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Jean-David Zeitoun,1 Yves Morvan2 1Département de Gastroentérologie et Nutrition, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris, Paris 75012, France; 2IPSOS Healthcare Department, Paris 75013, FranceCorrespondence: Yves MorvanIPSOS Healthcare Department, 35 rue du Val de Marne, Paris 75013, FranceTel +33 1 41 98 93 44Fax +33 1 41 98 99 99Email yves.morvan@ipsos.comPurpose: Treatment adherence is crucial in patients with rheumatoid arthritis (RA). The device used by the patients for self-injections may influence adherence to methotrexate (MTX) treatment. A MTX-autoinjector has been recently marketed in Europe. This crossover survey compared this MTX-autoinjector (MTX-autoinjector A) and an already existing MTX-autoinjector (MTX-autoinjector B) from the patients’ perspective.Patients and Methods: A total of 100 patients with moderate to severe RA using MTX-autoinjector A (N=35) or MTX-autoinjector B (N=65) were interviewed by an independent Global Market Research Company. Face-to-face interviews were performed using a computer-assisted personal interview system. Evaluation of the unfamiliar MTX-autoinjector was performed once the patients had received information, seen a demonstration, and performed a virtual testing.Results: A substantial advantage in favor of the MTX-autoinjector A was found with respect to all surveyed indicators. Respectively, 95% and 55% of the users of MTX-autoinjectors A and B claimed to be very or totally satisfied with their familiar MTX-autoinjector. With respect to several specific characteristics, 91% and 60% of the users of MTX-autoinjectors A and B were very or totally satisfied with their familiar MTX-autoinjector, 29% and 77% found the unfamiliar MTX-autoinjector better, and 26% and 73% were interested in trying the unfamiliar MTX-autoinjector. Injection mode (with no push button) and end-of-injection recognition system (with audible signal) were identified as key features explaining a stronger preference for MTX-autoinjector A.Conclusion: Even though deserving further studying, these findings are expected to guide clinicians when prescribing or renewing prescription of MTX-autoinjector, in particular in poor or non-compliant patients. In a context of growing interest in shared decision-making, the objective would be to choose with each patient the best suited MTX-autoinjector, and ultimately, to obtain a better treatment adherence.Keywords: decision making, shared, methotrexate, patient satisfaction, rheumatoid arthritis, self-injection device

Background: Delay in the diagnosis of neurodevelopmental disorders (NDDs) in toddlers and postnatal depression (PND) is a major public health issue. In both cases, early intervention is crucial but too rarely implemented in practice., Objective: Our goal was to determine if a dedicated mobile app can improve screening of 5 NDDs (autism spectrum disorder [ASD], language delay, dyspraxia, dyslexia, and attention-deficit/hyperactivity disorder [ADHD]) and reduce PND incidence., Methods: We performed an observational, cross-sectional, data-based study in a population of young parents in France with at least 1 child aged <10 years at the time of inclusion and regularly using Malo, an "all-in-one" multidomain digital health record electronic patient-reported outcome (PRO) app for smartphones. We included the first 50,000 users matching the criteria and agreeing to participate between May 1, 2022, and February 8, 2024. Parents received periodic questionnaires assessing skills in neurodevelopment domains via the app. Mothers accessed a support program to prevent PND and were requested to answer regular PND questionnaires. When any PROs matched predefined criteria, an in-app recommendation was sent to book an appointment with a family physician or pediatrician. The main outcomes were the median age of the infant at the time of notification for possible NDD and the incidence of PND detection after childbirth. One secondary outcome was the relevance of the NDD notification by consultation as assessed by health professionals., Results: Among 55,618 children median age 4 months (IQR 9), 439 (0.8%) had at least 1 disorder for which consultation was critically necessary. The median ages of notification for probable ASD, language delay, dyspraxia, dyslexia, and ADHD were 32.5 (IQR 12.8), 16 (IQR 13), 36 (IQR 22.5), 80 (IQR 5), and 61 (IQR 15.5) months, respectively. The rate of probable ADHD, ASD, dyslexia, language delay, and dyspraxia in the population of children of the age included between the detection limits of each alert was 1.48%, 0.21%, 1.52%, 0.91%, and 0.37%, respectively. Sensitivity of alert notifications for suspected NDDs as assessed by the physicians was 78.6% and specificity was 98.2%. Among 8243 mothers who completed a PND questionnaire, highly probable PND was detected in 938 (11.4%), corresponding to a reduction of -31% versus our previous study without a support program. Suspected PND was detected a median 96 days (IQR 86) after childbirth. Among 130 users who filled in the satisfaction survey, 99.2% (129/130) found the app easy to use and 70% (91/130) reported that the app improved follow-up of their child. The app was rated 4.8/5 on Apple's App Store., Conclusions: Algorithm-based early alerts suggesting NDDs were highly specific with good sensitivity as assessed by real-life practitioners. Early detection of 5 NDDs and PNDs was efficient and led to a possible 31% reduction in PND incidence., Trial Registration: ClinicalTrials.gov NCT06301087; https://www.clinicaltrials.gov/study/NCT06301087., (©Fabrice Denis, Florian Le Goff, Madhu Desbois, Agnes Gepner, Guillaume Feliciano, Denise Silber, Jean-David Zeitoun, Guedalia Peretz Assuied. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 18.06.2024.)

Competing Interests: S. Jérusalmy déclare être associée chez Elaia Partners. J.-D. Zeitoun déclare être investisseur à titre personnel dans une trentaine de start-up dans le domaine médical, environnemental ou alimentaire, et être souscripteur dans trois fonds d’investissement, dont Elaia. En dehors du contenu de l’article, il déclare des consultations occasionnelles ou des interventions pour des groupes pharmaceutiques, des assurances, des groupes hospitaliers privés, ou des fonds d’investissement.

Purpose: The aim of this study was to assess frequency and risk factors of severe bleeding after proctological surgery requiring hemostatic surgery observed after publication of the French guidelines for anticoagulant and platelet-inhibitor treatment., Methods: All patients who underwent proctological surgery between January 2012 and March 2017 in a referral center were included. Delay, severity of bleeding, and need for blood transfusion were recorded. Patients with severe postoperative bleeding were matched to controls at a 2:1 ratio adjusted on the operator, and the type of surgery., Results: Among the 8,890 operated patients, 65 (0.7%) needed a postoperative hemostatic procedure in an operating room. The risk of a hemostatic surgery was significantly increased after hemorrhoidal surgery compared with other procedures (1.9% vs. 0.5%, P<10-4) and was most frequent after Milligan-Morgan hemorrhoidectomy (2.5%). Mean bleeding time was 6.2 days and no bleeding occurred after day 15. Blood transfusion rate was 0.1%. Treatment with anticoagulants and platelet inhibitors were managed according to recommendations and did not increase the severity of bleeding. The risk of severe bleeding was significantly lower in active smokers vs. non-smokers in univariate (16.9% vs. 36.2%, P=0.007) and multivariate (odds ratio, 0.31; 95% confidence interval, 0.14-0.65) analysis whereas sex, age, and body mass were not significantly associated with bleeding., Conclusion: Severe postoperative bleeding occurs in 0.7% of patients, but varies with type of procedure and is not affected by anticoagulant or antiplatelet treatment. These treatments given in accordance with the new guidelines do not increase the severity of postoperative bleeding.

Background: In 2020, more than 250 eHealth solutions were added to app stores each day, or 90,000 in the year; however, the vast majority of these solutions have not undergone clinical validation, their quality is unknown, and the user does not know if they are effective and safe. We sought to develop a simple prescreening scoring method that would assess the quality and clinical relevance of each app. We designed this tool with 3 health care stakeholder groups in mind: eHealth solution designers seeking to evaluate a potential competitor or their own tool, investors considering a fundraising candidate, and a hospital clinician or IT department wishing to evaluate a current or potential eHealth solution., Objective: We built and tested a novel prescreening scoring tool (the Medical Digital Solution scoring tool). The tool, which consists of 26 questions that enable the quick assessment and comparison of the clinical relevance and quality of eHealth apps, was tested on 68 eHealth solutions., Methods: The Medical Digital Solution scoring tool is based on the 2021 evaluation criteria of the French National Health Authority, the 2022 European Society of Medical Oncology recommendations, and other provided scores. We built the scoring tool with patient association and eHealth experts and submitted it to eHealth app creators, who evaluated their apps via the web-based form in January 2022. After completing the evaluation criteria, their apps obtained an overall score and 4 categories of subscores. These criteria evaluated the type of solution and domain, the solution's targeted population size, the level of clinical assessment, and information about the provider., Results: In total, 68 eHealth solutions were evaluated with the scoring tool. Oncology apps (22%, 20/90) and general health solutions (23%, 21/90) were the most represented. Of the 68 apps, 32 (47%) were involved in remote monitoring by health professionals. Regarding clinical outcomes, 5% (9/169) of the apps assessed overall survival. Randomized studies had been conducted for 21% (23/110) of the apps to assess their benefit. Of the 68 providers, 38 (56%) declared the objective of obtaining reimbursement, and 7 (18%) out of the 38 solutions seeking reimbursement were assessed as having a high probability of reimbursement. The median global score was 11.2 (range 4.7-17.4) out of 20 and the distribution of the scores followed a normal distribution pattern (Shapiro-Wilk test: P=.33)., Conclusions: This multidomain prescreening scoring tool is simple, fast, and can be deployed on a large scale to initiate an assessment of the clinical relevance and quality of a clinical eHealth app. This simple tool can help a decision-maker determine which aspects of the app require further analysis and improvement., (©Nicolas Wagneur, Patrick Callier, Jean-David Zeitoun, Denise Silber, Remi Sabatier, Fabrice Denis. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 05.07.2022.)

Background: Delays in the diagnosis of neurodevelopmental disorders (NDDs) in toddlers and postnatal depression (PND) in mothers are major public health issues. In both cases, early intervention is crucial., Objective: We aimed to assess if a mobile app named Malo can reduce delay in the recognition of NDD and PND., Methods: We performed an observational, cross-sectional, data-based study in a population of young parents with a minimum of 1 child under 3 years of age at the time of inclusion and using Malo on a regular basis. We included the first 4000 users matching the criteria and agreeing to participate between November 11, 2021, and January 14, 2022. Parents received monthly questionnaires via the app, assessing skills on sociability, hearing, vision, motricity, language of their infants, and possible autism spectrum disorder. Mothers were also requested to answer regular questionnaires regarding PND, from 4-28 weeks after childbirth. When any patient-reported outcomes matched predefined criteria, an in-app notification was sent to the user, recommending the booking of an appointment with their family physician or pediatrician. The main outcomes were the median age of the infant at the time of notification for possible NDD and the median time of PND notifications after childbirth. One secondary outcome was the relevance of the NDD notification for a consultation as assessed by the physicians., Results: Among 4242 children assessed by 5309 questionnaires, 613 (14.5%) had at least 1 disorder requiring a consultation. The median age of notification for possible autism spectrum, vision, audition, socialization, language, or motor disorders was 11, 9, 17, 12, 22, and 4 months, respectively. The sensitivity of the alert notifications of suspected NDDs as assessed by the physicians was 100%, and the specificity was 73.5%. Among 907 mothers who completed a PND questionnaire, highly probable PND was detected in 151 (16.6%) mothers, and the median time of detection was 8-12 weeks., Conclusions: The algorithm-based alert suggesting NDD was highly sensitive with good specificity as assessed by real-life practitioners. The app was also efficient in the early detection of PND. Our results suggest that the regular use of this multidomain familial smartphone app would permit the early detection of NDD and PND., Trial Registration: ClinicalTrials.gov NCT04958174; https://clinicaltrials.gov/ct2/show/NCT04958174., (©Fabrice Denis, Laura Maurier, Kevin Carillo, Roxana Ologeanu-Taddei, Anne-Lise Septans, Agnes Gepner, Florian Le Goff, Madhu Desbois, Baptiste Demurger, Denise Silber, Jean-David Zeitoun, Guedalia Peretz Assuied, Olivier Bonnot. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 16.05.2022.)

The persistence of a leaky gut in HIV-treated patients leads to chronic inflammation with increased rates of cardiovascular, liver, kidney, and neurological diseases. Tissue regulatory T (tTreg) cells are involved in the maintenance of intestinal homeostasis and wound repair through the IL-33 pathway. In this study, we investigated whether the persistence of gut mucosal injury during HIV infection might be explained in part by a flaw in the mechanisms involved in tissue repair. We observed an increased level of IL-33 in the gut of HIV-infected patients, which is associated with an increased level of fibrosis and a low peripheral reconstitution of CD4 + T cells. Our results showed that intestinal Treg cells from HIV-infected patients were enriched in tTreg cells prone to support tissue repair. However, we observed a functional defect in tTreg cells caused by the lack of amphiregulin secretion, which could contribute to the maintenance of intestinal damage. Our data suggest a mechanism by which the lack of amphiregulin secretion by tTreg may contribute to the lack of repair of the epithelial barrier., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Background: Whether voting is a risk factor for epidemic spread is unknown. Reciprocally, whether an epidemic can deter citizens from voting has not been often studied. We aimed to investigate such relationships for France during the coronavirus disease 19 (COVID-19) epidemic., Methods: We performed an observational study and dynamic modelling using a sigmoidal mixed effects model. All hospitals with COVID-19 patients were included (18 March 2020-17 April 2020). Abstention rate of a concomitant national election was collected., Results: Mean abstention rate in 2020 among departments was 52.5% ± 6.4% and had increased by a mean of 18.8% as compared with the 2014 election. There was a high degree of similarity of abstention between the two elections among the departments (P < 0.001). Among departments with a high outbreak intensity, those with a higher participation were not affected by significantly higher COVID-19 admissions after the elections. The sigmoidal model fitted the data from the different departments with a high degree of consistency. The covariate analysis showed that a significant association between participation and number of admitted patients was observed for both elections (2020: β = -5.36, P < 1e-9 and 2014: β = -3.15, P < 1e-6) contradicting a direct specific causation of the 2020 election. Participation was not associated with the position of the inflexion point suggesting no effect in the speed of spread., Conclusions: Our results suggest that the surrounding intensity of the COVID-19 epidemic in France did not have any local impact on participation to a national election. The level of participation had no impact on the spread of the pandemic., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Competing Interests: J.-D. Zeitoun déclare conseiller ou intervenir auprès de Pierre Fabre, AbbVie, AstraZeneca, Biogen, Takeda, Johnson et Johnson, Boehringer Ingelheim, Novartis. Il intervient aussi pour certains cabinets de conseils ou fonds d’investissement. Il est investisseur à titre personnel dans plusieurs start-up médicales ou liées à l’éducation ou l’environnement. S. Jéruslamy déclare participer ou avoir participé à des interventions ponctuelles pour AbbVie, AstraZeneca, Biogen, Boehringer Ingelheim, Takeda, Novartis, Fujifilm, Johnson et Johnson, ainsi que des investissements personnels dans une quinzaine de startups médicales (digital et/ou intelligence artificielle).

Competing Interests: J.-D. Zeitoun déclare conseiller ou intervenir auprès des laboratoires pharmaceutiques suivants (au cours des trois dernières années) : Pierre Fabre, AbbVie, AstraZeneca, Biogen, Takeda, Johnson et Johnson, Boehringer Ingelheim, Novartis. Il intervient aussi pour certains cabinets de conseil ou fonds d’investissement. Il est investisseur à titre personnel dans plusieurs startups médicales ou liées à l’éducation ou l’environnement.

Objectives: Several epidemiological models have been published to forecast the spread of the COVID-19 pandemic, yet many of them have proven inaccurate for reasons that remain to be fully determined. We aimed to develop a novel model and implement it in a freely accessible web application., Design: We built an SIR-type compartmental model with two additional compartments: D (deceased patients); L (individuals who will die but who will not infect anybody due to social or medical isolation) and integration of a time-dependent transmission rate and a periodical weekly component linked to the way in which cases and deaths are reported., Results: The model was implemented in a web application (as of 2 June 2020). It was shown to be able to accurately capture the changes in the dynamics of the pandemic for 20 countries whatever the type of pandemic spread or containment measures: for instance, the model explains 97% of the variance of US data (daily cases) and predicts the number of deaths at a 2-week horizon with an error of 1%., Conclusions: In early performance evaluation, our model showed a high level of accuracy between prediction and observed data. Such a tool might be used by the global community to follow the spread of the pandemic., Competing Interests: Competing interests: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. No conflict of interest related to the current work was reported. Outside the submitted work, J-DZ reports being an advisor for several consulting firms linked with pharmaceutical industry (Oliver Wyman, Roland Berger). He also reports speaking fees from a manufacturers’ professional association, consulting fees from Ferring, Pierre Fabre, AbbVie, AstraZeneca, Biogen, Boehringer Ingelheim, Takeda and Johnson & Johnson. He is a personal investor in approximately 20 digital companies, medical device companies or biotech companies, and as a limited partner in an investment fund. He reports being a founding partner of Inato, a company involved in clinical research and whose customers are pharmaceutical companies. JHL reports fees from Ethicon, Takeda and MD Start, and invitation to a medical congress by Biomup. He is a consultant for Safeheal., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: The treatment of perianal fistulas in Crohn's disease remains challenging. Fibrin glue injection has previously shown short-term efficacy in a randomized controlled trial. No long-term data are available to assess the benefit of this treatment., Methods: This retrospective multicentre study included all patients with drained fistulas treated by at least one fibrin glue injection between January 2004 and June 2015 in three tertiary French centres. The primary end-point was the rate of complete clinical remission at 1 year after injection defined by the closure of all fistula tracts with no need for iterative anal surgery or for optimization of immunosuppressants and/or biologics., Results: In all, 119 patients (median age 33 years, complex fistulas 65%, median previous anal surgery two, median Harvey Bradshaw score 3, immunosuppressants exposure 50%, anti-tumor necrosis factor exposure 60% with median time of administration of 1.1 year) were analysed with a median follow-up of 18.3 months. The complete clinical remission rate at 1 year was 45.4%. The primary end-point was achieved in 63% of the cases in the combination therapy group and 37% in other patients. The only predictor of complete clinical remission at 1 year was combination therapy at the time of injection (P = 0.01). The rate of early reintervention after glue injection was 2.5%. The cumulative incidence of iterative anal surgery and ostomy in the whole population was 54% and 5.6% respectively at 5 years., Conclusion: An adjunct of fibrin glue to conventional medical therapy may be an effective and safe treatment for perianal fistulas in patients with Crohn's disease., (© 2020 The Association of Coloproctology of Great Britain and Ireland.)

Purpose: Anal fistula is a common condition in proctology, usually requiring surgical treatment. Few risk factors have been clearly identified based on solid evidence. Our research objective was to determine whether history of anal surgery was a risk factor for subsequent anal fistula., Methods: We conducted a case-control study from January 1, 2012 through December 31, 2013 in our tertiary center, comprising 280 cases that underwent surgery for anal fistula and 123 control patients seeking a consultation for upper gastrointestinal symptoms. Patients with inflammatory bowel disease were excluded. For both cases and controls, the following variables were recorded: sex, any prior anal surgery, diabetes mellitus, infection with human immunodeficiency virus, and smoking status. For each variable, confidence interval and odds ratio (OR) were calculated., Results: In univariate analysis, male sex (73.2% vs. 31.7%, P < 0.0001), active smoking (38.1% vs. 22%, P = 0.0015), and prior anal surgery (16.0% vs. 4.1%, P = 0.0008) were associated with higher risk of anal fistula. In multivariate analysis, only male sex (OR, 5.5; 95% confidence interval [CI], 5.42 to 9.10; P < 0.0001) and previous anal surgery (OR, 4.48; 95% CI, 1.79 to 13.7; P = 0.0008) remained independently associated with anal fistula occurrence., Conclusion: The epidemiology of anal fistula is poorly assessed despite the high frequency at which it is diagnosed. Our findings suggest that history of any kind of anal surgery is a risk factor for further onset of anal fistula. Surgeons and patients must be informed of this issue.

Objectives: We aimed to investigate possible differences in the aggregated hospital fatality rate from coronavirus disease 2019 (COVID-19) in France at the early phase of the outbreak and to determine whether factors related to population or healthcare supply before the pandemic could be associated with outcome differences., Study Design: This is a nationwide observational study including all French hospitals from January 24, 2020, to April 11, 2020., Methods: We analyzed the aggregated hospital fatality rate. A Poisson regression was performed to investigate associations between characteristics pertaining to populational health, socio-economic context and local healthcare supply at baseline, and the chosen outcome., Results: On April 11, 2020, a total number of 30,960 patients were hospitalized among the 3046 French healthcare facilities, including 6832 patients in the intensive care unit (ICU). A total of 8581 deaths due to COVID-19 had been recorded, with a median mortality rate per 10,000 people per department of 0.53 (interquartile range: 0.29-1.90). There were significant variations between the 95 French departments even after adjusting for outbreak inception (P < 0.001). After multivariable analysis, four factors were independently associated with a significantly higher aggregated hospital fatality rate: a higher ICU capacity at baseline (estimate = 1.47; P = 0.00791), a lower density of general practitioners (estimate = 0.95; P = 0.0205), a lower fraction of activity from the for-profit private sector (estimate = 0.99; P < 0.001), and the ratio of people older than 75 years (estimate = 0.91; P = 0.0023)., Conclusions: The aggregated hospital fatality rate from COVID-19 in France seems to vary among geographic areas, with some factors pertaining to local healthcare supply being associated with the outcome., (Copyright © 2020 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

While national authorities recommended and provided reimbursement for men who have sex with men under 27 in 2016 and 2017, respectively, we aimed to comprehensively analyze human papillomavirus (HPV) vaccine uptake in French men over a 4-year period surrounding these changes. Data regarding HPV vaccine sales to men in all French pharmacies from 2015 through 2018 were retrieved through query made to the national public insurance database. Data were classified according to the age of patients and the time of dispensation so as to display aggregate uptake according to age over time. Time-series analysis was conducted and an exponential smoothing extrapolation was selected to analyze the impact of the reimbursement. Overall, 12,814 HPV vaccines were dispensed in men over the study period. Age was available for the majority of cases (12,793; 99.8%), averaging 29. Dispensation data for each year were the following: 1,917 (2015), 1,921 (2016), 2,643 (2017), 6,312 (2018). Age analysis showed that vaccine uptake among men over 26 was substantial (n = 5974; 46.7%). The exponential increase in the number of vaccines sold started after the second quarter of 2017. In conclusion, we found that HPV vaccine uptake among French men is partly misaligned with recommendations and reimbursement in terms of age, and still moderate overall even though we found signs of marked increase in uptake over the most recent period, suggesting an effective impact of insurance coverage.

Competing Interests: J.-D. Zeitoun déclare être président de Clim Care, association loi 1901 dont l’objet est la protection de la santé contre les effets négatifs du changement climatique, et ne pas avoir d’autre lien d’intérêts en rapport avec le thème de cet article. Par ailleurs J.-D. Zeitoun déclare : être consultant pour plusieurs sociétés de conseil en lien avec l’industrie pharmaceutique (Cepton, Oliver Wyman, Roland Berger, Havas) ; donner des conférences pour une association professionnelle de laboratoires pharmaceutiques ; avoir des activités de conseil pour Ferring, Pierre Fabre, AbbVie, AstraZeneca, Biogen, Boehringer Ingelheim, Janssen Cilag ; être investisseur à titre personnel dans une vingtaine de start-up médicales, dans le domaine du digital, du dispositif médical ou des biotechnologies et souscripteur dans plusieurs fonds d’investissement, avoir des stockoptions dans Allurion technologies ; être cofondateur d’Inato, une société d’analyse de données dans le domaine de la recherche clinique et dont les laboratoires pharmaceutiques sont des clients. M. Cordiez déclare des liens durables et permanents (contrat de travail, rémunération régulière) avec le CEA. P. Ravaud déclare n’avoir aucun lien d’intérêts.

Background: It has been suggested that poor health has influenced vote for Brexit and the US presidential election. No such research has been published regarding the 2017 French presidential election., Methods: We performed a cross-sectional analysis using a comprehensive set of socioeconomic and health indicators, to be compared with voting outcome at the first round of the 2017 French presidential election. The 95 French departments were selected as the unit of analysis. Data were obtained from publicly available sources. The linear model was used for both univariate and multivariate analysis to investigate the relation between voting patterns and predictors. Sensitivity analyses were done using the elastic-net regularisation., Results: Emmanuel Macron and Marine Le Pen arrived ahead. When projected on the first factorial plane (~ 60% of the total inertia), Emmanuel Macron and Marine Le Pen tended to be in opposite directions regarding both socioeconomic and health factors. In the respective multivariate analyses of the two candidates, both socio-economic and health variables were significantly associated with voting patterns, with wealthier and healthier departments more likely to vote for Emmanuel Macron, and opposite departments more likely to vote for Marine Le Pen. Mortality (p = 0.03), severe chronic conditions (p = 0.014), and diabetes mellitus (p < 0.0001) were among the strongest predictors of voting pattern for Marine Le Pen. Sensitivity analyses did not substantially change those findings., Conclusions: We found that areas associated with poorer health status were significantly more likely to vote for the far-right candidate at the French presidential election, even after adjustment on socioeconomic criteria.

Anal fissure. Anal fissure is a painful proctological disease that most often affects young patients equally in both sexes. It significantly worsens the quality of life and requires rapid care. The anal fissure is most often located in the posterior anal commissure and frequently surmounted by a skin tag which can hide it and wrongly carry the diagnosis of hemorrhoids. Differential diagnoses such as carcinoma, Crohn's disease, sexually transmitted infection, etc. should be mentioned in case of atypical presentation. Its pathophysiology remains controversial, but in most cases, it results from the trauma of the passage of hard stools on an hypertonic anus. Medical treatment can cure just over half of patients. Surgery is reserved for failures of medical treatment and hyperalgesic fissure. In France, fissurectomy is the most commonly performed procedure while on the other side of the Channel or the Atlantic, lateral internal sphincterotomy is considered as the reference technique., Competing Interests: Les auteurs déclarent n’avoir aucun lien d’intérêts.

Background and Aims: Endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) has been proposed to obtain high-quality tissue samples for pancreatic tumors. We performed an observational study to compare EUS-FNB with a 20-gauge Procore® needle versus a 22-gauge Acquire® needle. Our primary endpoint was the quantity of the obtained tissue, as defined by the mean cumulative length of tissue core biopsies per needle pass. Methods: Sixty-eight EUS-FNB were consecutively performed on patients with a pancreatic mass. The choice of needle depended on availability at the time of admission: 34 punctures were performed with each needle. Histological material was studied in a blinded manner with respect to the needle, and the cumulative length of tissue core biopsies per needle pass was determined. Intraobserver and interobserver variability of this criterion was then evaluated. Results: There were no between-group differences. Histological diagnosis was achieved and core biopsy specimens were obtained in 28 out of 34 patients (82%) in the 20-gauge Procore® group and in 33 out of 34 patients (97%) in the 22-gauge Acquire® group ( p  = .1). The mean cumulative length of tissue core biopsies per needle pass was significantly higher with the 22-gauge Acquire® needle with 8.2 ± 4.2 mm versus 4.2 ± 3.8 mm for the 20-gauge Procore® needle ( p  < .01). No intra and inter-observer variability of this criterion was observed. Conclusions: Our results suggest significant differences, with a mean cumulative length of tissue core biopsies per needle pass significantly higher with the 22-gauge Acquire® needle. This simple criterion seems reliable and reproducible.

We examined whether drug-related characteristics-conditions, development, manufacturers, revenues-were associated with postmarketing research in terms of the number of trials and total population to be enrolled. We included 63 drugs, corresponding to 3,867 postmarketing trials of approved indications. On multivariable analysis, both the number of postmarketing trials and population to be enrolled were associated with expected length of treatment (ratio of means (RoM) = 2.35 and RoM = 8.65) and number of patients in pivotal trials (RoM = 1.11 and RoM = 1.25 per thousand patients). The number of postmarketing trials was increased for drugs approved with surrogate endpoints (RoM = 2.19), generating high revenues (RoM = 1.08 per billion dollars) and addressing greater disease burden (RoM = 1.90 per hundred million disability-adjusted life years). The population to be included was increased for drugs approved after an increased number of pivotal trials (RoM = 1.82) and those unaffected by safety concerns (RoM = 2.63). Postmarketing trials seem to be driven both by medical and market factors., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Background & Aims: Little is known about the magnitude of the risk of anal and rectal cancer in patients with anal and/or perineal Crohn's disease. We aimed to assess the risk of anal and rectal cancer in patients with Crohn's perianal disease followed up in the Cancers Et Surrisque Associé aux Maladies Inflammatoires Intestinales En France (CESAME) cohort., Methods: We collected data from 19,486 patients with inflammatory bowel disease (IBD) enrolled in the observational CESAME study in France, from May 2004 through June 2005; 14.9% of participants had past or current anal and/or perianal Crohn's disease. Subjects were followed up for a median time of 35 months (interquartile range, 29-40 mo). To identify risk factors for anal cancer in the total CESAME population, we performed a case-control study in which participants were matched for age and sex., Results: Among the total IBD population, 8 patients developed anal cancer and 14 patients developed rectal cancer. In the subgroup of 2911 patients with past or current anal and/or perianal Crohn's lesions at cohort entry, 2 developed anal squamous-cell carcinoma, 3 developed perianal fistula-related adenocarcinoma, and 6 developed rectal cancer. The corresponding incidence rates were 0.26 per 1000 patient-years for anal squamous-cell carcinoma, 0.38 per 1000 patient-years for perianal fistula-related adenocarcinoma, and 0.77 per 1000 patient-years for rectal cancer. Among the 16,575 patients with ulcerative colitis or Crohn's disease without anal or perianal lesions, the incidence rate of anal cancer was 0.08 per 1000 patient-years and of rectal cancer was 0.21 per 1000 patient-years. Among factors tested by univariate conditional regression (IBD subtype, disease duration, exposure to immune-suppressive therapy, presence of past or current anal and/or perianal lesions), the presence of past or current anal and/or perianal lesions at cohort entry was the only factor significantly associated with development of anal cancer (odds ratio, 11.2; 95% CI, 1.18-551.51; P = .03)., Conclusions: In an analysis of data from the CESAME cohort in France, patients with anal and/or perianal Crohn's disease have a high risk of anal cancer, including perianal fistula-related cancer, and a high risk of rectal cancer., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: The surgical standard of care for patients with chronic anal fissure is still disputed. We aimed to assess the natural course of idiopathic anal fissure and the long-term outcome of a fissurectomy as a surgical treatment., Methods: All consecutive patients referred to a single expert practitioner in a tertiary centre were primarily included. A fissurectomy was proposed in cases of refractory symptoms after 4 to 6 weeks of standard medical management. Only patients with idiopathic and noninfected anal fissures were included in this second subsample to undergo surgery. Conventional postoperative management was prescribed for all patients who had undergone surgery. The main outcome measures were the success rate (defined as a combination of wound healing and relief of pain) and postoperative anal continence., Results: Three hundred forty-nine patients were primarily recruited. Fifty patients finally underwent surgery for an idiopathic and noninfected fissure. Among them, 47 (94%) were cured at the end of primary follow-up, and 44 of the 47 (93.6%) could be confirmed as being sustainably cured in the longer-term follow-up. The mean time of complete healing was 10.3 weeks (range, 5.7-36.4 weeks). All patients were free of pain at weeks 42. The continence score after surgery was not statistically different from the preoperative score., Conclusion: A fissurectomy for the treatment of patients with an idiopathic noninfected fissure is associated with rapid pain relief and a high success rate even though complete healing may often be delayed. Moreover, it appears to have no adverse effect on continence.

Post-marketing research in oncology has rarely been described. We aimed to characterize post-marketing trials for a consistent set of anticancer agents over a long period. We performed a cross-sectional analysis of post-marketing trials registered at ClinicalTrials.gov through September 2014 for novel anticancer agents approved by both the US Food and Drug Administration and the European Medicines Agency between 2005 and 2010. All relevant post-marketing trials were classified according to indication, primary outcome, starting date, sponsors, and planned enrollment. Supplemental indications were retrieved from regulatory documents and publication rate was assessed by two different methods. Ten novel anticancer agents were eligible: five were indicated for hematologic malignancies and the remaining five for solid cancers (three for kidney cancer). We identified 2,345 post-marketing trials; 1,362 (58.1%) targeted an indication other than the originally approved one. We observed extreme variations among drugs in both number of post-marketing trials (range 8-530) and overall population to be enrolled per trial (1-8,381). Post-marketing trials assessed almost all types of cancers, the three most frequently studied cancers being leukemia, kidney cancer and myeloma. In all, 6.6% of post-marketing trials had a clinical endpoint as a primary outcome, and 35.9% and 54.1% had a safety or surrogate endpoint, respectively, as a primary outcome. Nine drugs obtained approval for supplemental indications. The publication rate at 10 years was 12.3 to 26.1% depending on the analysis method. In conclusion, we found that post-marketing research in oncology is highly heterogeneous and the publication rate of launched trials is low., (© 2017 UICC.)

Objectives: To characterise postmarketing studies for drugs that were newly approved by the US Food and Drug Administration and the European Medicines Agency., Design and Setting: Cross-sectional analysis of postmarketing studies registered in ClinicalTrials.gov until September 2014 for all novel drugs approved by both regulators between 2005 and 2010. Regulatory documents from both agencies were used., Primary and Secondary Outcome Measures: All identified postmarketing studies were classified according to planned enrolment, funding, status and geographical location, and we determined whether studies studied the originally approved indication., Results: Overall, 69 novel drugs approved between 2005 and 2010 were eligible for inclusion. A total of 6679 relevant postmarketing studies were identified; 5972 were interventional (89.4%). The median number of studies per drug was 55 (IQR 33-119) and median number of patients to be enrolled per study was 60 (IQR 28-183). Industry was the primary sponsor of 2713 studies (40.6%) and was a primary or secondary sponsor in 4176 studies (62.5%). In all, 2901 studies (43.4%) were completed, 487 (7.3%) terminated, 1013 (15.2%) active yet not recruiting, 1895 (28.4%) recruiting and 319 (4.8%) not yet recruiting. A total of 80% of studies were conducted in only one country and 84.4% took place in Europe and/or North America; 2441 (36.5%) studied another indication than the originally approved indication. Studies designed in the originally approved indication were found to be more industry-sponsored than others 68.7%vs53.7%; P<0.0001., Conclusions: Postmarketing pharmaceutical research was highly variable and predominantly located in North America and Europe. Postmarketing studies were frequently designed to study indications other than the originally approved one. Although some findings were reassuring, others question the lack of coordination of postmarketing research., Competing Interests: Competing interests: J-DZ reports that he serves as an advisor for several consulting firms and communication companies linked with the pharmaceutical industry (Cepton, Oliver Wyman, Roland Berger, McCann Healthcare, Omnicom, Grey Healthcare, Saatchi and Saatchi Healthcare, Sudler & Hennessey, TBWA, inVentiv Health France, Havas). He also reports compensation for lectures given to manufacturer professional associations; collaboration with Mayoly-Spindler, Merck, Teva, Johnson & Johnson and Menarini; unpaid consultancy for EY; conducting workshops funded by Amgen; and being invited to a French medical congress by AbbVie. JSR receives support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing; from the Centers of Medicare and Medicaid Services (CMS) to develop and maintain performance measures that are used for public reporting; from Medtronic and the US FDA to develop methods for postmarket surveillance of medical devices; from the Blue Cross Blue Shield Association to better understand medical technology evaluation and from the Laura and John Arnold Foundation to support the Collaboration on Research Integrity and Transparency (CRIT) at Yale., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Findings regarding the association of cohort changeovers with patient outcomes are mixed. We sought to examine the association of resident and fellow changeovers with a comprehensive set of indicators., Methods: We performed a cross-sectional comparative study including all French teaching and non-teaching hospitals. All-cause mortality and length of stay were assessed. Focused analysis for three medical conditions (myocardial infarction, intestinal hemorrhage, stroke) and three surgical procedures (colorectal, vascular and spine surgery) was performed regarding other quality and efficiency indicators (readmissions, intensive care unit admission, transfers)., Results: Overall, 34 330 716 patients were admitted in 2011 and 2012. Within the month following cohort changeovers, no increase in mortality was observed in teaching hospitals. Length of stay was longer in May and November in teaching hospitals (P < 0.0001) whereas it was shorter in the private sector. When focusing on six selected causes of hospitalization, we observed significant differences associated with resident changeovers, suggesting a decreased efficiency. In particular, readmissions rates and lengths of stay were found to be significantly higher (P < 0.0005) after intestinal hemorrhage and with a trend toward worse efficiency (P < 0.005) after colorectal surgery and stroke in teaching hospitals., Conclusion: Our findings provide some reassurance regarding cohort changeover and mortality even if they suggest a loss of efficiency in some cases., (© The Author 2017. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: Anoperineal lesion (APL) occurrence is a significant event in the evolution of Crohn's disease (CD). Management should involve a multidisciplinary approach combining the knowledge of the gastroenterologist, the colorectal surgeon and the radiologist who have appropriate experience in this area. Given the low level of evidence of available medical and surgical strategies, the aim of this work was to establish a French expert consensus on management of anal Crohn's disease. These recommendations were led under the aegis of the Société Nationale Française de Colo-Proctologie (SNFCP). They report a consensus on the management of perianal Crohn's disease lesions, including fistulas, ulceration and anorectal stenosis and propose an appropriate treatment strategy, as well as sphincter-preserving and multidisciplinary management., Methodology: A panel of French gastroenterologists and colorectal surgeons with expertise in inflammatory bowel diseases reviewed the literature in order to provide practical management pathways for perianal CD. Analysis of the literature was made according to the recommendations of the Haute Autorité de Santé (HAS) to establish a level of proof for each publication and then to propose a rank of recommendation. When lack of factual data precluded ranking according to the HAS, proposals based on expert opinion were written. Therefore, once all the authors agreed on a consensual statement, it was then submitted to all the members of the SNFCP. As initial literature review stopped in December 2014, more recent European or international guidelines have been published since and were included in the analysis., Results: MRI is recommended for complex secondary lesions, particularly after failure of previous medical and/or surgical treatments. For severe anal ulceration in Crohn's disease, maximal medical treatment with anti-TNF agent is recommended. After prolonged drainage of simple anal fistula by a flexible elastic loop or loosely tied seton, and after obtaining luminal and perineal remission by immunosuppressive therapy and/or anti-TNF agents, the surgical treatment options to be discussed are simple seton removal or injection of the fistula tract with biological glue. After prolonged loose-seton drainage of the complex anal fistula in Crohn's disease, and after obtaining luminal and perineal remission with anti-TNF ± immunosuppressive therapy, surgical treatment options are simple removal of seton and rectal advancement flap. Colostomy is indicated as a last option for severe APL, possibly associated with a proctectomy if there is refractory rectal involvement after failure of other medical and surgical treatments. The evaluation of anorectal stenosis of Crohn's disease (ARSCD) requires a physical examination, sometimes under anesthesia, plus endoscopy with biopsies and MRI to describe the stenosis itself, to identify associated inflammatory, infectious or dysplastic lesions, and to search for injury or fibrosis of the sphincter. Therapeutic strategy for ARSCD requires medical-surgical cooperation.

For oncology drugs that were approved by the US Food and Drug Administration (FDA) and required pharmacogenomic biomarker testing, we describe 1) the use of enrichment (biomarker-positive patients) and a randomized controlled design by pre-approval trials and 2) the treatment-by-biomarker interaction. From the 137 drugs included in the FDA table, we selected the 22 oncology drugs with required genetic testing in their labels. These drugs corresponded to 35 approvals supported by 80 clinical studies included in the FDA medical officer reviews of efficacy. For two thirds of approvals (24/35, 69%), all clinical studies were restricted to biomarker-positive patients (enriched). Among the 11 remaining approvals with at least one non-enriched trial, for five approvals, the non-enriched studies were non-randomized. The treatment-by-biomarker interaction was statistically significant for three approvals and missing for two. Among the six approvals with a non-enriched randomized controlled trial, three featured a statistically significant treatment-by-biomarker interaction (p < 0.10), for an enhanced treatment effect in the biomarker-positive subgroup. For two thirds of FDA approvals of anticancer agents, the requirement for predictive biomarker testing was based on clinical development restricted to biomarker-positive patients. We found only few cases with clinical evidence that biomarker-negative patients would not benefit from treatment.

Importance: Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making., Objectives: To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk., Design and Setting: Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017., Exposures: Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near-regulatory deadline approval, and regulatory review time., Main Outcomes and Measures: A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications., Results: From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near-regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02)., Conclusions and Relevance: Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event. Biologics, psychiatric therapeutics, and accelerated and near-regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.

Background: Prices of anti-cancer drugs are skyrocking. We aimed to assess the clinical benefit of new drugs for treating advanced solid tumors at the time of their approval by the US Food and Drug Administration (FDA) and to search for a relation between price and clinical benefit of drugs., Materials and Methods: We included all new molecular entities and new biologics for treating advanced solid cancer that were approved by the FDA between 2000 and 2015. The clinical benefit of drugs was graded based on FDA medical review of pivotal clinical trials using the 2016-updated of the American Society of Clinical Oncology Value Framework (ASCO-VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Characteristics of drugs and approvals were obtained from publicly available FDA documents and price was evaluated according to US Medicare, US Veterans Health Administration and United Kingdom market systems., Results: The FDA approved 51 new drugs for advanced solid cancer from 2000 to 2015; we could evaluate the value of 37 drugs (73%). By the ESMO-MCBS, five drugs (14%) were grade one (the lowest), nine (24%) grade two, 10 (27%) grade three, 11 (30%) grade four and two (5%) grade five (the highest). Thus, 13 drugs (35%) showed a meaningful clinical benefit (scale levels 4 and 5). By the ASCO-VF which had a range of 3.4-67, the median drug value was 37 (interquartile range 20-52). We found no relationship between clinical benefit and drug price (P = 0.9). No characteristic of drugs and of approval was significantly associated with clinical benefit., Conclusion: Many recently FDA-approved new cancer drugs did not have high clinical benefit as measured by current scales. We found no relation between the price of drugs and benefit to society and patients., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Surgical readmissions have been extensively studied in North America, but very few data from other countries are available. We aimed to describe surgical readmissions in France and to assess their association with hospital status, surgical volume, and day surgery activity., Methods: We performed a cross-sectional study encompassing all 1270 French hospitals, except for military hospitals and hospitals with very small volume. Data were retrieved from the national database regarding all patients undergoing surgery between January 1, 2010 and November 30, 2010. The main outcome measure was 30-day readmission rate. Association with hospital status, surgical volume, and the level of day surgery were assessed. Risk adjustment was performed based upon administrative categories., Results: After exclusion of deaths and hospital transfers, there were 1,686,602 patients in the study cohort. Thirty-day readmission rate was 5.9 %. Distribution was skewed, with 21.5 % of procedures accounting for 33.5 % of all 30-day readmissions. Early readmissions (≤3 days) were associated with higher mortality as compared to those occurring later (>7 days) (3.2 vs. 2.6 %; p < 0.0001). After multivariate analysis, University hospitals were shown to be affected by a significantly greater risk of 30-day readmission as compared to private hospitals (odds ratio 1.46 [95 % CI 1.42-1.5]). Other independent factors were as follows: male gender, longer initial hospital stay, and comorbidities., Conclusions: Surgical 30-day readmission rate was low, with early readmissions being associated with higher mortality. Conversely to prior research, University hospitals were shown to be associated with significantly higher risk of 30-day readmissions, even after risk adjustment.

Background: Clinical trial registries may allow for producing a global mapping of health research. However, health conditions are not described with standardized taxonomies in registries. Previous work analyzed clinical trial registries to improve the retrieval of relevant clinical trials for patients. However, no previous work has classified clinical trials across diseases using a standardized taxonomy allowing a comparison between global health research and global burden across diseases. We developed a knowledge-based classifier of health conditions studied in registered clinical trials towards categories of diseases and injuries from the Global Burden of Diseases (GBD) 2010 study. The classifier relies on the UMLS® knowledge source (Unified Medical Language System®) and on heuristic algorithms for parsing data. It maps trial records to a 28-class grouping of the GBD categories by automatically extracting UMLS concepts from text fields and by projecting concepts between medical terminologies. The classifier allows deriving pathways between the clinical trial record and candidate GBD categories using natural language processing and links between knowledge sources, and selects the relevant GBD classification based on rules of prioritization across the pathways found. We compared automatic and manual classifications for an external test set of 2,763 trials. We automatically classified 109,603 interventional trials registered before February 2014 at WHO ICTRP., Results: In the external test set, the classifier identified the exact GBD categories for 78 % of the trials. It had very good performance for most of the 28 categories, especially "Neoplasms" (sensitivity 97.4 %, specificity 97.5 %). The sensitivity was moderate for trials not relevant to any GBD category (53 %) and low for trials of injuries (16 %). For the 109,603 trials registered at WHO ICTRP, the classifier did not assign any GBD category to 20.5 % of trials while the most common GBD categories were "Neoplasms" (22.8 %) and "Diabetes" (8.9 %)., Conclusions: We developed and validated a knowledge-based classifier allowing for automatically identifying the diseases studied in registered trials by using the taxonomy from the GBD 2010 study. This tool is freely available to the research community and can be used for large-scale public health studies.

Purpose: The aim of this study was to describe pharmacogenomics-based inclusion criteria (enrichment) and the main characteristics of clinical trials involving oncology-targeted therapies., Methods: Clinical trials of oncology-targeted therapies approved after 2005 with pharmacogenomic testing required or recommended in their label were retrieved from a mapping of the ClinicalTrials.gov database., Results: We examined information for 12 drugs and 858 trials. Overall, 434 trials (51%) were enriched on the biomarker first mentioned in the label and 145 (17%) were enriched on another biomarker, whereas 270 trials (31%) included all patients. The median proportion of trials corresponding to both the drug's indication and drug's target was 35%. Of the 361 trials that tested drugs in another disease than the first one in the label, 219 (61%) were without enrichment and 87 (24%) were actually enriched but on another biomarker than the first one in the label., Conclusion: Several drugs have been tested in trials enriched on many different biomarkers. Nonetheless, most targeted therapies have been developed only using biomarker-positive patients; therefore, exclusion of biomarker-negative patients from treatment relies on only preclinical data and on biological understanding of the disease and target.Genet Med 18 8, 796-805.

Purpose: The aim of the study is to describe preapproval safety concerns expressed by the European Medicines Agency (EMA) following regulatory review and to compare those concerns with subsequent issuance of postmarket safety communications., Methods: All novel medicines approved by the EMA through the centralized authorization procedure from 2001 to 2010 were included. Preapproval safety concerns were identified through examination of information related to regulatory review publicly available on the EMA's website. Relevant postmarket safety events were identified through Dear Healthcare Professional Communications (DHPCs), including those resulting in a withdrawal, issued by at least one of four leading national regulators of the European Union., Results: Among the 184 novel medicines included, the EMA had expressed at least one preapproval safety concern for 110 (59.8%) of them. Then, at least one safety communication was issued for 53 (28.8%) medicines within the postmarket period of study, totaling 90 DHPCs and 5 withdrawals. Overall, these 95 DHPCs and withdrawals were pertaining to 66 different clinical safety events. The EMA had expressed a preapproval concern consistent with the postmarket safety event for 22.7% (15 of 66). The rate of issuance of a postmarket safety communication was not statistically different between medicines with or without any preapproval safety concern (31.8% vs. 24%, p = 0.25)., Conclusions: Preapproval safety concerns are frequently expressed by the EMA following regulatory review. However, when comparing postmarket safety communications with prior concerns, anticipation was low. Our findings emphasize the need to systematically conduct postmarket studies dedicated to safety evaluation. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: The role of physical trauma in the onset of symptoms in Ehlers-Danlos syndrome (EDS) has never been characterized. We sought to search and describe brain lesions EDS patients also having personal history of physical trauma. We systematically performed brain magnetic resonance imaging in a first cohort of patients with a hypermobility type of EDS which described the onset of their disease or its worsening after a physical trauma. Unexpected yet consistent findings that were thought to be related to the reported traumas led to perform brain imaging in all subsequent patients with similar symptoms regardless of a history of trauma and to search for a prior trauma by active questioning., Results: Fifty-nine patients were recruited and analyzed, among which 53 (89.8%) were women. Overall, 26 (44.1%) reported a personal history of physical trauma. Six signs pertaining to subcortical lesions and affecting white matter tracts were identified. Those included lesions of the reticular formation, the two lenticular nuclei, the corpus callosum and the arcuate fasciculus. Thirty-six patients (61.0%) had at least 5 of the 6 imaging signs. In case of a trauma before 18, patients had significantly more lesions of the reticular formation (100% vs. 50%; p = 0.0035)., Conclusions: Patients with EDS, hypermobility type, were found to have consistent and specific brain lesions involving white matter tracts. Moreover, the record of a physical trauma in a substantial proportion of cases suggests that these lesions could be post-trauma consequences. Therefore, physical trauma could be a triggering factor in EDS.

The challenge of digital technologies in healthcare. Digital technologies are just starting to find their place into healthcare systems. However, their potential seems huge. The need for a better cost control, for therapeutic innovation and the generalized connectivity appear to be the three main driving factors. Digital companies invent applications for mobile phone, software and services that aim to enable physician practices, to substitute to medical advice and to reduce the need for hospitalizations through better management and prevention. There are still weaknesses, hurdles and uncertainties yet it is likely that the medical community will benefit from digital deployment in the long run. To make it happen, we will need to involve ourselves into the conception of digital solutions and to contribute to the needed changes regarding our business models., Competing Interests: J.-D. Zeitoun remercie Nicolas Colin pour ses conseils et Antoine Zins pour ses échanges quotidiens.

Aims: Regulatory review time has been associated with post-market medication safety issues in the United States. Our objective was to evaluate whether regulatory review time and near deadline approval are associated with post-market safety events (PMSEs) for novel medicines approved by the European Medicines Agency (EMA)., Methods: We performed a cross-sectional analysis of all novel medicines approved by the EMA through the centralized authorization procedure between 2001 and 2010. PMSEs were defined as withdrawals and communications identified through Dear Healthcare Professional Communications (DHPCs). Regulatory review time was defined as the time that elapsed between the start of the assessment procedure and approval. Near regulatory deadline approval was defined as approval within the 30 days before the EMA's 210 day regulatory deadline., Results: Among 161 eligible medicines, PMSEs were identified for 49 (30.4%), 44 of which were DHPCs, five of which were withdrawals. Median regulatory review time was 337 days (IQR 276-406) and was not associated with PMSEs (P = 0.57). However, when categorized by regulatory review speed tertile, there were differences in risk of PMSEs, with higher rates among medicines in the middle tertile (25 of 55, 45.4%; P = 0.01). Finally, 26 medicines were approved near the 210 day regulatory deadline, but were not more likely to have PMSEs (38.5% vs. 28.7%; P = 0.32)., Conclusions: Neither faster EMA regulatory review speed nor approval near regulatory deadlines was associated with greater likelihood of PMSEs among recently approved novel medicines., (© 2015 The British Pharmacological Society.)

Background: The European Medicines Agency (EMA) and national regulators share the responsibility to communicate to healthcare providers postmarketing safety events but little is known about the consistency of this process. We aimed to compare public availability of safety-related communications and drug withdrawals from the EMA and European Union member countries for novel medicines., Methods and Findings: We performed a cross-sectional analysis using public Dear Healthcare Professional Communications (DHPCs) for all novel medicines authorized between 2001 and 2010 by the EMA and available for use in France, Netherlands, Spain, and the United Kingdom. Between 2001 and 2010, the EMA approved 185 novel medicines. DHPCs could not be ascertained for the EMA. Among the 4 national regulators, as of April 30, 2013, at least one safety DHPC or withdrawal occurred for 53 (28.6%) medicines, totaling 90 DHPCs and 5 withdrawals. Among these 53 medicines, all 4 national agencies issued at least one communication for 17 (32.1%), three of the four for 25 (47.2%), two of the four for 6 (11.3%), and one of the four for 5 (9.4%). Five drugs were reported to be withdrawn, three by all four countries, one by three and one by two. Among the 95 DHPCs and withdrawals, 20 (21.1%) were issued by all 4 national regulators, 37 (38.9%) by 3 of the 4, 22 (23.2%) by 2 of the 4, and 16 (16.8%) by one. Consistency of making publicly available all identified safety DHPC or withdrawal across regulator pairs varied from 33% to 73% agreement., Conclusions: Safety communications were not made publicly available by the EMA. Among the 4 European member countries with national regulators that make DHPCs publicly available since at least 2001, there were substantial inconsistencies in safety communications for novel medicines. The impact of those inconsistencies in terms of public health remains to be determined.

Background and Objectives: Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders. Gastrointestinal manifestations in EDS have been described but their frequency, nature and impact are poorly known. We aimed to assess digestive features in a national cohort of EDS patients., Methods: A questionnaire has been sent to 212 EDS patients through the French patient support group, all of which had been formally diagnosed according to the Villefranche criteria. The questionnaire included questions about digestive functional symptoms, the GIQLI (Gastrointestinal Quality of Life Index), KESS scoring system and the Rome III criteria., Results: Overall, 135 patients (64% response rate) completed the questionnaire and 134 were analyzable (123 women; 91%). Mean age and Body Mass Index were respectively 35±14.7 years and 24.3±6.1 kg/m(2). The most common EDS subtype was hypermobility form (n=108; 80.6%). GIQLI and KESS median values were respectively 63.5 (27-117) and 19 [13.5-22]. Eighty four percent of patients had functional bowel disorders (FBD) according to the Rome III criteria. An irritable bowel syndrome according to the same criteria was observed in 64 patients (48%) and 48 patients (36%) reported functional constipation. A gastro-esophageal reflux disease (GERD) was reported in 90 patients (68.7%), significantly associated with a poorer GIQLI (60.5±16.8 versus 75.9±20.3; p<0.0001). GIQLI was also negatively impacted by the presence of an irritable bowel syndrome or functional constipation (p=0.007). There was a significant correlation between FBD and GERD., Conclusions: Natural frequency of gastrointestinal manifestations in EDS seems higher than previously assessed. FBD and GERD are very common in our study population, the largest ever published until now. Their impact is herein shown to be important. A systematic clinical assessment of digestive features should be recommended in EDS.

Chronic constipation is a very common condition, which is responsible for a major socioeconomic burden. Primary management must rule out secondary constipation before recognizing chronic idiopathic constipation, which is the most common diagnosis. Initial treatment frequently associates simple lifestyle modifications, whose efficacy is limited, with osmotic laxatives or bulking agents. If those measures do not relieve symptoms, a switch of laxatives or a combination must be proposed. Pharmacological treatments of constipation represent a new alternative approach in case of failure of previously mentioned measures. In case of chronic constipation reluctant to all conservative therapies, specific tests are required before considering biofeedback intervention or exceptionally a surgical option., (Copyright © 2013. Published by Elsevier Masson SAS.)

Anal intraepithelial lesions are caused by chronic infection with oncogenic types of human papillomavirus. Their incidence and prevalence are increasing, especially among patients with HIV infection. Their natural history is not well known, but high-grade intraepithelial lesions seem to have an important risk to progress to squamous cell carcinoma. Their treatment can be achieved by many ways (surgery, coagulation, imiquimod, etc.) but there is a high rate of recurrent lesions. Pretherapeutic evaluation should benefit from high-resolution anoscopy. Periodic physical examination and anal cytology may probably be interesting for screening the disease among patients with risk factors. Vaccine against oncogenic types of papillomavirus may prevent the development of anal intraepithelial neoplasia., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Background and Objective: Infliximab, a monoclonal antibody directed against tumor necrosis factor α (TNFα), is commonly used during flares and on a regular basis to maintain the remission of inflammatory bowel diseases (IBD). It is usually administered in 2-hours infusion and 2 hours of monitoring after as recommended. However, recent reports suggest that infliximab infusions over a shorter period (30 minutes to 1 hour) are well tolerated. We aimed to compare the tolerability of 1-hour and 2-hours infliximab infusions in patients with IBD in our institution., Methods: We analyzed data from all patients treated with infliximab between 1999 and September 2010. Infliximab was administered in 1-hour infusion and 1 hour monitoring since 2009. Only the early adverse events were analyzed., Results: Adverse events during infusion were compared between one group of patients who had 1-hour infusion (989 infusions) and the other who had 2-hours infusion (2102 infusions). The incidence of adverse events was 10.6% in the 2-hours infusion group versus 6.3% in the 1-hour infusion group (P=0.36)., Conclusions: These results suggest that the occurrence of infliximab infusion-related adverse events is similar across the two groups, regardless of the infusion cycle. One-hour infusion could then be proposed safely for all patients., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Aim: The aim of this study was to analyse the characteristics of horseshoe tract formation in anal fistula., Method: We retrospectively analysed the data from all consecutive patients who underwent surgery for an anal fistula from November 2004 to March 2011. A horseshoe tract was defined as a circumferential extension connecting both sides of the anorectum., Results: During the period of analysis, 1876 patients were operated on for a fistula. Of these, 82 (4.4%) had a horseshoe extension. The majority (72%) were male and the median age was 46 (17-84) years. The primary tract was high transsphincteric in 90% of cases and the primary opening was posterior in 65% of cases. The location of the horseshoe extension was posterior in 66% of cases with spread in the deep perianal space in 62%. In all, 71% were cryptoglandular and 24% were seen in Crohn's disease (20). Of the 62 non-Crohn's patients previous treatment was common and included surgery (42), antibiotics alone (41) and non-steroidal anti-inflammatory drugs (21)., Conclusion: Horseshoe extension in anal fistula is uncommon. With Crohn's disease excepted, the majority had had previous treatment., (© 2012 The Authors. Colorectal Disease © 2012 The Association of Coloproctology of Great Britain and Ireland.)