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Michaël Benzimra,1 Béatrix Bonnamour,1 Martin Duracinsky,2 Christophe Lalanne,2 Jean-Pierre Aubert,2,3 Olivier Chassany,2,3 Isabelle Aubin-Auger,2,3 Isabelle Mahé1,2 1Internal Medicine Department, Hôpital Louis Mourier, APHP, Colombes, France; 2Méthodologies et Société (REMES) EA 7334, Recherche Clinique Ville-hôpital, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; 3General Medicine Deparment, Université Paris 7, Paris, France Introduction: Direct oral anticoagulants (DOACs) have shown noninferiority to vitamin K antagonists (VKA) in stroke prevention in patients with atrial fibrillation. DOAC treatment may be less demanding than VKA, improving quality of life. To date, there have been no studies of the real-life experience of outpatients receiving anticoagulation therapy for atrial fibrillation in France.Methods: An observational descriptive real-life epidemiological study used three validated questionnaires (EQ-5D, PACT-Q2, and MMAS-8 French Translation) to assess quality of life, treatment satisfaction, and adherence, respectively, in 200 patients managed on an outpatient basis for atrial fibrillation who were receiving anticoagulation therapy by VKA or DOAC for at least 3 months. Patients were distributed between four groups: primary VKA (P-VKA), switch from VKA to DOAC (S-DOAC), primary DOAC (P-DOAC), and switch from DOAC to VKA (S-VKA).Results: Two hundred patients responded to the questionnaires: 89, 50, 52, and 9 in the P-VKA, S-DOAC, P-DOAC and S-VKA groups, respectively. Only the first three groups were compared statistically, because of the small size of the S-VKA group. Quality of life and satisfaction were good in all three groups, with no significant difference in quality of life but significantly greater satisfaction with respect to the “convenience” and “satisfaction” dimensions for DOACs (S-DOAC and P-DOAC groups versus P-VKA group; p

Ingre Keita,1 Isabelle Aubin-Auger,2–4 Christophe Lalanne,4 Jean-Pierre Aubert,2–4 Olivier Chassany,2,4 Martin Duracinsky,4 Isabelle Mahé1,2,4 1Internal Medicine Department, Louis Mourier Hospital, APHP, Colombes, 2Paris 7 University, 3General Medicine Department, Université Paris 7, Paris, 4Recherche Clinique Ville-Hôpital, Méthodologies et Société (REMES) EA 7334, Université Paris Diderot, Sorbonne Paris Cité, Paris, France Introduction: Direct oral anticoagulants (DOACs) have shown non-inferiority and ease of use compared to vitamin K antagonists (VKA) in the treatment of venous thromboembolism (VTE). No study so far has been directed toward real-life experience of outpatients receiving anticoagulants for VTE in France.Methods: This is an observational descriptive real-life epidemiological study, using three validated questionnaires (Morisky Medication Adherence Scale-8, EQ-5D, and part 2 of the Perception of Anticoagulant Treatment Questionnaire), to assess adherence, quality of life, and satisfaction in 100 VTE outpatients receiving anticoagulation therapy by VKA (primary or switched from DOAC to VKA) or by DOAC (primary or switched from VKA to DOAC).Results: Patients were very much satisfied with their treatment in both DOAC and VKA groups. Despite advantages of DOACs, therapeutic adherence was only moderate. The best adherence scores were observed in the primary VKA switched to DOAC for at least 3 months (S-DOAC) subgroup. Quality of life was better in the DOAC group mainly because of the absence of the requirement for blood testing. Most of the complaints concerned the pain/discomfort dimension in the VKA group and anxiety/depression dimension in the DOAC group.Conclusion: Patients were satisfied with their anticoagulant treatment, especially when they were involved in choosing the anticoagulant, and the treatment suited them. Quality of life of patients in the DOAC group was better than in the VKA group, but adherence remains to be improved. This study highlights the importance of the physician–patient relationship, pretreatment initiation, and follow-up of any anticoagulation therapy throughout. Keywords: medication adherence, oral anticoagulant, deep venous thrombosis, pulmonary embolism, quality of life, treatment satisfaction

Objectives: To assess diagnoses and management of acute and chronic gout in primary care and rheumatology settings relative to 2006 European League Against Rheumatism (EULAR) gout recommendations. Secondary objectives were to describe patient demographics, clinical features, lifestyle modifications, and short- and mid-term outcomes.Methods: Prospective, cross-sectional, descriptive survey of patients with chronic gout, acute gout, or suspected gout, included by randomly selected general practitioners (GPs, n = 398) and rheumatologists (n = 109) between October 2008 and September 2009, in France. At the first visit, a structured questionnaire was completed. Each patient completed self-questionnaires at the first visit and 3 to 6 months later.Results: We included 1003 patients, including 879 (87.6%) males (mean age, 61.6 ± 11.4 years; 28.1% obese) and 124 (12.4%) females (70.2 ± 11.9 years; 33.1% obese). Mean disease duration was 8.0 ± 8.3 years and mean time since hyperuricemia diagnosis 8.2 ± 8.4 years. Mean annual number of flares was 1.9 ± 1.5. ACR criteria for gout were met in 855 pts. Gout was acute in 487 (48.6%) patients and chronic in 241 (24.4%). Tophi (19.4% of patients) were associated with disease duration but not gender or chronic kidney disease (CKD). The main co-morbidities were hypertension (53.8%), dyslipidemia (47.2%), and hyperglycemia/diabetes mellitus (15.0%). CKD 3-5 was present in 43% of patients but was identified by physicians in only 5.2%. CKD severity was significantly associated with age, gender, hypertension, and diuretic use.Conclusion: This cohort will prove valuable for addressing the concordance with EULAR recommendations and for future studies of gout in everyday practice, most notably regarding metabolic syndrome, other co-morbidities, and identification of difficult-to-treat patients. [ABSTRACT FROM AUTHOR]

Regular physical activity should benefit HIV-positive transgender women because they are a particularly vulnerable population. However, engaging in physical activity seems particularly difficult among this population. To inform the development of interventions to increase adherence to physical activity, we explored perceptions of physical activity in 10 semi-structured interviews with HIV-positive transgender women. Interviews were subjected to a qualitative approach named interpretative phenomenological analysis (IPA). Inspired by Cooley's theory, we chose to illustrate the results according to a three-level structure, i.e., confronting oneself to oneself with a specific identity, then confronting oneself with others on an interpersonal level, and eventually confronting oneself with society as a normative frame through the specific prism of physical activity, and thus relationship to one's body. The idea of practicing physical activity meant for them: having to face what they tried to be kept hidden, being ostracized by the cis population, and facing social heteronormativity. The fears about health were mostly about HIV and the transitioning process side effects. The psychological issues were mostly about the fear of developing male shaped bodies and worsened by traumatic life stories. External factors were often related to the passing concept and violence caused by stigma and discrimination. The group appeared as a strong motivation factor, facilitating self-acceptance and socialization., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There is a paucity of epidemiological data on asthma classified by disease severity in France. The ASTHMAPOP cross-sectional study aimed to review the prevalence and current management of asthma in people aged ≥18 years in France., Methods: A self-administered questionnaire was mailed to 19 676 people representative of the French population in age, gender, region, and socio-economic status. Asthma was classified by treatment steps per the 2017 Global Initiative for Asthma (GINA) report, according to prescribed treatments. Analyses were mostly descriptive., Results: The questionnaire return rate was 81.7% (n = 16 083), and 15 587 questionnaires were analyzed. The prevalence of lifetime asthma was 12.8% (95% confidence interval (CI):12.3-13.3%; n = 1 989) in 2018. The prevalence of current asthma (i.e., 12 months before the survey) was 6.4% (95% CI: 6.0-6.8%; n = 993); most of these respondents (95.3% [n = 946]) were receiving asthma treatment, and 49.4% (n = 491) were treated for mild asthma (GINA step 1 or 2). Of people with current asthma, 47.6% reported ≥1 asthma exacerbation in the past 12 months-defined as episodes (several days) during which symptoms (cough, sputum, and dyspnea) were worse than usual; 14.3% had ≥1 emergency visit, and 3.1% had ≥1 hospitalization due to asthma. Of those taking continuous asthma controller medications who answered all Morisky Medication Adherence Scale questions (n = 501), 46.4% were adherent (score=4) to their treatment regimen. Based on the 6-item Asthma Control Questionnaire scores, asthma was partially controlled or uncontrolled in 47.7% of 969 people., Conclusions: The prevalence of asthma in France has remained stable since 2006, but levels of asthma control and treatment adherence continue to be relatively poor. Asthma management in France requires improvement., Competing Interests: Declaration of Competing Interest C. Raherison-Semjen, A. Izadifar, M. Russier, J.-P. Aubert, and A. Didier received honoraria for their participation in the scientific committee of the investigation. C. Rolland is an employee of the Asthme & Allergies Association. C. Touboul is an employee of Kantar Health, which received funding from AstraZeneca to conduct the study. D. Leynaud and C. Fabry-Vendrand are employees of AstraZeneca., (Copyright © 2021. Published by Elsevier Masson SAS.)

Objectives: To describe the implementation and use of a computerized decision support system (CDSS) for antibiotic prescription in primary care in France (Antibioclic). The CDSS targets 37 infectious diseases and has been freely available on a website since 2011., Methods: Description and implementation of the architecture of a CDSS for antibiotic prescription in general practice. Analysis of the queries made between 2012 and 2018 on the CDSS by GPs. Analysis of two cross-sectional studies of users in 2014 and 2019., Results: The number of queries increased from a median of 796/day [IQR, 578-989] in 2012 to 11 125/day [5592-12 505] in 2018. Unique users increased from 414/day [245-494] in 2012 to 5365/day [2891-5769] in 2018. Time taken to make a query was 2 min [1.9-2.1]. Among 3 542 347 queries in 2018, 78% were for adults. Six situations accounted for ≥50% of queries: cystitis; acute otitis media; acute sinusitis; community-acquired pneumonia; sore throat; and pyelonephritis. Queries concerned pathologies for which antibiotic prescription was necessary (64%), was conditional on additional clinical steps (34%) or was not recommended (2%). Most users (81%) were GPs, with median age of 38 years [31-52] and 58% were female. Among the 4016 GPs who responded to the surveys, the vast majority (96%) reported using the CDSS during the consultation, with 24% systematically using Antibioclic to initiate an antibiotic course and 93% having followed the CDSS recommendation for the latest prescription. Most GPs were comfortable using the CDSS in front of a patient., Conclusions: Antibioclic has been adopted and is widely used in primary care in France. Its interoperability could allow its adaptation and implementation in other countries., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Many people in Europe remain undiagnosed for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV)., Objectives: To evaluate acceptability and effectiveness of a questionnaire designed to facilitate identification of risk factors for these viruses., Methods: We performed an observational study, in a prospectively enrolled cohort of patients in Paris (France) seen in 2014. Eighteen GPs administered a questionnaire to the first 50 patients, collecting information about risk factors. GPs were randomized into two groups: A (self-administered questionnaire) and B (GP-administered questionnaire). We used the overall response rate to assess the acceptability of the questionnaire. We used the rate of newly identified risk factors and compared the number of tests performed one year before and immediately after the intervention to assess the effectiveness of the questionnaire., Results: 842 patients were randomized: 349 (41.5%) in group A and 493 (58.5%) in group B. Acceptability was 88.5% (95%CI: 86.3-90.6); 93.1% (95%CI: 90.5-95.8) in-group A and 85.2% (95%CI: 82.1-88.3) in group B (P = 0.0004). Prevalence of risk factors was 51.8% (95%CI: 48.2-54.4) and 58.3% were newly identified (95%CI: 52.9-63.7). The number of HIV tests performed during the four weeks after intervention increased by 27% compared to the same period one year before (P = 0.22). It increased by 113% (P = 0.005) and 135% (P = 0.005) for HBV and HCV, respectively., Conclusion: The questionnaire proved acceptable and effective in identifying risk factors for HIV, HBV and HCV in general practice.

Objective: The primary endpoint was to evaluate the use of HIV testing methods by French primary care providers: Elisa laboratory screening, instant result HIV diagnostic test and rapid result HIV diagnostic test. The secondary endpoints were the population screening rate of unknown HIV status consulting during the study period, reasons for screening and for choosing the specific screening method, the investigators' satisfaction with the rapid diagnostic test (RDT) and problems encountered., Patients and Methods: National prospective interventional study with French family physicians (FP) from December 2013 to December 2014. FPs enrolled all consenting adults consulting for an HIV screening test during a 6-month period: the choice was an Elisa laboratory test or one of the two RDTs., Results: During the study period, 43 FPs included 981 patients. HIV screening was performed for the first time for 31.6% of patients; 767 (78.2%) Elisa laboratory test prescriptions and 214 (21.8%) RDTs were performed, leading to a screening rate of 1.3%. For 120 (15.7%) of the Elisa laboratory tests, the result was not reported and six RDTs were not valid. Nine patients were diagnosed as HIV-infected (0.9%): five with Elisa laboratory test and four with RDT. Almost 90% of FPs were willing to keep on using RDTs in their daily practice., Conclusion: In general practice, RDTs may be an important additional tool to traditional HIV screening. They could account for one in five tests prescribed in this context., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Anal disorders are largely underestimated in general practice. Studies have shown patients conceal anal symptoms leading to late diagnosis and treatment. Management by general practitioners is poorly described. The aim of this study is to assess the prevalence of anal symptoms and their management in general practice., Methods: In this prospective, observational, national study set in France, all adult patients consulting their general practitioner during 2 days of consultation were included. Anal symptoms, whether spontaneously revealed or not, were systematically collected and assessed. For symptomatic patients, the obstacles to anal examination were evaluated. The general practitioner's diagnosis was collected and a proctologist visit was systematically proposed in case of anal symptoms. If the proctologist was consulted, his or her diagnosis was collected., Results: From October 2014 to April 2015, 1061 patients were included by 57 general practitioners. The prevalence of anal symptoms was 15.6% (95% CI: 14-18). However, 85% of these patients did not spontaneously share their symptoms with their doctors, despite a discomfort rating of 3 out of 10 (range 1-5). Although 65% of patients agreed to an anal examination, it was not proposed in 45% of cases with anal symptoms. Performing the examination was associated with a significantly higher diagnosis rate of 76% versus 20% (p < 0.001). Proctologist and general practitioner diagnoses were consistent in 14 out of 17 cases., Conclusions: Patients' concealed anal symptoms are significant in general practice despite the impact on quality of life. Anal examination is seldom done. Improved training of general practitioners is required to break the taboo.

Objectives: The objective of this sub-study was to assess the use of colchicine for the treatment of gout flares in real life conditions in the GOSPEL cohort following the 2006 EULAR recommendations for gout management., Methods: This national cross-sectional epidemiologic survey included outpatients with gout suffering from acute flare followed by randomly selected primary care physicians (n=398) and private practice rheumatologists (n=109) between October 2008 and September 2009 in France. Data regarding patient characteristics and treatment prescription was collected by each physician. Glomerular filtration rate (eGFR) was estimated using the Cockroft-Gault formula. Patients included in the survey for a gout flare filled in a specific self-questionnaire including colchicine effective intake and pain relief (numeric scale)., Results: This analysis focused on the 349 patients presenting with gout flare and treated with colchicine. Mean (±SD) prescribed dose of colchicine was 2.8 (±0.7) mg within the first 24hours and the cumulative dose over the first three days of treatment was 6.9 (±1.8) mg. Patients with mild decline in eGFR (eDFG 60-80mL/min) were prescribed an average initial dose of 2.8mg (±0.8) mg (n=58), 2.7 (±0.8) mg in chronic kidney disease (CKD) stage 3 (n=43) and 2.5 (±0.7) mg in CKD stage 4 (n=2). Cumulative doses of colchicine did not take into account either renal impairment or age., Conclusions: This study draws attention to some misuse of colchicine in daily practice and the prescription of excessive doses especially in case of renal impairment. eGFR should be enforced in daily practice., (Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objective: To document the initial management of hypothyroidism in France with respect to diagnostic setting, investigations, and therapeutic approach., Design: Observational study of the management by primary care practitioners (PCPs) and endocrinologists of patients diagnosed with, and treated for, hypothyroidism during the enrollment period or the previous 6 months., Methods: A representative sample of PCPs and endocrinologists enrolled up to five consecutive patients and reported sociodemographic, clinical, therapeutic, and laboratory data. Data were submitted at baseline and at the first measurement of TSH after starting the treatment., Results: The analysis population comprised 1255 patients (mean (s.d.) age 52.8 (16.3) years; 84% female). Hypothyroidism was suspected on clinical grounds in 77% of patients, with goiter in 16%. Autoimmune thyroiditis, supported by positive anti-thyroid antibodies, was the most frequent diagnosis (59%), followed by iatrogenic causes (28%), of which thyroidectomy was the most common. The median baseline TSH was 8.6 mIU/l, suggesting a high incidence of subclinical hypothyroidism. Imaging studies were requested in over 75% of patients, with ultrasound performed in 98% and scintigraphy performed in 19% of these patients. Both groups of physicians treated their patients almost exclusively with levothyroxine. Endocrinologists were more likely than PCPs to provide counseling on how to take medication correctly., Conclusions: This observational study of a large cohort of patients with newly diagnosed hypothyroidism in France illustrates current practice and indicates some areas where physician education may be required to optimize adherence to guidelines and cost-effectiveness.

Background: In France, around 50,000 people were unaware of their HIV positivity at the end of 2008. The latest guidelines recommend routine screening of all adults. Family physicians have been identified as key persons for this new policy. Rapid HIV tests (RHT) have been proposed as an alternative to conventional blood tests., Objectives: The authors assessed the feasibility and acceptability of RHT test based screening in French community practice., Method: We made a prospective interventional study of the BioMerieux VIKIA(®) HIV 1/2 RHT among French family physicians. Data on the RHT was posted in the physician's waiting room., Results: Sixty-two French physicians, mostly family practitioners, included 383 patients with a mean age of 36.2 years, from June to October 2010. Twenty-two percent (83) of these patients had never been tested for HIV. The RHT was proposed and 382 tests were accepted and performed (acceptability rate of 99.7%). Sixty-five percent of the tests were made on the patient's request. The tested population represented 1.5% of consulting patients during the study period (feasibility rate). Patients were quite satisfied but physicians less so. Test steps and capillary blood sampling were the main source of difficulty mentioned. At the end of the study, 59% of physicians were ready to continue using RHT in their daily practice., Conclusion: Routine RHT screening in community practice is feasible and well accepted by patients. It was the first screening test for 22% of our patients. Its feasibility was limited by capillary blood sampling technique and time constraints during consultation., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Aim: The study aimed to determine the effectiveness and tolerability of rosiglitazone, and its profile in terms of treatment adherence, treated patients and prescribing recommendations under everyday conditions of care., Methods: This was a "real-life" observational longitudinal study including patients with type 2 diabetes mellitus (T2DM) starting treatment with rosiglitazone and followed for up to 2 years. A questionnaire was completed at the time of inclusion and during routine consultations at around 6, 12, 18 and 24 months following inclusion. Information was collected on sociodemographics, clinical history, treatments, co-morbidities, laboratory data and compliance with treatment. There were three primary outcome measures: treatment response (defined as an HbA1c ≤ 8.0% or a decrease in HbA1c ≥ 0.7%); switch to insulin (as considered necessary by the physician); and occurrence of adverse events requiring a change or discontinuation of treatment., Results: The evaluation included 670 patients (61.1%) treated with rosiglitazone/metformin as fixed-dose combination tablets and 427 (38.9%) with standard rosiglitazone tablets. Rates of HbA1c response, defined as an HbA1c less than or equal to 8.0% or a decrease in HbA1c greater than or equal to 0.7%, ranged from 80.6% to 92.1% depending on the follow-up time. The percentage of patients with an HbA1c less than 7% was 18.4% before rosiglitazone was prescribed, and ranged from 48.2% to 57.8% depending on the follow-up period. Sixty-two patients (6.1%, 95% CI: 4.6-7.6%) switched to insulin therapy during the follow-up period. Spontaneously reported adverse events leading to a change or discontinuation of treatment were seen in 45 patients (4.4%, 95% CI: 3.2-5.6%)., Conclusion: Rosiglitazone showed sustained efficacy, with around 90% of patients defined as responders to the treatment in terms of reduction in HbA1c, and was relatively well tolerated. The adverse-event profile was consistent with the known effects of rosiglitazone, and no signs of increased cardiovascular ischaemic risk were observed. These results are in agreement with previous studies on rosiglitazone., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Context: French interns in general practice are, like all medical students, exposed to medical errors during their training., Objective: To measure the professional and personal impact of medical errors on French general practitioner (GP) trainees., Design, Setting and Participants: Quantitative and qualitative study of medical errors and GP trainees enrolled at Paris Diderot University., Method: An online anonymous questionnaire was sent to all GP trainees at Paris Diderot University and recorded semi-structured interviews were conducted with 10 volunteers., Results: 70 of the 392 (18%) interns contacted replied to the questionnaire and 10 semi-structured interviews were then conducted. 97% of the participants had already made a medical error. Even with the extreme, conservative assumption that non-respondents would have reported no errors, the prevalence of self-reported medical errors in the whole sample would still have been 17%. 64% said they were at least strongly affected by their error and 74% made constructive changes to their work after the error. The interns revealed that the emotional impact of their errors were great with feelings such as guilt that could remain for more than 2 years after the event. 33% would have liked to talk more about the circumstances of their error with their superior. Most interns suggest more training on medical errors and more open-minded discussion when the error actually happens rather than formal training at the university., Conclusion: Medical errors remain a sensitive subject that is not broached enough in our university but interns need to talk about their experiences with their peers to improve risk management and prevent the recurrence of new errors.

The French Pandemic Influenza Plan ("Plan National de Prévention et de Lutte Pandémie Grippale") places general practitioners at the heart of the provision of care to patients through consultations and house calls. The purpose of this study was to determine whether GP practices are able to provide treatment to flu patients within their premises in the event of a highly pathogenic influenza pandemic. A simulation exercise conducted in a GP practice (SIMUGRIP-MG2) was carried out in the autumn of 2009. 3 general practitioners, the practice secretary, 33 patients and care staff took part in the exercise during a half day of practice. The study found that the quality of some hygiene practices and procedures was inadequate: the duration of handwashing was too short (mean: 11.8 seconds), gloves were not worn, and FFP2 masks were often handled. The study found that the implementation of these procedures required increased effort and attention from GPs. It was also found that this type of consultation requires additional preparation time (refitting, supply of materials) and generates additional costs (linked, for example, to storage issues). In seeking to improve the quality of care provided to infected patients in the event of an influenza pandemic, several factors must be considered, including recent data on the effectiveness of countermeasures, additional training to improve hygiene practices, and infrastructure modernization to improve ergonomics in GP practices.

A simulation exercise aimed at assessing the management and provision of ambulatory care in the context of a highly pathogenic influenza pandemic was conducted in a specifically dedicated consultation center (Centre de Consultation Dédié (CCD) à la grippe) based on official French guidelines. The exercise was carried out in a school in Paris equipped to simulate a "flu clinic". 3 practitioners provided treatment lasting 2 hours to nursing students acting as patients. The exercise highlighted a number of major organizational issues. Staff were found to be unable to manage the center and to perform patient transfers; face masks were not routinely and consistently worn by doctors and patients; and communication between professionals within the clinic was limited. The exercise showed that much remains to be done to ensure that "flu clinics" are effective and functional. The results suggest that the exercise will need to be repeated on a larger scale and over a longer period.

Aim: The aim of this study was to evaluate the efficacy of a continuing medical education (CME) website to improve ophthalmological management of diabetic retinopathy (DR)., Methods: A worldwide website called RETIDIAB® was created in which, to log on for first time, users had to take a preliminary test to evaluate their baseline level of knowledge. This allowed them free access to the entire website at any time with no time obligation. The website comprised a course of theoretical concepts and different types of training, including multiple-choice questionnaires (MCQ) focused on the course content, interpretation of diabetic fundus photographs and case reports. After perusing the entire RETIDIAB® website, users could take a second assessment test. Finally, they were asked to fill in a questionnaire evaluating the entire programme., Results: A total of 137 users were registered and, of these, 109 took only the preliminary test, while 28 took the second test and evaluated the entire website; of the latter, 75% were residents and 25% were practising physicians, and 15 were male and 13 were female, ranging in age from 26 to 42 (30.2 ± 3) years. Statistically significant progress was seen between the first and second evaluations (37.3 ± 14% correct answers vs 64 ± 10%, respectively), and the average time interval between the first and second evaluations was 40 ± 20 days. In addition, users expressed a high level of overall satisfaction with the site., Conclusion: This pilot study demonstrated the value and effectiveness of RETIDIAB®, a new CME website exclusively devoted to DR management., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Context: In 2004, 22% of French citizen were vaccinated against Hepatitis B Virus (HBV), 7.3% had previously been protected by a contact with HBV, and 0.65% were carriers of HBV Those rates are not known among migrant people, especially if they have no health insurance. It is not known whether those people have adequate personal strategies of prevention., Aims and Method: Prospective study to assess the effectiveness of an internet-accessible expert system in helping the GP to determine the most accurate strategy of prevention, related to the serologic HBV profile of each patient, and to apply this strategy, among migrant people coming from subsaharian Africa and Asia, attending their GP. The prevalence of each serologic profile was measured., Results: From 11.5.2007 to 12.31.2008, 28 GPs included 547 migrant people. 8% are HBV carriers, 33% have been protected by a contact with HBV, 16% are vaccinated, and 23% have had no contact with virus nor vaccination. A full accurate preventive information strategy could be carried out with help of the expert system, respectively among 100% of HBV carriers, 100% of vaccinated people, 98% of people protected by HBV contact, and 40% of people who had no marker A vaccination has been done among 64% of people who required it. For people whose only marker of HBV infection was anti HBc, 41% was considered protected by HBV contact, 48% was vaccinated, this result can be related to a lack of accuracy in international guidelines in this situation., Conclusion: Prevalence of contact with HBV is much higher in migrant people coming from subsaharian Africa and Asia, than in the average French population. An internet-accessible expert system is a useful tool for GPs in order to enhance strategies of prevention in HBV infection.

The human genes MUC2, MUC5AC, MUC5B and MUC6 are clustered on chromosome 11 and encode large secreted gel-forming mucins. The frequent occurrence of their silencing in cancers and the GC-rich structure of their promoters led us to study the influence of epigenetics on their expression. Pre- and post-confluent cells were treated with demethylating agent 5-aza-2'-deoxycytidine and histone deacetylase (HDAC) inhibitor, trichostatin A. Mapping of methylated cytosines was performed by bisulfite-treated genomic DNA sequencing. Histone modification status at the promoters was assessed by chromatin immunoprecipitation assays. Our results indicate that MUC2 was regulated by site-specific DNA methylation associated with establishment of a repressive histone code, whereas hypermethylation of MUC5B promoter was the major mechanism responsible for its silencing. DNA methyltransferase 1 was identified by small interfering RNA approach as a regulator of MUC2 and MUC5B endogenous expression that was potentiated by HDAC2. MUC2 and MUC5B epigenetic regulation was cell-specific, depended on cell differentiation status and inhibited their activation by Sp1. The expression of MUC5AC was rarely influenced by epigenetic mechanisms and methylation of MUC6 promoter was not correlated to its silencing. In conclusion, this study demonstrates the important role for methylation and/or histone modifications in regulating the 11p15 mucin genes in epithelial cancer cells.

MUC4 is a type-1 transmembrane glycoprotein and is overexpressed in many carcinomas. It is a heterodimeric protein of 930 kDa, composed of a mucin-type subunit, MUC4alpha, and a membrane-bound growth factor-like subunit, MUC4beta. MUC4 mRNA contains unique 5' and 3' coding sequences along with a large variable number of tandem repeat (VNTR) domain of 7-19 kb. A direct association of MUC4 overexpression has been established with the degree of invasiveness and poor prognosis of pancreatic cancer. To understand the precise role of MUC4 in pancreatic cancer, we engineered a MUC4 complementary DNA construct, mini-MUC4, whose deduced protein (320 kDa) is comparable with that of wild-type MUC4 (930 kDa) but represents only 10% of VNTR. Stable ectopic expression of mini-MUC4 in two human pancreatic cancer cell lines, Panc1 and MiaPaCa, showed that MUC4 minigene expression follows a biosynthesis and localisation pattern similar to the wild-type MUC4. Expression of MUC4 resulted in increased growth, motility, and invasiveness of the pancreatic cancer cells in vitro. Ultra-structural examination of MUC4-transfected cells showed the presence of increased number and size of mitochondria. The MUC4-expressing cells also demonstrated an enhanced tumorigenicity in an orthotopic xenograft nude mice model, further supporting a direct role of MUC4 in inducing the cancer properties. In conclusion, our results suggest that MUC4 promotes tumorigenicity and is directly involved in growth and survival of the cancer cells.

The human gene MUC4 encodes a large transmembrane mucin that is developmentally regulated and expressed along the undifferentiated pseudostratified epithelium, as early as 6.5 weeks during fetal development. Immunohistochemical analysis of Muc4 expression in developing mouse lung and gastrointestinal tract showed a different spatio-temporal pattern of expression before and after cytodifferentiation. The molecular mechanisms governing MUC4 expression during development are, however, unknown. Hepatocyte nuclear factors (HNF), forkhead box A (FOXA), GATA, and caudal-related homeobox transcription factors (TFs) are known to control cell differentiation of gut endoderm derived-tissues during embryonic development. They also control the expression of cell- and tissue-specific genes and may thus control MUC4 expression. To test this hypothesis, we studied and deciphered the molecular mechanisms responsible for MUC4 transcriptional regulation by these TFs. Experiments using small interfering RNA, cell co-transfection, and site-directed mutagenesis indicated that MUC4 is regulated at the transcriptional level by CDX-1 and -2, HNF-1 alpha and -1 beta, FOXA1/A2, HNF-4 alpha and -4 gamma, and GATA-4, -5, and -6 factors in a cell-specific manner. Binding of TFs was assessed by chromatin immunoprecipitation, and gel-shift assays. Altogether, these results demonstrate that MUC4 is a target gene of endodermal TFs and thus point out an important role for these TFs in regulating MUC4 expression during epithelial differentiation during development, cancer, and repair.

Context: In France, 43% to 63% of diabetics have an annual fundoscopy. Do the new screening tools, coupled with teletransmission of the images, allow for satisfying ophthalmological screening? It is an important matter given the foreseeable reduction in the number of French ophthalmologists in the forthcoming years., Objectives: To measure the quality of screening for diabetic retinopathy (DR), in the framework of a network, by the provision of a retinograph by numeric camera (with teletransmission of the images and centralised interpretation), in a screening centre located in town., Method: The study evaluated the quality of screening obtained in two comparable groups of general practitioners, one using the retinograph and the other using the classical method of screening by ophthalmologist. The screening was targeted at diabetics who had not had a fundoscopy in the preceding year, nor had known DR or a treating ophthalmologist (for the retinography group only)., Results: 667 patients were sampled in the retinography group (456 included) and 707 in the control group (426 included) between 1/04/02 and 1/11/02; 417 patients were followed until the end of the study in the 2 groups. A screening examination was considered effective if it was performed within the six months following its request, and by the presence of a report in the file of the general practitioner. The percentage of patients thus screened was 74% in the retinography group and 71,5% in the other group (not significant). 16% of diabetics in the retinography group had DR compared with 10% of patients in the control group. The analysis of the level of satisfaction of patients tended to show a preference for the system of screening by fundal photography., Conclusion: In the framework of a healthcare network, the availability of a retinograph by numeric camera, with the interpretation of photos by teletransmission of the images, obtained a high level of quality of screening for diabetic retinopathy that was at least as good as that obtained by a healthcare network using the classical ophthalmological screening method.

MUC4 mucin is a high molecular weight transmembrane glycoprotein that plays important roles in tumour biology. It is aberrantly expressed in pancreatic adenocarcinoma, while not being detectable in the normal pancreas. Previous studies have demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is defective in CF, is implicated in multiple cellular functions, including gene regulation. In the present study, using a CFTR-defective pancreatic cancer cell line and its derived subline expressing functional CFTR, we report that MUC4 expression is negatively regulated by CFTR. Short-interfering RNA (siRNA)-mediated silencing of CFTR also leads to an increased expression of MUC4. Additionally, our results suggest that CFTR-mediated regulation of MUC4 is cell density-dependent and is achieved by transcriptional and posttranslational mechanisms. Moreover, in a panel of pancreatic cancer cell lines and normal pancreas, we observed that CFTR was downregulated in pancreatic cancer cells and negatively correlated with MUC4 in most cases. An aberrant expression of MUC4 was also detected in the CF pancreas. Downregulation of CFTR in pancreatic adenocarcinoma and its inverse association with the tumour-linked mucin, MUC4, indicate novel function(s) of CFTR in pancreatic tumour biology and suggest the implication of new signalling pathway(s) in MUC4 regulation.

Aim: To investigate the expression of the four secreted gel-forming mucins (MUC2, MUC5AC, MUC5B and MUC6) in a series of gastric carcinomas, classified according Lauren's, Mulligan's, WHO and Goseki's classifications, with special attention to all the different components (major and minor) present in tumors and to follow up clinical data., Methods: Expression of MUC2, MUC5AC, MUC5B and MUC6 was investigated using immunohistochemistry and in situ hybridization., Results: Expression of secreted gel-forming mucins in gastric carcinoma was particularly complex, each mucin being not restricted to any histopathological type even considering all components (major and minor) present in a given tumor. There was a worst survival in patients with a higher content of mucus (Goseki II or IV) and high positive MUC2 expression., Conclusion: Complexity of mucin gene expression patterns in gastric cancer may reflect a precise state of differentiation at the cell level not recognized in used morphologic classification systems. High expression of MUC2 was nevertheless associated with mucinous subtype of the WHO classification and with group II of Goseki's classification identified by the major component of a particular tumor. The quantity and quality of mucus were related to survival.

A deregulation of several MUC genes (MUC1, MUC2, MUC3, MUC5AC, and MUC6) was previously demonstrated in breast carcinomas. Considering that recently we found the "non-mammary" MUC5B mRNA in primary breast tumors (Berois et al. 2003), we undertook the present study to evaluate the expression profile of MUC5B protein product in breast tissues, using LUM5B-2 antisera raised against sequences within the non-glycosylated regions of this apomucin. Expression of MUC5B by breast cancer cells was confirmed by immunocytochemistry, in situ hybridization, and Western blot on MCF-7 cancer cells. Using an immunohistochemical procedure, MUC5B apomucin was detected in 34/42 (81%) primary breast tumors, in 13/14 (92.8%) samples of non-malignant breast diseases, in 8/19 (42.1%) samples of normal-appearing breast epithelia adjacent to cancer, and in 0/5 normal control breast samples. The staining pattern of MUC5B was very different when comparing breast cancer cells (cytoplasmic) and non-malignant breast cells (predominantly apical and in the secretory material). We analyzed MUC5B mRNA expression using RT-PCR in bone marrow aspirates from 22/42 patients with breast cancer to compare with MUC5B protein expression in the primary tumors. Good correlation was observed because the six MUC5B-positive bone marrow samples also displayed MUC5B expression in the tumor. Our results show, for the first time at the protein level, that MUC5B apomucin is upregulated in breast cancer. Its characterization could provide new insights about the glycobiology of breast cancer cells.

The transmembrane mucin, MUC4, is aberrantly expressed with a high incidence in human pancreatic adenocarcinomas and plays an important role in the pathogenesis of the disease. Our recent studies have shown that interferon-gamma (IFNgamma) and retinoic acid (RA) are important regulators of MUC4 in pancreatic tumour cells. Induction of MUC4 by IFNgamma occurs via a novel pathway involving upregulation of the signal transducer and activator of transcription 1 (STAT-1), whereas its stimulation by RA requires mediation by the transforming growth factor beta-2 (TGFbeta-2). In this study, we have investigated the molecular mechanisms underlying the interaction of IFNgamma and RA in MUC4 regulation in pancreatic tumour cells. We demonstrate that these reagents exert a synergistic induction of MUC4. Interestingly, while the upregulation of STAT-1 by IFNgamma is partially inhibited by RA, IFNgamma is shown to repress RA-driven TGFbeta-2 induction, pointing to the involvement of alternative mechanism(s) in IFNgamma-RA synergism. Moreover, a dose-dependent and cooperative induction of MUC4 promoter activity suggests a regulation at the transcriptional level, most likely by STAT-1 and RAR/RXR (RA receptor/retinoic X receptor) or other IFNgamma/RA-induced secondary intermediate effectors. Our findings provide potential mechanisms that may account for the aberrant expression of MUC4 in pancreatic tumour cells and expose a novel molecular mechanism of gene induction, whereby a reprogramming of signalling pathway through alternative route(s) operates during a synergistic interaction of biological modifiers.

The human transmembrane mucin MUC4 is aberrantly expressed in 75% of pancreatic ductal adenocarcinomas, whereas no expression is found in normal pancreas. Therefore MUC4 appears as a useful biological marker for the diagnosis of ductal adenocarcinomas. Since rat Muc4 was shown to interact with ErbB-2 tyrosine kinase receptor and to either promote cell survival and differentiation or cell proliferation, it is postulated that MUC4 may also participate in pancreatic carcinogenesis. Our aim was to investigate in parallel the role of the Ets factor PEA3 in MUC4 and ErbB-2 transcriptional regulation in pancreatic cancer cells. Two MUC4-expressing WD (well-differentiated) (CAPAN-1 and -2) and one MUC4-non-expressing poorly differentiated (PANC-1) cell lines were used. The three cell lines express ErbB-2 at different levels. By co-transfection and site-directed mutagenesis, we show that PEA3 is a transactivator of the MUC4 promoter and that the -216 and -2368 PEA3 binding sites of the MUC4 promoter are essential. We also demonstrate that PEA3 acts in synergy with c-Jun and specificity protein 1 to transactivate the proximal region of the MUC4 promoter and increase MUC4 mRNA levels in WD cells. These results suggest that MUC4 is a new target gene of the Ets factor PEA3 in pancreatic cancer cells. In contrast, PEA3 represses the transcriptional activity of two fragments of the ErbB-2 promoter in a dose-dependent manner and decreases the endogenous ErbB-2 mRNA levels in WD cell lines. Thus, PEA3, by its capacity to up-regulate the epithelial marker MUC4 and to down-regulate the ErbB-2 oncogene, appears as a key regulator of the differentiation/proliferation balance in pancreatic cancer cells.

The mucus layer covering the gastrointestinal mucosa is considered the first line of defense against aggressions arising from the luminal content. It is mainly composed of high molecular weight glycoproteins called mucins. Butyrate, a short-chain fatty acid produced during carbohydrate fermentation, has been shown to increase mucin secretion. The aim of this study was to test 1) whether butyrate regulates the expression of various MUC genes, which are coding for protein backbones of mucins, and 2) whether this effect depends on butyrate status as the major energy source of colonocytes. Butyrate was provided at the apical side of human polarized colonic goblet cell line HT29-Cl.16E in glucose-rich or glucose-deprived medium. In glucose-rich medium, butyrate significantly increased MUC3 and MUC5B expression (1.6-fold basal level for both genes), tended to decrease MUC5AC expression, and had no effect on MUC2 expression. In glucose-deprived medium, i.e., when butyrate was the only energy source available, MUC3 and MUC5B increase persisted, whereas MUC5AC expression was significantly enhanced (3.7-fold basal level) and MUC2 expression was strikingly increased (23-fold basal level). Together, our findings show that butyrate is able to upregulate colonic mucins at the transcriptional level and even better when it is the major energy source of the cells. Thus the metabolism of butyrate in colonocytes is closely linked to some of its gene-regulating effects. The distinct effects of butyrate according to the different MUC genes could influence the composition and properties of the mucus gel and thus its protective function.

Objectives: Diabetic retinopathy (DR) remains a major cause of visual impairment in France, due to insufficient regular annual screening. Fundus photography is a sensitive alternative to ophthalmoscopy for DR screening. The aim of our study was to report the first telemedical approach to this screening in a primary care setting in France., Methods: A DR screening centre equipped with a nonmydriatic camera was opened in the 18th district of northern Paris and placed at the disposal of general practitioners (GPs) of the Réseau de Santé Paris Nord (North Paris Health Network). These GPs were invited to send their diabetic patients who had no known DR and had had no fundus examination for more than one year to this screening center. Retinal photographs were taken by an orthoptist without pupillary dilation and sent for grading through the Internet to the Lariboisière Hopital Ophthalmology Department., Results: During an 18-month period, 912 DR screening examinations were performed in 868 diabetic patients referred to the DR screening center by 240 GPs. Patients' mean +/- SD age was 59.9 +/- 11.1 years. Of these 868 patients, 260 (30%) said they never have had an ophthalmological examination. Diabetic retinopathy was detected in 197 patients (22.7%). The proportion of patients for whom fundus photographs of one or both eyes could not be assessed was 10.1%. 159 patients (18.3%) required referral to an ophthalmologist., Conclusion: Nonmydriatic photography, combined with teletransmission to a reading centre, proved to be a feasible valid method for the detection of DR. This screening method allowed the identification of patients requiring prompt referral to an ophthalmologist for further complete eye examination.

MUC4: encodes a large transmembrane mucin that is overexpressed in pancreatic adenocarcinomas. The molecular mechanisms responsible for that altered pattern of expression are unknown. TGF-beta, a pleiotropic cytokine, regulates numerous genes involved in pancreatic carcinogenesis via activation of the Smads proteins and MUC4 promoter is rich in Smad-binding elements. Our aim was to study whether the regulation of MUC4 expression by TGF-beta in pancreatic cancer cells was strictly dependent on Smad4 activity. Three pancreatic cancer cell lines, CAPAN-1 (MUC4+/Smad4-), CAPAN-2 (MUC4+/Smad4+) and PANC-1 (MUC4-/Smad4+), were used. By RT-PCR, transfection assays and immunohistochemistry, we show that (i) both MUC4 mRNA and apomucin expression are upregulated by TGF-beta, (ii) Smad2 positively cooperates with Smad4 to activate the promoter, (iii) activation of Smad4 by exogenous TGF-beta induces Smad4 binding to the promoter, (iv) Smad7 and c-ski both inhibit activation by Smad4. When Smad4 is mutated and inactive, TGF-beta activates MUC4 expression via MAPK, PI3K and PKA signaling pathways. Absence of expression in PANC-1 cells is due to histone deacetylation. Altogether, these results indicate that upregulation of MUC4 by TGF-beta is restricted to well-differentiated pancreatic cancer cells, and point out a novel mechanism for TGF-beta as a key molecule in targeting MUC4 overexpression in pancreatic adenocarcinomas.

Mucins are macromolecules lying the cells in contact with external environment and protect the epithelium against constant attacks such as digestive fluids, microorganisms, pollutants, and toxins. Mucins are the main components of mucus and are synthesized and secreted by specialized cells of the epithelium (goblet cells, cells of mucous glands) or non mucin-secreting cells. Human mucin genes show common features: large size of their mRNAs, large nucleotide tandem repeat domains, complex expression both at tissular and cellular level. Since 1987, 21 MUC symbols have been used to designate genes encoding O-glycoproteins containing tandem repeat domains rich in serine, threonine and proline. Some of these genes encode true mucins while others encode non mucin adhesion O-glycoproteins. In this paper, we propose a classification based on sequence similarities and expression areas. Two main families can be distinguished: secreted mucins or gel-forming mucins (MUC2, MUC5AC, MUC5B, MUC6), and membrane-bound mucins (MUC1, MUC3, MUC4, MUC12, MUC17). Muc-deficient mice will provide important models in the study of functional relationships between these two mucin families.