Antidopaminergic antiemetics and trauma-related hospitalization: A population-based self-controlled case series study.

AIMS: The aim of this study was to evaluate the risk of trauma associated with the use of antidopaminergic antiemetics in a real-world setting. METHODS: A self-controlled case series analysis was performed using the EGB database, the representative sample of the French national healthcare insurance system database. All subjects aged 18 years and over who presented with at least 1 trauma-related hospitalization and 1 supply for domperidone, metoclopramide or metopimazine between 2009 and 2014 were included in the study. Associations were evaluated by incidence rate ratios. RESULTS: Included exposed cases were 7610 for domperidone cohort, 2189 for metoclopramide and 3911 for metopimazine. Incidence rate ratio for trauma-related hospitalization during the first 7 days of exposure period compared to unexposed period was 1.53 (95% confidence interval 1.29-1.80) for domperidone, 2.00 (1.37-2.91) for metoclopramide and 2.30 (1.71-3.09) for metopimazine. CONCLUSION: We found an increased risk of hospitalizations for traumatic injuries for the main marketed antidopaminergic antiemetics during the first days of use. The highest risk was observed for metopimazine, which could relate to its pharmacological profile and central effects.

Risk of Intracranial Aneurysm and Dissection and Fluoroquinolone Use: A Case-Time-Control Study.

Background and Purpose- Fluoroquinolone use is associated with an increased risk of aortic aneurysm and dissection. We investigated this risk of arterial wall injury on intracranial arteries, given the similar pathophysiological mechanisms for aneurysm and dissection in both types of arteries. Methods- A case-time-control study was conducted using French National Insurance databases covering >60 million inhabitants. Cases were aged ≥18 years with first ruptured intracranial aneurysm and dissection between 2010 and 2015. For each case, fluoroquinolone use was compared between the exposure-risk window (day 30-day 1 before the outcome) and matched control windows (day 120-day 91, day 150-day 121, and day 180-day 151) and adjusted for time-varying confounders; potential time-trend for exposure was controlled using an age- and sex-matched reference group. Amoxicillin use was studied similarly for indication bias controlling. The potential excess of risk conveyed by fluoroquinolones was assessed by the ratio of OR for fluoroquinolones to that for amoxicillin. Results- Of the 7443 identified cases, 75 had been exposed to fluoroquinolones in the prior 180 days, including 16 in the 30-day at-risk window (385/97 cases exposed to amoxicillin, respectively). The adjusted OR for fluoroquinolones was 1.26 (95%CI, 0.65-2.41) and that for amoxicillin of 1.36 (95% CI, 1.05-1.78). Ratio of OR for fluoroquinolones to that for amoxicillin was estimated at 0.92 (95% CI, 0.46-1.86). Result was similar when extending outcome definition to unruptured events (ratio of OR for fluoroquinolones to that for amoxicillin, 0.97 [95% CI, 0.61-1.53]). Conclusions- This study did not evidence an excess of risk of intracranial aneurysm or dissection with fluoroquinolone use.

Impact of Secured Prescription Implementation for Zolpidem on Hypnotics Use in France: A Time-Series Analysis on National Data.

We evaluated the impact of the implementation of a requirement that zolpidem prescriptions be obtained via secured forms (April 2017) on zolpidem and other hypnotics use in France. We conducted a time-series analysis on data from the French national health care system, from January 1, 2015 to January 3, 2018, for all reimbursed hypnotics. An important and immediate decrease in zolpidem use (-161,873 defined daily doses [DDD]/month; -215,425 to -108,323) was evidenced, with a concomitant raise in zopiclone use (+64,871; +26,925 to +102,817). These findings suggest that the change in zolpidem prescribing policies was effective, but has resulted in a shift from zolpidem to zopiclone. Further interventions are needed to decrease hypnotics' overuse in France.

Primary Care of Opioid use Disorder: The End of "the French Model"?

BACKGROUND: In France, most patients with opioid use disorder (OUD) have been treated by buprenorphine, prescribed by general practitioners (GP) in private practice since 1996. This has contributed to building a 'French model' facilitating access to treatment based on the involvement of GPs in buprenorphine prescription. OBJECTIVES: Our study aimed to assess whether the involvement of primary care in OUD management has changed lately. MATERIALS AND METHODS: Using data from the French National Health Insurance database, we conducted a yearly repeated cross-sectional study (2009-2015) and described proportion of opioid maintenance treatment (OMT)-prescribing GPs and OMT-dispensing community pharmacies (CP); and number of patients by GP or CP. RESULTS: Whereas the number of buprenorphine-prescribing GPs in private practice remained quite stable (decrease of 3%), a substantial decrease in buprenorphine initial prescribers among private GPs was observed. In 2009, 10.3% of private GPs (6,297 from 61,301 French private GPs) prescribed buprenorphine for the initiation of a treatment, whereas they were 5.7% (n = 3,539 from 62,071 private GPs) in 2015 (43.8% decrease). GPs issuing initial prescriptions of buprenorphine tended to care for a higher number of patients treated by buprenorphine (14.6 ± 27.1 patients in 2009 to 16.0 ± 35.4 patients in 2015). The number of CPs dispensing buprenorphine remained quite stable (decrease of 2%), while there was a 7.5% decrease in the total number of French CPs across the study period. CONCLUSIONS: Our results suggest that primary care providers seem less engaged in buprenorphine initiation in OUD patients, while CPs have not modified their involvement towards these patients.

Impact of pioglitazone regulatory withdrawal on antidiabetic drug use and health in diabetic patients.

PURPOSE: In 2011, pioglitazone was withdrawn from the French market owing to a potential risk of bladder cancer. This study aimed at assessing the impact of this pioglitazone withdrawal (PW) considering (i) trends in antidiabetic uses and (ii) changes in hospitalization/death rates in diabetic patients following PW. METHODS: We first considered the general population of the Echantillon Généraliste des Bénéficiaires (EGB), a 1/97th representative sample of the French healthcare insurance system beneficiaries, for the 2010-2014 period. In this, for each non-insulinic antidiabetic drug class, changes within the numbers of monthly supplied drug units for 1000 subjects were studied through times series and Unobserved Component Models. Second, we identified from the EGB a cohort of patients who were delivered a non-insulinic antidiabetic between 01 April 2011 and 01 August 2011 (date of PW). In this, post-withdrawal incidences of all-cause hospitalization and death were compared amongst pioglitazone users and non-users using proportional subdistribution hazards models. RESULTS: PW was accompanied by an increase in metformin (+ 11.7; 95% CI 1.1-22.3) and glinide (+ 11.0; 95% CI 1.2-20.8) numbers of monthly supplied units for 1000 subjects. No significant change was found for GLP-1 agonists, DPP-4 inhibitors, sulphonylureas or alpha-glucosidase inhibitors. In the cohort of non-insulinic antidiabetic users at the time of PW (1093 pioglitazone users, 17,900 non-users), being a pioglitazone user at PW was not associated with a subsequently higher rate of hospitalization. CONCLUSIONS: If PW was accompanied with significant changes in the use of some antidiabetics, no adverse impact of PW on hospitalization or death rates of diabetic type 2 patients was found.

Clusterin expression in gastrointestinal neuroendocrine tumours is highly correlated with location and is helpful in determining the origin of liver metastases.

AIMS: Clusterin (CLU) is a sulphated glycoprotein implicated in many physiological and pathological processes, including tumorigenesis. We have previously demonstrated that CLU is highly expressed in pancreatic neuroendocrine tumours (NETs). The aims of this study were: to investigate CLU expression in gastrointestinal NETs; the potential correlation between this expression and different clinicopathological parameters; and its usefulness in the differential diagnosis of liver metastases. METHODS AND RESULTS: Immunohistochemistry using an anti-CLU antibody was performed on paraffin sections from 108 primary NETs [G3 (13 cases), G2 (18 cases), and G1 (77 cases), according to the 2010 WHO classification] and 60 metastases. Cytoplasmic positivity was scored qualitatively and quantitatively. The pattern of staining was also assessed. Two-step statistical analyses (univariate and multivariate logistic regression) were performed. More than 90% of small-intestine NETs were completely negative. The probability of obtaining a positive CLU score was higher for the appendix, the stomach, the duodenum and the rectum than for the small intestine and colon. All G3 NETs and most G2 NETs were negative as compared with G1. CLU expression in the metastatic foci was identical to that of the primary tumour. CONCLUSIONS: Clusterin expression in gastrointestinal NETs is highly correlated with location and probably also with grading, in both the primary tumour and metastases. Underexpression of CLU in small-intestine NETs is helpful for identifying the origin of liver metastases: a strong CLU score in a liver biopsy makes the small intestine highly unlikely as a primary site.

Detection of independent associations in a large epidemiologic dataset: a comparison of random forests, boosted regression trees, conventional and penalized logistic regression for identifying independent factors associated with H1N1pdm influenza infections.

BACKGROUND: Big data is steadily growing in epidemiology. We explored the performances of methods dedicated to big data analysis for detecting independent associations between exposures and a health outcome. METHODS: We searched for associations between 303 covariates and influenza infection in 498 subjects (14% infected) sampled from a dedicated cohort. Independent associations were detected using two data mining methods, the Random Forests (RF) and the Boosted Regression Trees (BRT); the conventional logistic regression framework (Univariate Followed by Multivariate Logistic Regression - UFMLR) and the Least Absolute Shrinkage and Selection Operator (LASSO) with penalty in multivariate logistic regression to achieve a sparse selection of covariates. We developed permutations tests to assess the statistical significance of associations. We simulated 500 similar sized datasets to estimate the True (TPR) and False (FPR) Positive Rates associated with these methods. RESULTS: Between 3 and 24 covariates (1%-8%) were identified as associated with influenza infection depending on the method. The pre-seasonal haemagglutination inhibition antibody titer was the unique covariate selected with all methods while 266 (87%) covariates were not selected by any method. At 5% nominal significance level, the TPR were 85% with RF, 80% with BRT, 26% to 49% with UFMLR, 71% to 78% with LASSO. Conversely, the FPR were 4% with RF and BRT, 9% to 2% with UFMLR, and 9% to 4% with LASSO. CONCLUSIONS: Data mining methods and LASSO should be considered as valuable methods to detect independent associations in large epidemiologic datasets.

DPP-4 Inhibitors in Combination with Lipid-Lowering Agents and Risk of Serious Muscular Injury: A Nested Case-Control Study in a Nationwide Cohort of Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: After a safety warning was issued for a risk of muscular injury associated with dipeptidyl peptidase-4 (DPP-4) inhibitor use, especially when co-prescribed with statins, spontaneous reporting analyses provided conflicting results. OBJECTIVE: The aim of this study was to investigate the association between DPP-4 inhibitor use and the risk of muscular injury in individuals with type 2 diabetes mellitus using statins or fibrates. METHODS: We conducted a nested case-control study amongst a cohort of individuals with type 2 diabetes using statins or fibrates, identified from a nationwide French health insurance database (2009-2014). Cases of serious muscular injury were defined as subjects hospitalized for rhabdomyolysis or myopathy, or for whom testing for myoglobin or creatine phosphokinase followed by a change in statin or fibrate prescription (dose decrease, treatment switch, or stop) was identified. Up to ten controls were matched to each case according to sex, age, and type of lipid-lowering agent. Associations between DPP-4 inhibitor use and serious muscular injury were estimated using a multivariate conditional logistic regression model, providing odds ratios (ORs) adjusted for alcoholism, chronic renal failure, hypothyroidism, and number of concomitant drugs. RESULTS: Within the 35,117 individuals with type 2 diabetes mellitus constituting the source cohort, 437 statin-user cases were identified who were matched to 4358 statin-user controls. Similarly, 54 fibrate-user cases were identified who were matched to 540 fibrate-user controls. The adjusted OR for DPP-4 inhibitor use and serious muscular injury was estimated at 1.0 (95% confidence interval [CI] 0.7-1.2) in statin users and 0.8 (95% CI 0.4-1.9) in fibrate users. CONCLUSION: In this study, DPP-4 inhibitor use was not associated with an increased risk of serious muscular injury among patients with type 2 diabetes mellitus using statins or fibrates.

Real-Life Benefits of Statins for Cardiovascular Prevention in Elderly Subjects: A Population-Based Cohort Study.

OBJECTIVES: The benefits of initiating statins in the elderly remains debated. We evaluated the effects of initiating statins in the elderly, according to cardiovascular risk. METHODS: This population-based cohort study used data of the representative sample of the French health care system database for the 2008-2015 period. New users of statins, aged 75 years and older, were dynamically included in the cohort and matched 1:1 to statin nonusers on age, sex, numbers of different drugs dispensed and medical consultations, and cardiovascular history. Patients were classified into 3 cardiovascular risk groups: secondary prevention (history of coronary heart disease), primary prevention with modifiable risk factors (diabetes or cardiovascular medications), and primary prevention without modifiable risk factors (none of the above). Effect of cumulative use of statins on occurrence of acute coronary syndrome or all-cause death was analyzed by using multivariable time-dependent Cox models stratified on cardiovascular risk at inclusion. RESULTS: Among the 7284 patients included, median follow-up was 4.7 years. Cumulative use of statins was associated with a lower risk of outcomes in the primary prevention with modifiable risk factors group (adjusted hazard ratio 0.93 per year of use; 95% confidence interval, 0.89-0.96; P < .01) and in the secondary prevention group (0.75; 0.63-0.90; P < .01), but not in the primary prevention without modifiable risk factors group (1.01; 0.86-1.18; P = .92). CONCLUSIONS: Statin treatment was not associated with a reduction in acute coronary syndrome or all-cause death in elderly without modifiable cardiovascular risk factor treated in primary prevention.

Use of Lipid-Lowering Drugs and the Risk of Cataract: A Population-Based Nested Case-Control Study.

Eye lens membrane cells require high cholesterol concentrations that might be counteracted by lipid-lowering drugs. Using a nationwide database, we conducted a nested case-control study to evaluate the risk of cataract development associated with the use of lipid-lowering drugs. Patients aged 45 years and over with first cataract surgery in 2014 (cases) and up to four controls matched on age, gender, diabetes, hypothyroidism, glucocorticoid use, cardiovascular risk, and area of residence were included in the study. Among the 2,811 cases and 11,106 matched controls included, analyses showed a significantly increased risk of cataract surgery for a cumulative exposure to fibrates exceeding 5 years (adjusted odds ratio (aOR) 1.58; 95% confidence interval (CI): 1.17-2.15), unlike cumulative exposure to statins, whatever the dose or duration of treatment (aORs from 1.00-1.08, none being significant). This study highlighted an increased risk of cataract surgery with prolonged use of fibrates but not of statins.

Risk of Drug-Drug Interactions in Out-Hospital Drug Dispensings in France: Results From the DRUG-Drug Interaction Prevalence Study.

Introduction: Drug interactions could account for 1% of hospitalizations in the general population and 2-5% of hospital admissions in the elderly. However, few data are available on the drugs concerned and the potential severity of the interactions encountered. We thus first aimed to estimate the prevalence of dispensings including drugs Contraindicated or Discommended because of Interactions (CDI codispensings) and to identify the most frequently involved drug pairs. Second, we aimed to investigate whether the frequency of CDI codispensings appeared higher or lower than the expected for the drugs involved. Methods: We carried out a study using a random sample of all drugs dispensings registered in a database of the French Health Insurance System between 2010 and 2015. The distribution of the drugs involved was described considering active principles, detailing the 20 most frequent ones for both contraindicated or discommended codispensings (DCs). To investigate whether the frequency of CDI codispensings appeared higher or lower than the expected for the drugs involved, we developed a specific indicator, the Drug-drug interaction prevalence study-score (DIPS-score), that compares for each drug pair the observed frequency of codispensing to its expected probability. The latter is determined considering the frequencies of dispensings of the individual drugs constituting a pair of interest. Results: We analyzed 6,908,910 dispensings: 13,196 (0.2%) involved contraindicated codispensings (CCs), and 95,410 (1.4%) DCs. For CCS, the most frequently involved drug pair was "bisoprolol+flecainide" (n = 5,036); four out of five of the most represented pairs involved cardiovascular drugs. For DCS, the most frequently involved drug pair was "ramipril+spironolactone" (n = 4,741); all of the five most represented pairs involved cardiovascular drugs. The drug pair involved in the CC with the highest score value was "citalopram+hydroxyzine" (DIPS-score: 3.7; 2.9-4.6); that with the lowest score was "clarithromycin+simvastatin" (DIPS-score: 0.2; 0.2-0.3). DIPS-score median value was 0.4 for CCs and 0.6 for DCs. Conclusion: This high prevalence of CDI codispensings enforces the need for further risk-prevention actions regarding drug-drug interactions (DDIs), especially for arrhythmogenic or anti-arrhythmic drugs. In this perspective, the DIPS-score we develop could ease identifying the interactions that are poorly considered by clinicians/pharmacists and targeting interventions.

Impact of cancer diagnosis on persistence of oral antidiabetic drugs.

AIMS: The purpose of this study was to determine the effects of cancer occurrence on persistence of oral antidiabetic drugs (OAD) in France. METHODS: A retrospective cohort including incident OAD users between 2006 and 2011 was set up using a permanent sample of health insurance beneficiaries (Echantillon Généraliste de Bénéficiaires, EGB). A Cox model was used to assess the association between cancer occurrence and OAD persistence. Non-persistence was defined as a gap in OAD treatment coverage between the end of a given prescription and a new one greater than or equal to 90 days. Cancer occurrence was studied as a time-dependent variable. RESULTS: The study included 13,943 OAD users. Median follow-up was 760 days. After adjustment for age, sex, first OAD used, type of prescriber and polypharmacy, non-persistence risk was higher after a diagnosis of cancer: (HR: 1.93 and IC 95% 1.69; 2.21). Subgroup analyses according to cancer localization found a higher risk of non-persistence for lung cancer (HR: 2.66 and IC 95% 1.68; 4.23) and colorectal cancer (HR: 2.02 and IC 95% 1.40; 2.91). CONCLUSIONS: Our findings indicate there is an association between cancer diagnosis and OAD non-persistence. Additional studies of this type would be useful to evaluate the association between cancer diagnosis and persistence of treatment of other chronic diseases.

Risk factors of pandemic influenza A/H1N1 in a prospective household cohort in the general population: results from the CoPanFlu-France cohort.

BACKGROUND: The CoPanFlu-France household cohort was set up in 2009 to identify risk factors of infection by the pandemic A/H1N1 (H1N1pdm09) virus in the general population. OBJECTIVES: To investigate the determinants of infection during the 2010-2011 season, the first complete influenza season of study follow-up for this cohort. PATIENTS/METHODS: Pre- and post-epidemic blood samples were collected for all subjects, and nasal swabs were obtained in all subjects from households where an influenza-like illness was reported. Cases were defined as either a fourfold increase in the serological titer or a laboratory-confirmed H1N1pdm09 on a nasal swab, with either RT-PCR or multiplex PCR. Risk factors for H1N1pdm09 infections were explored, without any pre-specified hypothesis, among 167 individual, collective and environmental covariates via generalized estimating equations modeling. We adopted a multimodel selection procedure to control for model selection uncertainty. RESULTS: This analysis is based on a sample size of 1121 subjects. The final multivariable model identified one risk factor (history of asthma, OR = 2.17; 95% CI: 1.02-4.62) and three protective factors: pre-epidemic serological titer (OR = 0.51 per doubling of the titer; 95% CI: 0.39-0.67), green tea consumption a minimum of two times a week (OR = 0.39; 95% CI: 0.18-0.84), and proportion of subjects in the household always covering their mouth while coughing/sneezing (OR = 0.93 per 10% increase; 95% CI: 0.86-1.00). CONCLUSION: This exploratory study provides further support of previously reported risk factors and highlights the importance of collective protective behaviors in the household. Further analyses will be conducted to explore these findings.

Causal analysis of H1N1pdm09 influenza infection risk in a household cohort.

BACKGROUND: Obtaining a comprehensive quantitative figure of the determinants of influenza infection will help identify priority targets for future influenza mitigation interventions. We developed an original causal model integrating highly diverse factors and their dependencies, to identify the most critical determinants of pandemic influenza infection (H1N1pdm09) during the 2010-2011 influenza season. METHODS: We used data from 601 households (1450 participants) included in a dedicated cohort. Structural equations were used to model direct and indirect relationships between infection and risk perception, compliance with preventive behaviours, social contacts, indoor and outdoor environment, sociodemographic factors and pre-epidemic host susceptibility. Standardised estimates (ßstd) were used to assess the strength of associations (ranging from -1 for a completely negative association to 1 for a completely positive association). RESULTS: Host susceptibility to H1N1pdm09 and compliance with preventive behaviours were the only two factors directly associated with the infection risk (ßstd=0.31 and ßstd=-0.21). Compliance with preventive behaviours was influenced by risk perception and preventive measures perception (ßstd=0.14 and ßstd=0.27). The number and duration of social contacts were not associated with H1N1pdm09 infection. CONCLUSIONS: Our findings suggest that influenza vaccination in addition to public health communication campaigns focusing on personal preventive measures should be prioritised as potentially efficient interventions to mitigate influenza epidemics.

Contribution of genome-wide association studies to scientific research: a bibliometric survey of the citation impacts of GWAS and candidate gene studies published during the same period and in the same journals.

In genetic epidemiology, genome-wide association studies (GWAS) are used to rapidly scan a large set of genetic variants and thus to identify associations with a particular trait or disease. The GWAS philosophy is different to that of conventional candidate-gene-based approaches, which directly test the effects of genetic variants of potentially contributory genes in an association study. One controversial question is whether GWAS provide relevant scientific outcomes by comparison with candidate-gene studies. We thus performed a bibliometric study using two citation metrics to assess whether the GWAS have contributed a capital gain in knowledge discovery by comparison with candidate-gene approaches. We selected GWAS published between 2005 and 2009 and matched them with candidate-gene studies on the same topic and published in the same period of time. We observed that the GWAS papers have received, on average, 30±55 citations more than the candidate gene papers, 1 year after their publication date, and 39±58 citations more 2 years after their publication date. The GWAS papers were, on average, 2.8±2.4 and 2.9±2.4 times more cited than expected, 1 and 2 years after their publication date; whereas the candidate gene papers were 1.5±1.2 and 1.5±1.4 times more cited than expected. While the evaluation of the contribution to scientific research through citation metrics may be challenged, it cannot be denied that GWAS are great hypothesis generators, and are a powerful complement to candidate gene studies.

Assignment of PolyProline II conformation and analysis of sequence--structure relationship.

BACKGROUND: Secondary structures are elements of great importance in structural biology, biochemistry and bioinformatics. They are broadly composed of two repetitive structures namely α-helices and ß-sheets, apart from turns, and the rest is associated to coil. These repetitive secondary structures have specific and conserved biophysical and geometric properties. PolyProline II (PPII) helix is yet another interesting repetitive structure which is less frequent and not usually associated with stabilizing interactions. Recent studies have shown that PPII frequency is higher than expected, and they could have an important role in protein-protein interactions. METHODOLOGY/PRINCIPAL FINDINGS: A major factor that limits the study of PPII is that its assignment cannot be carried out with the most commonly used secondary structure assignment methods (SSAMs). The purpose of this work is to propose a PPII assignment methodology that can be defined in the frame of DSSP secondary structure assignment. Considering the ambiguity in PPII assignments by different methods, a consensus assignment strategy was utilized. To define the most consensual rule of PPII assignment, three SSAMs that can assign PPII, were compared and analyzed. The assignment rule was defined to have a maximum coverage of all assignments made by these SSAMs. Not many constraints were added to the assignment and only PPII helices of at least 2 residues length are defined. CONCLUSIONS/SIGNIFICANCE: The simple rules designed in this study for characterizing PPII conformation, lead to the assignment of 5% of all amino as PPII. Sequence-structure relationships associated with PPII, defined by the different SSAMs, underline few striking differences. A specific study of amino acid preferences in their N and C-cap regions was carried out as their solvent accessibility and contact patterns. Thus the assignment of PPII can be coupled with DSSP and thus opens a simple way for further analysis in this field.