Impact of Smoking on Functional Prognosis after Ischemic Stroke according to Deprivation: A Prospective Cohort Study.

BACKGROUND: Smoking influence on poststroke prognosis remains controversial. These conflicting results could be due to some residual confounding factors not fully considered in previous studies, including social deprivation. This study aimed to assess the joint impact of deprivation and smoking on functional outcomes after ischemic stroke. METHODS: Between 2011 and 2014, 1,573 patients with a first-ever stroke were prospectively included in the French multicenter INDIA ("Inegalites sociales et pronostic des accidents vasculaires cerebraux à Dijon et Antilles-Guyane") cohort study. Patients with ischemic stroke and available data on smoking, deprivation, and outcome were considered for the analysis (n = 1,242). Deprivation was assessed using the EPICES "Evaluation de la Précarité et des Inégalites de santé dans les Centres d'Examen de Santé" score. Primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) score at 12 months. Association between smoking and moderate to severe disability (mRS score ≥3) was evaluated with logistic regression model. Interactions between smoking and deprivation were tested. RESULTS: Smokers (n = 189, 15.2%) were younger and more often deprived (EPICES score ≥30.17) than nonsmokers. A significant interaction was found between smoking status and deprivation on disability (p = 0.003). In nondeprived patients, the odds of moderate to severe disability at 12 months were twice as high in smokers as in nonsmokers (adjusted OR = 2.08, 95% CI: 1.04-4.18). This association was not observed in deprived patients (adjusted OR = 0.89, 95% CI: 0.49-1.61). CONCLUSION: The effect of smoking on functional prognosis after ischemic stroke varied according to deprivation status, with poorer outcomes observed in nondeprived patients.

Social deprivation and 1-year survival after stroke: a prospective cohort study.

BACKGROUND: Social deprivation may have a deleterious influence on post-stroke outcomes, but available data in the literature are mixed. AIM: The aim of this cohort study was to evaluate the impact of social deprivation on 1-year survival in patients with first-ever stroke. METHODS: Social deprivation was assessed at individual level with the EPICES score, a validated multidimensional questionnaire, in 1312 patients with ischemic stroke and 228 patients with spontaneous intracerebral hemorrhage, who were prospectively enrolled in six French study centers. Baseline characteristics including stroke severity and pre-stroke functional status were collected. Multivariable Cox models were generated to evaluate the associations between social deprivation and survival at 12 months in ischemic stroke and intracerebral hemorrhage separately. RESULTS: A total of 819 patients (53.2%) were socially deprived (EPICES score ≥ 30.17). In ischemic stroke, mortality at 12 months was higher in deprived than in non-deprived patients (16% vs. 11%, p = 0.006). In multivariable analyses, there was no association between deprivation and death occurring within the first 90 days following ischemic stroke (adjusted hazard ratio [aHR] 0.81, 95% CI 0.54-1.22, p = 0.32). In contrast, an excess in mortality was observed between 90 days and 12 months in deprived compared with non-deprived patients (aHR 1.97, 95% CI 1.14-3.42, p = 0.016). In patients with intracerebral hemorrhage, mortality at 12 months did not significantly differ according to deprivation status. CONCLUSIONS: Social deprivation was associated with delayed mortality in ischemic stroke patients only and, although the exact underlying mechanisms are still to be identified, our findings suggest that deprived patients in particular may benefit from an optimization of post-stroke care.

High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations.

AIMS: Mutations in PRKAG2, the gene encoding for the γ2 subunit of 5'-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations. METHODS AND RESULTS: A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recurrent p.Arg302Gln mutation, and the five others carried private mutations among which three had never been reported. In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%. The global survival at 60 years of age was 66%. Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant. Only one patient presented with significant skeletal muscle symptoms. No significant differences regarding the occurrence of VPE, ablation complications, or death incidence were observed between different mutations. CONCLUSION: This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications. Early recognition of this disease appears important to allow an appropriate management.

Responsiveness of the 36-item Short Form Health Survey and the Lupus Quality of Life questionnaire in SLE.

OBJECTIVES: This study aimed to estimate the responsiveness to change of a generic [the 36-item Short Form Health Survey (SF-36)] and a specific health-related quality of life questionnaire [the Lupus Quality if Life questionnaire (LupusQoL)] according to SLE patients' self-reported changes in health status. METHODS: In a cohort of 185 SLE patients, quality of life (QoL) was measured three times at 3 month intervals by the LupusQoL and SF-36 questionnaires. Anchors for responsiveness were defined by patients' global assessment of disease impact according to changes in a visual analogue scale (VAS), a 7-point Likert scale and a 0-3 scale of five patient-reported symptoms. Mean change and s.d. in worsening and improving patients according to anchors were estimated using mixed models for repeated measures. Standardized response means (SRMs) were calculated in each group. RESULTS: Patients [mean age 39.6 years (s.d. 10.5), mean Safety of Estrogen in Lupus Erythematosus National Assessment-SLEDAI score 2.6 (s.d. 3.5)] answered a total of 515 questionnaires. For the VAS and Likert global anchors, worsening patients showed a significant decrease in all LupusQoL domains except for burden to others, body image and fatigue and all SF-36 domains with low to moderate responsiveness. Improving patients had a significant increase in all LupusQoL domains except for intimate relationship and all SF-36 domains except for physical functioning and global health with low to moderate responsiveness. Regarding similar domains in the SF-36 and LupusQoL, SRMs were higher in LupusQoL domains in improving patients, while SF-36 domains had larger SRMs in worsening patients. CONCLUSION: Both the SF-36 and LupusQoL were responsive to changes in QoL in SLE patients over a 3 month interval. LupusQoL seems to be more appropriate to measure improvements in QoL.

Low preoperative cholesterol level is a risk factor of sepsis and poor clinical outcome in patients undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVES: Systemic inflammatory response syndrome and sepsis frequently occur after cardiac surgery with cardiopulmonary bypass. The aim of the present study was to investigate whether preoperative cholesterol levels can predict sepsis onset and postoperative complications in patients undergoing cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective observational study. SETTING: Surgical ICU of a French university hospital. PATIENTS: Two hundred and seventeen consecutive patients older than 18 years admitted for planned cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Measurements of plasma blood lipids and inflammation markers before anesthesia induction (baseline), at cardiopulmonary bypass start, at cardiopulmonary bypass end, and 3 and 24 hours after cardiac surgery. Outcomes were compared in systemic inflammatory response syndrome patients with sepsis (n = 15), systemic inflammatory response syndrome patients without sepsis (n = 95), and non-systemic inflammatory response syndrome patients (n = 107). MEASUREMENTS AND MAIN RESULTS: A gradual decrease in plasma cholesterol concentration occurred during surgery with cardiopulmonary bypass but was no longer present after correction for hemodilution. Corrected cholesterol levels were significantly lower at baseline in sepsis patients than in other subgroups, and it remained lower in the sepsis group during and after cardiopulmonary bypass. With regard to sepsis, the discriminatory power of baseline cholesterol was fairly good as indicated by receiver operating characteristic curve analysis (area under the curve, 0.78; 95% CI, 0.72-0.84). The frequency of sepsis progressively decreased with increasing baseline cholesterol level quintiles (18.6% and 0% in the bottom and top quintiles, respectively, p = 0.005). In multivariate analysis, baseline cholesterol levels and cardiopulmonary bypass duration were significant and independent determinants of the 3-hour postcardiopulmonary bypass increase in concentrations of procalcitonin and interleukin-8, but not of interleukin-6. CONCLUSIONS: Low cholesterol levels before elective cardiac surgery with cardiopulmonary bypass may be a simple biomarker for the early identification of patients with a high risk of sepsis.

A case-control study of pre-operative levels of serum neutrophil gelatinase-associated lipocalin and other potential inflammatory markers in colorectal cancer.

BACKGROUND: Chronic inflammation is a key feature of colorectal cancer (CRC), meaning that inflammatory biomarkers may be useful for its diagnosis. In particular, high neutrophil gelatinase-associated lipocalin (NGAL) expression has been reported in CRC. Thus, we investigated whether serum NGAL and NGAL/MMP-9 could be potential biomarkers for the early detection of CRC. Concurrently, we studied other inflammatory biomarkers such as soluble tumor necrosis factor receptor 1 and 2 (sTNFR-1, sTNFR-2), and C reactive protein (CRP). METHODS: The AGARIC multicenter case-control study was performed in eastern France and included patients admitted for elective surgery either for a priori non-metastatic incident CRC (n=224) or for benign causes (n=252). Pre-operative serum levels of NGAL, NGAL/MMP-9, sTNFR-1, sTNFR-2 and CRP were measured. RESULTS: Median values of serum NGAL, NGAL/MMP-9, sTNFR-1, sTNFR-2 and CRP were significantly higher in CRC patients than in controls. Receiver Operating Characteristic analysis provided relatively poor values of area under the curve, ranging from 0.65 to 0.58. Except for NGAL/MMP-9, all biological parameters were strongly correlated in CRC cases and, less strongly in controls. Multivariate odds ratio (OR) of CRC comparing the extreme tertiles of serum NGAL was 2.76 (95% confidence interval (CI): 1.59-4.78; p<0.001),. Lower but significant multivariate associations were observed for sTNFR-1, and sTNFR-2: OR=2.44 (95% CI : 1.34-4.45, p=0.015) and 1.93 (95% : CI 1.12-3.31), respectively. No independent association was found between case-control status and NGAL/MMP-9. Among CRC cases, maximal tumor size was an independent determinant of serum NGAL (p=0.028) but this association was reduced after adjustment for CRP (p=0.11). CONCLUSION: Despite a significant increase in serum NGAL and other inflammatory markers among CRC patients, our findings suggest that they may not be suitable biomarkers for the diagnosis and especially early detection of CRC.

Preoperative adipocytokines as a predictor of surgical infection after colorectal surgery: a prospective survey.

BACKGROUND: Infections are the leading cause of morbidity and mortality after colorectal surgery. Obesity is a well-known risk factor for wound infection, but it does not seem to increase the risk of other infectious complications. The aim of this study was to look for a relationship between the fatty tissue metabolism measured by adipocytokine levels and the risk of postoperative infection. PATIENTS AND METHODS: Preoperative plasma levels of eight adipocytokines, cholesterol, triglycerides, insulin and C-reactive protein (CRP) were measured in consecutive patients undergoing elective colorectal surgery between June 2008 and June 2011. Information about epidemiological and clinical characteristics was obtained for each patient. All infections in the 30 days following surgery were recorded. RESULTS: Among the 174 patients included, 49 (28 %) presented with a postoperative infection: 41 surgical site infections and 8 other infections. Preoperative leptin, insulin and CRP were significantly higher in patients with postoperative infection (p = 0.025, p = 0.020 and p = 0.044, respectively), but only leptin was predictive of infection in multivariate analysis (odds ratio (OR) = 1.89, 95 % confidence interval (CI) 1.18-3.03, p = 0.008). The predictive value of leptin was slightly lower for surgical site infection (OR = 1.65, 95 % CI 1.06-2.55, p = 0.025). Leptin levels were independent of the other adipocytokine levels but not of the body mass index. CONCLUSION: Although markers of inflammation and insulin resistance are also related to the onset of surgical infection, leptin correlates more closely with the risk of infection than does any other factor. However, its effect could be partially mediated by the body mass index.

CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.

BACKGROUND: The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma. METHODS: Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics. RESULTS: 97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation. CONCLUSIONS: Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD.

Long-term risk of colorectal cancer after adenoma removal: a population-based cohort study.

BACKGROUND: Previous studies examining the incidence of colorectal cancer after polypectomy have provided discordant findings. The aim of this study was to compare the risk of colorectal cancer after adenoma removal in routine clinical practice with the risk in the general population. DESIGN: Cohort study based on detailed data from a population-based registry that has collected all cases of both colorectal cancers and adenomas diagnosed in a clearly-defined population since 1976. SETTING: French administrative area of Côte-d'Or (Burgundy). METHODS: Residents of the area diagnosed for the first time with colorectal adenoma between 1990 and 1999 were included (n=5779). Initial and follow-up data until December 2003 were used to calculate the colorectal cancer standardised incidence ratio (SIR) and cumulative probabilities after adenoma removal. RESULTS: After a median follow-up of 7.7 years, 87 invasive colorectal cancers were diagnosed whereas 69 cases were expected. Compared with the general population, the overall SIR was 1.26 (95% CI 1.01 to 1.56). The risk of colorectal cancer depended on the characteristics of the initial adenoma (SIR 2.23 (95% CI 1.67 to 2.92) for advanced adenomas and 0.68 (95% CI 0.44 to 0.99) for non-advanced adenomas). In cases of advanced adenomas, the SIR was 1.10 (95% CI 0.62 to 1.82) in patients with colonoscopic follow-up and 4.26 (95% CI 2.89 to 6.04) in those without. The 10-year cumulative probabilities of colorectal cancer were, respectively, 2.05% (95% CI 1.14% to 3.64%) and 6.22% (95% CI 4.26% to 9.02%). CONCLUSIONS: In routine practice, the risk of colorectal cancer after adenoma removal remains high and depends both on initial adenoma features and on colonoscopy surveillance practices. Gastroenterologists should encourage patients to comply with long-term colonoscopic surveillance.

Prior transient ischemic attack and dementia after subsequent ischemic stroke.

Although functional recovery and survival after ischemic stroke seem to improve in patients with prior transient ischemic attack (TIA), little is known about the effect of prior TIA on poststroke cognition. To evaluate the impact of prior TIA on dementia, 1697 nonaphasic patients who survived the first month after their first-ever ischemic stroke were identified from the population-based registry of Dijon, France, from 1985 to 2007 and divided into 3 groups according to the time interval between prior TIA and stroke (<4 wk, ≥4 wk, no TIA). Outcome was dementia diagnosed by neurologists using Diagnostic and Statistical Manual of mental disorders-III or IV criteria over the first month after stroke. Multivariate analyses were performed using logistic regression models. The prevalence of dementia after stroke was 20.6% [95% confidence interval (CI), 18.5-22.7], 26.8% (95% CI, 13.3-40.4), and 33.1% (95% CI, 27.3-38.9) among patients without TIA, with a prestroke TIA≥4 weeks, and with a prestroke TIA<4 weeks, respectively. Patients with prestroke TIA<4 weeks (adjusted odds ratio: 1.83; 95% CI, 1.32-2.52; P=0.0003) had a higher risk of dementia than those without TIA.

Impact of emergency medical helicopter transport directly to a university hospital trauma center on mortality of severe blunt trauma patients until discharge.

INTRODUCTION: The benefits of transporting severely injured patients by helicopter remain controversial. This study aimed to analyze the impact on mortality of helicopter compared to ground transport directly from the scene to a University hospital trauma center. METHODS: The French Intensive Care Research for Severe Trauma cohort study enrolled 2,703 patients with severe blunt trauma requiring admission to University hospital intensive care units within 72 hours. Pre-hospital and hospital clinical data, including the mode of transport, (helicopter (HMICU) versus ground (GMICU), both with medical teams), were recorded. The analysis was restricted to patients admitted directly from the scene to a University hospital trauma center. The main endpoint was mortality until ICU discharge. RESULTS: Of the 1,958 patients analyzed, 74% were transported by GMICU, 26% by HMICU. Median injury severity score (ISS) was 26 (interquartile range (IQR) 19 to 34) for HMICU patients and 25 (IQR 18 to 34) for GMICU patients. Compared to GMICU, HMICU patients had a higher median time frame before hospital admission and were more intensively treated in the pre-hospital phase. Crude mortality until hospital discharge was the same regardless of pre-hospital mode of transport. After adjustment for initial status, the risk of death was significantly lower (odds ratio (OR): 0.68, 95% confidence interval (CI) 0.47 to 0.98, P = 0.035) for HMICU compared with GMICU. This result did not change after further adjustment for ISS and overall surgical procedures. CONCLUSIONS: This study suggests a beneficial impact of helicopter transport on mortality in severe blunt trauma. Whether this association could be due to better management in the pre-hospital phase needs to be more thoroughly assessed.

Impact of whole-body computed tomography on mortality and surgical management of severe blunt trauma.

INTRODUCTION: The mortality benefit of whole-body computed tomography (CT) in early trauma management remains controversial and poorly understood. The objective of this study was to assess the impact of whole-body CT compared with selective CT on mortality and management of patients with severe blunt trauma. METHODS: The FIRST (French Intensive care Recorded in Severe Trauma) study is a multicenter cohort study on consecutive patients with severe blunt trauma requiring admission to intensive care units from university hospital trauma centers within the first 72 hours. Initial data were combined to construct a propensity score to receive whole-body CT and selective CT used in multivariable logistic regression models, and to calculate the probability of survival according to the Trauma and Injury Severity Score (TRISS) for 1,950 patients. The main endpoint was 30-day mortality. RESULTS: In total, 1,696 patients out of 1,950 (87%) were given whole-body CT. The crude 30-day mortality rates were 16% among whole-body CT patients and 22% among selective CT patients (p = 0.02). A significant reduction in the mortality risk was observed among whole-body CT patients whatever the adjustment method (OR = 0.58, 95% CI: 0.34-0.99 after adjustment for baseline characteristics and post-CT treatment). Compared to the TRISS predicted survival, survival significantly improved for whole-body CT patients but not for selective CT patients. The pattern of early surgical and medical procedures significantly differed between the two groups. CONCLUSIONS: Diagnostic whole-body CT was associated with a significant reduction in 30-day mortality among patients with severe blunt trauma. Its use may be a global indicator of better management.

The motor component does not convey all the mortality prediction capacity of the Glasgow Coma Scale in trauma patients.

PURPOSE: We tested the hypothesis that the motor component of the Glasgow Coma Scale (GCS) conveys most of the predictive information of triage scores (Triage Revised Trauma Score [T-RTS] and the Mechanism, GCS, Age, arterial Pressure score [MGAP]) in trauma patients. METHOD: We conducted a multicenter prospective observational study and evaluated 1690 trauma patients in 14 centers. We compared the GCS, T-RTS, MGAP, and Trauma Related Injury Severity Score (reference standard) using the full GCS or its motor component only using logistic regression model, area under the receiver operating characteristic curve, and reclassification technique. RESULTS: Although some changes were noted for the GCS itself and the Trauma Related Injury Severity Score, no significant change was observed using the motor component only for T-RTS and MGAP when considering (1) the odds ratio of variables included in the logistic model as well as their discrimination and calibration characteristics, (2) the area under the receiver operating characteristic curve (0.827 ± 0.014 vs 0.831 ± 0.014, P = .31 and 0.863 ± 0.011 vs 0.859 ± 0.012, P = .23, respectively), and (3) the reclassification technique. Although the mortality rate remained less than the predetermined threshold of 5% in the low-risk stratum, it slightly increased for MGAP (from 1.9% to 3.9%, P = .048). CONCLUSION: The use of the motor component only of the GCS did not change the global performance of triage scores in trauma patients. However, because a subtle increase in mortality rate was observed in the low-risk stratum for MGAP, replacing the GCS by its motor component may not be recommended in every situation.

Influence of prior transient ischaemic attack on stroke prognosis.

BACKGROUND: To evaluate potential neuroprotection afforded by prior transient ischaemic attack (TIA) on functional and survival outcomes after ischaemic stroke. METHODS: All cases of first-ever ischaemic strokes, diagnosed between 1985 and 2008, were identified from the Dijon Stroke Registry. Patients were analysed in three groups according to the time interval between prior TIA and stroke (<4 weeks, ≥ 4 weeks, no TIA) or the duration of TIA (≤ 30 min, >30 min, no TIA). Outcomes were severe functional handicap (unable to walk, bedridden or death) at hospital discharge or at outpatient consultation, and 1-month and 1-year any-cause mortality. Stratified analyses were performed by stroke subtypes (non-lacunar, lacunar). Generalised linear mixed models and Cox proportional hazard models with a sandwich covariance matrix accounting for the treatment centre as a random effect were used for multivariate analyses. RESULTS: Among the 3015 patients with first-ever ischaemic stroke, 389 had had a prestroke TIA <4 weeks and 97 a prestroke TIA ≥ 4 weeks. Patients with TIAs had better ambulatory status (adjusted OR 0.61, 95% CI 0.45 to 0.81; p = 0.008) and better survival at 1 month (adjusted HR 0.76, 95% CI 0.65 to 0.89; p = 0.0006) and at 1 year (adjusted HR 0.72, 95% CI 0.67 to 0.76; p<0.0001) than those with no TIAs. Prestroke TIA <4 weeks and TIA duration ≤ 30 min also significantly improved the outcomes in overall, non-lacunar and lacunar strokes. CONCLUSIONS: Recent prestroke TIA was associated with better functional outcome and lower 1-month and 1-year mortality after stroke, suggesting a neuroprotective effect.

Prognosis factors in probands with an FBN1 mutation diagnosed before the age of 1 year.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder. Diagnostic criteria of neonatal MFS (nMFS), the most severe form, are still debated. The aim of our study was to search for clinical and molecular prognostic factors that could be associated with length of survival. Probands ascertained via the framework of the Universal Marfan database-FBN1, diagnosed before the age of 1 y and presenting with cardiovascular features (aortic root dilatation or valvular insufficiency) were included in this study. Clinical and molecular data were correlated to survival. Among the 60 individuals, 38 had died, 82% died before the age of 1 y, mostly because of congestive heart failure. Three probands reached adulthood. Valvular insufficiencies and diaphragmatic hernia were predictive of shorter life expectancy. Two FBN1 mutations were found outside of the exon 24-32 region (in exons 4 and 21). Mutations in exons 25-26 were overrepresented and were associated with shorter survival (p = 0.03). We report the largest genotyped series of probands with MFS diagnosed before 1 y of life. In this population, factors significantly associated with shorter survival are presence of valvular insufficiencies or diaphragmatic hernia in addition to a mutation in exons 25 or 26.

Flexible modeling of the effects of continuous prognostic factors in relative survival.

Relative survival methods permit separating the effects of prognostic factors on disease-related 'excess mortality' from their effects on other-causes 'natural mortality', even when individual causes of death are unknown. As in conventional 'crude' survival, accurate assessment of prognostic factors requires testing and possibly modeling of non-proportional effects and, for continuous covariates, of non-linear relationships with the hazard. We propose a flexible extension of the additive-hazards relative survival model, in which the observed all-causes mortality hazard is represented by a sum of disease-related 'excess' and natural mortality hazards. In our flexible model, the three functions representing (i) the baseline hazard for 'excess' mortality, (ii) the time-dependent effects, and (iii) for continuous covariates, non-linear effects, on the logarithm of this hazard, are all modeled by low-dimension cubic regression splines. Non-parametric likelihood ratio tests are proposed to test the time-dependent and non-linear effects. The accuracy of the estimated functions is evaluated in multivariable simulations. To illustrate the new insights offered by the proposed model, we apply it to re-assess the effects of patient age and of secular trends on disease-related mortality in colon cancer.

Geographic variations of multiple sclerosis in France.

France is located in an area with a medium to high prevalence of multiple sclerosis, where its epidemiology is not well known. We estimated the national and regional prevalence of multiple sclerosis in France on 31 October 2004 and the incidence between 31 October 2003 and 31 October 2004 based on data from the main French health insurance system: the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés. The Caisse Nationale d'Assurance Maladie des Travailleurs Salariés insures 87% of the French population. We analysed geographic variations in the prevalence and incidence of multiple sclerosis in France using the Bayesian approach. On the 31 October 2004, 49 417 people were registered with multiple sclerosis out of the 52 359 912 insured with the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés. Among these, 4497 were new multiple sclerosis cases declared between 31 October 2003 and 31 October 2004. After standardization for age, total multiple sclerosis prevalence in France was 94.7 per 100,000 (94.3-95.1); 130.5 (129.8-131.2) in females and 54.8 (54.4-55.3) in males. The national incidence of multiple sclerosis between 31 October 2003 and 31 October 2004 was 7.5 per 100,000 (7.3-7.6); 10.4 (10.2-10.6) in females and 4.2 (4.0-4.3) in males. The prevalence and incidence of multiple sclerosis were higher in North-Eastern France, but there was no obvious North-South gradient. This study is the first performed among a representative population of France (87%) using the same method throughout. The Bayesian approach, which takes into account spatial heterogeneity among geographical units and spatial autocorrelation, did not confirm the existence of a prevalence gradient but only a higher prevalence of multiple sclerosis in North-Eastern France and a lower prevalence of multiple sclerosis in the Paris area and on the Mediterranean coast.

Medical pre-hospital management reduces mortality in severe blunt trauma: a prospective epidemiological study.

INTRODUCTION: Severe blunt trauma is a leading cause of premature death and handicap. However, the benefit for the patient of pre-hospital management by emergency physicians remains controversial because it may delay admission to hospital. This study aimed to compare the impact of medical pre-hospital management performed by SMUR (Service Mobile d'Urgences et de Réanimation) with non-medical pre-hospital management provided by fire brigades (non-SMUR) on 30-day mortality. METHODS: The FIRST (French Intensive care Recorded in Severe Trauma) study is a multicenter cohort study on consecutive patients with severe blunt trauma requiring admission to university hospital intensive care units within the first 72 hours. Initial clinical status, pre-hospital life-sustaining treatments and Injury Severity Scores (ISS) were recorded. The main endpoint was 30-day mortality. RESULTS: Among 2,703 patients, 2,513 received medical pre-hospital management from SMUR, and 190 received basic pre-hospital management provided by fire brigades. SMUR patients presented a poorer initial clinical status and higher ISS and were admitted to hospital after a longer delay than non-SMUR patients. The crude 30-day mortality rate was comparable for SMUR and non-SMUR patients (17% and 15% respectively; P = 0.61). After adjustment for initial clinical status and ISS, SMUR care significantly reduced the risk of 30-day mortality (odds ratio (OR): 0.55, 95% CI: 0.32 to 0.94, P = 0.03). Further adjustments for the delay to hospital admission only marginally affected these results. CONCLUSIONS: This study suggests that SMUR management is associated with a significant reduction in 30-day mortality. The role of careful medical assessment and intensive pre-hospital life-sustaining treatments needs to be assessed in further studies.

Cardiovascular manifestations in men and women carrying a FBN1 mutation.

AIMS: In patients with Marfan syndrome and other type-1 fibrillinopathies, genetic testing is becoming more easily available, leading to the identification of mutations early in the course of the disease. This study evaluates the cardiovascular (CV) risk associated with the discovery of a fibrillin-1 (FBN1) mutation. METHODS AND RESULTS: A total of 1,013 probands with pathogenic FBN1 mutations were included, among whom 965 patients [median age: 22 years (11-34), male gender 53%] had data suitable for analysis. The percentage of patients with an ascending aortic (AA) dilatation increased steadily with increasing age and reached 96% (95% CI: 94-97%) by 60 years. The presence of aortic events (dissection or prophylactic surgery) was rare before 20 years and then increased progressively, reaching 74% (95% CI: 67-81%) by 60 years. Compared with women, men were at higher risk for AA dilatation [≤ 30 years: 57% (95% CI: 52-63) vs. 50% (95% CI: 45-55), P = 0.0076] and aortic events [≤ 30 years: 21% (95% CI: 17-26) vs. 11% (95% CI: 8-16), P < 0.0001; adjusted HR: 1.4 (1.1-1.8), P = 0.005]. The prevalence of mitral valve (MV) prolapse [≤ 60 years: 77% (95% CI: 72-82)] and MV regurgitation [≤ 60 years: 61% (95% CI: 53-69)] also increased steadily with age, but surgery limited to the MV remained rare [≤ 60 years: 13% (95% CI: 8-21)]. No difference between genders was observed (for all P> 0.20). From 1985 to 2005 the prevalence of AA dilatation remained stable (P for trend = 0.88), whereas the percentage of patients with AA dissection significantly decreased (P for trend = 0.01). CONCLUSION: The CV risk remains important in patients with an FBN1 gene mutation and is present throughout life, justifying regular aortic monitoring. Aortic dilatation or dissection should always trigger suspicion of a genetic background leading to thorough examination for extra-aortic features and comprehensive pedigree investigation.

[Congenital toxoplasmosis: randomised comparison of strategies for retinochoroiditis prevention]. / Toxoplasmose congénitale : comparaison randomisée de stratégies de prévention des rétinochoroïdites.

In France, children with confirmed congenital toxoplasmosis receive a treatment for a period of 12 to 24 months. Such prolonged treatment may generate potentially severe risks, in particular hematologic and cutaneous. Our objective is to compare the effectiveness of two therapeutic strategies on the prevention of retinochoroiditis by a randomized, non-inferiority, open-label, parallel study including 486 children, 3 to 6 months of age with a non-severe form of congenital toxoplasmosis. Following randomization, pyrimethamine-sulphonamide treatment is initiated for a period of three months, followed by a treatment with Fansidar(®) for 9 months, or therapeutic abstention. Follow-up visits during a two-year period will include an examination of the eye, a blood test, and questionnaires to evaluate the children's quality of life and their parents' anxiety. Confirming the non-inferiority of the effectiveness of a short-term treatment will improve the quality of life of parents and children.