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Background In critically ill patients, positive fluid balance is associated with excessive mortality. The POINCARE-2 trial aimed to assess the effectiveness of a fluid balance control strategy on mortality in critically ill patients. Methods POINCARE-2 was a stepped wedge cluster open-label randomized controlled trial. We recruited critically ill patients in twelve volunteering intensive care units from nine French hospitals. Eligible patients were ≥ 18 years old, under mechanical ventilation, admitted to one of the 12 recruiting units for > 48 and ≤ 72 h, and had an expected length of stay after inclusion > 24 h. Recruitment started on May 2016 and ended on May 2019. Of 10,272 patients screened, 1361 met the inclusion criteria and 1353 completed follow-up. The POINCARE-2 strategy consisted of a daily weight-driven restriction of fluid intake, diuretics administration, and ultrafiltration in case of renal replacement therapy between Day 2 and Day 14 after admission. The primary outcome was 60-day all-cause mortality. We considered intention-to-treat analyses in cluster-randomized analyses (CRA) and in randomized before-and-after analyses (RBAA). Results A total of 433 (643) patients in the strategy group and 472 (718) in the control group were included in the CRA (RBAA). In the CRA, mean (SD) age was 63.7 (14.1) versus 65.7 (14.3) years, and mean (SD) weight at admission was 78.5 (20.0) versus 79.4 (23.5) kg. A total of 129 (160) patients died in the strategy (control) group. Sixty-day mortality did not differ between groups [30.5%, 95% confidence interval (CI) 26.2–34.8 vs. 33.9%, 95% CI 29.6–38.2, p = 0.26]. Among safety outcomes, only hypernatremia was more frequent in the strategy group (5.3% vs. 2.3%, p = 0.01). The RBAA led to similar results. Conclusion The POINCARE-2 conservative strategy did not reduce mortality in critically ill patients. However, due to open-label and stepped wedge design, intention-to-treat analyses might not reflect actual exposure to this strategy, and further analyses might be required before completely discarding it. Trial registration POINCARE-2 trial was registered at ClinicalTrials.gov (NCT02765009). Registered 29 April 2016.

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.

Bone function requires a good repair system. The quantitative role of each healing component, mainly periosteum and bone marrow/endosteum and of their interactions is not clearly known. To evaluate more precisely the role of periosseous tissues in bone formation, we chose a bone lengthening model in rabbits. Nineteen purebred immature male New Zealand white rabbits were fitted with a femoral lateral external fixator and randomly assigned to 4 intervention groups: 1) Periosteum (PS) and bone marrow (BM) preservation; 2) PS preservation and BM destruction; 3) PS destruction and BM preservation; 4) PS and BM destruction. Animals were killed on day 30 and histology showed different bone regeneration modes. The most frequent ossification in the centre of the distraction gap was enchondral ossification. For bone formed between cortices only group 1 showed a difference (p=0.034). Density of the formed bone at the periosteal site showed a positive effect only with PS preservation, with an interaction of BM and PS. Density of group 4 was different from groups 1 (p=0.028), and 2 (p=0.001). No difference was present between groups at the endosteal sites. PS had a positive effect on the thickness of the formed bone at the periosteal site, with an interaction between PS and BM, but not at the endosteal site. A difference in thickness was noted between group 2 and 4 (p=0.018). Periosteum forms more bone and more likely to spread than bone marrow, but for restoration of the cortical wall, preservation of both shows optimal density results. Bone does not seem to form from surrounding tissues when both periosteum and bone marrow are destroyed.

Histological analysis of chondrogenic differentiation. Pellets slides were cut and stained with Alcian Blue and Red Kernechtrot (A–C) or Sirius Red (D–F) to determine proteoglycan and collagen synthesis, respectively. A semiquantitative study of the distribution of stained descriptors was processed using Image J (National Institutes of Health, Bethesda, MD, USA). A custom-written Image J program was used to measure the percentage area from the whole section of the pellet. A chromatic segmentation of each histological stain was performed using the hue, saturation, and brightness properties of the images with the «Color Thresholder ImageJ» function. (DOCX 2164 kb)

Histological analysis of chondrogenic differentiation. Pellets slides were cut and stained with Alcian Blue and Red Kernechtrot (A–C) or Sirius Red (D–F) to determine proteoglycan and collagen synthesis, respectively. A semiquantitative study of the distribution of stained descriptors was processed using Image J (National Institutes of Health, Bethesda, MD, USA). A custom-written Image J program was used to measure the percentage area from the whole section of the pellet. A chromatic segmentation of each histological stain was performed using the hue, saturation, and brightness properties of the images with the «Color Thresholder ImageJ» function. (DOCX 2164 kb)

Maternal factors. Table S2. Labor and delivery factors. Table S3 Newborn factors. Table S4. Impact of pre-thawing parameters on proliferation and chondrogenic differentiation. (DOCX 47 kb)

Maternal factors. Table S2. Labor and delivery factors. Table S3 Newborn factors. Table S4. Impact of pre-thawing parameters on proliferation and chondrogenic differentiation. (DOCX 47 kb)

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.

Background: No data on snoring prevalence obtained with a standard questionnaire exist for France. Major nose-throat abnormalities have been demonstrated in cases with obstructive sleep apnea; evidence of ‘minor’ abnormalities in community studies is scarce. Objectives: The fist objective of our study was to estimate the prevalence of habitual snoring in a sample of middle-aged active males in France. The second objective was to test the hypothesis that ‘minor’ nose-throat abnormalities could be associated with habitual snoring in a field survey. Methods: Three hundred thirty-four male employees of a local university volunteered for the study (93.6% of those contacted by mail); 300 returned a sleep questionnaire. The protocol also included anthropometry and a noninvasive nose-throat examination. Results: Complete data were obtained in 299 subjects aged 23–63 years. When ‘habitual snorers’ (= 32%) were compared with never-snorers, significant differences were found for all anthropometric variables, except height. In univariate analysis, habitual snoring was associated with a large number of variables, including a large soft palate, a large uvula, and altered nose patency. A logistic regression model retained 8 factors independently associated with snoring: age, neck circumference, tobacco consumption, breathing pauses during sleep, not feeling rested during the day, need for coffee to stay awake, blocked or running nose at night and a large soft palate. Conclusions: The prevalence of habitual snoring in this sample of middle-aged French males was 32%. We confirmed the significant association of habitual snoring with age, weight excess, and tobacco smoking, and identified two further factors: blocked nose at night and a large soft palate.

Sleep-disordered breathing (SDB) and lower socio-professional status have in common a series of risk factors for ill health such as sedentary lifestyle, weight excess, heavy alcohol and tobacco consumption. We hypothesised that SDB will be more prevalent in lower socio-professional groups. A total of 496 male middle aged subjects (23–66 years) were tested with a protocol including a self-completed structured sleep questionnaire (translation of the Madison sleep cohort study form), anthropometry (including neck, waist and hip girth) and a simple, non-invasive nose–throat examination by a specialist physician. The subjects were classified according to the 10 major groups of the ISCO-88 classification (International Labour Office). Our sampling base did not contain subjects in the major groups 1 (senior officials, legislators), 6 (fishery and agricultural workers), and zero (armed forces), thus these groups were not represented in the analysis. To improve the power of the statistical analysis, groups 3 and 4, 5 and 7, 8 and 9 were merged, the analysis thus including four categories. The differences in demographic data were negligible; as expected, smoking was more prevalent in low socio-occupational groups (difference non-significant). A history of chronic bronchitis was more frequent in low socio-occupational groups, while a low physical job labour was more frequent in higher occupational groups. We did not find any differences in the prevalence of sleep-related respiratory disturbances (snoring, sleep apnoeas). This first study of the possible association between socio-occupational factors and sleep disordered breathing was negative, but we believe further studies, on larger samples, with a more homogeneous distribution of social groups are warranted.

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.

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 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.

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.

2067 Background: Diffuse WHO grade II and III gliomas (DGII/IIIG) are rare tumors (incidence ≤ 2/105person-years). Specific epidemiological studies are very rare. The main objective of this work is to study the geographical distribution of all newly diagnosed and histologically confirmed DGII/IIIG in metropolitan France. Methods: The methodology is based on a multidisciplinary national network already established by the French Brain Tumor DataBase. Personal addresses at the moment of the surgical procedure for all DGII/IIIG cases were collected for the years 2006-2009. For each area, the incidence of DGII/IIIG was analyzed and standardized on age and sex distribution of the French population (pop). Results: The total number of patients with newly diagnosed and histologically confirmed DGII/IIIG was 4790 (1220, 1190, 1228, and 1152 for years 2006-2009). The Table shows the number of tumors by histology, sex and median age at diagnosis. The overall crude rate was 19.4/106. To enable international comparisons, standardized rates were calculated as follows: 19.8/106 (reference pop, Europe), 18.8/106 (reference pop, US 2000), and 16.0/106 (reference pop, world). The geographic distribution by regions in France showed significant differences. For example, the standardized rates (for 106person-years, 95% confidence intervals, reference pop: France) for Auvergne, Champagne-Ardenne, and Basse-Normandie, were 30.9 (26.4-35.5), 28.5 (24.0-33.0), and 13.9 (10.9-17.0), respectively. Conclusions: To our knowledge, this work is the first to study the geographical distribution of DGII/IIIG across one entire country, and it shows significant heterogeneity. These results will enable to look for different environmental and genetic factors in these different regions. [Table: see text]

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.