Analyse de facteurs déterminants de la substitution par des médicaments génériques en Suisse

Cadre de l'étude La part des dépenses de santé dans les budgets des pays occidentaux est importante et tend à croître depuis plusieurs décennies. Une des conséquences, notamment pour la Suisse, est une augmentation régulière des primes d'assurance maladie, dont l'impopularité incite les responsables politiques à trouver des stratégies de frein à la croissance des coûts de la santé. Les médicaments, qui contribuent notablement à l'augmentation de ces coûts, constituent l'une des cibles classiques d'interventions visant à une réduction des dépenses de santé. Le niveau de coûts des médicaments représente plus de 20% des dépenses de soins du domaine ambulatoire à la charge de l'assurance obligatoire des soins (AOS), soit une dépense annuelle de plus de 4 milliards de francs. Différentes mesures peuvent être utilisées par le gouvernement pour contenir cette facture à charge de la collectivité : baisse du prix des médicaments, limitation du nombre de produits remboursés par l'assurance de base et incitations à la concurrence sur les prix en autorisant les importations parallèles. Depuis que de plus en plus de brevets pour des médicaments sont arrivés à échéance, un autre angle d'attaque s'est concrétisé avec l'incitation à la prescription de médicaments génériques. Les génériques sont définis comme des produits thérapeutiques chimiquement identiques à des composés déjà utilisés, appelés médicaments originaux. En principe, une économie substantielle devrait pouvoir être réalisée sur les coûts totaux des médicaments si tous les génériques disponibles sur le marché étaient systématiquement prescrits par les professionnels et acceptés par les patients. Les résultats publiés par les caisses maladie et les offices fédéraux sont des estimations globales et les montants publiés par l'industrie pharmaceutique concernent l'ensemble du marché, incluant les médicaments utilisés dans les séjours hospitaliers, sont par ailleurs exprimés en prix de fabrique. De plus, aucune étude n'a tenu compte de la substituabilité des produits d'un point de vue pharmaceutique. L'objectif général de la thèse est d'évaluer aussi précisément que possible l'économie pouvant être encore réalisée dans le secteur ambulatoire en substituant aux médicaments originaux les produits génériques présents sur le marché et de caractériser plusieurs facteurs qui influencent la substitution générique. Pour cette étude, nous avons pu disposer de l'ensemble des factures pharmaceutiques de la caisse maladie CSS, pour tous ses assurés des cantons d'Argovie, du Tessin et de Vaud, soit plus de 169'000 assurés représentant les trois régions linguistiques de la Suisse. Les 1'341'197 prescriptions médicales qui ont été analysées concernent l'année 2003. C'est un moment critique dans l'histoire des génériques en Suisse, approprié pour établir un premier bilan après l'entrée en vigueur de la première mesure relative au droit de substituer octroyé en 2001 aux pharmaciens et, pour identifier idéalement les principaux déterminants de la substitution par les praticiens avant l'introduction de la quote-part différenciée en 2006. La présence d'un même principe actif n'est pas une condition suffisante pour permettre une substitution et pour ce travail des critères tenant compte des caractéristiques pharmaceutiques des produits ont été établis et appliqués pour valider la substituabilité des originaux par les génériques disponibles sur le marché. Ces critères concernent notamment le mode d'administration, le dosage et le nombre de doses dans l'emballage. L'étude a été réalisée selon deux approches, d'abord par une analyse descriptive sur l'ensemble de la population source pour estimer le marché des génériques et ensuite par une analyse statistique (régression logit multivariée) sur 173'212 prescriptions agrégées, qui concernent spécifiquement soit un générique soit un original substituable, pour caractériser les facteurs déterminants de la substitution générique. Résultats Dans l'ensemble de la population source, les génériques et les originaux substituables représentent 17,4% du marché en termes de coûts facturés, avec 3,4% de génériques et 14,0% d'originaux substituables ce qui correspond à un taux de substitution de 19,5%. En termes de dépenses, les substitutions génériques réalisées représentent une économie de 1,3% du total du marché étudié alors qu'il reste un potentiel notable d'économie par la substitution de 4,6%. Les taux de substitution sont très variables selon les cantons : 10,1% au Tessin, 29,0% pour le canton de Vaud et 35,8% pour Argovie. L'analyse univariée des 173'212 prescriptions de génériques ou d'originaux substituables, montre des taux de substitution plus élevés chez les patients jeunes et lorsqu'il y a d'importantes différences de prix entre les originaux et les génériques. Des taux de substitution peu élevés sont observés chez les patients les plus âgés et pour ceux qui ont des traitements médicamenteux complexes. Les patients ayant plus de 10 médicaments différents durant la même année, présentent une probabilité relative de substituer inférieure (-24%) par rapport aux patients ayant 6 à 10 médicaments différents dans l'année. Cependant, l'analyse multivariée montre que l'effet négatif sur le taux de substitution de l'âge combiné à la complexité des traitements n'excède pas 3%. Bien que le niveau de franchises et la participation financière à la quote-part soient liées à une augmentation de la prescription de génériques, leurs effets sont modérés pour les patients avec des franchises supérieures à 300 francs (effet marginal de 1%) et pour les patients qui n'ont pas atteint le plafond de participation (effet marginal de 2%). La différence de taux substitution entre les médecins hospitaliers et les spécialistes est diminuée de façon notable (effet marginal de -13%) et elle est cependant moins marquée avec les médecins généralistes (effet marginal de -3%). Les facteurs associés au marché ont une influence notable sur la substitution générique et des effets positifs sont observés avec l'augmentation de la taille du marché, du nombre de génériques pour un même original substituable et de l'économie relative entre l'original et le générique. Par contre, la diversification des formes galéniques et des tailles d'emballages au niveau de l'offre des médicaments originaux a des effets fortement négatifs sur la substitution générique (-7%). Le canton de domicile a aussi un impact notable sur la substitution et le canton du Tessin présente un taux plus bas (-26%) que le canton d'Argovie. Conclusion et perspectives Ce travail a montré qu'il y a encore un important potentiel d'économies à réaliser par la substitution générique, calculé à plus de 4% des dépenses pharmaceutiques prises en charge par l'AOS en ambulatoires. Une extrapolation à l'ensemble du marché suisse, qui doit être faite avec prudence, fait apparaître un potentiel d'économies de 127 millions pour les médicaments délivrés par les pharmacies en 2003. L'étude a mis en évidence un certain nombre de déterminants qui freinent la substitution générique, notamment la prescription par un médecin hospitalier. Sur ce point la prescription en DCI (dénomination commune internationale) pourrait favoriser la dispensation de génériques moins chers. Un taux de substitution plus faible est observé chez les patients âgés avec des traitements complexes. Ce constat peut être mis en relation avec la crainte d'avoir un traitement moins efficace ou moins bien supporté et les risques de confusion lors du passage d'un original substituable à un générique ou d'un générique à un autre générique. Sur ces éléments, l'indication claire et précise du nom de la substance, aussi bien sur les emballages des originaux substituables que sur ceux des génériques, pourrait rassurer les patients et diminuer les risques d'erreurs dans la prise des médicaments. Certaines précautions à prendre lors de la prescription de génériques sont reconnues, notamment pour les médicaments à faible marge thérapeutique, et des informations sur la bioéquivalence, régulièrement mises à jour et à disposition des professionnels, pourraient augmenter la confiance dans l'utilisation des génériques. Les industries pharmaceutiques préservent par différentes tactiques leurs parts de marché et notamment avec succès en introduisant de nouvelles formes galéniques juste avant l'expiration des brevets. Des directives complémentaires sur la fixation des prix pour le remboursement, en particulier l'introduction d'un prix de référence quelle que soit la forme galénique, pourraient diminuer l'effet de barrage des médicaments originaux. Les incitations économiques, telles que la franchise et les participations sont efficaces si l'on considère l'impact sur les taux de substitution. Leur effet global reste toutefois modeste et il serait nécessaire de mesurer concrètement l'impact de l'introduction en 2006 de la quote-part différenciée. Les différences de prix entre les originaux et les génériques exigées à 50% pour les gros marchés, c'est-à-dire de plus de 16 millions, devraient aussi avoir un impact qu'il serait opportun de mesurer.

Lesion Recognition in Multiple Sclerosis: A Sequence Comparison and Quantification Study at 3T

Introduction Lesion detection in multiple sclerosis (MS) is an essential part of its clinical diagnosis. In addition, radiological characterisation of MS lesions is an important research field that aims at distinguishing different MS types, monitoring drug response and prognosis. To date, various MR protocols have been proposed to obtain optimal lesion contrast for early and comprehensive diagnosis of the MS disease. In this study, we compare the sensitivity of five different MR contrasts for lesion detection: (i) the DIR sequence (Double Inversion Recovery, [4]), (ii) the Dark-fluid SPACE acquisition schemes, a 3D variant of a 2D FLAIR sequence [1], (iii) the MP2RAGE [2], an MP-RAGE variant that provides homogeneous T1 contrast and quantitative T1-values, and the sequences currently used for clinical MS diagnosis (2D FLAIR, MP-RAGE). Furthermore, we investigate the T1 relaxation times of cortical and sub-cortical regions in the brain hemispheres and the cerebellum at 3T. Methods 10 early-stage female MS patients (age: 31.64.7y; disease duration: 3.81.9y; disability score, EDSS: 1.80.4) and 10 healthy controls (age and gender-matched: 31.25.8y) were included in the study after obtaining informed written consent according to the local ethic protocol. All experiments were performed at 3T (Magnetom Trio a Tim System, Siemens, Germany) using a 32-channel head coil [5]. The imaging protocol included the following sequences, (all except for axial FLAIR 2D with 1x1x1.2 mm3 voxel and 256x256x160 matrix): DIR (TI1/TI2/TR XX/3652/10000 ms, iPAT=2, TA 12:02 min), MP-RAGE (TI/TR 900/2300 ms, iPAT=3, TA 3:47 min); MP2RAGE (TI1/TI2/TR 700/2500/5000 ms, iPAT=3, TA 8:22 min, cf. [2]); 3D FLAIR SPACE (only for patient 4-6, TI/TR 1800/5000 ms, iPAT=2, TA=5;52 min, cf. [1]); Axial FLAIR (0.9x0.9x2.5 mm3, 256x256x44 matrix, TI/TR 2500/9000 ms, iPAT=2, TA 4:05 min). Lesions were identified by two experienced neurologist and radiologist, manually contoured and assigned to regional locations (s. table 1). Regional lesion masks (RLM) from each contrast were compared for number and volumes of lesions. In addition, RLM were merged in a single "master" mask, which represented the sum of the lesions of all contrasts. T1 values were derived for each location from this mask for patients 5-10 (3D FLAIR contrast was missing for patient 1-4). Results & Discussion The DIR sequence appears the most sensitive for total lesions count, followed by the MP2RAGE (table 1). The 3D FLAIR SPACE sequence turns out to be more sensitive than the 2D FLAIR, presumably due to reduced partial volume effects. Looking for sub-cortical hemispheric lesions, the DIR contrast appears to be equally sensitive to the MP2RAGE and SPACE, but most sensitive for cerebellar MS plaques. The DIR sequence is also the one that reveals cortical hemispheric lesions best. T1 relaxation times at 3T in the WM and GM of the hemispheres and the cerebellum, as obtained with the MP2RAGE sequence, are shown in table 2. Extending previous studies, we confirm overall longer T1-values in lesion tissue and higher standard deviations compared to the non-lesion tissue and control tissue in healthy controls. We hypothesize a biological (different degree of axonal loss and demyelination) rather than technical origin. Conclusion In this study, we applied 5 MR contrasts including two novel sequences to investigate the contrast of highest sensitivity for early MS diagnosis. In addition, we characterized for the first time the T1 relaxation time in cortical and sub-cortical regions of the hemispheres and the cerebellum. Results are in agreement with previous publications and meaningful biological interpretation of the data.

Trends in cancer mortality in Brazil, 1980-2004.

Scanty information, limited to selected areas of the country, is available on cancer mortality in Brazil. Age-standardized (world population) mortality rates between 1980 and 2004, derived from the WHO database, were computed for all cancers and 24 major cancer sites in Brazil. Joinpoint regression analyses were used to identify the significant changes in trends and estimate annual percent change (APC) in rates. Total cancer mortality rates increased over the last decade in men (APC = 0.5) to reach 101.2/100 000, and in women (APC = 0.3) to reach 71.3/100 000. In men, upward trends were observed for cancers of the oral cavity and pharynx with a rate of 5.9/100 000 in 2000-2004, intestines (whose rate, however was low, i.e. 7.6), prostate (12.2), and leukemias (3.4). Male lung cancer increased until 1993 (APC = 1.39) and decreased thereafter (APC = -0.29), with a relatively low rate of 16.2/100 000 in 2000-2004. In women, there were steady upward trends for cancers of the lung (APC = 2.3), reaching 6.2/100 000 in 2000-2004, and leukemias (2.5). Breast cancer mortality leveled off at around 10/100 000 in the last decade, whereas declines were observed for cancers of the uterus, whose rate (8.3) however, remained comparatively high. Declines were observed for stomach cancer in both sexes, with rates of 11.1 in men and 4.6 in women. In conclusion, the key issues of cancer mortality in Brazil are the high rates of head and neck cancers in men and (cervix) uterine cancer in women, that is, in principle cancers that are largely avoidable through prevention, screening, and early diagnosis.

Coronary MR angiography: comparison of quantitative and qualitative data from four techniques.

OBJECTIVE: The optimal coronary MR angiography sequence has yet to be determined. We sought to quantitatively and qualitatively compare four coronary MR angiography sequences. SUBJECTS AND METHODS. Free-breathing coronary MR angiography was performed in 12 patients using four imaging sequences (turbo field-echo, fast spin-echo, balanced fast field-echo, and spiral turbo field-echo). Quantitative comparisons, including signal-to-noise ratio, contrast-to-noise ratio, vessel diameter, and vessel sharpness, were performed using a semiautomated analysis tool. Accuracy for detection of hemodynamically significant disease (> 50%) was assessed in comparison with radiographic coronary angiography. RESULTS: Signal-to-noise and contrast-to-noise ratios were markedly increased using the spiral (25.7 +/- 5.7 and 15.2 +/- 3.9) and balanced fast field-echo (23.5 +/- 11.7 and 14.4 +/- 8.1) sequences compared with the turbo field-echo (12.5 +/- 2.7 and 8.3 +/- 2.6) sequence (p < 0.05). Vessel diameter was smaller with the spiral sequence (2.6 +/- 0.5 mm) than with the other techniques (turbo field-echo, 3.0 +/- 0.5 mm, p = 0.6; balanced fast field-echo, 3.1 +/- 0.5 mm, p < 0.01; fast spin-echo, 3.1 +/- 0.5 mm, p < 0.01). Vessel sharpness was highest with the balanced fast field-echo sequence (61.6% +/- 8.5% compared with turbo field-echo, 44.0% +/- 6.6%; spiral, 44.7% +/- 6.5%; fast spin-echo, 18.4% +/- 6.7%; p < 0.001). The overall accuracies of the sequences were similar (range, 74% for turbo field-echo, 79% for spiral). Scanning time for the fast spin-echo sequences was longest (10.5 +/- 0.6 min), and for the spiral acquisitions was shortest (5.2 +/- 0.3 min). CONCLUSION: Advantages in signal-to-noise and contrast-to-noise ratios, vessel sharpness, and the qualitative results appear to favor spiral and balanced fast field-echo coronary MR angiography sequences, although subjective accuracy for the detection of coronary artery disease was similar to that of other sequences.

Laparoscopic Roux-en-Y gastric bypass: initial 2-year experience.

BACKGROUND: Roux-en-Y gastric bypass (RYGBP)-essentially a restrictive bariatric procedure-is currently considered the gold standard for the surgical treatment of morbid obesity. Open surgery in obese patients is associated with a high risk of cardiopulmonary complications, wound infection, and late incisional hernia. Laparoscopic surgery has been shown to reduce perioperative morbidity and to improve postoperative recovery for various procedures. Herein we present our results with laparoscopic RYGBP after an initial 2-year experience. METHODS: A prospective database was created in our department beginning without the first laparoscopic bariatric procedure. To provide a complete follow-up of 6 months, the results of all patients operated on between June 1999 and August 2001 were reviewed. Early surgical results, weight loss, correction of comorbidities, and improvement of quality of life were evaluated. RESULTS: A total of 107 patients were included. There were 82 women and 25 men, with a mean age of 39.7 years (range, 19-58). RYGBP was a primary procedure in 80 cases (49 morbidly obese and 31 superobese patients) and a reoperation after failure or complication of another bariatric operation in 27 cases. Mean duration of surgery was 168 min for morbidly obese patients, 196 min for surperobese patients, and 205 min for reoperated patients (p <0.01). Conversion to open surgery was necessary in two cases. A total of 22 patients (20.5%) developed complication. Nine of them (8.4%) required reoperation for leak (five cases, or 4.6%), bowel occlusion (three cases, or 2.8%), or subphrenic abscess (one case, or 0.9%). mortality was 0.9%. Major morbidity decreased over time (first two-thirds, 12.5%, last third, 2.7%). major morbidity decreased over time (first two-thirds, 12.5%; last third, 2.7%). Excess weight loss of -50% was achieved in >80% of the patients, corresponding to a loss of 15 body mass index (BMI) units in morbidly obese patients and 20 BMI units in superobese patients. In the vast majority of patients, comorbidities improved or disappeared over time and quality of life improved. CONCLUSIONS: Laparoscopic Roux-en-Y gastric bypass is feasible, but it is a very complex operation. Indeed, it is associated with a long and steep learning curve, as reflected in the high number of major complications among our first 70 patients. The learning curve probably includes between 100 and 150 patients. With increasing experience, the morbidity rate becomes more acceptable and comparable to that of open RYGBP. The results in terms of weight loss and correction of comorbidities are similar to those obtained after open surgery, at least in the short term. However, only surgeons with extensive experience in advanced laparoscopic as well as bariatric surgery should attempt this procedure.

Reduced quality of life associated adverse events in intermediate hepatocellular carcinoma patients treated with PRECISION TACE with drug eluting beads: Results from the PRECISION V randomized trial

Purpose: To evaluate the extent of quality of life (QoL) associated adverse events (AEs) following PRECISION TACE with DC Bead compared with conventional transarterial chemoembolisation (cTACE). Methods and Materials: 201 intermediate HCC patients were treated with DC Bead (PRECISION TACE) or conventional TACE (cTACE) with doxorubicin in the PRECISION V clinical study. 93 patients were treated with DC Bead and 108 Patients with cTACE every 2 months and followed up for 6 months. AEs were classified according to the South West Oncology Group criteria. QoL associated AEs were defined as alopecia, constipation, nausea, vomiting, pyrexia, chills, asthenia, fatigue, and headache. Results: The biggest difference in QoL associated AEs was for alopecia: 2 patients (2.2%) for DC-Bead versus 21 patients (19.4%) for cTACE. For other clinical symptoms, constipation (n=10; 10.8% vs. n=13; 12%), vomiting (n=10; 10.8% vs. n=14; 13.0%), pyrexia (n=16; 17.2% vs. n=26; 24.1%), chills (n=1; 1.1% vs. n=5; 4.6%), and headache (n=2; 2.2% vs. n=8; 7.4%) showed lower incidence in the DC Bead group versus cTACE. Nausea, n= 15; 13.9% (n=15; 16.1%) and fatigue, n=6; 5.6% (n=13; 14.0%) were lower for cTACE. Total dose of doxorubicin was on average 35% higher in the DC Bead group. Conclusion: Although patients in the DC Bead group received a higher doxorubicin dose, less QoL associated AEs were reported for this group. Alopecia, the most obvious outward sign of toxicity, was only reported in a tenth of DC Bead patients. Thus, PRECISION TACE with DC Bead improves quality of life associated adverse events.

Should Hyperglycemia in Critically Ill Children Be Treated?

Introduction: In adults, strict control of hyperglycemia reduces mortality and morbidity. There is controversy in medical patients and neurological patients who can suffer of neuroglucopenia. Objectives: To determine prevalence and prognostic significance of hyperglycemia among critically ill non-diabetic children. To evaluate which patients will best benefit of insulin treatment. Methods: Retrospective study using blood glucose levels (GLUC: 9015 values, 923 patients) in our PICU from 01.2003 to 12.2005. 11 Patients with DKA were excluded. Overall PICU mortality was 3.7%. Hyperglycemia was defined at 6.1 mmol/L and different cutoff values (6.1, 8.3 and 11.1 mmol/l) were analyzed for glycemia at admission (GLUC). Sustained hyperglycemia was evaluated with the area under the curve normalized per hour (48h-AUC/h) for the first 48 h. The prevalence of hypo (_3mmol/L), hyperglycemia and PICU death were analyzed. Results: Trough the use of different cutoff values (_6.1, _8.3 and _11.1 mmol/l), prevalence of hyperglycemia at admission was 31.8 %, 16.8% and 10.3%; associated mortality was 2.8%, 4.0% and 15.2% respectively, significantly correlated to cutoff values (r_0.95, p_0.05). Prevalence of hypoglycemia at admission was low (0.9% with no death). 48h-AUC(mmol/L/h) was computed in 747 children (30 deaths). Prevalence of hyperglycemic 48h-AUC values was 47.5%, 17.3% and 4.0% with a respective mortality of 3.4%, 6.3% and 20.7% (r_0.97, p_0.03). For those with high GLUC and high 48h-AUC (_ 11.1 mmol/L) mortality was high (31.5%), but it decrease dramatically to 5.5% when 48h-AUC decrease spontaneously to values _8.3 mmol/L/h. Finally, when patients with severe neurological lesions (GCS_3, n_22) where excluded, increased mortality was observed only for GLUC (n_ 86) and 48h-AUC (n_26) higher than 11.1 mmol/L. Conclusions: Hyperglycemia at admission and even more sustained hyperglycemia (AUC) are highly correlated to mortality in PICU. But children who will have benefit of insulin therapy represent only 3% of our population, much lower than for adults.

Effects of added dead space on sleep disordered breathing at high altitude

Introduction: Sleep disordered breathing with central apnea or hypopnea frequently occurs during sleep at high altitude. The aim of this study was to assess the effects of added dead space (DS) on sleep disordered breathing and transcutaneous CO2 (PtcCO2) level during sleep at high altitude. Methods: Full night sleep recordings were obtained on 12 unacclimatized mountaineers (11 males, 1 female, mean age 39 ± 12 y.o.) during one of the first 4 nights after arrival in Leh, Ladakh (3500 m). In random order, half of the night was spent with a 500 ml increase in dead space through a custom designed full face mask and the other half without it. PtcCO2 was measured in 3 participants. Results: Baseline recordings reveled two clearly distinct groups: one with severe sleep disordered breathing (n = 5) and the other with mild or no disordered breathing (n = 7). Added dead space markedly improved breathing in the first group (baseline vs DS): apnea hypopnea index (AHI) 70.3 ± 25.8 vs 29.4 ± 6.9 (p = 0.013), oxygen desaturation index (ODI): 72.9 ± 24.1/h vs 42.5 ± 14.4 (p = 0.031), whereas it had no significant effect in the second group. Added dead space did not have a significant effect on mean oxygen saturation level. Respiratory events were almost exclusively central apnea or hypopnea except for one subject. Only a minor increase in mean PtcCO2 (n = 3) was observed: 33.6 ± 1.8 mm Hg at baseline and 35.0 ± 2.62 mm Hg with DS. Sleep quality was preserved under dead space condition, since the microarousal rate remained unchanged (16.8 ± 8.7/h vs 19.4 ± 18.6/h (p = 0.51). Conclusion: In mountaineers with severe sleep disordered breathing at high altitude, a 500 ml increase in dead space through a fitted mask significantly improves nocturnal breathing.

L'effet de la gémellité associée à la prématurité sur l'interaction précoce et les processus d'attachement

Objectif Le but de cette recherche est d'observer un possible rôle de la gémellité dans la qualité de l'interaction précoce mère-enfant et dans le développement de l'attachement à une année par rapport à des non-jumeaux respectivement prématurés et non prématurés selon l'observation directe selon la description des enfants par leurs mères. Méthode Il s'agit d'une étude longitudinale exploratoire qui vise à comparer les compétences sociales et communicatives de trois populations: prématurés respectivement jumeaux et non- jumeaux ainsi qu'enfants nés à terme non-jumeaux à 4, 6, 12 et 18 mois. Cette recherche est réalisée dans le cadre de deux études prospectives menées au Service Universitaire de Psychiatrie de l'Enfant et de l'Adolescent sur le devenir des grands prématurés. Les outils utilisés sont le CARE-Index qui évalue la qualité de l'interaction mère-enfant, la situation étrange qui détermine le type d'attachement de l'enfant et le Toddler tempérament scale (TTS) qui permet d'apprécier le tempérament de l'enfant tel que perçu par leurs mères. Limites Les deux principales limites de ce travail sont certainement le nombre restreint de sujets observés et le fait que les sujets étudiés proviennent de deux études différentes et soient comparés entre eux. Les questionnaires du TTS remplis par les mères représentent également une limite car peuvent comporter une part de "désirabilité sociale". Résultats Cette étude a permis de retrouver les résultats de certaines théories de base de l'interaction mère-enfant et du processus d'attachement en les appliquant à un groupe de jumeaux prématurés. Nous avons retrouvé des différences significatives dans les résultats du CARE- Index qui suggère que la gémellité influencerait la qualité de l'interaction précoce. Celle-ci ne semble par contre pas empêcher le développement d'un attachement secure à une année.

Adjuvant intra-arterial hepatic fotemustine for high-risk uveal melanoma patients

Uveal melanoma metastases occur most commonly in the liver. Given the 50% mortality rate in patients at high risk of developing liver metastases, we tested an adjuvant intra-arterial hepatic (i.a.h.) chemotherapy with fotemustine after proton beam irradiation of the primary tumour. We treated 22 high-risk patients with adjuvant i.a.h. fotemustine. Planned treatment duration was 6 months, starting with four weekly doses of 100 mg/m(2), and after a 5-week rest, repeated every 3 weeks. The survival of this patient group was compared with that of a 3 : 1 matched control group randomly selected from our institutional database. Half of the patients experienced > or =grade 3 hepatotoxicity (one patient developing cholangitis 8 years later). Catheter-related complications occurred in 18%. With a median follow-up of 4.6 years for the fotemustine group and 8.5 years for the control group, median overall survival was 9 years [95% confidence interval (CI) 2.2-12.7] and 7.4 years (95% CI 5.4-12.7; P=0.5), respectively, with 5-year survival rates of 75 and 56%. Treatment with adjuvant i.a.h. fotemustine is feasible. However, toxicities are important. Although our data suggest a survival benefit, it was not statistically significant. Confirming such a benefit would require a large, internationally coordinated, prospective randomized trial.

Pharmacological inhibition of interleukin-15 prevents colitis and associated bone loss in IL-10 knockout mice

Bone loss secondary to inflammatory bowel diseases (IBD) is largely explained by activated T cells producing cytokines that trigger osteoclastogenesis and accelerate bone resorptionwhile inhibiting bone formation. In IBD, elevated expression of interleukin (IL)-15, a T cell growth factor, plays a central role in T cell activation, pro-inflammatory cytokine production and the development of colitis. We previously reported that IL-15 enhances RANKL-induced osteoclastogenesis and that an IL-15 antagonist, CRB-15, prevents weight and bone loss in a mousemodel of dextran sulfate sodium-induced colitis.We hypothesized that inhibition of IL-15 signalingmight prevent bone loss in IL-10 deficient (IL10−/−) mice, that develop spontaneous bowel inflammation associatedwith osteopeniawhen they are no longer raised under germ-free conditions.Mice received anIL-15 antagonist (CRB-15, 5 μg/day, n=5) or IgG2a (5 μg/day, n=4) fromweek 10 to 14 of age. The severity of colitis was assessed by histology and bowel cytokine gene expression by real time PCR. Bone mass and architecturewere evaluated by ex vivo DXA on femur and micro-computed tomography on femur and vertebra. Bodyweight gainwas similar in the two groups. After 4 weeks, colonwas 29% shorter in CRB-15 treatedmice (p<0.006), a sign of reduced inflammation. Histological analysis indicated a transmural infiltration of inflammatory cells, lymphoepithelial lesions and increased size of villi (histological score=4/6) in IgG2a treated mice, whereas colon from CRB-15 treated mice exhibited mild infiltration of inflammatory cells of the lamina propria, no mucosal damages and a minimal increased size of villi (histological score=1.6/6). Levels of TNFα, IL-17 and IL-6 mRNA in the colon were significantly reduced in CRB-15 treated mice (p<0.04 vs IgG2), indicating a decrease in colon inflammation. CRB-15 improved femur BMD (+10.6% vs IgG2a, p<0.002), vertebral trabecular bone volume fraction (BV/TV, +19.7% vs IgG2a, p<0.05) and thickness (+11.6% vs IgG2a, p<0.02). A modest but not significant increase in trabecular BV/TV was observed at the distal femur. Cortical thicknesswas also higher at themidshaft femur in CRB-15 treatedmice (+8.3% vs IgG2a, p<0.02). In conclusion, we confirm and extend our results about the effects of CRB-15 in colitis. Antagonizing IL-15 may exert favorable effects on intestinal inflammation and prevent bone loss and microarchitecture alterations induced by colitis. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: B. Brounais-Le Royer Grant / Research Support from Novartis Consumer Health Foundation, S. Ferrari-Lacraz: none declared, D. Velin: none declared, X. Zheng: none declared, S. Ferrari: none declared, D. Pierroz: none declared.

Mechanical properties of rat cardiac skinned fibers are altered by chronic growth hormone hypersecretion.

Chronic growth hormone (GH) hypersecretion in rats leads to increased isometric force without affecting the unloaded shortening velocity of isolated cardiac papillary muscles, despite a marked isomyosin shift toward V3. To determine if alterations occurred at the level of the contractile proteins in rats bearing a GH-secreting tumor (GH rats), we examined the mechanical properties of skinned fibers to eliminate the early steps of the excitation-contraction coupling mechanism. We found that maximal active tension and stiffness at saturating calcium concentrations (pCa 4.5) were markedly higher in GH rats than in control rats (tension, 52.9 +/- 5.2 versus 38.1 +/- 4.6 mN.mm-2, p < 0.05; stiffness, 1,105 +/- 120 versus 685 +/- 88 mN.mm-2.microns-1, p < 0.01), whereas values at low calcium concentrations (pCa 9) were unchanged. In addition, the calcium sensitivity of the contractile proteins was slightly but significantly higher in GH rats than in control rats (delta pCa 0.04, p < 0.001). The crossbridge cycling rate, reflected by the response to quick length changes, was lower in GH rats than in control rats (62.0 +/- 2.6 versus 77.4 +/- 6.6 sec-1, p < 0.05), in good agreement with a decrease in the proportion of alpha-myosin heavy chains in the corresponding papillary muscles (45.5 +/- 2.0% versus 94.6 +/- 2.4%, p < 0.001). The changes in myosin heavy chain protein phenotype were paralleled by similar changes of the corresponding mRNAs, indicating that the latter occurred mainly at a pretranslational level. These results demonstrate that during chronic GH hypersecretion in rats, alterations at the myofibrillar level contribute to the increase in myocardial contractility observed in intact muscle.

Trends in overweight and obesity levels in Geneva: time for optimism?

Background/Introduction: ln Switzerland, most trends in overweight and obesity levels have been assessed using reported data, a methodology which is prone to reporting bias. ln this study, we aimed at assessing trends in overweight and obesity levels using objectively measured data. Methods: We used independent cross-sectional data collected between 2005 and 2011 by the Bus Santé study on representative samples of the Geneva population. Trends were assessed overall and according to different characteristics of the participants. Overweight and obesity were defined as a body mass index (BMI) between 25 and 29.9 kg/m2 and >=30 kg/m2, respectively. Results: Data from 4093 participants (2012 men) was assessed. Mean BMI was 25.2 ± 4.3 kg/m2 (mean ±standard deviation) in 2005 and 25.4 ± 4.3 in 2011 (p for trend using linear regression=0.98). For men, mean BMI was 26.3 ± 3.8 kg/m2 in 2005 and 26.1 ± 3.7 in 2011 (p for trend=0.37); for women, the corresponding values were 24.3 ± 4.6 and 24.7 ± 4.7 kg/m2 (p for trend=0.42). Overall prevalence of overweight and obesity was 32.2% and 13.3%, respectively, in 2005 and 33.6% and 13.7% in 2011 (p for trend using polytomous logistic regression adjusting for gender, age and smoking=0.49 and 0.94 for overweight and obesity, respectively). For men, prevalence of overweight and obesity was 45.9% and 12.2% in 2005 and 42.1 % and 14.6% in 2011 (P for trend=0.03 for overweight and 0.81 for obesity); for women, the corresponding values were 20.4% and 14.2% in 2005 and 25.4% and 12.9% in 2011 (p for trend=0.13 for overweight and 0.99 for obesity). Conclusion: Overweight and obesity levels appear to have levelled in Geneva, with a possible decrease in overweight levels in men. These favorable findings should be replicated in other geographical locations.

Effects of increased intensity of intermittent training in runners with differing VO2 kinetics.

The purpose of this study was to test the hypothesis that athletes having a slower oxygen uptake ( VO(2)) kinetics would benefit more, in terms of time spent near VO(2max), from an increase in the intensity of an intermittent running training (IT). After determination of VO(2max), vVO(2max) (i.e. the minimal velocity associated with VO(2max) in an incremental test) and the time to exhaustion sustained at vVO(2max) ( T(lim)), seven well-trained triathletes performed in random order two IT sessions. The two IT comprised 30-s work intervals at either 100% (IT(100%)) or 105% (IT(105%)) of vVO(2max) with 30-s recovery intervals at 50% of vVO(2max) between each repeat. The parameters of the VO(2) kinetics (td(1), tau(1), A(1), td(2), tau(2), A(2), i.e. time delay, time constant and amplitude of the primary phase and slow component, respectively) during the T(lim) test were modelled with two exponential functions. The highest VO(2) reached was significantly lower ( P<0.01) in IT(100%) run at 19.8 (0.9) km(.)h(-1) [66.2 (4.6) ml(.)min(-1.)kg(-1)] than in IT(105%) run at 20.8 (1.0) km(.)h(-1) [71.1 (4.9) ml(.)min(-1.)kg(-1)] or in the incremental test [71.2 (4.2) ml(.)min(-1.)kg(-1)]. The time sustained above 90% of VO(2max) in IT(105%) [338 (149) s] was significantly higher ( P<0.05) than in IT(100%) [168 (131) s]. The average T(lim) was 244 (39) s, tau(1) was 15.8 (5.9) s and td(2) was 96 (13) s. tau(1) was correlated with the difference in time spent above 90% of VO(2max) ( r=0.91; P<0.01) between IT(105%) and IT(100%). In conclusion, athletes with a slower VO(2) kinetics in a vVO(2max) constant-velocity test benefited more from the 5% rise of IT work intensity, exercising for longer above 90% of VO(2max) when the IT intensity was increased from 100 to 105% of vVO(2max).

Activity of polymethylmethacrylate (PMMA) bone cement loaded with daptomycin, vancomycin and gentamicin against Staphylococcus epidermidis biofilms

Background: Local antibiotics may significantly improve the treatmentoutcome in bone infection without systemic toxicity. For impregnationof polymethylmethacrylate (PMMA), gentamicin, vancomycin and/orclindamycin are currently used. A new lipopeptid antibiotic,daptomycin, is a promising candidate for local treatment due to itsspectrum against staphylococci and enterococci (including multiresistantstrains), and concentration-dependent rapid bactericidalactivity. We investigated activity of antibiotic-loaded PMMA againstStaphylococcus epidermidis biofilms using an ultra-sensitive bacterialheat detection method (microcalorimetry).Methods: Staphylococcus epidermidis (strain RP62A, susceptibleto daptomycin, vancomycin and gentamicin) at concentration 106bacteria/ml was incubated with 2 g-PMMA block (Palacos, HeraeusMedical, Hanau, Germany) in 25 ml tryptic soy broth (TSB)supplemented with calcium. PMMA blocks were preloaded withdaptomycin, vancomycin and gentamicin each at 2 g/40 mg (= 100 mg/block) PMMA. After 72 h-incubation at 35 °C under static conditions,PMMA blocks were rinsed in phosphate-buffered solution (PBS) 5times and transferred in 4 ml-microcalorimetry ampoule filled with 1 mlTSB. Bacterial heat production, which is proportional to the quantityof biofilm on PMMA surface, was measured by isothermalmicrocalorimetry. The detection time was calculated as the time untilthe heat flow reached 20 microwatt.Results: Biomechanical properties did not differ between antibioticloadedand non-loaded PMMA blocks. The mean detection time (±standard deviation) of bacterial heat was 6.5 ± 0.4 h for PMMA withoutantibiotics (negative control), 13.5 ± 4.6 h for PMMA with daptomycin,14.0 ± 4.1 h for PMMA with vancomycin and 5.0 ± 0.4 h for PMMAwith gentamicin.Conclusion: Our data indicates that antibiotics at 2 g/40 mg PMMAdid not change the biomechanical properties of bone cement. Daptomycinand vancomycin were more active than gentamicin against S.epidermidis biofilms when all tested at 2 g/40 mg PMMA. In the nextstep, higher concentrations of daptomycin and their elution kineticneeds to be determined to optimize its antibiofilm activity before usingin the clinical setting.