Social deprivation and stroke severity on admission: a French cohort study in Burgundy and the West Indies - Guyana region.

BACKGROUND AND PURPOSE: Although there is growing and convincing evidence that socially deprived patients are at higher risk of stroke and worse outcomes, it remains controversial whether or not they suffer more severe stroke. This study aimed to evaluate the influence of social deprivation on initial clinical severity in patients with stroke. METHODS: A total of 1536 consecutive patients with an acute first-ever stroke (both ischaemic stroke and intracerebral hemorrhage) were prospectively enrolled from six French study centers. Stroke severity on admission was measured by the National Institutes of Health Stroke Scale score. Social deprivation was assessed at the individual level by the Evaluation de la Précarité et des Inégalités de santé dans les Centres d'Examen de Santé (EPICES) score, a validated multidimensional questionnaire, and several additional single socioeconomic indicators. Polytomous logistic regression analyses were performed to evaluate the association between social deprivation and stroke severity. RESULTS: In univariate analysis, the EPICES score (P = 0.039) and level of education (P = 0.018) were the only two socioeconomic variables associated with stroke severity. Multivariate analysis of the association between EPICES and National Institutes of Health Stroke Scale scores showed that more deprived patients presented a significantly higher risk of both mild and moderate/severe stroke (odds ratio for mild versus minor stroke, 1.39; 95% confidence interval, 1.06-1.84; odds ratio for moderate/severe versus minor stroke, 1.44; 95% confidence interval, 1.09-1.92). A non-significant trend towards a higher risk of both mild and moderate/severe stroke in less educated patients was observed. CONCLUSIONS: Social deprivation was associated with a more severe clinical presentation in patients with stroke. These findings may contribute to the worse outcome after stroke in deprived patients, and underline the need for strategies to reduce social inequalities for stroke.

The lupus impact tracker is responsive to changes in clinical activity measured by the systemic lupus erythematosus responder index.

Objective The lupus impact tracker (LIT) is a 10-item patient reported outcome tool to measure the impact of systemic lupus erythematosus or its treatment on patients' daily lives. Herein, we describe the responsiveness of the LIT and LupusQoL to changes in disease activity, using the systemic lupus erythematosus responder index (SRI). Methods A total of 325 adult systemic lupus erythematosus patients were enrolled in an observational, longitudinal, multicentre study, conducted across the USA and Canada. Data (demographics, LIT, LupusQoL, BILAG, SELENA-SLEDAI) were obtained three months apart. Modified SRI was defined as: a decrease in SELENA-SLEDAI (4 points); no new BILAG A, and no greater than one new BILAG B; and no increase in the physician global assessment. Standardised response mean and effect size for LIT and LupusQoL domains were calculated among SRI responders and non-responders. Wilcoxon's test was used to compare the LIT and LupusQoL variation by SRI responder status. Results Of the participants 90% were women, 53% were white, 33% were of African descendant and 17% were Hispanic. Mean (SD) age and SELENA-SLEDAI at baseline were 42.3 (16.2) years and 4.3 (3.8), respectively. Mean (SD) LIT score at baseline was 39.4 (22.9). LIT standardised response mean (effect size) among SRI responders and non-responders were -0.69 (-0.36) and -0.20 (-0.12), respectively ( P = 0.02). For LupusQoL, two domains were responsive to SRI: standardised response mean (effect size) for physical health and pain domains were 0.42 (0.23) and 0.65 (0.44), respectively. Conclusions LIT is moderately responsive to SRI in patients with systemic lupus erythematosus. Inclusion of this tool in clinical care and clinical trials may provide further insights into its responsiveness. This is the first systemic lupus erythematosus patient reported outcome tool to be evaluated against composite responder index (SRI) used in clinical trials.

[Cost of multiple sclerosis in France]. / Coûts de la sclérose en plaques en France.

Multiple sclerosis (MS) is one of the 30 chronic conditions specifically listed by the French healthcare system as a long-term disease (affections de longue durée [ALD]) for which the main health insurance fund (Caisse nationale d'assurance maladie des travailleurs salariés [CNAMTS]) provides full (100%) coverage of healthcare costs. The CNAMTS insures 87% of the French population (52,359,912 of the 60,028,292 inhabitants). The objectives of this study were to evaluate the direct and indirect medical costs of MS among the entire population insured by the CNAMTS in France in 2004. The CNAMTS provided us with access to the ALD database of patients with MS that contains different MS-related expenditures made in 2004. We calculated the overall direct and indirect cost of MS and the cost per patient and per item of expenditure. In 2004, 49,413 patients were registered on the ALD list for MS. Direct cost for MS patients was 469,719,967 €. The direct cost per patient and per year was 9,506 € with variations between regions (French administrative divisions) ranging from 10,800 € in northeastern France (Champagne-Ardenne) to 8,217 € in western France (Pays de la Loire). The different items of expenditure were treatments (44.5%), hospitalization (27.9%), nursing care (5.8%), physiotherapy (5.7%), transport (4%), biology (1.1%), and other (1.5%). During the course of the disease, the overall cost of MS increased slowly during the first 15 years (from 8,000 to 11,000 €), but dramatically the last year of life (23,410 €). The costs of immunomodulator treatments were higher during the first six years after registration on the ALD list. Conversely, physiotherapy costs increased linearly with time during the course of MS. Indirect costs were an estimated 116 million euros in 2004. A disability pension (8,918 € per patient) was perceived by 9,430 patients (19.1%) and a daily allowance (3,317 € per patient) by 9,894 patients (20%). In France, MS has an important economic impact, comparable to human immunodeficiency virus infection.

Annual diagnosis rate of superficial vein thrombosis of the lower limbs: the STEPH community-based study.

BACKGROUND: The incidence of superficial vein thrombosis (SVT) in the general adult population remains unknown. OBJECTIVES: To assess the annual diagnosis rate of symptomatic, objectively confirmed lower limb SVT, associated or not with concomitant deep vein thrombosis and/or symptomatic pulmonary embolism. METHODS/PATIENTS: We conducted, from November 14, 2011, to November 13, 2012, a multicenter, community-based study in the Saint-Etienne urban area, France, representing a population of 265 687 adult residents (according to the 2009 census). All 248 general practitioners located within the area were asked to refer any patient with clinically suspected lower limb acute SVT to a vascular physician for systematic compression ultrasonography. All 28 vascular physicians located within the area participated in the study. The annual diagnosis rate, with the corresponding 95% confidence interval (CI), was calculated as the number of patients with symptomatic, objectively confirmed SVT divided by the number of person-years at risk defined by population data of the area. All venous thromboembolic events were validated by an independent central adjudication committee. RESULTS: Overall, 171 patients with symptomatic, confirmed SVT were reported. The annual diagnosis rate was 0.64& (95% CI, 0.55%-0.74&), was higher in women, and increased with advancing age regardless of gender [corrected]. Concomitant deep vein thrombosis (20 proximal) was observed in 42 patients (24.6% [95% CI, 18.3%-31.7%]), and concomitant symptomatic pulmonary embolism was observed in eight patients (4.7% [95% CI, 2.0%-9.0%]). CONCLUSIONS: This first community-based study showed that symptomatic SVT with confirmed diagnosis is a relatively common disease frequently associated with thromboembolic events in the deep venous system.

Statement of severe trauma management in France; teachings of the FIRST study.

INTRODUCTION: The blunt trauma victim management is still a matter of debate and comparing studies involving different emergency medical services and health care organization remains fictitious. Hence, the French Intensive care Recorded in Severe Trauma (FIRST) was conducted in order to describe the severe blunt trauma management in France. The present paper aimed at recalling the main results of FIRST study. METHODS: The FIRST study was based on a multicenter prospective cohort of patients aged 18 or over with severe exclusive blunt trauma requiring admission to university hospital care unit within the first 72h and/or managed by medical-Staffed Emergency Mobile Unit (SMUR). Multiple data were collected about patient characteristics, clinical initial status, typology of trauma and the main endpoints were 30-day mortality. RESULTS: Sixty-one percent of trauma patients were road traffic victims and 30% were domestic, sport or leisure trauma. Patients who benefited from medical pre-hospital management were globally more severely injured than those who received basic life support care by fire brigades. Therefore, they were delivered more aggressive treatment in the pre-hospital setting and the median time for their hospital admission was lengthened. However, their 30-day mortality was significantly reduced. The probability of death was also decreased when casualties were transported by SMUR helicopter directly to the university hospital. In the in-hospital setting, the performance of a whole-body computed tomography (CT) was associated with a significant reduction in the mortality risk compared with a selective CT. CONCLUSION: The FIRST study suggests the benefit of a medical management in the pre-hospital setting on the survival of trauma patients. The emergency physician (EP) expertise in the pre-hospital and initial hospital phases would lead to the concept of the appropriate care for the appropriate trauma patient. It also highlights the necessity to set up organized regional sectors of care and registries.

National estimate of multiple sclerosis incidence in France (2001-2007).

BACKGROUND: In France, the incidence of multiple sclerosis (MS) is not well known, and MS is one of the 30 long-term illnesses for which patients are covered for 100% of their health care costs. OBJECTIVE: To estimate the incidence of MS in France and its geographic variations. METHODS: We estimated the national rate for notification of MS to the main French health insurance system, and its confidence interval (CI), between November 2000 and October 2007, which covers 87% of the population. We analysed geographic variations using a Bayesian approach. RESULTS: Between November 2000 and October 2007, among a covered population of 52,449,871, some 28,682 individuals were registered as having MS. After age standardization according to the European population, the notification rate for MS was 6.8 per 100,000 (6.7-6.9), 9.8 (9.7-10.0) in women and 3.7 (3.6-3.8) in men. When the under-notification rate (11.5% and 29%) was taken into account, the notification rate per 100,000 inhabitants was estimated between 7.6 and 8.8. The notification rate was higher in north-eastern France, and lower on the Atlantic coast and in the Alps as well as on both sides of the Rhône River. CONCLUSIONS: This study, conducted on a representative French population, provides for the first time national estimates of MS incidence between November 2000 and October 2007.

The new Ghent criteria for Marfan syndrome: what do they change?

The diagnosis of Marfan syndrome (MFS) is challenging and international criteria have been proposed. The 1996 Ghent criteria were adopted worldwide, but new diagnostic criteria for MFS were released in 2010, giving more weight to aortic root aneurysm and ectopia lentis. We aimed to compare the diagnosis reached by applying this new nosology vs the Ghent nosology in a well-known series of 1009 probands defined by the presence of an FBN1 mutation. A total of 842 patients could be classified as MFS according to the new nosology (83%) as compared to 894 (89%) according to the 1996 Ghent criteria. The remaining 17% would be classified as ectopia lentis syndrome (ELS), mitral valve prolapse syndrome or mitral valve, aorta, skeleton and skin (MASS) syndrome, or potential MFS in patients aged less than 20 years. Taking into account the median age at last follow-up (29 years), the possibility has to be considered that these patients would go on to develop classic MFS with time. Although the number of patients for a given diagnosis differed only slightly, the new nosology led to a different diagnosis in 15% of cases. Indeed, 10% of MFS patients were reclassified as ELS or MASS in the absence of aortic dilatation; conversely, 5% were reclassified as MFS in the presence of aortic dilatation. The nosology is easier to apply because the systemic score is helpful to reach the diagnosis of MFS only in a minority of patients. Diagnostic criteria should be a flexible and dynamic tool so that reclassification of patients with alternative diagnosis is possible, requiring regular clinical and aortic follow-up.

Heparin-associated thrombocytopenia in 24,401 patients with venous thromboembolism: findings from the RIETE Registry.

BACKGROUND: Whether the treatment of venous thromboembolism (VTE) with unfractionated heparin (UFH) confers a higher risk of thrombocytopenia than does treatment with low molecular weight heparin (LMWH) remains controversial, and very few data are available from routine clinical practice. OBJECTIVES: We assessed the incidence, risk factors and prognosis of heparin-associated thrombocytopenia (HAT) according to the type of heparin therapy, UFH or LMWH. PATIENTS/METHODS: Data were obtained from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE), which included 25,369 patients with confirmed VTE until February 2009. Among them, 24,401 patients were treated either with UFH or with LMWH, and had available information about the 6-month occurrence of confirmed thrombocytopenia, defined as a platelet count ≤ 150,000 mm(-3) . RESULTS: One hundred and forty-one patients receiving UFH and/or LMWH developed thrombocytopenia within a 6-month period. The incidence of HAT was significantly higher in the UFH group (1.36%, 95% confidence interval [CI] 0.79-2.17) than in the LMWH group (0.54%, 95% CI 0.44-0.64). As compared with LMWH, UFH significantly increased the risk of HAT in female patients (adjusted hazard ratio [HR] 4.90%, 95% CI 2.58-9.31, P = 0.001) but not in male patients (adjusted HR 1.60%, 95% CI 0.64-3.97, P = 0.31); P = 0.027 for comparison. In each gender, the UFH-associated excess risk was confined to patients with VTE unrelated to cancer. The poor prognosis of patients with thrombocytopenia was not influenced by the type of heparin therapy. CONCLUSIONS: In routine clinical practice, treatment of VTE with UFH seems to confer a higher risk of thrombocytopenia than does treatment with LMWH, especially in women and non-cancerous patients.

Abdominal and pelvic injuries caused by road traffic accidents: characteristics and outcomes in a French cohort of 2,009 casualties.

BACKGROUND: The frequency, characteristics, and effect on outcome of abdominal and pelvic injuries (API) caused by road traffic accidents are not well known. We studied them in a well-defined geographical area in France. METHODS: The medical data of all hospitalized victims of road traffic accidents that occurred over a 3-year period were recorded. Injuries were coded according to the Abbreviated Injury Scale (AIS). The Injury Severity Score (ISS) was calculated. Continuous and qualitative variables were described by means and standard deviations or medians and percentages, respectively. Proportions and means were compared using the χ2 and Student tests, respectively. RESULTS: Of 6,977 victims of road traffic accidents, 2,009 were hospitalized (mean ISS=7.9). API were present in 9.3% (n=186) of all hospitalized victims and in 32.2% (n=82) of the most severely injured (ISS≥16, n=255) hospitalized victims. The most frequently seriously injured abdominopelvic organs (AIS≥3) were the spleen, the retroperitoneal organs, and the liver. The mean ISS and the mortality rate were significantly higher for victims with API than those without API (17.5 vs. 6.9, P<0.001; 9.7% vs. 1.9%, P<0.001). In multivariate analysis, the presence of severe API increased the mortality rate by a factor of 2.5. CONCLUSIONS: In this study, API were present in one third of the most severely injured victims of road traffic accidents and were a significant factor of gravity and mortality. This study, conducted in France where there is no National Trauma Registry, underlined the need for establishing such registry.

Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'etude des Tumeurs Endocrines.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) disease is an autosomal dominant syndrome that is believed to equally affect men and women. This assumption has never been confirmed. OBJECTIVE: The aims of this study were to evaluate the impact of gender on the prevalence of MEN1 lesions, on their lifetime probability of occurrence, and on the diagnosis of MEN1. DESIGN: Data regarding a study of 734 cases of MEN1 from the multicenter 'Groupe d'étude des Tumeurs Endocrines' were analyzed. RESULTS: There were 57.8% females. The prevalence and probability of pancreatic tumors were higher in males than in females (P=0.06, P=0.0004). This difference was due to gastrinomas. The prevalence and probability of developing pituitary tumors were significantly greater in females (P<0.001, P<0.0001). Thymic tumors were exclusively found in men. There were no significant gender differences in the prevalence and the probability of developing hyperparathyroidism, or adrenal and bronchial tumors, or in the proportion of positive genetic tests. A family history of MEN1 was more frequently found in men than in women at the time of diagnosis (P=0.02). In the case of pituitary tumor, the proportion of patients diagnosed with MEN1 at the time of the first lesion was lower in women (44.2%) than in men (67.3%). CONCLUSION: The phenotype expression of the MEN1 disease gene was different in males and females. In female patients, the possibility of MEN1 is not sufficiently taken into account. Any patient presenting a lesion that belongs to the MEN1 spectrum, such as a pituitary tumor, should be closely questioned about their family history and should be tested for hypercalcemia.

Written information to patients in clinical genetics: what's the impact?

In all countries of the European Union, oral information must be given to the patient. Written information is generally optional, but physicians are tending more and more to send a copy of the clinical report to the patient. In this study, we aimed to evaluate the impact on patients of sending them written information after a clinical consultation in a French genetics department. During a period of three months, two geneticists and one genetic counselor offered to send each patient a copy of the letter sent to their general practitioners. A questionnaire was sent with this copy. Three hundred and seventy-five patients were seen and 64% of the questionnaires were sent back. Of these, 99% showed that this practice was considered a good idea, and 80% reported that the letter reflected the clinical aspects well. Seventy-two percent thought that receiving this letter improved their understanding of the clinical situation. In general, patients found the words understandable (83%), too medical (20%) or even shocking (3%). Sixty-three percent said that they would have asked their general practitioner to give them the letter. Their main motivation for wanting a copy of this letter was to remember the information in the future, to have the information to pass on to other physicians involved in their health in the future, or to have information concerning the family. Finally, 58% would have preferred a letter sent specifically to them rather than a copy, and suggestions for the contents of such a letter should be further studied.

The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.

BACKGROUND: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. METHODS: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p(R117H)), on either intron 8 T5 or T7 background, and F508del (p(F508del)) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. RESULTS: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p(F508del) was 1.06%, p(R117H;T7) 0.27% and p(R117H;T5)<0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. CONCLUSIONS: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.

Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion.

Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with "other type I fibrillinopathy." In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete "clinical" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.

Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation.

Mutations in the FBN1 gene cause Marfan syndrome (MFS) and a wide range of overlapping phenotypes. The severe end of the spectrum is represented by neonatal MFS, the vast majority of probands carrying a mutation within exons 24-32. We previously showed that a mutation in exons 24-32 is predictive of a severe cardiovascular phenotype even in non-neonatal cases, and that mutations leading to premature truncation codons are under-represented in this region. To describe patients carrying a mutation in this so-called 'neonatal' region, we studied the clinical and molecular characteristics of 198 probands with a mutation in exons 24-32 from a series of 1013 probands with a FBN1 mutation (20%). When comparing patients with mutations leading to a premature termination codon (PTC) within exons 24-32 to patients with an in-frame mutation within the same region, a significantly higher probability of developing ectopia lentis and mitral insufficiency were found in the second group. Patients with a PTC within exons 24-32 rarely displayed a neonatal or severe MFS presentation. We also found a higher probability of neonatal presentations associated with exon 25 mutations, as well as a higher probability of cardiovascular manifestations. A high phenotypic heterogeneity could be described for recurrent mutations, ranging from neonatal to classical MFS phenotype. In conclusion, even if the exons 24-32 location appears as a major cause of the severity of the phenotype in patients with a mutation in this region, other factors such as the type of mutation or modifier genes might also be relevant.

Empirical study of the dependence of the results of multivariable flexible survival analyses on model selection strategy.

Flexible survival models, which avoid assumptions about hazards proportionality (PH) or linearity of continuous covariates effects, bring the issues of model selection to a new level of complexity. Each 'candidate covariate' requires inter-dependent decisions regarding (i) its inclusion in the model, and representation of its effects on the log hazard as (ii) either constant over time or time-dependent (TD) and, for continuous covariates, (iii) either loglinear or non-loglinear (NL). Moreover, 'optimal' decisions for one covariate depend on the decisions regarding others. Thus, some efficient model-building strategy is necessary.We carried out an empirical study of the impact of the model selection strategy on the estimates obtained in flexible multivariable survival analyses of prognostic factors for mortality in 273 gastric cancer patients. We used 10 different strategies to select alternative multivariable parametric as well as spline-based models, allowing flexible modeling of non-parametric (TD and/or NL) effects. We employed 5-fold cross-validation to compare the predictive ability of alternative models.All flexible models indicated significant non-linearity and changes over time in the effect of age at diagnosis. Conventional 'parametric' models suggested the lack of period effect, whereas more flexible strategies indicated a significant NL effect. Cross-validation confirmed that flexible models predicted better mortality. The resulting differences in the 'final model' selected by various strategies had also impact on the risk prediction for individual subjects.Overall, our analyses underline (a) the importance of accounting for significant non-parametric effects of covariates and (b) the need for developing accurate model selection strategies for flexible survival analyses.

Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands.

BACKGROUND: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. METHODS: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. RESULTS: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. CONCLUSIONS: Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.

Time trends in first-diagnosis rates of colorectal adenomas: a 24-year population-based study.

BACKGROUND: Little is known about the descriptive epidemiology of colorectal adenomas diagnosed in the population. AIM: To describe time trends in the rate of first diagnosis of colorectal adenomas and estimate the proportion of adenoma-bearing individuals detected over a 24-year period. METHODS: A total of 11,027 patients were first-diagnosed with colorectal adenomas among Côte-d'Or residents (France) between 1976 and 1999. Annual percentage changes were estimated using a Poisson regression model. The proportion of diagnosed adenoma-bearing individuals was estimated using the prevalence of adenomas in an autopsy study performed in the area. RESULTS: Standardized diagnosis rates were 89.6/100,000 men and 50.3/100,000 women. During the period 1976-1993, diagnosis rates significantly increased with annual percentage changes in men and women of respectively +17.1% and +22.3% for proximal adenomas, +7.5% and +9.1% for distal adenomas and +7.2% and +8.0% for advanced adenomas. Changes were less marked during the period 1994-1999. The estimated proportion of adenoma-bearing individuals diagnosed during the 24-year period was 20.0% in men and 16.0% in women. CONCLUSION: Despite a marked increase in the rate of first adenoma diagnosis, the proportion of diagnosed adenoma-bearing individuals seems too low to induce a significant decrease in colorectal cancer incidence.

Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.

Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

Low compliance with colonoscopic screening in first-degree relatives of patients with large adenomas.

BACKGROUND: Little is known about compliance with colonoscopy as a screening method in first-degree relatives of patients with large adenomas. Aims To evaluate the compliance with screening colonoscopy among this population, and its determinants. METHODS: Data were obtained from the family part of the GEADE study, a study on genetic factors of colorectal adenomas. Index cases were 306 patients with adenomas > or = 10 mm. All living first-degree relatives aged 40-75 who could be contacted by the index case were asked to undergo a colonoscopy, unless they had had one in the previous 5 years. RESULTS: Among 674 eligible relatives, 56 had had a colonoscopy within the preceding 5 years and 114 underwent a screening colonoscopy resulting in a compliance with screening colonoscopy of 18%. This was not related to most characteristics of index cases. Compliance was significantly lower when the index case lived in the Greater Paris area than when he/she lived in other areas (12% vs. 21%). It was higher in siblings (18%) and offspring (23%) than in parents (9%) and in relatives under 55 years old (22%) than in relatives aged 55 and over (15%). CONCLUSIONS: Compliance with colonoscopy was low in first-degree relatives of patients with large adenomas. The reasons for this should be determined and appropriate strategies developed to increase compliance.