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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.

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.

OBJECTIVESCharacterize the incidence, clinical and etiologic features and outcomes of advanced congestive heart failure.BACKGROUNDThis condition is frequent, severe and costly, yet no population-based epidemiological data are available that take into account modern advances in diagnosis and therapy.METHODSThe EPICAL (EPidémiologie de l’Insuffisance Cardiaque Avancée en Lorraine) study was based on a comprehensive registration of patients with ACHF (defined as hospital admission for presence of NYHA class III or IV symptoms, radiological and/or clinical signs of pulmonary congestion and/or signs of peripheral edema, left ventricular ejection fraction 60%) in patients aged 20–80 years during year 1994, in the community of the Lorraine region in France (n = 1,592,263). Average follow-up for readmission to hospital and mortality was 18 months (12–24 months).RESULTSFrom 2,576 registered patients, 499 were enrolled into the study among which, 358 were new presentations. This represents a crude incidence rate of 225 per million. 46.3% had a coronary heart disease. One-year mortality rate was 35.4% and the rate of mortality and/or readmission to hospital was 81%. Patients were admitted to hospital 2.05 times per year (64% of these for worsening heart failure), spending 27.6 days per year in hospital. Twenty received a heart transplant (4%). On discharge, 74.8% were using ACE inhibitors and 49.6% digitalis.CONCLUSIONSMortality and hospitalization rate of advanced CHF remain very high despite recent therapeutic progress. Major therapeutic and managed-care research is required.

Background Monitoring of EBV DNAemia after allogeneic hematopoietic stem cell transplantation (HSCT) is necessary, but not sufficient, to identify patients at risk of EBV-induced post-transplantation lymphoproliferative disorders (PTLD). Combining this with quantifying EBV-specific cellular immunity was shown to be helpful. In this study, we evaluated the value of IFNγ-Elispot assay in monitoring EBV DNAemia after HSCT. Methods EBV-DNA load in whole blood was monitored at least weekly using real-time PCR in 40 recipients of HSCT. Quantitative and qualitative T-cell recoveries, including EBV-specific T-cell quantification by Elispot assay, were studied 60, 100, 180 and 360 days after HSCT. Results Among the 35 evaluable patients, 14 (35%) presented EBV DNAemia, only 2/14 (14%) needing pre-emptive treatment with rituximab. The greatest risk factor for EBV DNAemia was the presence of anti-thymocyte globulin (ATG) (p = 0.005). EBV-specific cellular immune recovery was monitored by IFNγ-Elispot assay. Using multivariate analysis, four factors were found to significantly influence IFNγ-Elispot results at defined times post-HSCT: EBV DNAemia, young age, global T-cell recovery and severe acute GVHD. In those cases where EBV DNAemia occurred and cleared spontaneously, Elispot results gave more than 1000 spot-forming cells (SFC)/106 PBMC. Conclusion Elispot assay may be usefully combined with EBV-DNA load monitoring to determine when a patient should receive pre-emptive treatment, or when the clinician should avoid Rituximab use which severely immunocompromises patients.

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.

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.

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.

8001 Background: The MP-T combination has been shown to be the standard treatment in newly diagnosed MM patients (pts) aged 65 to 75 years (Facon et al; JCO 2006; 24, A1). However, no specific therapeutic recommendation exists for pts older than 75 years regarding the benefit of adding Thalidomide to MP. Methods: The IFM 01–01 trial was initiated in 04/2002. Patients > 75 years with untreated MM were randomized to receive MP (Melphalan 0.2mg/kg/d + Prednisone 2 mg/kg/d day1–4, 12 courses at 6-weeks intervals) + placebo (MP-placebo) vs MP + daily Thalidomide 100mg/d (MP-T). No anti-VTE prophylaxis was given. The primary end-point was overall survival (OS). Secondary end points were progression-free survival (PFS), response to treatment and toxicity. A first interim analysis was performed after the inclusion of 150 patients and a data safety monitoring board recommended a second analysis after the accrual of 200 patients. We here present the preliminary results of this analysis. Results: At the reference date of November 1, 2006, 232 pts were randomised. In all, 200 pts were analysed (100 per group), with 33.5% of pts >80 years (median age, 78.4 years). There were no differences between the 2 groups regarding baseline characteristics. Data were analysed on an intent-to-treat basis. After the completion of therapy the rates of partial response and very good partial response were 31% and 8% respectively with MP-placebo vs 61% and 22% respectively with MP-T. The median PFS time was 19 months (95%-CI 14.6–21.5) with MP-placebo vs 24.1 months (95%-CI 19.4–29.7) with MP-T (p=0.004 log-rank test). In the MP-T arm, 43/100 pts stopped treatment due to toxicity (10 due to neuropathy) versus 11/100 in the MP-placebo arm. Toxicity (Grade 2–4) included peripheral neuropathy (18%), somnolence (7%) and DVT (7%) with MP-T, vs 6%, 6% and 1% respectively, with MP-placebo. Final results including OS data will be presented at the meeting. Conclusion: MPT is an effective combination with acceptable toxicity in patients with MM = 75 years of age, with a significant improvement in PFS. No significant financial relationships to disclose.