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There is growing evidence to suggest that culturally and linguistically diverse (CALD) patients cost the health system more than non-CALD patients because of a higher burden of disease and increased resource consumption. The present study aimed to compare the ED resource utilisation of CALD and non-CALD patients at a tertiary hospital in Sydney, Australia.The total ED resource utilisation was calculated by separating each visit into diagnostic test cost and time spent in ED components. The time component was calculated using the product of the total length of stay and a resource cost per unit time measure. Diagnostic tests were costed using the Australian Medicare Benefit Schedule. A generalised additive model was developed to estimate the isolated effect of CALD status on the resource utilisation during an ED visit.CALD patients had a higher median resource utilisation than non-CALD patients ($736.93 vs $701.36, P 0.0001); however, the generalised additive model demonstrated that CALD status was not independently associated with increased resource utilisation.CALD status is not an independent influence on ED resource utilisation but other explanatory variables such as increased age and altered case-mix appear to have a much greater influence. There may, however, be other reasons to consider CALD loading such as equity in healthcare and to address poorer overall health outcomes for CALD patients.

To determine whether there is a temporal association between arthritis and uveitis activity among children with juvenile idiopathic arthritis-associated uveitis (JIA-U).Uveitis and arthritis data from patients with JIA-U age ≤21 years were collected from July 2013 to December 2019 at a tertiary care center. Arthritis activity was assessed at each rheumatology visit, and the primary outcome was the presence of active uveitis at ophthalmologic examination within 45 days of the rheumatology visit. Repeated-measures logistic regression was used to evaluate the temporal association between any uveitis activity within 45 days of arthritis activity. Models were adjusted for demographic-, disease-, and treatment-related factors.A total of 98 patients were included: 81 (83%) female, 67 (69%) antinuclear antibody positive, 59 (60%) oligoarticular, and 13 (13%) enthesitis-related arthritis (ERA) subtypes. There were 1,229 rheumatology visits, with a median of 13 visits per patient (interquartile range 7-18). Concordance between arthritis and uveitis activity was observed 73% of the time (694 of 947). There was an independent temporal association between uveitis and arthritis activity (odds ratio 2.47 [95% confidence interval 1.72-3.54]; P 0.01), adjusted for demographic and disease characteristics. Use of combination biologic and nonbiologic disease-modifying antirheumatic drugs, female sex, HLA-B27 positivity, and ERA and polyarticular (rheumatoid factor negative) subtypes were associated with decreased odds of active uveitis at any time point.In patients with JIA-U, there is a significant temporal association between arthritis and uveitis disease activity. These novel results suggest that an arthritis flare should prompt an expedited referral to the ophthalmologist.

Objective To map utilisation of bed resources within an ED over time, in order to determine the proportions of patient stay spent receiving emergency care versus non-emergent care. To produce visualisations that effectively convey this bed utilisation. Methods This was a retrospective cohort study using routinely collected administrative data, derived from the ED electronic health record (FirstNet; Cerner, North Kansas City, MO, USA), on all patients presenting to a single tertiary-level ED during a 1-month period and who were triaged to an acute area bed in order to undergo their emergency care. Resuscitation, subacute, fast track and paediatric area patients were excluded from analysis as firstly, in our institution the acute area processing appears to contribute most to barriers to patient flow and secondly, using acute area patients allowed us to approximate standardisation of acuity. Lost bed capacity (LBC) was defined as the time spent in an ED bed after an emergency clinician indicated that they were ready to depart the ED, as recorded in the electronic medical record. Results The overall proportion of time spent in an ED bed after completion of emergency care was 38.5% (interquartile range 21.8-47.2%). This time differed significantly between 'discharged' (1 min), 'admitted-ward' (72 min) and 'admitted-critical care' (110 min) groups. This was clearly revealed in our novel LBC heatmaps. Conclusions A considerable proportion of ED length of stay is because of patients remaining in an ED bed after their emergency care is concluded. Absolute time is much greater for admitted patients than for discharged patients, and therefore efforts to reduce LBC are likely to reduce overall ED length of stay. LBC heatmaps may provide an intuitively useful, potentially automated tool to understand these problems.

AIMS Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC). METHODS EREBUS is a French cohort study of wild-type (wt) KRAS unresectable mCRC patients initiating a first-line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression-free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression. RESULTS A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver-only metastases 39%, 33% and 40%. Median progression-free survival was 8.0 months [5.9-9.3] for patients with RASmt/BRAFany, 6.0 months [2.3-7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5-11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9-23.3], 9.7 months [6.9-16.6] and 29.3 months [26.3-36.1]. In multivariate analyses, progression (HR = 2.71 [1.79-4.10]) and death (HR = 2.79 [1.81-4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients. CONCLUSIONS BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first-line treatment.

AIMS Pictograms on medicine boxes warn of potential drug-related driving hazard; we studied their association with serious accidents. METHODS Prospective study in emergency departments of the hospitals in Bordeaux and Perigueux (France), of drivers with serious (admitted at least 24 hours) or nonserious vehicular accidents. Minors, passengers, pedestrians or subjects incapable of answering an interview were excluded. Interviews ascertained driver and accident characteristics, use of drugs with or without pictograms, use of alcohol and abuse substances, sleepiness, distractions, and mind wandering at the time of the accident, RESULTS: Between 18 October 2016 and 26 December 2018, 1200 of the 6212 drivers admitted to the hospital emergency rooms, 741 nonserious, 459 serious, were interviewed. Serious accidents were associated with male sex (odds ratio 1.89, 95% confidence interval [1.36-2.64]), age above 60 years (3.64 [2.21-6.00]), driving on local roads (3.34 [2.34-4.76]), driving a motorcycle (3.39 [2.29-5.00]), having drunk alcohol within 6 hours (2.89 [1.85-4.51]) and using a drug with a pictogram during the 24 hours previous to the accident (1.57 [1.06-2.32]). From 207 police reports, 101 drivers were not responsible, and 106 were responsible, associated with age below 40 years, driving in overcast or rainy weather (2.62 [1.29-5.33]), on local roads (3.89 [1.90-7.95]), and use of at least 1 pictogram drug in the previous week (3.12 [1.31-7.41]). CONCLUSION The known risks of alcohol and pictogram drugs, of riding motorcycles and using local roads were confirmed. As measured, behavioural sleepiness did not predict accidents.

It remains uncertain how perennial grasses with different photosynthetic pathways respond to fire, and how this response varies with stress at the time of burning. Resprouting after fire was examined in relation to experimentally manipulated pre-fire watering frequencies. We asked the following questions: are there response differences to fire between C3 and C4 grasses? And, how does post-fire resprouting vary with pre-fire drought stress? Fifty-two perennial Australian grasses (37 genera, 13 tribes) were studied. Three watering frequencies were applied to simulate increasing drought. Pre-fire tiller number, tiller density, specific leaf area and leaf dry matter content were measured as explanatory variables to assess response. Most species (90%) and individuals (79%) resprouted following experimental burning. C4 grasses had higher probabilities of surviving fire relative to C3 grasses. Responses were not related to phylogeny or tribe. High leaf dry matter content reduced the probability of dying, but also reduced the re-emergence of tillers. Post-fire tiller number increased with increasing drought, regardless of photosynthetic type, suggesting that drought plays a role in the ability of grasses to recover after fire. This has implications for understanding the persistence of species in landscapes where fire management is practiced.

Purpose To investigate sunitinib in the real-life first-line treatment of metastatic renal cell carcinoma (mRCC). Methods SANTORIN is a French observational multicentre cohort. Patients initiating sunitinib in first-line mRCC therapy were included (January 2008 to April 2010) and followed for 24 months. Data were collected from medical files. The outcomes were 24-month overall survival (OS) and progression-free survival (PFS), response and safety. Results Three hundred two patients were included: median age, 64.8 years; male, 73.2%; clear cell mRCC, 83.1%; prior nephrectomy, 85.4%; >1 metastatic sites, 64.2%; brain metastases, 6.3%; ECOG-PS ≥ 2, 9.9%. Median duration of first-line therapy with sunitinib was 10.7 months. Initial sunitinib dose was 50 mg/day for 83.4% of patients; dose reduction occurred in 65.2%. Sunitinib was discontinued in 73.2% of the patients: for progression (61.1%), death (31.2%) or adverse events (6.8%). More than half (58.3%) had grade ≥3 adverse events, mainly hypertension (12.6%) and hand–foot syndrome (12.3%). The 24-month OS and PFS rates [95%CI] were 49.5% [43.7;55.0] and 16.4% [12.5;20.9], respectively. Median OS was 23.6 months [20.2;–] and median PFS 8.4 months [7.6;9.9]. Overall best response rate was 31.1%. Conclusions Results from this large observational study suggest that effectiveness of sunitinib in first-line mRCC as predicted by clinical trials is maintained in real-life clinical practice. The expected benefit in poor-prognosis patients that were not evaluated in the pivotal clinical trial remains; however, questionable and long-term safety monitoring is still warranted. Copyright © 2017 John Wiley & Sons, Ltd.

Aims Dexmedetomidine (dexdor®) is approved in the European Union (EU) for sedation of adults in the intensive care unit (ICU). The present observational, retrospective study was requested by the European Medicines Agency to investigate dexmedetomidine use in clinical practice, with a particular focus on off-label use, including the paediatric population. Methods Study countries and sites were chosen from those with highest dexmedetomidine use, based on sales. Site selection (blind) was conducted by a multispecialist, independent group. Anonymized data on demographics, treatment indication, dexmedetomidine dosing, concomitant medications and treatment effectiveness were collected retrospectively from records of all dexmedetomidine-treated patients at the site during the enrolment period. Informed consent was waived, to avoid influencing the prescribing of dexmedetomidine. Recruitment was completed within 18 months of first site initiation. Results Data from 2000 patients were collected from 16 hospitals in four EU countries (Finland 750, Poland 505, Germany 470, Austria 275). The median age was 62 years, with more males (70.2%) than females. Dexmedetomidine was primarily used in the adult ICU (86.0%) for ICU sedation (78.6%) and mostly dosed according the product label. The intended sedative effect was obtained in 84.9% of administrations. Paediatric use (5.9% of patients, mostly in Austria and Finland) occurred mainly in the adult or paediatric ICU (75.6%) for sedation (67.2%). Conclusions Overall, most patients were treated with dexmedetomidine according to the product labelling. Use in children was limited but significant and similar in scope to that in adults. Administrations not fully according to the product labelling usually occurred in an ICU environment and reflected extensively investigated clinical uses of dexmedetomidine.

Aims The present study aims to describe real-life outcomes in stable patients after-myocardial infarction (MI) similar to those in the PEGASUS-TIMI 54 trial (PEGASUS), which found long-term benefits of ticagrelor in patients with a history of MI. Methods One-year event-free post-MI patients were identified in the French claims database representative 1/97 sample (2005–2010) and followed for up to 3 years. A PEGASUS-like (PL) population included patients with age ≥ 65 years, or age ≥ 50 and diabetes, renal dysfunction or prior MI, without stroke, end-stage renal failure or oral anticoagulation. Outcomes were: a composite of all-cause death or hospital admission for MI or stroke; individual events; major bleeding. Results There were 1585 post-MI patients totalling 3926 person–years including 865 PL patients (2114 PY); 68% were male; mean age was 66 (standard deviation 15) in post-MI, 74 (10) in PL. Outcomes per 100 person–years [95% confidence interval] were, respectively, in post-MI and PL 6.3 [5.6–7.1] and 7.8 [6.7–8.9] for the composite outcome; 5.1 [4.4–5.8] and 6.5 [5.5–7.6] for death; 1.0 [0.7–1.3] and 1.0 [0.6–1.4] for MI; 0.6 [0.4–0.9] and 0.9 [0.5–1.2] for stroke; 1.3 [0.9–1.6] and 1.4 [0.9–1.9] for major bleeding. Event rates were stable over the 3 study years. Placebo patients in the PEGASUS-TIMI54 Study were younger, more often male and had lower event rates, especially for all-cause death and major bleeding. Conclusions Patients selected using the criteria described in PEGASUS were older with more comorbidities, resulting in higher all-cause death and bleeding rates, but similar MI recurrence rates.

Purpose The secondary prevention treatment for acute coronary syndrome (ACS) is based on the combined use of drugs from four therapeutic classes (beta-blockers, antiplatelet agents, statins, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers). The objective of this study was to compare the long-term effectiveness of the recommended therapeutic combination with those of incomplete combinations in secondary prevention of ACS. Methods This cohort study used data from a representative sample of the French national healthcare insurance system database. Patients hospitalised for an incident ACS between 2006 and 2011 and aged ≥20 years at the time of ACS were included in the study. Effectiveness in preventing the composite outcome ACS, transient ischemic attack, ischemic stroke or all-cause-death was estimated using time-fixed and time-dependent Cox proportional hazards models with different definitions of exposure (at inclusion or determined daily during follow-up) and adjustment for patient characteristics, co-morbidities and co-medications. Results Of the 2874 patients included in the study, 33.9% were women; median age was 67 years (interquartile range: 56–77). The median duration of follow-up was 3.6 years (interquartile range: 2.2–5.3). Compared with the use of recommended combination, use of combination with three classes increased the risk of the composite outcome from 1.25 (95% confidence interval (95%CI), [1.07–1.47]) in the time-fixed model and from 1.40 (95%CI, [1.15–1.70]) or 1.42 (95%CI, [1.13–1.79]) in the time-dependent models. Conclusions After ACS, the use of incomplete drugs combinations compared with the recommended four drugs combination was associated with a higher risk of cardiovascular morbidity and all-cause mortality. Copyright © 2017 John Wiley & Sons, Ltd.

AIMS: To assess potential change in medicine exposure and association with the risk of road traffic crash across a time period that started before the implementation of a grading system warning of the effect of medicine on driving performances. METHODS: Data from three French national databases were extracted and matched: the national health care insurance database, police reports, and the national police database of injurious crashes. Drivers involved in an injurious crash in France, from July 2005 to December 2011, and identified by their national identifier were included. Association with the risk of crash was estimated using a case-control analysis comparing benzodiazepine and z-hypnotic use among drivers responsible or not for the crash. RESULTS: 69,353 responsible and 73,410 non-responsible drivers involved in an injurious crash were included. Exposure to benzodiazepine anxiolytics was associated with an increased risk of being responsible for a road traffic crash during the pre-intervention period (OR = 1.42 [1.24-1.62]). The association disappeared in the post-intervention period, but became significant again thereafter. The risk of being responsible for a crash increased in users of z-hypnotics across the study period. CONCLUSIONS: Our results question the efficacy of the measures implemented to promote awareness about the effect of medicines on driving abilities. Prevention policies relating to the general driving population, but also to healthcare professionals, should be reviewed.This article is protected by copyright. All rights reserved. Language: en

Ethnopharmacology aims to identify new therapeutic agents based on their traditional use. It begins by the identification of disease states, and of the traditional therapies for these, most commonly herbals. Herbals of interest are selected from ethnopharmacological surveys, and tested on experimental models of the diseases of interest. Once the activity of the traditional remedy is demonstrated, including dose-dependence, if possible comparatively to reference medications, the active ingredients can be explored, if possible using bioguided extraction. Identified molecules can then be further developed as medicinal products or pharmaceutical medicines (e.g., artemisine), or the herbal product can be developed as such (e.g. St John's wort). We provide examples of various study programmes, concerning the antiplatelet and antithrombotic effects of Armagnac extracts from Southwest France; antithrombotic and antihypertensive effects of extracts of Ocimum basilicum L; antithrombotic, antihypertensive and antihyperlipidemic effects of Cydonia oblonga; Antiproliferative and antithrombotic effects of Abnorma Savda Munziq of traditional Uyghur medicine; and the antidiabetic and hepatoprotective effects of Centaurium erythraea Rafn, Artemisia herba-alba Asso and Trigonella foenum-graecum L., all in collaboration between University of Bordeaux, France, Xinjiang Medical University in Urumqi, China and University Mentouri in Constantine, Algeria.

Aims The aim of the present study was to describe the real-life usage patterns of paracetamol. Methods The Echantillon Generaliste de Beneficiaires (EGB) database, the permanent 1/97 representative sample from the French national healthcare insurance system, was searched in 2011 to identify usage patterns, concomitant chronic diseases and use of cardiovascular medication in users prescribed single-ingredient (SP) and combination (CP) paracetamol, representing 85% of all sales. Results Of 526 108 subjects aged ≥15 years in the EGB, 268 725 (51%) had paracetamol dispensed on ≥1 occasion; of these, 207 707 (77%) were dispensed only SP and 61 018 (23%) received CP with or without SP. SP users were younger (48.3 years vs. 50.5 years), and 57% of SP users vs. 58% of CP users were female. Chronic comorbidities were more common in CP than SP users. SP users had, on average, 3.4 dispensings per year vs. 5.0 for CP users, for 36 defined daily doses (DDD, 3 g) of SP vs. 53 DDD per year for CP; 49% SP users bought 14 DDD or fewer; 15% bought >60 DDD. Use of paracetamol increased with age from about 16 DDD per year in 15–30-year-olds to over 90 DDD per year in patients above the age of 75; 53% of patients ≤60 years bought fewer than 14 DDD per year, whereas 55% of those >60 bought more than 30 DDD per year. More than half the dispensings exceeded the legal per-box limit of 8 g. Conclusions Over 50% of the French adult population were dispensed paracetamol at least once over the course of a year, generally for short-term use. Considering recent misgivings on the real efficacy and safety of paracetamol, such widespread use might have important public health consequences.

Aims This study aimed to describe the real-life incidence of bleeding, arterial thrombotic events and death during vitamin K antagonist (VKA) treatment in atrial fibrillation (AF). Methods This was a cohort study in Echantillon Generaliste de Beneficiaires, the 1/97 sample of the French national healthcare claims and hospitalization database, of new VKA users with definite or probable AF and no other indication, and of patients without AF, from 2007 to 2011. Prespecified outcomes were all-cause death, hospitalization for bleeding, arterial thrombotic event (ATE), or acute coronary syndrome (ACS) or any of the above (composite outcome). Results Of 8894 new VKA users, 3345 had probable or certain AF, 51.7% were male, mean age was 75.1 years, 87.1% had a CHA2DS2-VASc score ≥ 2 and 11.6% a HAS-BLED score > 3. Among AF patients, during VKA exposure the incidence rate of bleeding was 2.8 [95% confidence interval (CI) 2.2, 3.4] per 100 patient-years, including 0.6 (95% CI 0.3, 0.8) cerebral, 1.0 (95% CI 0.7, 1.3) digestive and 1.4 (95% CI 1.0, 1.7) other bleeds. There were 1.6 (95% CI 1.2, 2.0) ACS, 1.5 (95% CI 1.1, 1.8) ATE and 3.8 (95% CI 3.2, 4.4) deaths per 100 patient-years. The incidence rate of the composite outcome was 9.1 per 100 patient-years (95% CI 8.2, 10.0). When patients stopped VKA, bleeding decreased (RR 0.67, 95% CI 0.43, 1.04)), but death or thrombosis increased (RR 3.06, 95% CI 2.46, 3.81 and 1.75, 95% CI 1.14, 2.70, respectively). During VKA exposure non-AF patients had similar rates of bleeding, but fewer deaths, ACS and ischaemic events. Conclusions Real-life rates for bleeding, arterial thrombotic events, ACS and deaths in AF patients treated with VKA were similar to those observed in clinical trials.

Aim We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS). Methods We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications. Results DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (

Background and purpose The incidence and prevalence of Parkinson's disease are important for public health planning yet there is a lack of representative, up-to-date estimations for France. Methods For this cross-sectional study, subjects with suspected Parkinson's were identified in the EGB database, a 1/97 random sample of the national healthcare insurance database, linked to the national hospital-discharge summary database. Incidence and prevalence were estimated using a specific definition that included those with a diagnosis (hospitalization or listed as a long-term chronic disease for full reimbursement) and a sensitive definition that also included those with an indicative drug reimbursement profile. Estimations were extrapolated to the national population, standardizing on age and gender. Results According to either the specific or the sensitive definitions, the annual incidence of Parkinson's disease during the study period was respectively 36 and 49 per 100 000 person-years and prevalence in 2010 was 308–410 per 100 000 persons in the population as a whole. According to the age groups 55–64, 65–74, 75–84 and ≥85 years incidence was respectively 33–46, 139–172, 301–363 and 442–560 per 100 000 person-years amongst men and 32–55, 81–117, 203–270 and 251–313 per 100 000 person-years amongst women. The 2010 prevalence stratified by the same age groups was 293–376, 898–1161, 2524–3011 and 3760–4578 per 100 000 persons amongst men and 199–351, 618–889, 1910–2433 and 2504–3263 per 100 000 persons amongst women. Conclusions The specific and sensitive definitions of disease bracket the true values; the relatively small range indicates that the current study provides good estimations of incidence and prevalence of Parkinson's disease for recent years in France.

Aims Most risks of nonsteroidal anti-inflammatory drugs (NSAIDs) are pharmacological, dose and duration dependent. Usage patterns of prescription-only (POM) or ‘over-the-counter (OTC)’ NSAIDs may influence risks, but are not commonly described. Methods The Echantillon Generaliste de Beneficiaires database, the permanent 1/97 representative sample from the French national healthcare insurance systems, was queried over 2009–2010 to identify usage patterns, concomitant chronic diseases and cardiovascular medication in OTC and POM NSAID users. Results Over 2 years, 229 477 of 526 108 patients had at least one NSAID dispensation; 44 484 patients (19%) were dispensed only OTC NSAIDs (93% ibuprofen) and 121 208 (53%) only POM NSAIDs. The OTC users were younger (39.9 vs. 47.4 years old) and more often female (57 vs. 53%); 69% of OTC users and 49% of POM users had only one dispensation. A mean of 14.6 defined daily doses (DDD) were dispensed over 2 years for OTC vs. 53 for POM; 93% OTC vs. 60% POM patients bought ≤ 30 DDD over 2 years, and 1.5 vs. 12% bought ≥ 90 DDD. Chronic comorbidities were found in 19% of OTC users vs. 28% of POM users; 24 vs. 37% had at least one dispensation of a cardiovascular drug over the 2 years. Conclusions Most of the use of NSAIDs appears to be short term, especially for OTC-type NSAIDs, such as ibuprofen. The validity of risk estimates for NSAIDs extrapolated from clinical trials or from observational studies not including OTC-type usage may need to be revised.

Purpose To test an automated method to decrease the number of false-positive (FP) signals of disproportionate reportings (SDRs) generated by co-prescription. Methods Automated backward stepwise removal of reports concerning the drug associated with the highest ranked SDR for an event was tested for gastric and oesophageal haemorrhages (GOH), central nervous system haemorrhages and cerebrovascular accidents (CNSH), ischaemic coronary artery disorders and muscle pains (MP) using the reporting odds ratio in the French spontaneous reporting research database. After ranking SDRs detected in the complete dataset on the lower limit of the reporting odds ratio 95% confidence interval, reports concerning the drug with the highest ranked SDR were removed. In the dataset thus generated, SDRs were again identified, ranked and reports related to the drug involved in the newly highest ranked SDR removed. The process was repeated until no signal was detected. Initially detected SDRs eliminated using this technique were assessed regarding the summary of products characteristics and the literature to determine their FP nature. Results Seventeen SDRs were successively eliminated for GOH, 37 for CNSH, 15 for ischaemic coronary artery disorders, and 36 for MP. Four were FP for GOH, 29 for CNSH, 7 for ACI and none were FP for MP. The positive predictive value of the backward stepwise removal procedure in identifying FP SDRs ranged from 0% (MP) to 78.4% (CNSH). Conclusions Although further adjustment is needed to improve the method presented herein, our results suggest that numerous FP signals because of co-prescription bias could be eliminated using an automated method. Copyright © 2013 John Wiley & Sons, Ltd. key words—pharmacovigilance; spontaneous reporting; adverse reaction; signal detection; bias; methods; pharmacoepidemiology

Studies assessing the impact of epilepsy and its medication on the risk of road traffic crashes have shown inconsistent results. The aim in this study was to assess this risk using French databases. Data from three French national databases were extracted and matched: the national health care insurance database, police reports, and the national police database of injurious crashes. Only antiepileptics prescribed predominantly in epilepsy were studied (phenobarbital, phenytoin, ethosuximide, valproic acid, vigabatrin, tiagabin, levitiracetam, zonisamide, and lacosamide). A case-control analysis comparing responsible and non-responsible drivers and a case-crossover analysis were performed. Drivers (72 685) involved in an injurious crash in France between July 2005 and May 2008, were included. Drivers exposed to prescribed antiepileptic medicines (n = 251) had an increased risk of being responsible for a crash (OR 1.74 [1.29-2.34]). The association was also significant for the most severe epileptic patients (n = 99; OR = 2.20 [1.31-3.69]). Case-crossover analysis found no association between crash risk and treatment prescription. Patients with prescription of antiepileptic drugs should be cautioned about their potential risk of road traffic crash. This risk is however more likely to be related to seizures than to the effect of antiepileptic medicines.

Purpose The effect of denominator options on event rates was tested on the French part of the Study of Acute Liver Transplant (SALT). Methods SALT is a case population study of acute liver failure registered for transplantation (ALFT), exposed to non-steroidal anti-inflammatory drugs (NSAIDs) or non-overdose paracetamol, from 2005 to 2007. Population exposure was computed from the Intercontinental Medical Services' (IMS) and the French national healthcare insurance system's data as the number of defined daily doses (DDDs) sold or dispensed and the number of exposed patients. Results Nine ALFT cases were exposed to 10 NSAIDs and 49 to non-overdose paracetamol. NSAID sales ranged from 0.04 billion (niflumic acid) to 0.5 billion (ibuprofen) DDDs, amounting to 2.5 billion DDDs for all NSAIDs. The mean per-person exposure ranged from 13.1 (niflumic acid) to 43.2 (ketoprofen) DDDs, reaching 60.5 DDDs for any NSAID. The number of users ranged from 2 million (niflumic acid) to 13 million (ibuprofen), which was 26.6 million for all NSAIDs. The ALFT rates per billion DDDs ranged from 0 to 26 for individual NSAIDs and amounted to 4.6 for all NSAIDs. The ALFT rates per billion DDDs were inversely correlated with the average per-patient exposure (R2 = 0.935, p = 0.0016). The ALFT rates per million users ranged from 0.31 to 0.49, which was 0.41 for all NSAIDs, with no difference between drugs and no effect of mean per-patient exposure (R2 = 0.01, p = 0.9). Whether measured per DDD or per user, the event rate with paracetamol was three to five times higher than with NSAIDs. Conclusion ALFT risk with NSAID seems to be user dependent rather than person-time (exposure) dependent. Choosing the wrong denominator in case population studies might give erroneous results. Copyright © 2012 John Wiley & Sons, Ltd.

Computerized hospital databases are used for clinical and economic research. In France, the hospital administrative database, Programme de medicalisation des systemes d'information (PMSI), could be an interesting means for identifying cases of abuse and dependence in hospitals. PURPOSE: To assess the capability of PMSI to identify cases of abuse and dependence (medicines or illicit drugs; tobacco and alcohol not included). METHODS: Cross-sectional study, from October 1 to December 31, 2008, in teaching hospitals of Bordeaux. All hospitalizations with an ICD-10 code related to possible abuse or dependence were selected. Cases were validated by a committee composed of three pharmacologists using discharge summaries. RESULTS: Among the 34 816 patients registered in the PMSI during the study period, a total of 227 patients were pre-selected as potential cases; 21 patients, hospitalized for abuse or dependence, or complications of which, were included in the analysis. Mean age was 35 years. Substances implicated were buprenorphine (n = 8), benzodiazepines (n = 7), cannabis (n = 6), cocaine (n = 4), heroin (n = 3), amphetamine, ecstasy, morphine, codeine, and tramadol (n = 1, respectively); there was polydrug use in six cases. CONCLUSIONS: The PMSI database can be useful to identify certain cases of abuse and dependence. This pilot study has been conducted at a local level; as the PMSI is available in all hospital settings in France, further analysis could be done at the regional and national levels. Such data could be a valuable indicator to analyze trends and assess the medical consequences of substance abuse. Copyright © 2012 John Wiley & Sons, Ltd. Language: en

Purpose Fear of discontinuing concomitant anti-epileptic drugs (AEDs) may lead to potentially unnecessary and perhaps unsafe polypharmacy. The effect of withdrawing concomitant AEDs on epilepsy control was therefore studied in long-term users of levetiracetam. Methods The EULEV cohort followed patients initiating levetiracetam in France in 2005 or 2006 for one year. In those maintaining levetiracetam throughout the study period, the association of a reduction in the number of concomitant AEDs during the first six months with seizure-freedom during the last six months of follow-up was investigated using logistic regression. Results Of the 356 patients continuing levetiracetam for at least 1 year, 140 (39.3%) were seizure-free during the last six months of follow-up. Partial symptomatic or generalised idiopathic epilepsy were associated with greater seizure-freedom than partial cryptogenic disease. Factors associated with seizures were: longer disease duration, initial incapacity, increased number of seizures in the six months preceding levetiracetam initiation, and number of consultations for epilepsy in the six months preceding levetiracetam initiation. There was a trend for the association between the early reduction in the number of concomitant AEDs and seizure-free status later during follow-up, which however did not reach statistical significance in the final propensity score-adjusted multivariate model (OR = 1.8, 95%CI [0.8;4.0]). Conclusions Taking into account the various risk factors for seizures, the early reduction of concomitant AEDs was not associated with worse seizure rates during follow-up in real-life users of levetiracetam. Copyright © 2012 John Wiley & Sons, Ltd.

Purpose: For pharmacoepidemiological studies in Europe, accessing data should require only authorisation by the relevant data protections committees, as expected from the 1995 Data Protection Directive (95/46/EC). Our experience from a multinational observational study across seven European countries shows that this is certainly not the case. Methods: The study was a multicentre, multinational, case-population study in European liver transplant centres in seven countries, retrospectively evaluating a 3-year period. Before data collection started, the procedures to obtain the necessary authorisations for the participating countries were defined. Remarks: In France, a single opinion from a single data protection committee was enough to start the study. In Italy, Portugal, Greece and the UK, there was a national authority, but the hospitals requested the approval by their local committees/bodies irrespective of whether the authorisation of the national committee came after or before that of local ones. In Ireland, only one hospital participated, and the opinion of its ethics committee was sufficient. In the Netherlands, the opinion of the institutional review board of the local coordinating centre was necessary to obtain the opinions from the institutional review boards of the other hospitals. The information requested by the different committees and the time to obtain the approvals varied, even within the same country. Conclusion: This degree of complexity and disharmony, and resulting cost, was observed in a simple retrospective study. Regulators will need to be aware that these time-consuming, expensive and useless complexities must be factored in when estimating the time and cost of a study.

Purpose To determine healthcare claim patterns associated using nonsteroidal anti-inflammatory drugs (NSAIDs) for rheumatoid arthritis (RA). Methods The CADEUS study randomly identified NSAID users within the French health insurance database. One-year claims data were extracted, and NSAID indication was obtained from prescribers. Logistic regression was used in a development sample to identify claim patterns predictive of RA and models applied to a validation sample. Analyses were stratified on the dispensation of immunosuppressive agents or specific antirheumatism treatment, and the area under the receiver operating characteristic curve was used to estimate discriminant power. Results NSAID indication was provided for 26 259 of the 45 217 patients included in the CADEUS cohort; it was RA for 956 patients. Two models were constructed using the development sample (n = 13 143), stratifying on the dispensation of an immunosuppressive agent or specific antirheumatism treatment. Discriminant power was high for both models (AUC > 0.80) and was not statistically different from that found when applied to the validation sample (n = 13 116). Conclusions The models derived from this study may help to identify patients prescribed NSAIDs who are likely to have RA in claims databases without medical data such as treatment indication. Copyright © 2012 John Wiley & Sons, Ltd.

Objective: The prevalence of benzodiazepine use among community-dwelling older persons varies between 10% and 30%. The aim of this study was to explore the association between leisure activities and the use of benzodiazepine among older persons living at home. Methods: The study population included 4848 persons aged 65years and over living in either of two French cities. Information was collected from a questionnaire administered to the respondents by trained psychologists during face-to-face interviews at home and from a self-administered questionnaire. Baseline examination included socio-demographic characteristics, drug use and leisure activities. We classified as benzodiazepine users subjects who reported use of at least one benzodiazepine during the month preceding the interview. The association between the use of benzodiazepine and leisure activities was assessed by logistic regression adjusted on known potential confounders. Results: More than 18% of participants reported use of at least one benzodiazepine. The adjusted odds ratio (OR) of benzodiazepine use associated with no or lower participation versus participation in the following activities were as follows: OR=1.31 (95% confidence interval (CI): 1.09 to 1.58) for mental activity; OR=1.50 (CI: 1.12 to 2.03) for physical activity; OR=1.28 (CI: 1.05 to 1.55) for productive activity and OR=0.82 (CI: 0.69 to 0.97) for recreational activity. Conclusion: Low engagement in stimulating activities and high engagement in sedentary activities were associated with recent benzodiazepine use. Copyright # 2011 John Wiley & Sons, Ltd.

Introduction of new agents for the treatment for colorectal cancer (CRC) has been accompanied by the publication of guidelines. The COLCHIC cohort was set up to evaluate CRC treatment practices and the use of these innovative and expensive agents. Patients initiating CRC treatment at the Bordeaux teaching hospital between 1 March 2005 and 1 March 2006 were identified, and treatment courses from 1 March 2005 to 31 December 2006 were studied; 192 patients were included, 188 with analysable data: 43 patients initiated 51 courses for non-metastatic cancer, 153 initiated 366 courses for metastatic cancer, eight patients initiated courses for both non-metastatic and metastatic cancer. Most treatments were used for indications found in guidelines published during the study (83.9%). Of the others, nearly half were approved in guidelines published subsequently. In this teaching hospital, prescribing practice was generally in line with recommendations, with an anticipation of future guidelines. This mostly concerned monoclonal antibodies, which were new at the time of the study.

Purpose Life-threatening hyperkalemia may be induced by drugs and preventable in at-risk patients. This study was designed to describe cases of 'serious' drug-associated hyperkalemia. Methods Adult subjects with a serum potassium concentration above 6.5 mmol/L detected at admission or during hospital stay in nephrology, cardiology, geriatric, emergency or intensive care units were identified by biology laboratories of hospitals and clinics located in Midi-Pyrenees (southwest France). Patients dialyzed for end-stage kidney disease were excluded. Data were collected from medical files. Hyperkalemia was defined as drug-associated if at least one drug known to increase serum potassium concentration was taken when hyperkalemia occurred (among drugs taken in outpatient care for hyperkalemia detected at admission and among drugs taken in outpatient care and continued at hospital and drugs introduced from admission for hyperkalemia detected during hospital stay). Results Of 168 hyperkalemia cases, 102 (60.7%) were classified as drug-associated. They concerned elderly patients (mean age: 76.1 years) often having arterial hypertension and/or cardiac diseases (88.2%). Risk factors, mainly acute kidney failure, were observed in almost all cases (98.0%). Drugs predominantly involved were angiotensin-converting enzyme inhibitors (47.1%), spironolactone (41.2%), angiotensin II receptor antagonists (23.5%) and potassium supplements (23.5%). In 10% of cases, death could be attributed to hyperkalemia. Conclusions Laboratory databases allowed an exhaustive identification of hyperkalemia cases. The frequency of drug-related hyperkalemia and their characteristics suggest that treatment with drugs known to increase serum potassium concentration can be inappropriate, especially regarding associations or indications, and is highly risky for predisposed patients. Copyright © 2011 John Wiley & Sons, Ltd. Language: en

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Levetiracetam has shown good safety/tolerability and efficacy in regulatory trials. This was confirmed in observational investigations performed soon after marketing by using continuation or retention rates as a composite measure. • When an anti-epileptic drug first becomes available; however, there is evidence of channelling to more severe patients than thereafter. WHAT THIS STUDY ADDS • This study was performed several years after marketing of levetiracetam and found high rates of continuation. • It also further explores this measure by determining the continuation in the absence of initiation of additional anti-epileptic drugs. AIMS To investigate real-life effectiveness of levetiracetam in patients initiating treatment in a stable market situation. METHODS Epileptic adults who had initiated levetiracetam between 1 January and 31 August in 2005 or 2006 were included and followed for 1 year by hospital or nonhospital neurologists practising in France. One-year continuation rates were estimated using Kaplan–Meier analysis. Among those still treated at end of study, treatment goals were investigated. Factors associated with discontinuation were investigated using Cox proportional hazards regression. RESULTS A total of 794 subjects were included in the cohort, and 753 subjects were followed up and included in the analysis. Among these, mean (SD) age was 42.6 (±17.0) years, 51.1% were female, 76.6% had partial epilepsy, 93.5% had seizures in the 6 months preceding levetiracetam initiation and 82.9% had at least one concomitant anti-epileptic drug when starting levetiracetam. One-year levetiracetam continuation rate was 83.5% (95% confidence interval, 80.5–86.0%). Of the 579 patients still using levetiracetam at end of study, 46.8% were seizure free during the last 6 months, and 24% were on levetiracetam monotherapy. Reasons for discontinuation (n= 122) were adverse events (45%), lack of efficacy (38%) or both (9%). Levetiracetam discontinuation was most strongly associated with previous exposure to more than four anti-epileptic drugs, whereas continuation was most strongly associated with presence of seizure-related falls in the 6 months preceding levetiracetam initiation. CONCLUSIONS This population-based cohort study in a stable market situation found a high 1 year levetiracetam continuation rate compared with previous studies done sooner after market introduction.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Determining bacterial aetiology of acute sinusitis is difficult without employing invasive procedures. • Most episodes of acute sinusitis resolve spontaneously. • Antibiotics have demonstrated efficacy for the treatment of acute bacterial sinusitis in clinical trials yet little is known of their effectiveness in real-life treatment settings. WHAT THIS STUDY ADDS • Most cases of untreated acute sinusitis resolved spontaneously. Antibiotics were more effective when given within the first 10 days of treatment. This had no effect on later recurrence. • Patients with poor oro-dental condition or recent antibiotic use may derive the most benefit from an antibiotic prescription and this should be considered by prescribers. • The antibiotics used were found to be equally effective. • Existing recommendations to identify acute sinusitis with high probability of bacterial origin, such as the French recommendations, fever or duration of symptoms fail to identify patients in whom antibiotics are more effective. AIMS To assess the effectiveness of antibiotics in acute bacterial sinusitis. METHODS This was a prospective cohort study with 2 months follow-up of 5640 patients with acute sinusitis included by a random sample from 1174 GPs and 120 ENT specialists. Main outcomes were short-term initial success, defined as the absence of prescription of (another) antibiotic or sinus lavage within 10 days, and lack of recurrence between the 11th and 60th day, after initial success. RESULTS Initial success was found in 88.7% (95% CI 85.1, 91.4%) of patients without antibiotic prescription at inclusion and 96.2% (95% CI 95.7, 96.7%) of patients prescribed antibiotics. The 10 day adjusted hazard ratio (HR) for treatment failure (new antibiotic prescription or sinus drainage) with initial antibiotics compared with no antibiotics was 0.30 (95% CI 0.21, 0.42) with no difference between antibiotics. Antibiotics were more effective in patients with poor oro-dental condition (HR 0.04, 95% CI 0.01, 0.20) and in patients who had already used antibiotics during the previous 2 months (HR 0.09, 95% CI 0.03, 0.28). For patients without failure at 10 days, recurrence between the 11th and 60th day was similar whether or not they had initially been prescribed an antibiotic, 94.1% (95% CI 93.4, 94.7%) and 93.4% (95%CI 90.3, 95.5%), respectively. CONCLUSION Most acute sinusitis cases not prescribed antibiotics resolve spontaneously. Antibiotics reduced by 3.3-fold the risk of failure within 10 days, without impact on later recurrence. The greatest benefit of antibiotics was found for patients with poor oro-dental condition or with antibiotic use within the previous 2 months.

Purpose To identify factors associated with one-year persistence of cholinesterase inhibitor (ChI) treatments. Methods A retrospective cohort study was performed using the reimbursement database of the Echantillon Generaliste des Beneficiaires, a 1/96e representative sample of subjects affiliated to the French National Healthcare Insurance System. Among this, patients who initiated a ChI treatment between 1 January 2004 and 31 December 2005 and for whom 1 year of follow-up in the database after treatment initiation was available were identified. One-year persistence of ChI treatment was defined as an ongoing treatment without dispensing interval exceeding 60 consecutive days during the 12 months following treatment initiation. Drug switches were not considered as treatment discontinuation. A multivariate logistic regression was conducted to identify, among patients characteristics (sociodemographic, drug uses), factors associated with one-year persistence of ChI treatments. Results Among the 942 patients who initiated a treatment with ChI during the study period, 72.4% were women; mean age was 79.6 years (SD = 7.4). Patients used eight other different drugs in median (Inter-Quartile Range: 5–11); 63.7% used psychotropics, 63.6% used cardiovascular drugs. One-year persistence of ChI treatments was estimated at 45.3%. Persistence of ChI treatments was lower in patients aged 80 years and over (OR = 0.74, 95%CI: 0.57–0.96); it was higher in patients using antidepressants at ChI treatment initiation (OR = 1.38, 95%CI: 1.05–1.82). Conclusions One-year persistence of ChI treatment was estimated at 45.3% in this French sample. To optimize persistence of ChI treatment in the demented, patients poorly symptomatic and/or aged over 80 years should be especially monitored. Copyright © 2010 John Wiley & Sons, Ltd.

Thomas SHL, Drici MD, Hall GC, Crocq MA, Everitt B, Lader MH, Le Jeunne C, Naber D, Priori S, Sturkenboom M, Thibaut F, Peuskens J, Mittoux A, Tanghoj P, Toumi M, Moore ND, Mann RD. Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP) Objective: To explore whether sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone. Method: Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia. Results: After 14147 person-years, there was no effect of treatment on overall mortality (sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three sertindole, one risperidone). Cardiac mortality was higher with sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044). Conclusion: Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with sertindole.

SUMMARY Study objectives were to determine the prevalence of sleepy driving accidents and to explore the factors associated with near-miss driving accidents and actual driving accidents in France. An epidemiological survey based on telephone interviews was conducted on a representative sample of French drivers. The questionnaire included sociodemographics, driving and sleep disorder items, and the Epworth sleepiness scale. Of 4774 drivers (response rate: 86%), 28% experienced at least one episode of severe sleepiness at the wheel (i.e. requiring to stop driving) in the previous year; 11% of drivers reported at least one near-miss accident in the previous year (46% sleep-related); 5.8% of drivers reported at least one accident, 5.2% of these being sleep related (an estimate of 90 000 sleep-related accidents per year in France). Sleepy driving accidents occurred more often in the city (53.8%), during short trips (84.6%) and during the day (84.6%). Using logistic regression, the best predictive factor for near-misses was the occurrence of at least one episode of severe sleepiness at the wheel in the past year [odds ratio (OR) 6.50, 95% confidence interval (CI), 5.20–8.12, P < 0.001]. The best predictive factors for accidents were being young (18–30 years; OR 2.13, 95% CI, 1.51– 3.00, P < 0.001) and experiencing at least one episode of severe sleepiness at the wheel (OR 2.03, 95% CI, 1.57–2.64, P < 0.001). Sleepiness at the wheel is a risk factor as important as age for traffic accidents. Near-misses are highly correlated to sleepiness at the wheel and should be considered as strong warning signals for future accidents.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Traditional or COX-2-specific (coxib) nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used. • Their use is associated with gastrointestinal toxicity and cardiovascular events. WHAT THIS STUDY ADDS • The low event rates observed for gastrointestinal bleeding and myocardial infarction in the real-life conditions of NSAID use (traditional and coxib) in France preclude their exploration using realistic field studies. • Large population healthcare databases are required to study such risks. AIMS To assess hospital admission rates for gastrointestinal (GI) or cardiovascular (CV) events in real-life use of nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS CADEUS is a real-life population-based cohort study of 23 535 coxib (celecoxib or rofecoxib) and 22 919 traditional NSAID (tNSAID) users. Each hospitalization reported between index day (NSAID delivery) and questionnaire submission (median = 75 days) was explored using hospital discharge summaries. An expert committee validated blindly serious GI and CV events according to predefined criteria. RESULTS Coxib users were older and had more GI history than tNSAID users. There were 21 hospitalizations for GI events, 12 in the coxib cohort and nine in the tNSAID cohort (respectively one and three upper GI haemorrhages and no ulcer perforations). Rates of GI events were 0.39 per 1000 patients [95% confidence interval (CI) 0.18, 0.75] for tNSAID users and 0.51 per 1000 patients (95% CI 0.26, 0.89) for coxib users. There were 21 hospitalizations for CV events, 13 in the coxib cohort and eight in the tNSAID cohort. None was fatal. Rates of CV events were, respectively, 0.59 (95% CI 0.24, 1.22), 0.51 (95% CI 0.19, 1.11) and 0.35 (95% CI 0.15, 0.69) per 1000 patients for celecoxib, rofecoxib and tNSAIDs. GI or CV event rates were not different between products even for patients >60 years old. CONCLUSIONS Hospitalization rates for GI bleeding were 10–20 times lower than expected from published randomized clinical trials, probably because of differences in drug usage and concomitant gastroprotection. CV event rates conformed to those expected from general population data. These results emphasize the necessity of developing population healthcare databases to explore such low event rates.

PURPOSE: To evaluate the quality of epidemiological research into effects of medicinal drugs on traffic safety and the current knowledge in this area. DATA SOURCES: The bibliographic search was done in Medline electronic database using the keywords: ((accident* or crash*) and traffic and drug*) leading to 1141 references. Additional references were retrieved from the Safetylit website and the reference lists of selected studies. Original articles published in English or French, between 1 April 1979 and 31 July 2008, were considered for inclusion. We excluded descriptive studies, studies limited to alcohol or illicit drug involvement and investigations of injuries other than from traffic crashes. Studies based on laboratory tests, driving simulators or on-the-road driving tests were also excluded. Eligible studies had to evaluate the causal relationship between the use of medicinal drugs and the risk of traffic crashes. Study quality was assessed by two independent experts, according to a grid adapted from the strengthening the reporting of observational studies in epidemiology (STROBE) statement. RESULTS: Twenty two studies of variable methodological quality were included. Definition of drug exposure varied across studies and depended on the data sources. Potential confounding due to the interaction between the effects of the medicinal drug and disease-related symptoms was often not controlled. The risk of motor-vehicle crashes related to benzodiazepines has been amply studied and demonstrated. Results for other medicinal drugs remain controversial. CONCLUSION: There is a need for large studies investigating the role of individual substances in the risk of road traffic crashes. Language: en

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • To our knowledge, no study has ever described the intensity of nonsteroidal anti-inflammatory drug (NSAID) utilization in an employed population by occupation. • As the use of NSAIDs carries a well-known risk of adverse effects, this risk adds to the burden of musculoskeletal disorders in employed populations. • Information on utilization of NSAIDs in this context will help to better characterize and prevent this risk. WHAT THIS STUDY ADDS • In spite of a previous history of dyspepsia, blue collar workers had the highest rate of chronic and continuous utilization of nonselective NSAIDs. • No clustering of cyclooxygenase-2 selective NSAID utilization according to a previous history of dyspepsia was observed among blue collar workers. • The association between chronicity of NSAID utilization and occupation was independent of medical indication for the prescription and other lifestyle factors. AIM The aim of this study was to compare patterns of utilization of NSAIDs for musculoskeletal disorders (MSD) by occupation in a general employed population. METHODS This was a secondary analysis of the CADEUS cohort study on 5651 actively employed patients, who submitted at least one claim for the reimbursement of a NSAID dispensation for a MSD between August 2003 and July 2004, in the French National Healthcare Insurance database. Questionnaires were sent to prescribing physicians to obtain diagnoses and the medical history, and to patients for their occupation, height and weight and smoking status. Multivariate logistic regression was used to study the determinants of a heavy use of NSAIDs defined as ‘over four dispensations in one year with less than two months between any two’. RESULTS Factors associated with heavy use of NSAIDs were age (Odds ratio (OR): 1.8 (ten years), 95% confidence interval (CI): 1.6–1.9), osteoarthritis (versus back pain) (OR: 1.8, 95% CI: 1.5–2.1), body mass index (superior to 30) (OR: 1.8, 95% CI: 1.5–2.2), and occupation (blue collar versus white collar workers) (OR: 1.4, 95% CI: 1.2–1.6). Blue collar workers also had a 20% higher prevalence of 5-year history of dyspepsia. No difference was observed between sexes or in the use of COX-2 selective inhibitors between occupations. CONCLUSION Factors associated with occupational constraints that contribute to the severity of MSDs, may explain the heavier use of NSAIDs among blue collar workers in spite of a concurrent and past medical history of adverse reactions to this type of medication.

SUMMARY Purpose To evaluate the prevalence of cholinesterase inhibitor (ChI) treatment in subjects with dementia in European countries. Methods We studied the prevalence of treatment in subjects with dementia among European countries in 2004 (Belgium, France, Germany, Italy, the Netherlands, Poland, Portugal, Spain and the United Kingdom) by using estimates of prevalence of dementia and of ChI treatments according to sales and reimbursement data. Results In 2004, estimated prevalence of ChI use among subjects with dementia ranged from 3.0% in the Netherlands to 20.3% in France. It was 17.5% in Spain, 6.7% in the UK and 5.9% in Italy. Donepezil was used by more than 60% of patients usingasingleChI andrepresentedalmost50%ofreimbursementsforpatientsthathadusedatleast twodifferent ChIsduring theyear.Galantamine andrivastigminewererespectivelyusedby22 and18%ofsubjectsusingasingledrugand27 and23% ofreimbursementsforpatients thathadused atleast two different ChIs.Nevertheless,different patterns ofusewere foundfor individual countries. Conclusions Prevalence of treatment by ChIs among subjects with dementia remains weak and varies greatly across Europe. Differences in reimbursement rates and health policies could partly explain these variations, as ChIs could have failed to convince health authorities because the outcomes considered for trials are not used by clinicians in their everyday practice. If donepezil was highly predominant across countries, variations in rivastigmine and galantamine importance could reflect local market specificities. Copyright # 2008 John Wiley & Sons, Ltd. key words—dementia; Alzheimer’s disease; drug therapy; cholinesterase inhibitor; prevalence

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Spontaneous reporting is a valuable way to provide early detection for safety signals related to drug use. • Due to the increasing size of pharmacovigilance databases, data-mining and other automated methods for signal generation are more and more often used. • Even if these methods are very useful, they do not allow, for every particular association, an automated exploration of the multiple sources of confounding. WHAT THIS STUDY ADDS • An association between angiotensin receptor blockers use and hypoglycaemia was found in the French pharmacovigilance database. • This signal disappeared after stratification on antidiabetic drug use, suggesting confounding by indication. • The association between hypoglycaemia and angiotensin receptor blocker use was actually less than expected in concomitant antidiabetic drug users. AIMS To study reporting of hypoglycaemia in angiotensin receptor blocker (ARB) users, and to investigate the possibility of confounding. METHODS The French pharmacovigilance database was examined for an association between hypoglycaemia and ARBs or other drugs using reports notified between 1996 and 2005. This association was also tested in patients taking or not taking antidiabetic agents (ADAs) using reporting odds ratios (ROR). RESULTS Hypoglycaemia was mentioned in 807 of the 174 595 reports entered during the study period. Overall hypoglycaemia was associated with the use of ARBs [ROR 2, 95% confidence interval (CI) 1, 3] and with the use of ADAs (ROR 32, 95% CI 27, 37). Moreover, the use of ARBs was associated with the use of ADAs (OR 7, 95% CI 6, 8). Considering separately reports with and without ADA, the association of ARB use with a higher risk of hypoglycaemia disappeared (OR 0.4, 95% CI 0.2, 0.8 and OR 2, 95% CI 1, 3, respectively). CONCLUSION A signal indicating an association between ARB use and hypoglycaemia was found in the French pharmacovigilance database. This signal disappeared after stratification on ADA use, thus suggesting confounding by indication. Moreover, the association between ARB use and hypoglycaemia was negative in ADA users.

What is already known about this subject • In pharmacovigilance, many methods have been proposed for causality assessment of adverse drug reactions. • Expert judgement is commonly used to evaluate the causal relationship between a drug treatment and the occurrence of an adverse event. This form of judgement relies either explicitly or implicitly on causality criteria. What this study adds • Our study compares the judgements of five senior experts using global introspection about drug causation and seven causality criteria on a random set of putative adverse drug reactions. • Even if previous publications have shown poor agreement between experts using global introspection, few have compared judgements of well trained pharmacologists, familiar with using a standardized causality assessment method. Aims To evaluate agreement between five senior experts when assessing seven causality criteria and the probability of drug causation. Methods A sample of 31 adverse event-drug pairs was constituted. For each pair, five experts separately assessed (i) the probability of drug causation, which was secondarily divided into seven causality levels: ruled out (0–0.05), unlikely (0.06–0.25), doubtful (0.26–0.45), indeterminate (0.46–0.55), plausible (0.56–0.75), likely (0.76–0.95), and certain (0.96–1); and (ii) seven causality criteria. To test discrepancies between experts, the kappa index was used. Results The agreement of the five experts was very poor (kappa = 0.05) for the probability of drug causation. Among the seven levels of causality, only ‘doubtful’ showed a significant rate of agreement (kappa = 0.32, P

Purpose To describe the characteristics of users of cyclo-oxygenase (COX)-2 inhibitors and traditional nonselective non-steroidal anti-inflammatory drugs (tNSAIDs) in France. Methods Between 1 August 2003 and 31 July 2004, patients who received at least one dispensing of celecoxib, rofecoxib or tNSAIDs were randomly sampled with a 1:1:2 target ratio within the French National Healthcare Insurance database. Patients and prescribers were asked to fill a questionnaire on socio-demographic characteristics, NSAID indication and use and previous medical history. For each respondent, healthcare resources used in the 6 months before inclusion were extracted from the database. Multivariate logistic regression was used to study the determinants of a first COX-2 inhibitor dispensing. Results Of the 45 217 patients included, 13 065 COX-2 inhibitors and 13 553 tNSAID users had prescriber data. Ninety seven per cent of COX-2 inhibitor prescriptions were for ‘rheumatological’ indications, whereas 37% of tNSAIDs use was for benign diseases (n = 2643) or analgesia (n = 2318). Among patients with rheumatological indications (n = 4730) and a first COX-2 inhibitor (n = 2427) or tNSAID (n = 2303) dispensing, multivariate analysis of factors associated with COX-2 inhibitors dispensing showed that, compared to new tNSAID users, new COX-2 inhibitor users were older, more often female, on sick leave or unemployed. COX-2 use was also associated with previous gastrointestinal history and previous gastroprotective agent dispensing, but not with previous cardiovascular (CV) history. Conclusion The choice of NSAID depended largely on indication and on previous gastrointestinal history, in line with the recommendations of the French health authorities. Possible knowledge of CV risk associated with COX-2 inhibitors did not influence prescribing. Copyright © 2007 John Wiley & Sons, Ltd.

Background A regulatory signal suggested that sertindole was associated with a 10-fold increased risk of death. This observational study aimed to identify deaths and their causes in patients treated with sertindole. Methods Sertindole-treated patients in Germany, Austria, Belgium, Hungary, The Netherlands and the United Kingdom were identified and their vital status ascertained. Eventual cause of death and patient and treatment characteristics were ascertained. A nested case-control study compared on-treatment cardiac or unexplained deaths with randomly selected survivors matched on age and gender for potential risk factors. Results Eight thousand six hundred eight patients were identified as having initiated treatment with sertindole, for a total 3819 person-years exposure. Thirty-five had died since (all-cause mortality rate 0.92 per 100 person-years exposed). Of these, 15 (43%) had been previously reported to the regulatory authorities. Eight deaths were suicides, of which 2 (25%) had been previously reported; 11 were cardiac deaths, of which 8 (73%) had been reported. On average, patients who died because of cardiac disorders were older, and patients who committed suicide were younger than the other patients who died. The nested case-control study revealed that patients receiving sertindole were at a higher risk of premature cardiac or unexplained death if they had hypertension or other cardiovascular disorders associated with diabetes or metabolic disorder. Conclusion Overall and cardiovascular death rates were similar or lower than those observed in premarketing clinical trials. There was a very high reporting rate of all-cause and cardiovascular deaths that could have contributed to the regulatory alert. Copyright © 2007 John Wiley & Sons, Ltd.

Purpose We describe drug–drug interactions (DDIs) encountered with antifungals in clinical practice. Methods Retrospective observational study of hospitalized adults receiving systemic antifungal treatment in the intensive care unit (ICU) and in the infectious diseases unit (IDU) of the University Hospital of Bordeaux, France between 1996 and 2001. All treatment episodes with antifungal agent were examined and all prescribed concomitant medication identified for potential drug–drug interactions (PDDI)-serious events occurring during treatment were adjudicated for clinical DDI. Results There were 150 treatment episodes with antifungal agent in 105 patients. Fluconazole was used in 48% of the treatment episodes, amphotericin B in 46%, itraconazole in 4.7% and flucytosine in 1.3%. One hundred and sixteen PDDIs were identified related to the use of amphotericin B (81.0%), fluconazole (17.2%) or itraconazole (1.7%). Of these, 22 were associated with a clinical evidence of adverse interaction (hypokalemia, increased creatininemia or nephrotoxicity). All these clinical drug–drug interactions (CDDIs) were with amphotericin B. They were due to furosemide (36.4%), cyclosporine (31.8%) and hydrocortisone (18.2%). PDDIs were mostly associated with leukaemia (40.4%), HIV infection (24.6%) and cancer (10.5%). Conclusions In ICU and IDU, systemic antifungal treatments lead to many PDDIs, mainly related to the type of antifungal used and to the pathology treated. Clinical DDI seem more common with amphotericin. Copyright © 2007 John Wiley & Sons, Ltd.

Purpose At the request of the French Health authorities, a study called CADEUS (COX-2 inhibitors and NSAIDs: description of users) aimed to describe the users of cyclo-oxygenase (COX)-2 inhibitors and traditional non-selective non-steroidal anti-inflammatory drugs (tNSAIDs). We report here the methodology, logistics and study design performances. Methods CADEUS is a cohort study designed to include 40 000 patients randomly sampled monthly in the French National Healthcare Insurance database, who received at least one dispensation of celecoxib, rofecoxib or tNSAIDs (1:1:2), from September 2003 to August 2004. Patients and prescribers were asked to fill a questionnaire on indication, medical history, risk factors and hospitalizations since drug acquisition. There was no reminder. For each respondent, healthcare resources used for the 6 months before and after inclusion were extracted from the database. Response rate, response delay, responders and non-responders characteristics were assessed. Results Of the 222 879 patients and their prescribers contacted, 20.8% patients and 32.6% prescribers responded. Median response delay was 16 days for patients and 17 days for physicians. Factors associated with patient response were age, cohort, type of prescriber and period of inclusion. Conclusion This is the first study of this design in France, combining data from a claims database and direct patient and prescriber questionnaires. Copyright © 2006 John Wiley & Sons, Ltd.

Objective: To describe and compare general practitioners’ (GPs) opinions on antidepressant drugs and their prescriptions to depressed patients. Method: Between November 2000 and July 2001 a representative sample of French GPs was asked their opinion of the 15 most prescribed antidepressants, and then to describe the treatments of the current depressive episode of four depressive patients each, their changes and the reasons thereof. Results: One hundred and eighty-one GPs and 778 patients participated. The best-ranked antidepressants by the GPs were paroxetine, fluoxetine, sertraline and clomipramine for efficacy, and paroxetine, tianeptine, sertraline and fluoxetine for tolerability. In patients, the drugs most often prescribed were fluoxetine, paroxetine, and sertraline. Those least often stopped for intolerance were moclobemide (0%), dosulepine (0%), venlafaxine (4.5%) and citalopram (5.0%), and maprotiline (0%), citalopram (1.7%) and venlafaxine (2.3%) for lack of efficacy. The best predictor for prescription of antidepressants was the GPs’ overall ranking, itself depending on opinions of the tolerability and efficacy of the drug. However, opinions of tolerability and efficacy were not related to the rates of treatment discontinuation for intolerability or inefficacy. Conclusion: Prescriber opinion does not seem related to actual product performance.

No studies of seagrass decay have examined effects of the number of species contained within the detrital pool. Given the importance of decay for nutrient cycling and long-term productivity, we tested how three seagrass species affected decay in litterbags. Experimental results clearly showed that species identity was the predominant driver of mass loss, with total loss not differing between bags containing one, two and three species. Furthermore, we show there were also non-additive effects of mixing litter that were not predicted from single-species decay rates. The nature of the non-predictable mass loss varied both through time and with the number of species in the mixtures. This indicates that species richness indeed plays a role in this important ecosystem function but one that is of less importance than species identity. The concordance of these results with terrestrial studies suggests that mechanisms responsible for mixed-species decay rates may be broadly applicable across ecosystems.

In our 24-h society, nocturnal sleep-related accidents are common. Because all individuals are not equal in their responses to sleep loss, it is very important to identify predictors of vulnerability to sleep deprivation in normal subjects. We investigated the performance of a cognitive test of sustained attention, electroencephalogram theta/alpha power, subjective sleepiness, and two circadian markers (core temperature and melatonin) in 18 healthy men (nine morning types and nine evening types, 21.4 +/- 1.9 years) during a 36-h sleep deprivation in a constant routine protocol. Sleep need (self-reported) and baseline sleep structure were also investigated. Nighttime performance impairment was defined as the difference between the mean nocturnal number of lapses (00:00-07:30 [corrected] hours) and the mean diurnal number of lapses (07:30-20:30 hours) expressed as a percentage. Feeling fully alert in the morning just after awakening and/or sleepy in early afternoon were the only two factors (Multiple R > 0.80, > 60% of explained variance) which better predicted the decrease in performances of nocturnal operational tasks requiring sustained attention.

Purpose To describe the use of psychotropic drugs in children aged 0–5 years, in the Aquitaine region of South-west France and identify associated socio-demographic, familial and medical factors. Methods Data used in this study come from the regional drug claims database of the National Health Insurance System of Aquitaine and from postal self-questionnaires sent to parents and prescribing physicians. Results In Aquitaine, psychotropic drugs were redeemed at least once in 2002 for 3.2% of young children. Hydroxyzine, niaprazide or diazepam were claimed at least once by 2.7% of children registered in the database. Prescribers were mostly general practitioners (76.7%) and pediatricians (20.1%). Psychotropic claims were more frequent in children having the highest number of medical consultations in 2002 (more than 7: odds ratio (OR) = 1.5 [95% confidence interval (CI): 1.3–1.7]) or of drug deliveries (7–15 deliveries: OR = 1.8 [95%CI: 1.6–2.1]; more than 15 deliveries: OR = 3.2 [95%CI: 2.7–3.9]). Psychotropic claim frequency increased with age. No association of psychotropic use with parental psychotropic use, socio-professional category and familial situation was found. Conclusions Psychotropic delivery prevalence in Aquitaine in young children was below 5% in 2002. It notably concerned drugs of which the use is not devoid of toxicity because of anticholinergic properties. Copyright © 2006 John Wiley & Sons, Ltd.

Abnormal Savda Munziq (ASMq) is a traditional Uighur medicinal herbal preparation commonly used to treat diseases such as diabetes, cardiovascular diseases, chronic asthma and especially digestive cancer. Earlier studies have shown that ASMq is a free radical scavenger and could prevent mitochondrial and DNA oxidative damage. In this study, we tested the effects of aqueous extract of ASMq on human hepatoma cells (HepG2) to explore the possible mechanism of its putative anticancer properties. Aqueous extract of ASMq was tested on HepG2 proliferation (MTT assay) at 72 h, cell viability at 48 h (neutral red assay), lactate dehydrogenase release over 48 or 72 h as a measure of cytoplasmic leakage, lipid peroxidation (malondialdehyde-thiobarbituric acid adducts) at 48 h, and incorporation of [ 3 H]-leucine, [ 3 H]-thymidine and [ 3 H]-uridine into cellular protein, DNA and RNA, respectively, at 24 or 48 h to assess the inhibition effects to cellular macromolecule synthesis. Our results showed a significant (P < 0.05) time- and concentration-dependent inhibition of HepG2 proliferation and viability, with increased cytoplasmic leakage, and time- and concentration-dependent inhibition of protein, DNA and RNA synthesis. No lipid peroxidation was found at these concentrations. The results of the present study suggest that the putative anticancer mechanisms of ASMq may at least involve cytotoxicity.