squibb Company, Princeton, New Jersey, USA), Alain Saraux (HU de Brest, Service de Rhumatologie, Univ Brest, Inserm, UMR1227, Lymphocytes B et Autoimmunité, Univ Brest, Inserm, LabEx IGO, Brest, France), Athanasios Tzioufas (Rheumatology Clinic, Department of Medical area, University of Udine, ASUFC, 33100 Udine, Italy), Gwenny Verstappen (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Arjan Vissink, Marie Wahren-Herlenius (Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden). We thank the following experts: Esen Karamursel Akpek, Alan Baer, Chiara Baldini, Elena Bartoloni, Marí-Alfonso Begona, Johan Brun, Vatinee Bunya, Laurent Chiche, Troy Daniels, Paul Emery, Robert Fox, Roberto Giacomelli, John Gonzales, John Greenspan, Robert Moots, Susumu Nishiyama, Elizabeth Price, Christophe Richez, Caroline Shiboski, Roser Solans Laque, Muthiah Srinivasan, Peter Olsson, Tsutomu Takeuchi, Frederick Vivino, Paraskevi Voulgari, Daniel Wallace, Ava Wu, Wen Zhang. We thank the anonymous patients from the NECESSITY Patient Advisory Group and the Sjögren Foundation for their valuable contribution to the Delphi process. We thank EW StClair and AN Baer who generated the baminercept data and made them publicly available.Disclosure of InterestsRaphaèle Seror Consultant of: GlaxoSmithKline, Boehringer, Janssen and Novartis, Grant/research support from: GlaxoSmithKline and Amgen, Gabriel Baron: None declared, Marine Camus: None declared, Divi Cornec Consultant of: GlaxoSmithKline, Bristol Myers Squibb, Janssen, Amgen, Pfizer and Roche, Elodie Perrodeau: None declared, Simon J. Bowman Consultant of: Abbvie, Astra Zeneca, Galapagos and Novartis Pharmaceuticals, Michele Bombardieri Consultant of: UCB, Amgen/Medimmune, Janssen, and GlaxoSmithKline, Grant/research support from: Amgen/Medimmune, Janssen, and GlaxoSmithKline, Hendrika Bootsma: None declared, Jacques-Eric Gottenberg Consultant of: AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, Sanofi, Novartis, MSD, CSL-Behring and Genzyme, Grant/research support from: Bristol Myers Squibb, Benjamin Fisher Speakers bureau: Bristol Myers Squibb and Novartis, Consultant of: Novartis, Bristol Myers Squibb, Janssen and Servier, Grant/research support from: Servier, Galapagos and Janssen, Wolfgang Hueber Shareholder of: Novartis Pharma, Employee of: Novartis Pharma, Joel van Roon: None declared, Valerie Devauchelle-Pensec: None declared, Peter Gergely Shareholder of: Novartis Pharma, Employee of: Novartis Pharma, Xavier Mariette Consultant of: Bristol Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer and UCB, Grant/research support from: Ose Pharmaceuticals, Raphaël Porcher: None declared

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Background:Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Its use has been associated with hypersensitivity pneumonitis and diffuse lung disease. Whether MTX exposure increases the risk of interstitial lung disease (ILD) in patients with RA is disputed.Objectives:We aimed to evaluate the association of antecedent MTX use with development of RA-ILD.Methods:Through a case-control study design with derivation and international validation samples, we examined the association of MTX exposure with ILD in 482 patients with RA-ILD and 741 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques.Results:Analysis of the derivation sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted odds ratio [OR], 0.48; 95% confidence interval [CI], 0.25 to 0.92; P=0.028), which was confirmed in the validation samples (pooled adjusted OR, 0.39; 95% CI, 0.23 to 0.68; PConclusion:Our results suggest that MTX is not a risk factor for RA-ILD and support a possible disease modifying effect of MTX on development of RA-ILD.Disclosure of Interests:Pierre-Antoine Juge: None declared, Joyce S. Lee Consultant of: Celgene, Genentech, Boehringer Ingelheim, Jessica Lau: None declared, Leticia Kawano: None declared, Jorge Rojas-Serrano: None declared, Marco Sebastiani: None declared, Gouri Koduri: None declared, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Karina Bonfiglioli Consultant of: Roche, Abbvie, Pfizer, Janssen and BMS, Marcio Sawamura: None declared, Ronaldo Kairalla: None declared, Lorenzo Cavagna: None declared, Emanuele Bozzalla Cassione: None declared, Andreina Manfredi: None declared, Mayra Mejia: None declared, Pedro Rodríguez Henríquez: None declared, Montserrat I. Gonzalez-Perez: None declared, Ramcés Falfan-Valencia: None declared, Ivette Buendia-Roldan: None declared, Glora Perez-Rubio: None declared, Esther Ebstein Consultant of: BMS, Employee of: BMS, Steven Gazal: None declared, Raphael Borie Consultant of: Roche, Boehringer Ingelheim, Sebastien Ottaviani: None declared, Caroline Kannengiesser: None declared, Benoît Wallaert Consultant of: Roche, Boehringer Ingelheim, Yurdagul Uzunhan Consultant of: Roche, Boehringer Ingelheim,, Hilario Nunes: None declared, Dominique Valeyre Consultant of: Astra Zeneca, Roche, Boehringer Ingelheim, Nathalie Saidenberg Kermanac’h: None declared, marie-Christophe Boissier: None declared, Lidwine Wemeau Stervinou Consultant of: Roche, Janssen, BMS, Boehringer Ingelheim, Rene-Marc Flipo Speakers bureau: Novartis, Janssen, Lilly, Sylvain Marchand-Adam Consultant of: Roche, Novartis, Boehringer Ingelheim, Pascal Richette: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi, Claire Dromer: None declared, Marie-Elise Truchetet: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Thierry Schaeverbeke: None declared, Huguette Lioté: None declared, Gabriel Thabut Employee of: Astra Zeneca, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Joshua Solomon: None declared, Tracy Doyle: None declared, Jay H. Ryu: None declared, Ivan O. Rosas Consultant of: Boehringer Ingelheim, Gerentech, Three Lakes Partners, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Catherine Boileau: None declared, Marie-Pierre Debray: None declared, Raphaël Porcher: None declared, David A. Schwartz Consultant of: NuMedii, Robert Vassallo Shareholder of: Pfizer, BMS, SunPharma, Bruno Crestani Shareholder of: Apellis, Boehringer Inghelheim, Medillune, Roche, Consultant of: Boehringer Ingelhiem, Astra Zeneca, Roche, Sanofi, Philippe Dieudé: None declared

Background: Triple-negative (TN) breast cancers exhibit major initial responses to neoadjuvant chemotherapy, but generally have a poor outcome. Because of the lack of validated drug targets, chemotherapy remains an important therapeutic tool in these cancers. Methods: We report the survival of two consecutive series of 267 locally advanced breast cancers (LABC) treated with two different neoadjuvant regimens, either a dose-dense and dose-intense cyclophosphamide–anthracycline (AC) association (historically called SIM) or a conventional sequential association of cyclophosphamide and anthracycline, followed by taxanes (EC-T). We compared pathological responses and survival rates of these two groups and studied their association with tumours features. Results: Although the two regimens showed equivalent pathological complete response (pCR) in the whole population (16 and 12%), the SIM regimen yielded a non-statistically higher pCR rate than EC-T (48% vs 24%, P=0.087) in TN tumours. In the SIM protocol, DFS was statistically higher for TN than for non-TN patients (P=0.019), although we showed that the TN status was associated with an increased initial risk of recurrence in both regimens. This effect gradually decreased and after 2 years, TN was associated with a significantly decreased likelihood of relapse in SIM-treated LABC (hazard ratio (HR)=0.25 (95% CI: 0.07–0.86), P=0.028). Conclusions: AC dose intensification treatment is associated with a very favourable long-term survival rate in TN breast cancers. These observations call for a prospective assessment of such dose-intense AC-based regimens in locally advanced TN tumours.

Le score de propension est defini comme la probabilite d’un sujet de recevoir un traitement specifique conditionnellement a ses caracteristiques observees. Les methodes utilisant le score de propension ont ete de plus en plus utilisees dans la litterature medicale durant les dix dernieres annees. Toutefois, la qualite de l’utilisation de ces methodes et du rapport des etudes les utilisant pourrait etre amelioree, en particulier dans la litterature de reanimation. Apres une presentation de la theorie des scores de propension, illustree d’un exemple, cette mise au point propose des recommandations pour les investigateurs dans le but d’ameliorer la qualite du rapport des etudes utilisant des methodes de score de propension.

Objectives: In cerebral small vessel disease, white-matter hyperintensities (WMH) and lacunes are both related to cognition. Still, their respective contribution in older people remains unclear. The purpose of this study is to assess the topographic distribution of lacunes and determine whether it has an impact on cognitive functions in a sample of non-disabled patients with age-related white-matter changes. Methods: Data were drawn from the baseline evaluation of the LADIS (Leucoaraioisis and Disability study) cohort of non-disabled subjects beyond 65 years of age. The neuropsychological evaluation was based on the Mini Mental Status Examination (MMSE), a modified Alzheimer Diseases Assessment Scale for global cognitive functions, and compound Z scores for memory, executive functions, speed and motor control. WMH were rated according to the Fazekas scale; the number of lacunes was assessed in the following areas: lobar white matter, putamen/pallidum, thalamus, caudate nucleus, internal/external capsule, infratentorial areas. An analysis of covariance was performed after adjustment for possible confounders. Results: Among 633 subjects, 47% had at least one lacune (31% at least one within basal ganglia). The presence of lacunes in the thalamus was associated with lower scores of MMSE (β = −0.61; p = 0.043), and worse compound scores for speed and motor control (β = −0.25; p = 0.006), executive functions (β = −0.19; p = 0.022) independently of the cognitive impact of WMH. There was also a significant negative association between the presence of lacunes in putamen/pallidum and the memory compound Z score (β = −0.13; p = 0.038). By contrast, no significant negative association was found between cognitive parameters and the presence of lacunes in internal capsule, lobar white matter and caudate nucleus. Conclusion: In non-disabled elderly subjects with leucoaraisosis, the location of lacunes within subcortical grey matter is a determinant of cognitive impairment, independently of the extent of WMH.

Resume Introduction. – Cinq ans apres la mise en place des permanences d’acces aux soins de sante (PASS), il etait necessaire d’en analyser leurs fonctionnements et leurs activites. Materiel et methode. – Un systeme informatique de recueil et d’evaluation de l’activite medicosociale des PASS a ete mis en place dans 11 CHU et dix CHG. La saisie des donnees a ete effectuee du 1er janvier au 30 juin 2003. Resultats. – Les patients consultant sont jeunes (moyenne d’âge 35 ans) et cumulent plusieurs facteurs de precarite : precarite du logement, des liens sociaux et des ressources entre autres. Ils ne beneficient pour la plupart d’aucune couverture sociale. Le public des PASS est donc bien celui pour lequel le dispositif a ete mis en place. Les facteurs de risque de precarite varient en fonction de l’origine geographique : les Francais etant le plus souvent isoles, alors que les etrangers se retrouvent plus souvent sans ressources. La majeure partie des consultants est d’origine etrangere et plus d’un tiers d’entre eux ne parlent pas francais, ce qui constitue un facteur d’exclusion supplementaire. Les pathologies les plus souvent retrouvees sont les pathologies digestives, avec neanmoins des differences entre patients francais et patients etrangers : si les pathologies digestives et osteoarticulaires sont plus frequentes chez les etrangers, les troubles psychiques et les conduites addictives sont plus retrouves chez les Francais. Un certain nombre de patients sont orientes vers des medecins de ville (9 %) et vers des services sociaux exterieurs (39,5 %). Discussion. – Cette etude a permis, pour la premiere fois en France, de disposer de donnees homogenes concernant l’activite des PASS. L’utilite de l’outil informatique et son acceptabilite permettent d’en envisager les modalites de diffusion, avec des adaptations possibles a chacune, tout en gardant une base commune.

The determination of the order of an autoregressive model is of central interest when using a nonparametric modeling approach. While theory for kernel estimates of the autoregression function is well developed, dimensionality issues may arise when the order of the process increases. In this respect, multivariate adaptive regression splines offer an alternative worth considering because of their ability to efficiently control both bias and model dimension. Here, we present a penalized least-squares approach to order selection using multivariate adaptive regression splines to approximate the unknown regression function. The performance of the method is investigated through numerical simulations of linear and nonlinear models of different orders. Results suggest that the proposed method has a high probability of correct order selection, provided the sample size is sufficiently large with respect to the true order of the series. An analysis of electroencephalogram data is presented as an illustration.

We have carried out a prospective, randomised study designed to compare the long-term stability of the stem of cementless femoral implants with differing surface configurations. A total of 50 hips (46 patients) was randomised into two groups, according to whether the medullary stem had been grit blasted (GB) or coated with hydroxyapatite (HA). Both femoral prostheses were of the same geometrical design. We used Ein Bild Roentgen Analyse femoral component analysis (EBRA-FCA) to assess the stability of the stem. The mean follow-up was for 8.66 years. The mean migration of the stem was 1.26 mm in the HA group compared with 2.57 mm in the GB group (Mann-Whitney U test, p = 0.04). A mixed model ANOVA showed that the development of subsidence was statistically different in the two groups during the first 24 months. After this subsidence increased in both groups with no difference between them. Our results indicate that, with the same design of stem, HA coating enhanced the stability of the femoral stem when compared with GB stems.

The aim of the study was to demonstrate the noninferiority of polyacrylamide hydrogel (PH) vs. polylactic acid (PLA) for the treatment of facial lipoatrophy in HIV-infected adults.A randomized, blinded, multicentre, noninferiority 96-week study was carried out. Patients with facial lipoatrophy were randomly assigned to receive intradermal injections with PH or PLA, and were blinded to the filler. The primary efficacy endpoint was patient satisfaction at week 48 assessed using a visual analogue scale score (VAS). Secondary efficacy end-points included cheek thickness and skin-fold, lipoatrophy grading and quality of life. Safety was assessed by the reporting of adverse events.A total of 148 patients were included in the study; 93% were men, the median age was 47 years, the median CD4 count was 528 cells/μL, and the median duration of antiretroviral therapy was 12 years. Mean VAS increased from 2.8 at baseline to 7.1 and 7.5 in the PLA and PH arms, respectively, at week 48 (P=0.0002 for noninferiority) and was sustained at week 96 (6.7 and 7.9 in the PLA and PH arms, respectively; P=0.003 for noninferiority). Cheek thickness and skin-fold increases and lipoatrophy improvement were similar in the two arms. Quality of life remained unchanged or improved depending on the questionnaire used. In injected patients, subcutaneous nodules emerged in 28 (41%) and 26 (37%) patients in the PLA and PH arms, respectively (P=0.73). Four patients in the PH arm developed severe inflammatory nodules, a median of 17 months after the last injection.PH and PLA have similar efficacies in the treatment of facial lipoatrophy, but PH may be associated with more delayed inflammatory nodules.

Previous studies have recommended that several repeat measurements of nuchal translucency (NT) be obtained to optimize sensitivity of the screening process. However, truncation is applied within the risk calculation for small NT measurements; therefore, repeating NT measurements in the lower range may be unnecessary. The aim of this study was to determine the optimal number of NT measurements and whether this is dependent on the initial value obtained.We simulated the expected distribution of sets of five repeat NT measurements and their corresponding likelihood ratios (LR) for a variety of crown-rump length (CRL) values at 11-14 weeks' gestation, based on the published mixture model for first-trimester NT measurements and on published data regarding NT measurement variability. The ratio between LR obtained from the highest and the initial measurement in each set were computed, with a ratio of 1 indicating that repeat measurements would have no effect on risk estimation. We calculated NT cut-offs below which a change in estimated LR would occur in fewer than 10% of cases if repeat measurements were obtained, and we tested this approach on a real first-trimester screening dataset.The simulations performed indicated that repeating NT measurements when the first NT obtained ranged between ≤ 0.9 and ≤ 1.6 mm at CRLs of 45 and 84 mm, respectively, is not useful. When applied to a real dataset, our approach allowed avoiding repetition of measurements in 47/165 cases (28%).Although there is some variability in NT measurements, repeat assessment is not useful to optimize screening performance for the smallest NT measurements due to lower truncation limits that are applied in risk calculation. Our study provides NT cut-off values, in relation to CRL, below which it appears that there is no need to repeat measurements once a good quality image has been obtained.

The recommended duration of pulmonary tuberculosis therapy is 6 months. For extrapulmonary tuberculosis, treatment duration depends on tuberculosis involvement and HIV status. The objective of this study was to describe the main characteristics of a cohort of extrapulmonary tuberculosis patients, to compare patients with a 6-month treatment to those with more than a 6-month treatment, and to analyze the compliance of medical centres with recommended duration of treatment.A retrospective cohort study of 210 patients with extrapulmonary tuberculosis was carried from January 1999 to December 2006 in two hospitals in the north-east of Paris. These patients were treated with quadruple therapy during two months, followed by dual therapy during 4 months (n=77) or more (n=66). The characteristics of each group were compared by uni- and multivariate analysis. The primary endpoint was the rate of relapse or treatment failure at 24-month follow-up after treatment completion.No relapse was observed after 24 months of follow-up after the end of treatment in the two groups. In univariate analysis, patients with lymph node tuberculosis were more often treated for 6 months than at other sites of tuberculosis (respectively 61% versus 40.9%; P=0.02); the decision of treatment duration was related to medical practices (79.2% treated 6 months in one hospital versus 20.7% in the other, P0.001); patients living in private residence were more often treated during 6 months than patients living in residence (24.2% versus 10.3%, P=0.042). In multivariate analysis, only hospital (P=0.046), sex (P=0.007) and private residence were significantly different in each group.A period of 6 months seems to be sufficient to treat extrapulmonary tuberculosis (except for neuromeningeal localization).

A case-control study was conducted to identify risk factors for Pneumocystis jirovecii pneumonia (PCP) in renal transplant recipients. Eleven cases of PCP were matched with 22 controls. Cases occurred a median of 18 months after transplantation, and none of the recipients was receiving prophylaxis. Univariate analysis showed that graft rejection, duration of steroid use, use of mammalian target of rapamycin (mTOR) inhibitors and lymphocytopenia at the time of prophylaxis discontinuation were risk factors for PCP. In the multivariate model, only graft rejection (OR 8.66, p 0.017) remained significantly associated with PCP. In patients with a history of graft rejection, PCP prophylaxis should be maintained, especially among those with lymphocytopenia.

To report the rules and the activity of the institutional review board of the French college of obstetricians and gynecologists (Comité d'éthique de la recherche en obstétrique et gynécologie [CEROG]) created in 2008. The submission requirements are also described.Retrospective study.The Ethical Review Committee [institutional review board of the French college of obstetricians and gynecologists (CNGOF)] CEROG have examined 65 project studies in 2008. The median number of submitted studies was 5.5 per month (IQR: 3.75-6.25). The origins of the submission were as follows: tertiary care university hospitals (n=63, 97 %), Inserm (n=1), INRA (n=1). Researches were found to be in conformity with the French laws and regulations, to conform to generally accepted scientific principles and medical research ethical standards in 44 cases (68 %). In 13 cases (20 %), the study has been forwarded to the Persons Protection Committee (PPC) since it concerned biomedical research or "usual care research" (soin courant). In six cases (9 %), the investigators have not responded to IRB suggestions. In two cases (3 %), the information form has been judged unsatisfactory.The CEROG is the first national IRB in obstetrics and gynecology. This new committee clarifies IRB submission procedure in France concerning non-interventional studies in the field of obstetrics and gynecology.

Numerous studies investigating the efficacy of TNF-alpha antagonists in moderate-to-severe plaque-type psoriasis have been published. We present a graphic synthesis of efficacy data based on a systematic review of the published studies.The Medline, Embase and Cochrane Library bibliographic databases were searched for studies based on the following selection criteria: 1. Original studies, 2. Using infliximab, etanercept or adalimumab as the sole systemic treatment for plaque-type cutaneous psoriasis, 3. Minimum follow-up of 10 weeks, 4. Use of the PASI75 index (improvement of at least 75% from baseline PASI score) as an endpoint. Twenty-one articles were selected and PASI75 scores and corresponding 95% confidence intervals were calculated at three, six and 12 months.At M3, success rates were about 80% with infliximab and adalimumab once-weekly, around 50% with etanercept 50mg twice-weekly and adalimumab fortnightly; and 30% with etanercept 25mg twice-weekly. Maintenance regimens after three months ensured success rates above 50% with all three treatments, although the long-term results were based on fewer studies.Our graphic synthesis and tolerance data for the three drugs should guide clinicians in their therapeutic choices in moderate-to-severe plaque-type psoriasis. Additional studies with better reporting of loss to follow-up are needed to better assess the long-term efficacy of these drugs.

Thresholds of sperm parameters associated with intrauterine insemination (IUI) success are controversial. This entails heterogeneous practices and leads to low success rate (approximately 8% per attempt). The aim of this study was to evaluate the influence of sperm parameters on the outcome of IUI.This study included 248 cycles of IUI. Parameters of the raw and selected sperm, as well as the main female characteristics, have been prospectively tabulated and compared, according to the presence or not of a clinical pregnancy.In all, 28 clinical pregnancies were obtained (11.3% per cycle). Thresholds of 10% for the forward motility "a" in the whole sperm and of 20% for the percentage of typical spermatozoa in the selected sperm were related to the success of IUI. The number of motile inseminated spermatozoa, concentration and overall motility of sperm, determined before or after selection, did not have any significant influence on the outcome of IUI.Thresholds determined in our study should help to optimize the use of IUI.

Study A comparative study which compared PPD skin testing inserted according to the French Society of Pneumology's recommendations and interferon gamma release assay (IGRA) (QuantiFERON ® TB Gold In-tube, QF–TB–IT, Cellestis, Carnegie, Australia) was performed during a tuberculosis contact investigation in our hospital. Patients Nineteen French health-care workers (HCWs) volunteered to participate. All of the HCW enrolled were BCG vaccinated and had a normal chest X-ray at entry. Results Among the HCW, 68.4% were TST positive. By comparison, only 31.6% had a positive QF-TB-IT result. We took advantage of the negative tube and the corresponding plasma for antibody detection by ELISA. None were ELISA positive. Fourteen HCWs were followed up. None of the HCWs accepted a course of antiTB chemoprophylaxis. Despite the difficulty in establishing a trend in kinetics, we saw the complexity of interpretation of a dynamic T-cell response after contact with an index case. Conclusion This initial and first French picture provides us with the observation that only 44% of TST-positive HCW were IGRA positive, and the IGRA test allowed the detection of LTBI in two TST negative HCWs.

Multiple embryo transfer is responsible for a high rate of multiple pregnancies (ICSI), with subsequent risks of premature birth and perinatal death. This prospective non randomized study aimed to assess the ability of an elective single-embryo transfer (eSET) policy to reduce the twin pregnancy rate, compared to a double embryo transfer (DET) approach.Between March 2005 and May 2006, 180 eligible women were proposed to benefit from an eSET transfer rather than a DET. Inclusion criteria were (i) age less than 37 years old; (ii) at least two good quality embryos available (three to five cells at day 2 or six to nine cells at day 3; less than 20% fragmentation and the absence of multinucleates blastomeres), after IVF or ICSI and (iii) no more than one previous failed treatment cycle. Outcome analysis included cycles with frozen-thawed embryo transfer (FET).According to patients' decision, 107 and 73 women had an eSET (59.4%) and a DET (40.6%) respectively. No differences were found between eSET and DET groups regarding demographics and biologicals parameters. The clinical pregnancy rate (PR) per transfer was 43.9% in eSET group and 57.5% in DET group (p=0.07). The twin pregnancy rates were 0 and 14.3%, in eSET and DET groups, respectively (p=0.007). The cumulative PR per patient, including the outcome of performed FET cycles, was 63.6% in eSET group and 61.6% in DET group. In this case, the cumulative twin pregnancy rates were 2.9 and 15.6% in eSET and DET groups, respectively (p=0.02).Our data show that in a selected population of women, transferring one fresh embryo and then, if required, one or two frozen-thawed embryos significantly reduces the twin pregnancy rate without decreasing the overall pregnancy rate. This study supports the policy of eSET in this subgroup of patients.

Tuberculosis (TB) is a persistent public health problem in European cities. France has been unable to report on treatment outcomes until now, and it is not known whether the World Health Organization (WHO) target cure rate of 85% has been met.All patients placed under treatment in four hospitals and five out-patient Social Medical Centres in Paris were followed up between 1996 and 2005. Patient monitoring and evaluation were performed using a new software programme, TB-INFO.In a cohort of 1127 patients, 76% had pulmonary TB, of whom 39% were smear-positive, 81% were foreign-born and 9.3% were human immunodeficiency virus positive. At the end of the follow-up, 16% were cured and 54% had completed treatment. Among the 1118 non-multidrug-resistant patients, these percentages were 17% and 46%, respectively, for smear-positive pulmonary patients. Some patients died (1.9%) or failed treatment (0.1%), but many more defaulted (20.5%) as they interrupted treatment (1.5%), were lost to follow-up (19.5%) or were transferred out (7.9%).This 10-year follow-up of TB patients, managed with TB-INFO software, shows that a patient monitoring system can be implemented in France, providing essential information. Treatment success in this cohort of patients was far below the WHO target.

To describe management of vaginal mesh erosion following transvaginal repair of acystocele by placement of a polypropylene mesh.Retrospective analysis of 34 consecutive cases of vaginal mesh erosion following transvaginal repair of cystocele using synthetic mesh (Gynemesh or Gynemesh-Soft). We have analyzed the results of both medical and surgical management of this complication. Furthermore, we also assessed sexual and urinary morbidity in women with mesh erosion (n = 34) and in women who had undergone the same procedure but without mesh erosion (n = 111).Among the 34 patients with vaginal mesh erosion, 23 (68%) have undergone local therapy using Colposeptine (Chlorquinaldol + Promestriène). In 12 (52%) cases no modification of the surface of the erosion was observed. In 6 (26%) cases, a decrease of the surface of the mesh erosion was observed. In 5 (22%) cases the mesh erosion had completely disappeared, with a follow-up of 2 to 9 months. Nineteen symptomatic patients (19/32, 59%) required partial (n = 18) or complete (n = 1) excision of the mesh, associated with vaginal mucosal closure, under general anaesthesia. Duration of operation ranged from 15 to 40 minutes for partial excision of the mesh. This procedure was successful in 14 cases (77%). Four women required repeated resection of the mesh because of recurrence. The incidence of de novo dyspareunia was 12% in patients with vaginal mesh erosion, and 11% in patients without mesh erosion (p = 0.81). The incidence of urge urinary symptoms and voiding dysfunction symptoms was respectively 8% versus 9% (p = 0.95), and 8% versus 10% (p = 0.81) in the 2 groups.Management of vaginal mesh erosion is simple and is associated with a low rate of morbidity. However, patients should be informed that vaginal erosion of the mesh can occur.

Five years after introducing the Permanent Access to Healthcare activity (PASS), it became necessary to analyse how it works.A computerized data collection and assessment system intended to evaluate the PASS health activities has been set up in 11 University Hospitals and ten General Hospitals. From January 1st to June, 30th 2003 data was captured in a computer.The patients requiring medical advice are young (with an average age of 35 years) and present several signs of poverty in terms of accommodation, social relationships and financial means. Besides, almost all of them are uninsured. The PASS public corresponds completely to the created system. Poverty risk factors vary according to the geographic origin. Indeed, French people often suffer from isolation, whereas foreign patients present financial problems. The major part of patients are foreigners and more than a third of them do not speak French, which is an additional obstacle to care. Most of the time, the PASS patients present digestive disorders, nevertheless there are some differences between French and foreign patients. Indeed, foreigners very frequently have digestive and osteoarticluar problems, whereas French patients suffer from psychic disorders and present addictive behaviours. Some patients are sent to physicians downtown (9%) and to external medicosocial assistance centres (39.5%).This study (first one in France) provides us with homogenous data regarding the activities of PASS centres nationwide. The usefulness of computers and its acceptability facilitate data diffusion, with possibilities of adapting to each centre while preserving a common basis.

To incorporate quality-of-life considerations in assessing high dose therapy (HDT) for patients with Multiple Myeloma (MM).A quality-adjusted survival analysis. using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method, was applied to two randomized clinical trials conducted in patients with MM which compared randomized assignment to HDT vs. conventional chemotherapy (CCT) alone (MAG91) or followed by HDT (MAG90). Treatment benefit in terms of mean Q-TWiST was assessed through threshold utility analyses, i.e., sensitivity analyses of the choice of the utility coefficients over all possible values of utility weights.In both trials, results slightly favored the first-line HDT group over the first-line CCT group, with an average gain in TWiST of about 5.5 months over the 58 month-median follow-up period (27.8 vs. 22.3 months, respectively) in the MAG90 trial and 5.8 months over the 56 month-median follow-up period (19.1 vs. 13.3 months, respectively) in the MAG91 trial. The utility threshold analyses revealed that the first-line HDT group had a statistically increased mean quality-of-life adjusted time compared to the other group for a broad range of utility coefficient values.The development of such understandable and intuitive measures of expressing the relative benefit of complex treatment strategies is expected to be used in clinical decision making in the near future.

Immune recovery after cord blood transplantation (CBT) is of concern owing to the low number of lymphocytes transferred with the graft and their immaturity. Risk factors influencing lymphocyte subset reconstitution related to disease, patient, donor and transplant were studied in 63 children (16 years), given either related (n = 14) or unrelated (n = 49) CBT for malignant (n = 33) or non-malignant diseases (n = 30). Only children with sustained myeloid engraftment were analysed. Absolute numbers of T (CD3(+), CD4(+), CD8(+)), B and natural killer (NK) cells were reported 2--3, 6, 9, 12 and 12--24 months after CBT. Median patient age was 4.0 years (0--15) and median follow-up was 23 months (1.7--61.0). Twenty-six patients received human leucocyte antigen (HLA)-matched CBT and 37 received HLA-mismatched CBT. The median number of nucleated cells (NCs) collected/recipient weight was 6.1 x 10(7)/kg. In this selected population, the estimate 2 year survival was 85%. Lymphocyte reconstitution (defined as the median time to reach the normal value of age-matched healthy children) was 3, 6 and 8 months for NK, B and CD8(+) cells, while it was 11.7 months for both CD3(+) and CD4(+) lymphocytes. In the multivariate analysis, factors favouring T-cell recovery were: related donor (P = 0.002); higher NCs/kg (P = 0.005) and recipient cytomegalovirus (CMV)-positive serology (P = 0.04). Presence of acute graft-versus-host disease (GVHD) delayed T-cell recovery (P = 0.04). To summarize, in children with sustained myeloid engraftment the concern that lymphocyte recovery after CBT could be delayed does not appear to be substantiated by our results.

When intramedullary pinning is used to treat metacarpal fractures, as recently described by Förstner (1994) and Foucher (1995), the closed reduction technique developed by Jahss (1938) is applied in the same way as for conservative fracture treatment. It is not always possible to achieve complete anatomical reduction using this closed technique. The intramedullary pinning technique, that we have applied since 1989, involves a Kirschner wire which is bent at one end. Apart from reducing the fracture, the pre-set Kirschner wire serves as a butressing internal fixator. The elastic clamping of the wire acts as an internal wire spring splint, permitting early mobilisation. We have operated on 62 metacarpal fractures using the above-mentioned technique over a period of 6 years until 1995. Anatomic reduction was realized in 50 of 62 fractures. In the follow-up of 32 fractures, we noticed four complications: one infection, two paraesthesias, and one non-union.

Objectifs Evaluer l’efficacite et les complications de deux traitements percutanes des osteomes osteoides, resection a la trephine et photocoagulation au laser. Materiels et methodes Etude retrospective de 127 patients ayant un osteome osteoide traite par resection percutanee (26 patients) ou par laser (101 patients) sous controle scanographique, suivis de 6 a 99 mois. Resultats Dans le groupe traite par resection, 92 % de succes a 6 mois et 88 % a 24 mois ont ete obtenus, avec 3(11%) complications transitoires (1 meralgie, 2 brulures cutanees). L’incidence des echecs etait plus elevee (p 12 mois). L’incidence des echecs etait plus elevee (p = 0.02) chez les moins de 18 ans, et tendait a etre plus elevee (p = 0.11) pour les osteomes > 10 mm. Conclusion Les traitements percutanes des osteomes osteoides sont une bonne alternative a la chirurgie.

Objectifs Determiner les signes IRM differenciant un TVNT poro-tique et malin. Materiels et methodes Etude multicentrique prospective de 78 patients explores en IRM pour TVNT avec suivi a un an obtenu pour le diagnostic final : 37 benins et 41 malins. Plus de 50 variables ont ete recueillies independamment par deux lecteurs. Ont ete etudiees : la reproductibilite intra et inter-observateur et la performance diagnostique de chaque variable dont la reproductibilite inter-observateur etait superieure a 0,8. Resultats Signes discriminatifs pour le diagnostic de TVNT malins : presence d’une lyse (VVP 70 %), hyposignal diffus T1 (VVP 80 %), masse intracanalaire (VVP 79 %), masse paravertebrale (VVP 71 %), convexite mur posterieur (VVP 86 %), aspect heterogene de la prise de contraste (VVP 67 %), evidement du corps vertebral (VVP 82 %), hypersignal nodulaire ou diffus (VVP 66 %) et a distance du plateau (VVP 66 %). Presence de nodule sur le reste du rachis (Sp 90 %) ; signes discriminatifs pour le diagnostic de TVNT benins : hyposignal T1 partiel ou absent (VVP 81 %), presence d’un recul du mur posterieur (VVP 68 %), presence d’une corticale fracturee ou normal (VVP 87 %). Les anomalies du pedicule ne sont pas discriminatifs d’un diagnostic (malins (39 cas), benins (21 cas)). Conclusion L’IRM est un examen discriminant pour differencier un TVNT porotique vs malin.