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International audience; A high number of recent studies have shown that a positive fluid balance is independently associated with impaired prognosis in specific populations of patients hospitalized in intensive care unit (ICU): acute kidney injury, acute respiratory distress syndrome (ARDS), sepsis, high risk surgery. However, to date, there is no evidence that control of fluid overload reduces mortality in critically ill patients. The main objective is to assess the efficacy of a strategy limiting fluid overload on mortality in unselected critically ill patients hospitalized in ICU. We hypothesized that a strategy based on a weight-driven recommendation of restricted fluid intake, diuretics, and ultrafiltration initiated from 48h up to 14days after admission in critically ill patients would reduce all-cause mortality as compared to usual care. We use a stepped wedge cluster randomized controlled trial combined with a quasi-experimental (before-and-after) study. Patients under mechanical ventilation, admitted since \textgreater48h and\textless72h in ICU, and with no discharge planned for the next 24h are eligible. A total of 1440 patients are expected to be enrolled in 12 ICUs. Sociodemographic and clinical data are collected at inclusion, and outcomes are collected during the follow-up. Primary outcome is all-cause mortality at 60days after admission. Secondary outcomes are patients weight differences between admission and day7 (or day 14), 28-day, in-hospital, and 1-year mortality, end-organ damages, and unintended harmful events. Analyses will be held in intention-to-treat. If POINCARE-2 strategy proves effective, then guidelines on fluid balance control might be extended to all critically ill patients. Trial registration: ClinicalTrials.govNCT02765009.

Diffuse WHO grade II and III gliomas (DGII/IIIG) are rare tumors, with few specific epidemiological studies. We aimed at describing the geographical distribution of a homogeneous series of histologically confirmed DGII/IIIG, over a four-year period (2006-2009), at a national level. The methodology is based on a multidisciplinary national network already established by the French Brain Tumor DataBase and data collected directly from every neuropathology department. Personal home addresses were collected for confirmed cases. For each region, the incidence of DGII/IIIG was analyzed and standardized on the age and sex distribution of the French population. The number of patients with newly diagnosed, histologically confirmed DGII/IIIG was 4,790. The overall crude rate was 19.4/10(6). To enable international comparisons, standardized rates were calculated as follows: 19.8/10(6), 18.8/10(6) and 16.0/10(6) (reference population, Europe, US and world, respectively). The geographical distribution by region showed significant differences, with higher incidence rates in Northeast and central parts of France. This work is the first studying the geographical distribution of a pure series of DGII/IIIG at a national level. It demonstrates significant heterogeneity in the distribution, and raises the question of the role of environmental and/or genetic risk(s) factor(s) for DGII/IIIG.

OBJECTIVES: To measure the frequency of and risk factors for rheumatic manifestations after chikungunya virus (CHIKV) infection and to assess their impact on quality of life (QoL). METHODS: In a cohort study among 509 cases diagnosed in France, demographic and clinical characteristics were collected at baseline, and QoL status by 36-item short-form health survey (SF-36), a short form of the Arthritis Impact Measurement Scales 2 (AIMS2-SF) and General Health Questionnaire (GHQ-12) at follow-up. SF-36 scores were compared with population norms. Factors associated with QoL were identified in multivariate linear regression models. RESULTS: A total of 391 (77%) patients participated (53.5% female, mean age 50.2 years). Median time from onset at follow-up was 23.4 months. Among 176 recovered patients, a shorter duration of symptoms was observed in younger age groups and male patients. The probability of full recovery at 1 year was 0.39. Those not recovered were older, had more comorbidities and a longer acute stage with joint swelling. Scores of physical and mental components of the SF-36 and GHQ-12 were low. The AIMS2-SF was affected mainly in symptoms, psychological and social dimensions. Recovered patients did not differ significantly from age- and gender-matched population SF-36 norms. Older age (P = 0.01-0.002) was associated with lower SF-36 scores. Other factors associated with lower SF-36, lower GHQ12 scores and higher AIMS2-SF dimensions were lack of recovery (P = 0.017 to

Purpose Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma. Patients and Methods Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival. Results After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003). Conclusion This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

International audience; Background: Epstein-Barr virus (EBV) infection is a major cause of morbidity following hematopoietic stem cell transplantation. EBV-infected B cells may not respond to rituximab treatment and may lead to a life-threatening post-transplantation lymphoproliferative disorder. Adoptive cellular immunotherapy using EBV-lymphoblastoid cell lines (LCL) as stimulating antigen has proved effective in restoring specific immunity. However, EBV presents several immunodominant antigens, and developing a swift and effective clinical-grade immunotherapy relies on the definition of a Good Manufacturing Practices (GMP) universal stimulating antigen.Methods: Peripheral blood mononuclear cells (PBMCs) from six donors with a cellular immune response against EBV were immunoselected after stimulation with a new EBV antigen associated with an EBNA3 peptide pool.Results: After immunoselection, a mean of 0.53 ± 0.25 × 106 cells was recovered consisting of a mean of 24.77 ± 18.01% CD4+-secreting interferon (IFN)-γ and 51.42 ± 26.92% CD8+-secreting IFN-γ. The T memory stem cell sub-population was identified. EBV-specific T cells were expanded in vitro, and their ability to secrete IFN-γ and to proliferate after re-stimulation with EBV antigen was confirmed. A specific lysis was observed against autologous target cells pulsed with EBV peptide pools (57.6 ± 11.5%) and against autologous EBV-LCL (18.3 ± 7.3%). A mean decrease of 94.7 ± 3.3% in alloreactivity against third-party donor mononuclear cells with EBV-specific T cells was observed compared with PBMCs before selection.Conclusions: Our results show that a combination of peptide pools including EBNA3 is needed to generate EBV-specific T cells with good specific cytotoxicity and devoid of alloreactivity, but as yet GMP grade is not fully achieved.

International audience; OBJECTIVE:To assess the prevalence of systemic sclerosis (SSc) in the Lorraine region, France.METHODS:Data from three sources - general practitioners and community and hospital specialists, medical records departments, and regional and national laboratories-and a capture-recapture method with log-linear models were used to estimate SSc prevalence in the region. Double recording was checked, and reported cases were validated after a review of medical records.RESULTS:We identified 560 records of suspected SSc cases corresponding to 327 unique suspected SSc cases existing on June 30, 2006, in Lorraine. On the basis of the 193 validated cases (22 [11.4%] with diffuse disease, 136 [70.5%] with limited disease, 31 [16.1%] with limited involvement and 4 unknown), the observed overall crude prevalence of SSc was 105.4 cases per million adult inhabitants (95% confidence interval [CI]: 91.0; 121.4). With the capture-recapture method, the estimated number of SSc cases was 233 (95% CI: 217.3; 260.0), so an estimated 40 cases were not identified by the three sources. The estimated overall prevalence was 132.2 cases per million adult inhabitants (95% CI: 115.8; 154.0).CONCLUSIONS:Our study provides the first estimate of SSc prevalence in the Lorraine region. The capture-recapture method allowed us to estimate an additional 21% of unobserved cases and is a good alternative to the community-based study design for estimating the prevalence of rare diseases.

Background: Inflammatory pathways may promote extracellular matrix (ECM) remodeling and chronic heart failure (CHF) progression. The relationship between markers of inflammation and of ECM remodeling, and their influence oil functional status and outcomes has not been examined in a large cohort of CHF patients. Methods and Results: We measured baseline blood serum collagen (amino-terminal propeptide of collagen III [PIIINP], metalloproteinase I [MMP-1], tissue inhibitor of metalloproteinase I [TIMP-1]), and inflammatory (high-sensitivity C-reactive protein [(hsCRP], interleukin [IL]-18, IL-10) markers in 1009 patients enrolled in the Research into Etanercept Cytokine Antagonism in ventricular Dysfunction (RECOVER) trial. A positive correlation was detected between the 2 classes of markers (PIIINP to IL-18, MMP-1 and TIMP-1 to CRP, TIMP-1 to IL-18, MMP-1 to IL-10). In the adjusted multivariable model including all biomarkers, only PIIINP (P =.03) and MMP-1 (P=.048) were independent predictors of 6-minute walk test (6-MWT), whereas in another model including only inflammatory biomarkers, IL-18 was an independent predictor. PIIINP (P =.001) was the only biomarker independently associated with death and CHF hospitalization. Conclusions: The independent associations of PIIINP and MMP-1 with 6-MWT and PIIINP with CHF morbi-mortality suggest that excessive ECM turnover may be associated with functional capacity deterioration and poor outcome.

International audience; BACKGROUND: Since 1996, the allocation of grafts in France has been based on a hierarchical three-level system: national, regional and local. The objective of this study was to determine whether the shipment of cadaveric kidneys according to these new exchange rules affects allograft outcome in the Eastern region of France. METHODS: This retrospective study analysed all renal transplants performed in the four centres of the French Eastern region during 3 years (1996 to 1998). All patients were followed up until death, return to dialysis, last information date or the end of June 2003. Information regarding the donors, recipients and treatments, as well as patient and graft outcome, was recorded. Factors associated with graft loss were analysed using Cox proportional hazard methods. RESULTS: 542 transplants were analysed, 287 (53%) kidneys were transplanted locally, 229 (42.2%) kidneys coming from exchanges within the region and 26 (4.8%) from another region. There were statistically significant differences between the four centres for donors' and recipient' characteristics and for immunosuppressive treatment, but there was no difference between centres regarding patient survival (94.4% at 5 years), graft survival (83.7% at 5 years) or death-censored graft survival (87.8% at 5 years). Compared to locally transplanted grafts, shipped grafts had significantly better human leukocyte antigen (HLA) matching (2.5 +/- 1.3 versus 2.1 +/- 1.0 matches, P = 0.0005 but a longer cold ischaemia time (23.2 +/- 7.9 versus 19.2 +/- 7.8 h, P < 0.0001). Three independent factors were associated with a reduced graft survival: at least one acute rejection, delayed graft function and a shipped graft. CONCLUSION: The results of this study suggest that the shipment of cadaveric renal allografts in a regional distribution system is associated with better HLA matching but is a significant predictor of graft loss at 5 years. It would be advisable to restrict graft sharing to patients whose access to transplantation is limited, taking special care to avoid any additional factors having a detrimental effect on the outcome.

Haemorheological changes have been described in hypertension as well as in diabetes mellitus. Antihypertensive treatment improves rheology in hypertensive patients. The aim of this study was to describe the haemorheological profile and its impact on shear stress in hypertensive type 2 diabetes mellitus patients (HT + DM) and to investigate the effect of antihypertensive therapy on blood rheology using a double-blind randomized protocol, comparing the calcium antagonist amlodipine with the angiotensin-converting enzyme (ACE) inhibitor enalapril. A total of 144 patients with hypertension and type 2 diabetes (64 of transversal study and 80 of randomized clinical trial) were compared with 92 controls belonging to a transversal study. Secondarily, in a separate analysis, therapeutic effects of calcium antagonist amlodipine and ACE inhibitor enalapril were compared in a longitudinal, randomized trial in the patients. We assessed whole-blood viscosity, plasma viscosity, partial and total disaggregation times, haematocrit and fibrinogen. Radial artery systolic flow velocity was measured by pulsed Doppler. Shear stress was calculated as the product of flow velocity x whole-blood viscosity. Compared with controls, patients had significantly higher whole-blood viscosity for all shear rates (P < 0.001) as well as higher arterial diameter and systolic blood flow velocity (2.8 +/- 0.3 vs. 2.6 +/- 0.3 mm, P < 0.001; and 50.8 +/- 11.6 vs. 45.6 +/- 9.8 cm/s, P = 0.01, respectively). Whole-blood viscosity at shear rate gamma = 128/s tended to increase with amlodipine (+1.13%) and decrease with enalapril (-2.47%) (P = 0.028 for inter-group difference). In hypertensive diabetic patients, hyperviscosity contributes to increased shear stress. Haemorheological disturbances in these patients are not significantly influenced by blood pressure lowering with antihypertensive therapy by ACE inhibitor enalapril or calcium antagonist amlodipine. Other factors potentially contributing to rheology and arterial changes may be more critical in HT + DM patients and need further investigation.

The aim of the present study was to test the hypothesis that unmarried (single) men have more sleep-disordered breathing symptoms due to a higher prevalence of obesity and a less healthy lifestyle than men living with a partner. Men (499) aged 23–66 years completed a structured questionnaire, had standard anthropometric measurements and a simple, noninvasive nose-throat examination. Of the 499, 496 subjects answered the question concerning their marital status; 86% of them were married or lived with a partner (reference group) and the other 14% had never been married, divorced, or widowed (“single” group, considered at risk). Single subjects were younger, included slightly more smokers (30 vs. 23%) and more subjects with a history of chronic bronchitis, and less frequently had a large soft palate. The prevalence of sleep-disordered symptoms was not significantly different between the two groups. However, a study involving a larger number of subjects with information regarding alcoholic consumption may be needed to further evaluate this question.

The duration of action of antihypertensive drugs may be assessed by several methods using ambulatory blood pressure monitoring (ABPM). The aim of this double-blind, randomized study was to compare the time-effect profile of once daily Trandolapril (Tra) 2 mg vs. Quinapril (Qui) 20 mg in 92 patients with mild-to-moderate hypertension. All patients received placebo during a 30-day run-in period followed by 2 months of active therapy and 1-day medication omission. ABPM was conducted on each period. 24 h antihypertensive coverage was assessed by trough:peak ratio (T/P) and smoothness index (SI) methods. Residual lowering of blood pressure after single-blind, 1 day medication omission was investigated as the SBP/DBP 48-h trough effect. There were no statistically significant differences between treatment groups in the mean SBP/DBP peak or trough effect. Individual T/P were not normally distributed and had very large variations explained by BP random- and activity-related fluctuations. Group T/P were 0.85 for Tra and 0.62 for Qui. The SI values were normally distributed and not statistically different between the two treatment groups. After dose omission, Qui was ineffective at 48-h trough while Tra retained a significant effect (SBP/DBP = -3.4/-4.3 mmHg) and this difference was even greater in ABPM-responders. Comparison of the trough:peak ratios and smoothness indexes of Tra and Qui failed to show any statistically significant difference on 24-h antihypertensive coverage. Nevertheless, residual lowering of blood pressure at 48-h trough suggests that Tra had a longer duration of action than Qui.

Study objectives: To assess the prevalence of occasional snoring in a group of middle-aged men, and to compare anthropometric variables and prevalence of sleep-related symptoms of subjects who occasionally snore with those of other snoring categories. Design: A field survey of a sample of middle-aged men in France. Participants: Male employees of a local university and subjects from the community attending a preventive medicine center. Participation rate was 93.5%. Measurements: Anthropometric variables were recorded in 499 subjects aged 23 to 66 years (mean, 44.3 years). The subjects completed a standard sleep questionnaire and were classified according to the snoring frequency as never, rarely, sometimes, occasional, several nights per week, and every night. The subjects who snore occasionally represented 8.6% of the total. Results: The anthropometric data of subjects who snore occasionally were similar to those of subjects who habitually snore. When compared with subjects who do not snore, older age and a larger neck girth were significant. Subjects who snore occasionally were also significantly more often subjects who snore loudly, and tended more frequently to have breathing stops during sleep. Conclusions: Our epidemiologic study shows that approximately 9% of a sample of middle-aged men snore occasionally. Subjects who snore occasionally have anthropometric characteristics close to those of subjects who snore habitually. The prevalence of the main sleep-related symptoms is between that of subjects who do not snore and of subjects who snore habitually. In an epidemiologic setting, inclusion of subjects who snore occasionally as subjects who do not snore or subjects who snore habitually will lead to bias. The present results suggest they should be identified and considered as a separate category. (CHEST 2002; 122:562–568)

Objectives. Several studies suggest a beneficial overall effect of spa therapy in chronic musculoskeletal diseases. The present open controlled study investigated the effects of spa therapy at Bourbonne-Les-Bains, France, in patients with hip or knee osteoarthritis or low back pain. Patients and methods. In 1998, 102 men and women older than 50 years were included in the study. All had low back pain or lower limb osteoarthritis, and none had contraindications to spa therapy. Quality of life was assessed three times at intervals of 4 weeks, twice before and once immediately after 3 weeks of spa therapy, using the Duke Health Profile (five dimensions and five dysfunctions). Results. Mean age was 66.4 years, and 67% of the patients were women. Quality of life was markedly decreased as compared to the population at large (1996, CFES). The two pretreatment evaluations produced similar quality-of-life scores. Spa therapy was associated with significant improvements in overall quality of life (P=0.004), self-esteem (P=0.009), and pain (P=0.01). Conclusion. These findings support those of other studies conducted in France and in other European countries. They indicate that patients report meaningful improvements in their quality of life after spa therapy.

In patients with obstructive sleep apnoea (OSA) anatomic and functional upper airway abnormalities are frequent and severe. Invasive methods are used to identify and quantitate the obstruction, to precisely locate its site, etc. as part of pre-treatment or of preoperative evaluations. These methods (lateral skull radiographs, computerized tomography, MRI, fibroscopies, etc) are too expensive and too invasive to be utilized in field surveys. To the classical sleep questionnaires and anthropometric measurements, some simple nose-throat examinations, easily accepted by the volunteers in a population study, could add useful information for the identification of the subjects at risk for sleep-disordered breathing. The present paper is a review of these examinations and of their utility.

Background Angiotensin-converting enzyme (ACE) inhibitors have been demonstrated to reduce morbidity and mortality rates in patients with heart failure with left ventricular systolic dysfunction. Nevertheless, these drugs are underutilized in current practice and prescribed at doses below those usually recommended. The aim of this work was to identify the social, demographic, laboratory, clinical, and therapeutic factors associated with nonprescription of ACE inhibitors and/or their prescription at doses below those recommended in the treatment of severe long-term congestive heart failure (CHF). Methods and Results An epidemiologic observational study, EPICAL (EPidemiologie de l'Insuffisance Cardiaque Avancee en Lorraine), studied 417 patients with severe CHF surviving after the index hospitalization. Multivariate logistic regression determined the factors associated with ACE inhibitor nonprescription and with their prescription at lower-than-recommended doses. ACE inhibitors were taken by 75% of the patients but 38% took lower-than-recommended doses. Factors shown to be associated with nonprescription included patients >65 years of age with renal impairment (odds ratio 19.5, confidence interval [Cl] 7.9–48.0), nonsinus cardiac rhythm (odds ratio 2.0, Cl 1.2–3.2), and prescription of potassium-sparing diuretics (odds ratio 2.4, Cl 1.2–4.7). Renal impairment was the single most important factor associated with prescription of lower-than-recommended doses, particularly in elderly patients. Conclusions Our results underline the need for optimal and better use of ACE inhibitor therapy. CHF treatment guidelines must be more uniformly applied by all physicians caring for patients with heart failure.

Various types of visual analogue scales (VAS) are used in epidemiologic and clinical research. This paper reports on a randomized controlled trial to investigate the effects of variations in the orientation and type of scale on bias and precision in cross-sectional and longitudinal analyses. This trial was included in the pilot study of the SU.VI.MAX (supplementation by antioxidant vitamins and minerals) prevention trial in France in 1994. Six types of VAS (simple, middle-marked, graphic rating, graduated, graduated-numbered, and numerical rating) and two orientations (horizontal and vertical) were used to measure three symptoms of ear, nose, and throat infection at 2-month intervals in 870 subjects. Differences between scales were analyzed by comparing variances (Levene's test) and means (variance-covariance analysis for repeated measures). Scale characteristics were shown to influence the proportion of zero and low values (i.e., there was a floor effect), but not mean scores. The precision of measurements varied cross-sectionally according to the type of scale, but no differences were observed in the precision of measurement of change over time. In conclusion, the characteristics of VAS seem to be important in cross-sectional studies, particularly when symptoms of low or high intensity are being measured. Researchers should try to reach a consensus on what type of VAS to use if studies are to be compared.