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The clinical picture of SARS-CoV-2 infection is variable, ranging from moderate to severe and critical forms. Various studies have shown that disturbances in certain biochemical parameters are correlated with the severity of the disease. They can be used to predict the risk of complications, allowing early and appropriate care of these patients. The aim of our study is to evaluate the correlation between admission ferritin levels and mortality in COVID-19 patients. We used data from the records of patients with positive RT-PCR admitted to the Mohamed V Military Training Hospital in Rabat between april 2020 and december 2021. Demographic and biologic data were exctracted from DxLab LIS of Dedalus. 1.310 patients are included; the average age is 56 years and 72% of patients are male. The all-cause mortality of seriously ill hospitalized patients in the intensive care units are 23%. 73% of patients who died were over 60 years. The mean ferritinemia at admission was 2040 ng/ml for patients who died versus 521 ng/ml for the survivors (p

Background Polycystic ovary syndrome (PCOS) is considered one of the most common endocrine disorders affecting females in their reproductive age. In PCOS, an imbalance between androgens, anti-Müllerian hormone (AMH) and follicle stimulating hormone (FSH), cause a halt of follicular growth. Insulin resistance (IR) is another important component of PCOS. There is increasing evidence that vitamin D affects insulin and glucose metabolism, Vitamin D plays a vital role in the regulation of glucose-insulin homeostasis. Objectives to assess the efficacy of vitamin D supplementation in improving ovulation induction in PCOS women (1ry outcome) and increasing pregnancy rate (secondary outcome). Patients and Methods 120 women diagnosed PCOS according to Rotterdam criteria and were resistant to CC treatment were randomly allocated into equal two groups: Group V: number of 60 patients received cholecalciferol + Metformin for 2 months. Group C: 60 patients received Metformin 2 months. After two months from the start:Both study groups started induction with Clomiphene Citrate added every month starting from the 3rd month to the 5th month (3 cycles of ovulation induction) in addition to previous drugs mentioned. Results In our study results, regulation of menstrual cycle occured in 63.6% of women who recieved vitamin D + metformin (group V) and ovulation was confirmed in 34.5% of the total number (55 women). Later, 18% of them got pregnant after 3 months of treatment. Added to that 16 women out of 39 (41%) got pregnant by the end of the follow up period with cumulative pregnancy rate (53%). On the other hand menstrual regularity in (group C: metformin) recorded 61% with ovulation percentage of 26.9% (n = 54). Followed by 14.8% pregnancy rate at the 3rd month., which increased to 27.5% by the end of the study out of 47.5% ovulated women (n = 40). Cumulative pregnancy rate 40%. Conclusion From the current study we can conclude that there is no significant difference of adding vitamin D to CC resistant PCOS regarding ovulation and pregnancy rates. However, it can augment metformin action and improves its outcome.

Background Diagnosis performances of case-identifying algorithms developed in healthcare database are usually assessed by comparing identified cases with an external data source. When this is not feasible, intra-database validation can present an appropriate alternative. Objectives To illustrate through two practical examples how to perform intra-database validations of case-identifying algorithms using reconstituted Electronic Health Records (rEHRs). Methods Patients with 1) multiple sclerosis (MS) relapses and 2) metastatic castration-resistant prostate cancer (mCRPC) were identified in the French nationwide healthcare database (SNDS) using two case-identifying algorithms. A validation study was then conducted to estimate diagnostic performances of these algorithms through the calculation of their positive predictive value (PPV) and negative predictive value (NPV). To that end, anonymized rEHRs were generated based on the overall information captured in the SNDS over time (e.g. procedure, hospital stays, drug dispensing, medical visits) for a random selection of patients identified as cases or non-cases according to the predefined algorithms. For each disease, an independent validation committee reviewed the rEHRs of 100 cases and 100 non-cases in order to adjudicate on the status of the selected patients (true case/ true non-case), blinded with respect to the result of the corresponding algorithm. Results Algorithm for relapses identification in MS showed a 95% PPV and 100% NPV. Algorithm for mCRPC identification showed a 97% PPV and 99% NPV. Conclusion The use of rEHRs to conduct an intra-database validation appears to be a valuable tool to estimate the performances of a case-identifying algorithm and assess its validity, in the absence of alternative.

Introduction Bien que les medicaments indiques dans l’osteoporose aient deja fait preuve de leur efficacite dans les essais cliniques contre placebo, les donnees sur leur efficacite en situation reelle de soins sont a ce jour limitees. Patients et methodes Une etude de cohorte a ete realisee a partir des donnees de l’Assurance maladie francaise, le SNDS, incluant toute femme de 55 ans et plus initiant un traitement pour l’osteoporose (i.e., denosumab, acide zoledronique (AZ), bisphosphonates oraux (BPO), estrogenes, teriparatide et raloxifene) entre le 1er janvier 2014 et le 31 decembre 2016 selon une approche hierarchique qui suit l’ordre de commercialisation de ces medicaments en France. Les patientes incluses etaient traitees pendant au moins 6 mois par le traitement index et etaient suivies au moins 2 ans. L’incidence des fractures etait comparee au sein d’un meme groupe de traitement, en comparant le taux d’incidence des 3 mois suivant la date d’initiation (risque fracturaire de reference), avec celui des 12, 18 et 24 mois suivants. Les resultats des analyses autocontrolees « sous traitement » ont ete presentes en termes d’Incidence Rate Ratio (IRR) et de son intervalle de confiance a 95 % (IC95 %). Resultats Parmi les 200 496 patientes inclues, 33 % avaient initie du denosumab, 26 % des BPO, 21 % de l’AZ, 10 % des estrogenes, 6 % du raloxifene et 4 % du teriparatide. Les patientes avaient en moyenne entre 63 ans (SD ± 8 ans) dans le groupe estrogene et 76 ans (±9 ans) dans le groupe teriparatide. Un traitement prealable par un medicament anti-osteoporotique etait plus frequemment retrouve dans le groupe denosumab (55 %). Le risque fracturaire de reference etait variable entre les groupes de traitement ; il etait le plus eleve dans les groupes AZ (fracture de la hanche) et teriparatide (fractures vertebrales) et le plus bas dans le groupe estrogene. En comparaison avec les 3 mois suivant l’initiation, les fractures vertebrales faisant l’objet d’une hospitalisation etaient significativement reduites dans les 12, 18 et 24 mois suivants avec le denosumab (IRRs : 0,7 [0,5 ; 0,8], 0,6 [0,5 ; 0,7] et 0,6 [0,5 ; 0,7]), l’AZ (IRR : 0,4 [0,3 ; 0,4] pour les 3 periodes), le teriparatide (IRRs : 0,4 [0,3 ; 0,6], 0,4 [0,2 ; 0,5] et 0,3 [0,2 ; 0,5]) et les BPO (IRRs : 0,6 [0,4 ; 0,8] pour les 3 periodes). Comparativement aux 3 premiers mois suivant la date index, l’incidence de fracture de la hanche etait significativement plus faible avec le denosumab dans les 18 et 24 mois suivants (IRRs : 0,8 [0,6 ; 0,9]) mais significativement plus elevee pour les BPO pour l’ensemble des 3 periodes (IRRs : 1,6 [1,1 ; 2,2] dans les 12 mois suivants, et 1,7 [1,2 ; 2,3] dans les 18 et les 24 mois suivants), alors qu’aucune difference significative n’etait observee avec l’AZ et le teriparatide. Une diminution significative de l’incidence des fractures peripheriques etait observee uniquement dans le groupe denosumab pour les 3 periodes (IRRs : 0,85 [0,75 ; 0,96] dans les 12 mois suivants, 0,83 [0,73 ; 0,94] dans les 18 mois suivants et 0,82 [0,73 ; 0,92] dans les 24 mois suivants). Discussion L’incidence des fractures vertebrales a ete reduite par le traitement avec des therapies contre l’osteoporose. Une diminution significative des fractures de hanche et peripheriques a ete observee uniquement avec le denosumab. Conclusion Le traitement avec des medicaments contre l’osteoporose est efficace dans en situation reelle.

Objectives: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse (ARR) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real life setting. Methods: A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between July 1, 2015 and December 12, 2017, with 4.5 years of database history and 1 to 3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional Propensity Score. Negative binomial regression and a logistic regression models were used to estimate the relative risk (RR ± [95% CI]) of ARR and the Odds Ratio (OR ± [95% CI]) of disability progression, respectively. Results: Overall, 9 304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF- IMM, patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARR compared to IMM (RR 0.72 [0.61 - 0.86]) and TERI (0.81 [0.68 - 0.96]) and did not show any significant difference when compared with FTY The risk of the progression of MS specific disability was not significantly different for any matched cohorts. Interpretation: DMF is associated with lower risk of relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM).

Objectives: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse (ARR) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real life setting. Methods: A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between July 1, 2015 and December 12, 2017, with 4.5 years of database history and 1 to 3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional Propensity Score. Negative binomial regression and a regression logistic models were used to estimate the relative risk (RR ± [95% CI]) of ARR and the Odds Ratio (OR ± [95% CI]) of disability progression, respectively. Results: Overall, 9 304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF- IMM, patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARR compared to IMM (RR 0.72 [0.61 - 0.86]) and TERI (0.81 [0.68 - 0.96]). The risk of the progression of MS specific disability was not significantly different for any matched cohorts.Interpretation: DMF is associated with lower risk of relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM).

Additional file 1: Algorithm for the identification of multiple sclerosis relapses.

Additional file 2: Algorithm performance indicators before setting adjustment resulting from expert inputs.

Objective The aim of the present study was to investigate the association of I/D polymorphisms of ACE gene is associated with resistant hypertension and essential controlled hypertension. Results Our results show that the homozygous mutant genotype DD was more represented among resistant than controlled (58.1% vs 41.9% respectively), however the homozygote wild was more represented among controlled than resistant (70.6% vs 29.4% respectively). But more heterozygous ID among controlled than resistant patients (63.6% vs 36.4% respectively). The difference was statistically significant (p = 0.04). Analysis of clinical parameters indicated that physical activity contributes to resistant hypertension (P Based on our findings, the homozygous mutant for DD of ACE gene is associated with resistant hypertension in our population. Further studies with larger sample sizes are needed to confirm the results of this study.

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.

Introduction Dans le cadre de la reinscription a cinq ans du dimethylfumarate (Tecfidera®) par la Haute Autorite de sante en 2020, une etude de cohorte a ete menee dans le Systeme national des donnees de sante (SNDS). Objectifs Evaluer l’efficacite en vie reelle de dimethylfumarate dans la sclerose en plaques (SEP) comparativement aux autres traitements oraux (teriflunomide, fingolimod), et aux traitements immunomodulateurs injectables (IID). Methode Cohorte de patients identifies dans le SNDS avec un premier traitement de SEP (patients naifs) entre le 01/07/15 et le 31/12/16, un historique de 4,5 annees, et suivis jusqu’au 31/12/17. Le nombre annuel de poussees a ete compare entre deux traitements durant la periode d’exposition pour des patients apparies 1 :1 sur un score de propension a haute dimension, avec un modele de regression binomiale negative et un resultat exprime en risque relatif (RR [IC95 %]). Resultats Sur 1,5 ans, 5812 patients naifs ont ete identifies en France, 1930 initiant le teriflunomide (33,2 %), 1800 un IID (31,0 %), 1775 le dimethylfumarate (30,6 %) et 307 le fingolimod (5,3 %). Pour les 940 patients dimethylfumarate apparies a 940 patients teriflunomide, le nombre moyen annuel de poussees etait de 0,14 versus 0,17 (RR = 0,79 [0,63–1,00], p = 0,0457), et pour les 1019 patients dimethylfumarate apparies a 1019 patients IID, de 0,14 versus 0,18 (RR = 0,71 [0,56–0,90], p = 0,0051). Discussion Les poussees ont ete identifiees avec un algorithme complexe base sur des episodes de soins (hospitalisation et forte dose de corticotherapie) qui a fait l’objet d’une validation par des cliniciens en aveugle de l’algorithme, avec une valeur predictive negative de 100 % et positive de 95,2 %. Le faible nombre de patients fingolimod et leurs caracteristiques n’ont pas permis d’effectuer de comparaison. Conclusion Cette etude en pratique courante a montre un risque de poussees significativement plus faible avec le dimethylfumarate que le teriflunomide et les IID pour des patients partageant les memes caracteristiques.

Introduction Le dabigatran et le rivaroxaban ont montre un meilleur rapport benefice-risque compare aux antivitamines K pour la prevention des accidents vasculaires cerebraux (AVC) dans la fibrillation auriculaire non-valvulaire (FANV), mais aucun essai clinique randomise n’a compare le dabigatran au rivaroxaban. Nos precedentes analyses et d’autres etudes en vie reelle ont montre des resultats similaires ou meilleurs avec le dabigatran quelle que soit la dose a un ou deux ans de suivi. Objectif Comparer le risque en vie reelle a trois ans des evenements hemorragiques, AVC et embolies systemiques (AVC-ES), syndromes coronariens aigus (SCA) et deces chez les patients initiant un traitement par dabigatran ou rivaroxaban a dose standard ou reduite pour une FANV : dabigatran 150 mg versus rivaroxaban 20 mg, et dabigatran 110 mg versus rivaroxaban 15 mg. Methode Cohorte de patients initiant un traitement par dabigatran ou rivaroxaban en 2013 pour une FANV, sans antecedent de traitement anticoagulant dans les trois ans, identifies et suivis pendant trois ans dans le SNDS. La FANV etait definie par un diagnostic de FA sans antecedent de pathologie valvulaire (ALD, hospitalisation ou procedure). Pour chaque comparaison, les patients ont ete apparies 1 :1 sur sexe, âge, date de premiere delivrance d’anticoagulant et score de propension haute dimension (hdPS) incluant les facteurs de risque arteriel thrombotique et hemorragique. Les hazard ratios (HR [IC95 %]) ont ete estimes pendant l’exposition au traitement par un modele de Cox pour le deces et le critere composite des quatre evenements, ou de Fine and Gray pour les autres evenements cliniques etudies, definis par un diagnostic principal d’hospitalisation. Resultats En 2013, 56 403 patients initiant un traitement par dabigatran ou rivaroxaban pour FANV ont ete identifies : 10 847 traites par dabigatran 150 mg, 15 532 par dabigatran 110 mg, 18 829 par rivaroxaban 20 mg et 11 195 par rivaroxaban 15 mg. Parmi eux, 8195 patients par groupe ont ete apparies pour la dose standard (76 % des patients dabigatran 150 mg) et 7651 pour la dose reduite (68 % des patients rivaroxaban 15 mg), avec une tres bonne comparabilite (differences standardisees Conclusion Cette etude de cohorte nationale en vie reelle de patients initiant un traitement par dabigatran ou rivaroxaban pour une FANV et suivis trois ans confirme les resultats a deux ans et ceux d’autres etudes observationnelles, avec une efficacite similaire ou meilleure du dabigatran a dose standard ou reduite compare au rivaroxaban et un risque d’hemorragie plus faible.

Introduction L’absence de marqueur direct de poussees de Sclerose en plaques (SEP) dans le Systeme national des donnees de sante (SNDS) necessite le developpement d’algorithme complexe base essentiellement sur les hospitalisations et les episodes therapeutiques de forte dose de corticotherapie. Objectifs Evaluer la valeur predictive positive et negative (VPP et VPN) d’un algorithme complexe developpe pour identifier les poussees de SEP dans le SNDS comparativement au jugement de quatre experts neurologues. Methode Un tirage au sort a ete realise parmi les patients traites pour une SEP pour en selectionner 100 avec au moins une poussee d’apres l’algorithme et 100 patients sans poussee durant un suivi de 1 a 1,5 ans. L’ensemble des donnees de consommations de soins et d’hospitalisation de chaque patient a ete revu independamment par deux neurologues en aveugle de l’algorithme. Les cas discordants entre deux neurologues etaient revus collegialement afin d’obtenir un consensus. Resultats Parmi les 37 986 patients traites pour SEP identifies dans le SNDS entre juillet 2015 et decembre 2016, 9,6 % ont presente au moins une poussee d’apres l’algorithme. Parmi les patients selectionnes, les neurologues en ont confirme 95 avec poussee(s) et 96 sans poussee, soit une VPP de 95 % et une VPN de 96 %. Apres ajustement de l’algorithme en fonction des conclusions des neurologues, la VPP et la VPN etaient respectivement de 95,2 % et 100 %. Discussion La richesse des donnees du SNDS permet une vue holistique du patient dans l’ensemble du systeme de prise en charge, et rend possible la definition d’algorithmes de detection d’evenements complexes comme les poussees de SEP, mais aussi d’etudes de validation de ces algorithmes via la reconstitution de quasi-dossiers medicaux 100 % anonymises, permettant ensuite d’ajuster ces algorithmes afin d’ameliorer leur performance. Conclusion Les resultats montrent que l’algorithme presente permet une tres bonne identification des poussees de SEP dans le SNDS et pourra etre utilise pour de futures etudes observationnelles sur la SEP.

Resistant hypertension is a public health problem, which is due to the interaction between genetic and environmental factors. It represents the severe form of hypertension, so it is necessary to highlight the different genetic factors involved, which can play a major role in this pathology. The aim of our studies is to evaluate the association between the polymorphisms of ATIR A1166C, RGS2 (-638 A/G and -391G/C) gene and resistant hypertension in Moroccan population. And we attempt to analyze and identify potentially interaction genetic markers that modulate the risk of resistant hypertension. The study was conducted in 160 hypertensive cases from Moroccan population: 70 with resistant hypertension (RH) and 90 with well-controlled hypertension (HT). Polymerase chain reaction followed by restriction fragment analysis length was used to identify -1166A/C AT1R, -395G/C and -638A/G RGS2 genotypes. Statistical analysis was performed by SPSS. Our results suggest that, RGS2 (-395 G/C; -638A/G) and ATIR 1166A/C analyzed separately not fond any significant association P 0.05, although the mutants genotypes are more represented among resistant hypertensive patients to controlled hypertensive subjects. While, the study of haplotypes formed by the combination of alleles of the -638A/G polymorphism and the -395G/C polymorphism of the RGS2 gene showed that the risk of developing resistance was multiplied by 47, OR [(95% CI) = 47 (1.5–1422)]; p = 0.02. The interaction between variant alleles at two candidate loci exhibit trending associations with resistant hypertension, AG-AC combination (2.9 (0.8–9.6)), P value = 0.07. Hypertension is a public health problem worldwide. Despite the number of antihypertensive classes used and available, as well as the many recommendations, it remains insufficiently controlled. Identification of genetic influences on resistance to current therapies might also lead to development of new therapeutic targets. However it is important to understand that a single genetic variant may not reveal significant associations with resistant hypertension because their effects may be dependent on gene-gene or gene-environment interactions.

Background Dabigatran (D) and rivaroxaban (R) showed better benefit-risk than VKA for stroke prevention in non-valvular atrial fibrillation (NVAF), but no randomized trial compared D versus R. Purpose To compare the 2-year risk of major events for D vs. R new users for NVAF in real-life: standard dosage (D150 mg vs. R20 mg) and reduced dosage (D110 mg vs. R15 mg). Methods Cohort of D or R new users for NVAF in 2013 identified and followed for 2 years in the SNDS French nationwide claims database. NVAF was defined from long-term disease registration, hospitalisation diagnosis or procedure for atrial fibrillation without valvular disease (3-year database history). D and R patients were 1:1 matched according to standard or reduced dosage, on gender, age, drug start date and high-dimensional propensity scores (hdPS) including individual stroke and bleeding risk factors from CHA2DS2-VASc and HAS-BLED. Hazard ratios (HR) [95% confidence interval] were estimated on treatment using Cox proportional hazard risk or Fine and Gray models. Results From the 10,847 D150, 15,532 D110, 18,829 R20 and 11,195 R15 new users for NVAF in 2013, 8290 D150/R20 per arm, and 7639 D110/R15 per arm were matched, i.e. 76% and 68% of patients of the lowest group (D150 and R15 groups), respectively; with very good overlap of hdPS distributions, all standardized differences Conclusion This nationwide study of new anticoagulant users for NVAF shows a better benefit-risk of dabigatran standard and reduced dosages compared to rivaroxaban in real-world setting.

The AP-1 transcription factor complex is a key player in regulating inflammatory processes, cell proliferation, differentiation, and cell transformation. The aim of the present study is to investigate C-Jun (one of AP-1complex) expression and its proliferative role in skin samples of lichen planus, psoriasis as common inflammatory skin diseases and squamous cell carcinoma using immunohistochemical method. The present study was carried out on skin biopsies of 15 psoriatic patients, 15 lichen planus patients, 15 SCC, and 15 normal skin biopsies. Nuclear expression of C-Jun was detected in basal and few suprabasal layers of epidermis of normal skin. C-Jun was expressed in the whole epidermal layers of both psoriasis (14/15) and lichen planus (15/15) in addition to its expression in lymphocytic infiltrate in the latter in about half of cases (8/15). C-Jun was also expressed in 93.3% (14/15) of SCC in a percentage lower than that of psoriasis, lichen planus, and normal skin. The percentage of C-Jun expression in SCC was significantly associated with an early stage (p = 0.000), free surgical margins (p = 0.022), and small tumour size (p = 0.003).The marked reduction of C-Jun in SCC in comparison to normal skin and inflammatory skin dermatoses may refer to its tumour suppressor activity. C-Jun expression in SCC carries favourable prognosis. Absence of significant association between C-Jun and Ki-67 either in SCC or inflammatory skin diseases indicates that it does not affect proliferative capacity of cells.

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.

Introduction Comparer les risques a deux ans des hemorragies, accidents vasculaires cerebraux et embolies systemiques (AVC-ES), syndromes coronaires aigus (SCA) et deces chez les patients initiant un traitement par dabigatran (D) ou rivaroxaban (R) a dose standard ou reduite pour fibrillation auriculaire non valvulaire (FANV) : D150 mg versus R20 mg, et D110 mg versus R15 mg. Methodes Cohorte de patients initiant un traitement par D ou R en 2013 pour FANV, sans antecedent de traitement anticoagulant dans les trois ans, identifies et suivis pendant deux ans dans le Systeme national des donnees de sante (SNDS). La FANV etait definie par un diagnostic de FA sans antecedent de pathologie valvulaire (ALD, hospitalisation ou procedure). Pour chaque comparaison, les patients etaient apparies 1 :1 sur sexe, âge, date de premiere delivrance d’anticoagulant et score de propension haute dimension. Les hazard ratios (HR [IC95 %]) ont ete estimes pendant l’exposition au traitement par un modele de Cox ou de Fine and Gray. Resultats Parmi les 56 403 patients identifies, 8290 par groupe ont ete apparies pour la dose standard et 7639 pour la dose reduite, avec une tres bonne comparabilite (differences standardisees faibles voire nulles). L’âge moyen des patients etaient de 66,9 ans pour la dose standard, avec un CHA2DS2-VASc > 2 pour 58,9 % et un HAS-BLED ≥ 3 pour 15,6 % contre respectivement 80,4 ans, 94,0 % et 34,0 % pour la dose reduite. Les HR D versus R pour la dose standard et la dose reduite etaient respectivement de 0,55 [0,43–0,70] et 0,77 [0,64–0,92] pour les hemorragies hospitalisees, 0,92 [0,67–1,26] et 0,73 [0,56–0,94] pour les AVC-ES, 0,93 [0,66–1,29] et 0,95 [0,71–1,26] pour les SCA, 0,84 [0,65–1,11] et 0,95 [0,83–1,09] pour les deces, et 0,74 [0,64–0,86] et 0,88 [0,79–0,97] pour le critere composite des quatre evenements. Discussion/Conclusion Cette etude montre une utilisation majoritaire des doses reduites chez les patients les plus âges avec beaucoup de facteurs de risque et un meilleur benefice-risque des deux doses de dabigatran comparativement au rivaroxaban dans la FANV.

Objective Estimate the effect of lifestyle adjustment activities in patients with metabolic syndrome treated by prescribed balneotherapy. Methods Observational pilot cohort study with 12-month follow-up after multidimensional lifestyle training (physical, dietary, educational) during 3-week standard stay in the spa town of Eugenie-les-Bains. Results Of 145 eligible patients, 97 were included; 63 were followed and analysable. At inclusion all had ≥ 3 National cholesterol education program-Adult treatment panel III (NCEP-ATPIII) criteria defining metabolic syndrome, 76.2% were female, mean age was 61.2 years. At the end of follow-up (median:10.4 months, Inter-Quartile Range: [6.7;11.4]), 48 of these 63 patients (76.2%) no longer had metabolic syndrome (95%CI [65.7;86.7]). These 48 patients without metabolic syndrome at the end of follow-up represented 49.5% of the 97 included (95%CI [39.5;59.4]). Conclusions Future studies of lifestyle interventions taking advantage of the spa environment can be expected to find least one third of patients free of metabolic syndrome at the end of 12-month follow-up in the intervention group.

The aim of the present study was to describe the real-life usage patterns of paracetamol.The Echantillon Généraliste de Bénéficiaires (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.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% bought60 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 those60 bought more than 30 DDD per year. More than half the dispensings exceeded the legal per-box limit of 8 g.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.

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.

Aims/hypothesis Using the Echantillon Généraliste de Bénéficiaires: random 1/97 permanent sample of the French national healthcare insurance system database (EGB), we investigated whether, as previously suspected, the risk of cancer in insulin glargine (A21Gly,B31Arg,B32Arg human insulin) users is higher than in human insulin users. The investigation period was from 1 January 2003 to 30 June 2010. Methods We used Cox proportional hazards time-dependent models that were stratified on propensity score quartiles for use of insulin glargine vs human insulin, and adjusted for insulin, biguanide and sulfonylurea possession rates to assess the risk of cancer or death in all or incident exclusive or predominant (≥80% use time) users of insulin glargine compared with equivalent human insulin users. Results Only type 2 diabetic patients were studied. Exposure rates varied from 2,273 and 614 patient-years for incident exclusive users of insulin glargine or human insulin, respectively, to 3125 and 2341 patient-years for all patients predominantly using insulin glargine or human insulin, respectively. All-type cancer HRs with insulin glargine vs human insulin ranged from 0.59 (95% CI 0.28, 1.25) in incident exclusive users to 0.58 (95% CI 0.34, 1.01) in all predominant users. Cancer risk increased with exposure to insulin or sulfonylureas in these patients. Adjusted HRs for death or cancer associated with insulin glargine compared with human insulin ranged from 0.58 (95% CI 0.32, 1.06) to 0.56 (95% CI 0.36, 0.87). Conclusions/interpretation There was no excess risk of cancer in type 2 diabetic patients on insulin glargine alone compared with those on human insulin alone. The overall risk of death or cancer in patients on insulin glargine was about half that of patients on human insulin, thereby excluding a competitive risk bias.

Background Imatinib has dramatically improved the prognosis of advanced gastrointestinal stromal tumours (GISTs). Clinical trial data showed that patients with trough imatinib plasma concentrations (Cmin) below 1100 ng/ml (quartile 1) had shorter time to progression, but no threshold has been defined. The main objective of this study was to investigate in advanced GIST whether a Cmin threshold value associated with a longer progression-free survival (PFS) could be specified. This would be the first step leading to therapeutic drug monitoring of imatinib in GIST. Patients and methods Advanced GIST patients (n = 96) treated with imatinib 400 mg/d (41 stomach, 34 small bowel, and 21 other primary site localisations) were prospectively included in this real-life setting study. Routine plasma level testing imatinib (Cmin) and clinical data of were recorded prospectively. Results Small bowel localisation was associated with an increased relative risk of progression of 3.09 versus stomach localisation (p = 0.0255). Mean Cmin (±standard deviation) was 868 (±536) ng/ml with 75% inter-individual and 26% intra-patient variability. A Cmin threshold of 760 ng/ml defined by log-rank test was associated with longer PFS for the whole population (p = 0.0256) and for both stomach (p = 0.043) and small bowel (p = 0.049) localisations when analysed separately. Multivariate Cox regression analysis found that Cmin above 760 ng/ml was associated with 65% reduction risk of progression (p = 0.0271) in the whole population independently of the anatomical localisation. Conclusion Concentration of imatinib significantly influences duration of tumour control treatment in GIST patients with a Cmin threshold of 760 ng/ml associated with prolonged PFS in real-life setting.

Background: Anti-tumour necrosis factor (TNF) agents, through their intense immunoregulatory effect, have been suspected to increase the risk of malignant lymphoma. However, the classical epidemiological approaches conducted over about the last 10 years have not totally succeeded in addressing the question of a causal or artifactual association. Therefore, the analysis of a substantial set of case reports, although usually considered as poorly generalizable to the general population, could be particularly informative. Two main sources of case reports in postmarketing settings are available; publications in medical journals and reports to pharmacovigilance systems. Objective: The aim of the study was to compare the characteristics of case reports from both these sources in order to understand whether they provided the same information for the investigation of the causal link between lymphoma and anti-TNF agents. Methods: All case reports of malignant lymphoma in patients treated with an anti-TNF agent published in MEDLINE and all reports to the French pharmacovigilance system up to 1 February 2010 were identified. Cases of malignant lymphoma identified in postmarketing surveillance from both sources were compared regarding the following variables: age, sex, anti-TNF agent involved, indication for use, type of lymphoma, prior or concomitant immunosuppressive drugs and time to onset of lymphoma. Results: A total of 81 published case reports and 61 cases reported to the French pharmacovigilance system were compared. In published reports, patients were younger (p = 0.03) and more frequently receiving a first anti-TNF treatment (p = 0.03), particularly infliximab (p = 0.03). Conversely, in the pharmacovigilance system reports, a succession of different anti-TNFs (p = 0.03) and adalimumab (p< 0.0001) were more frequently reported. Lymphomas in patients treated with anti-TNF agents for Crohn’s disease were more prevalent in published cases than in pharmacovigilance reports (p< 0.0001), and in particular involved hepatosplenic T-cell lymphoma. Conversely, rheumatoid arthritis was the main indication for anti-TNF agents in pharmacovigilance reports (p = 0.01). Time to onset was markedly shorter in published cases (median 12 months) than in pharmacovigilance reports (median 30 months; p = 0.0001). Conclusions: Characteristics of published cases and those reported to the French pharmacovigilance system differed markedly for all characteristics tested, except sex and the use of prior or concomitant immunosuppressive drugs. Published case reports favoured convincing arguments for drug causation whereas cases reported to the pharmacovigilance system were more disparate but could describe more accurately the reality of lymphoma occurrence in this particular population. These results argue for the use of the pharmacovigilance reports when case reports are used to investigate the causal link between lymphoma and anti-TNF agents at the population level. Data from cases notified to the French pharmacovigilance system did not indicate an increased risk of lymphoma during the early phase of anti-TNF treatment. To confirm this hypothesis, a study combining pharmacovigilance reports from several countries, or, if feasible, a cohort study both with a large sample size and a long duration of follow-up would be required.

Objectif Evaluer les ressources de sante consommees et leurs couts associes chez les patients debutant un traitement par anticoagulant oral direct (AOD) ou antivitamine K (AVK) dans la fibrillation auriculaire non valvulaire (FANV). Methode Etude de cohorte de patients debutant un traitement par AOD (Pradaxa® ou Xarelto®) ou AVK dans la FANV au cours du premier semestre 2013, identifies et suivis dans l’EGB, echantillon aleatoire permanent de la base nationale du Sniiram et du PMSI. Les patients etaient suivis six mois apres la date index ; la date index etant definie comme la date de premiere delivrance du traitement d’interet avec trois ans d’historique dans la base de donnees. Deux populations FANV ont ete definies : (i) une population specifique incluant les patients avec une information diagnostique de FANV dans l’EGB (ALD ou hospitalisation pour fibrillation auriculaire sans antecedent de pathologie valvulaire), et sans autre indication probable ; (ii) une population sensible composee de la population precedente avec en plus, les patients ayant une information probabilistique de FANV, et sans autre indication probable. Les ressources consommees et leurs couts associes, couts totaux et specifiques de la maladie, ont ete estimes selon la perspective de l’assurance maladie. Resultats Parmi les 1 750 patients debutant un traitement par AOD (Pradaxa® ou Xarelto®) ou AVK durant la periode d’etude, 282 correspondaient a la definition de la population FANV specifique (AOD : 152 patients, AVK : 130 patients). Le sex-ratio etait proche de 1, l’âge moyen a la date index etait de 77 ans (AOD : 75 ans, AVK : 78 ans), avec un score CHA2DS2-VASc ≥ 2 pour 89 % des patients (AOD : 86 %, AVK : 93 %), et un score HAS-BLED ≥ 3 pour 47 % (AOD : 38 %, AVK : 58 %). Au cours des six mois de suivi, le nombre median de delivrances du traitement d’interet par patient etait de 6 (AOD : 7, AVK : 5), et 47 % ont ete hospitalises au moins une fois (AOD : 38 %, AVK : 58 %). Le cout total moyen par patient sur les six mois de suivi etait de 6 289 € (AOD : 4 232 €, AVK : 8 693 €), dont 28 % pour les hospitalisations non cardiovasculaires, 13 % pour les hospitalisations cardiovasculaires, 5 % pour les medicaments cardiovasculaires et antidiabetiques. Le cout medical total moyen specifique de la FANV par patient etait de 875 € (AOD : 824 €, AVK : 933 €), dont 45 % pour les hospitalisations, et 28 % pour les medicaments. Les resultats dans la population FANV sensible (n = 505, 285 AOD, 220 VKA) etaient similaires. Conclusion Cette etude montre que les couts specifiques de la maladie representent moins de 15 % des couts totaux et suggere des couts totaux et specifiques differents entre les AOD et les AVK dans la FANV. Toutefois, en l’absence d’ajustement du fait d’un nombre trop faible de sujets, ceci pourrait correspondre a des differences de caracteristiques entre les deux groupes et sera evalue de facon adequate sur l’ensemble du Sniiram avec des analyses appariees et ajustees.

Objectif Estimer l’incidence en vie reelle des evenements hemorragiques, evenements arteriels thrombotiques (EAT), syndromes coronaires aigus (SCA), et deces chez les patients debutant un traitement par anti-vitamines K (AVK) dans la fibrillation auriculaire (FA), avant l’arrivee des anticoagulants oraux directs (AOD). Methode Etude de cohorte de patients debutant un traitement par AVK entre le 01/01/2007 et le 31/12/2011, identifies et suivis dans une base de donnees de remboursement de soins et d’hospitalisation, l’EGB, echantillon aleatoire permanent de la base nationale du SNIIRAM et du PMSI. Les patients etaient suivis trois ans maximums apres la date index, avec une censure au 31/12/2012 ; la date index etant definie comme la date de premiere delivrance d’AVK, avec deux ans d’historique dans la base de donnees. Les patients FA etaient ceux presentant soit une information diagnostique (ALD ou hospitalisation), soit une information probabilistique d’apres les donnees de l’EGB, et sans autre indication probable des AVK. La population FANV etait definie par les patients de la population FA sans antecedent de pathologie valvulaire. Le taux d’incidence etait estime durant l’exposition aux AVK pour les evenements hospitalises : hemorragie, EAT, SCA, ainsi que pour le deces. Resultats Parmi les 8894 patients debutant un traitement par AVK durant la periode d’etude, 3345 correspondaient a la definition de la population FA avec 3977 personnes-annee (PA) suivies. La moitie des patients etaient des hommes (52 %), l’âge moyen etait de 75 ans, 87 % presentaient un score CHA2DS2-VASc ≥2, et 12 % un score HAS-BLED > 3. Le taux d’incidence des hemorragies pour 1000 PA exposees aux AVK etait de 28 patients (IC 95 % [23–34]), incluant 6 [3–8] hemorragies cerebrales, 10 [7–13] digestives, et 14 [10–17] autres hemorragies. Le taux d’incidence des autres evenements pour 1000 PA exposees aux AVK etaient de 16 [12–20] pour les SCA, 15 [11–18] pour les EAT, et 38 [32–44] pour les deces. Les resultats etaient identiques lorsque seuls les patients avec une information diagnostique (ALD ou hospitalisation) etaient pris en compte. Les caracteristiques des patients et les taux d’incidence estimes dans la population FANV ( n = 2818) etaient egalement tres similaires : 28 [22–34] pour les hemorragies, 16 [12–20] pour les SCA, 15 [11–19] pour les EAT, et 35 [29–41] pour les deces pour 1000 PA exposees aux AVK. L’incidence annuelle en France a ete estimee entre 12 200–19 200 cas d’hospitalisation pour hemorragie (IC 95 %), 6300–11 400 cas de SCA hospitalises, 5900–10 800 cas d’EAT hospitalises, et 15 700–23 700 deces durant une exposition aux AVK pour une FANV. Conclusion Cette etude apporte des valeurs de reference en termes de risques hemorragiques, de risques thrombotiques arteriels et de deces, avant l’arrivee des AOD dans la FANV, avec des taux d’incidence de meme ordre avec ou sans antecedent de pathologie valvulaire.

Objectif Les scores de propension ont ete developpes pour resumer des variables qui predisent le fait de recevoir une intervention A ou B dans une etude non randomisee et ainsi reduire le risque de confusion dans la comparaison de l’impact de ces deux interventions sur un outcome. Les scores de propension haute dimension (hdPS) permettent de prendre en compte un tres grand nombre de variables, qui de plus peuvent collectivement etre des proxy de facteurs de confusion non disponibles dans les donnees. L’objectif de cette analyse etait d’estimer l’impact d’un hdPS avec les donnees du SNDS, sur les differences initiales entre les patients initiant un traitement par dabigatran (150 mg ou 110 mg) et les AVK pour une fibrillation auriculaire non valvulaire (FANV) ; le dabigatran 150 mg etant le dosage standard et le 110 mg recommande chez le sujet âge et/ou a risque hemorragique eleve, ou en cas d’insuffisance renale moderee. Methode Cohorte de tous les patients initiant un traitement par dabigatran ou un AVK en 2013 pour une FANV dans le SNDS. Pour chaque comparaison (150 mg versus AVK, 110 mg versus AVK), un hdPS a ete defini avec un modele de regression logistique prenant en compte le sexe, l’âge, les facteurs de risque thromboembolique et hemorragique, ainsi que 500 indicatrices selectionnees automatiquement pour maximiser le biais entre exposition et outcome etudie (algorithme de Bross), parmi plus de 2000 variables de soins reparties en quatre dimensions : ALD, diagnostics CIM10 d’hospitalisation (trois ans d’historique), medicaments (ATC niveau 7), actes medicaux avec la specialite, actes paramedicaux et examens biologiques (un an d’historique). L’impact du hdPS a ete evalue avec les courbes de distribution du hdPS brute et apres appariement, ainsi que les differences standardisees brutes, ajustees sur le hdPS et pour les patients apparies 1 :1 sur le hdPS (methode Greedy avec caliper 0,05). Resultats En 2013, 103 101 patients FANV initiant un traitement anticoagulant ont ete identifies : 10 847 traites par dabigatran 150 mg, 15 532 par le 110 mg et 44 653 par AVK avec des distributions de hdPS et des caracteristiques nettement differentes. Parmi eux, 77 % des patients dabigatran 150 mg (n = 8389) et 93 % des patients dabigatran 110 mg (n = 14 442) ont ete apparies a un patient AVK avec des distributions de hdPS tout a fait superposables, un âge moyen de 67,3 ans, 67 % d’hommes et 65 % de CHA2DS2-VASc ≥ 2 pour les patients dabigatran 150 mg et VKA apparies, 78,6 ans, 49 % d’hommes et 91 % de CHA2DS2-VASc ≥ 2 pour les patients dabigatran 110 mg et AVK apparies, et des differences standardisees ≤ 5 % pour 500 variables descriptives etudiees, voire ≤ 2 % pour la plupart, et par ailleurs non necessairement selectionnees parmi les indicatrices du hdPS. Conclusion Cette etude montre des differences importantes entre les patients FANV traites par dabigatran 150 mg ou 110 mg et les AVK en pratique courante, avec une utilisation preferentielle du 110 mg chez les patients les plus âges. La methode du hdPS a permis de construire une variable d’appariement performante pour constituer des groupes tres comparables pour la comparaison de deux traitements dans le SNDS.

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.

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.

To evaluate the prevalence of nocturnal symptoms in a large sample of asthmatic patients, and to assess the agreement between patients' complaints and general practitioners' (GPs') reports in primary care.Cross-sectional survey involved 3,526 GPs and 751 specialists (pulmonologists and allergists) and included 13,493 patients with persistent asthma. Symptoms, treatment, and social and medical data were collected in real time by the patients and their GPs.France.Prevalence of nocturnal symptoms was 60%. A total of 7,989 patients with nocturnal symptoms had complete data for both patients and GPs; 3,849 (48.1%) had perfect agreement between GP and their complaints for nocturnal symptoms (agreement group; [kappa = 1]); 3,376(42.2%) declared having no symptoms during the night, but these were detected by the GP during the visit (underestimated by patients and detected by GPs); 773(9.6%) declared having nocturnal symptoms, but these were not detected by GPs. Patients with a good agreement with their GP's opinion were significantly more frequently followed-up by a specialist than other patients (p = 0.002).Nocturnal symptoms appear to be underdeclared by patients. GPs should therefore systematically ask their patients about nocturnal symptoms to increase control of asthma and to adequately manage its treatment.

To describe adverse events occurring after mass vaccination with conjugate and nonconjugate vaccines and to assess the incidence of serious adverse effects. A mass immunisation campaign against meningococcal C disease was conducted in two French administrative areas, Landes and Pyrenees atlantiques, for 2 months (from October to December 2002). Adverse events were reported by families and physicians by means of a specific reporting form returned to the pharmacovigilance centre 15 days after vaccination. The target population was 260,630 individuals aged between 2 months and 24 years. About 179,000 children and young adults were vaccinated. A total of 92,711 report forms were received by the pharmacovigilance centre, and 12,695 subjects presented at least one adverse event. The most frequently involved systems/disorders were application site disorders (48.4%), whole-body general disorders (21.8%), central and peripheral nervous system disorders (14.6%), and gastrointestinal system disorders (4.7%). Most of these adverse events were transient and not serious. There were 13 serious adverse events: one each of syncope, fever, headache with fever, neuralgia, serum sickness, arthritis, purpura, facial paralysis, multiple sclerosis, lipoma, and meningism, and two cases of bronchospasm. No significant difference was found in rates of adverse event reports between both vaccines. The estimated incidence of serious adverse effect reports was 7 per 100,000. This campaign was the second immunisation campaign undertaken in France involving both physicians and families as reporters. Although unlabeled adverse effects were identified during this campaign, they were mostly nonserious and have been known to occur with other vaccines.

Objective: To assess whether current use of psychoactive substance(s) is a prognostic factor during hospitalization for intentional drug overdose (IDO). Method: Current intoxication with psychoactive substance(s) [cannabis, opiate, buprenorphine, amphetamine/ecstasy, cocaine, lysergic acid diethylamide (LSD)] was identified using toxicological urinalysis in 671 patients with IDO. An IDO was a priori defined as serious if associated with one of the following events: death, hospitalization in intensive care unit longer than 48 h, respiratory support, use of vasopressive drugs, cardiac massage or dialysis. Results: Subjects positive for toxicological assays were twice as likely to present with serious IDO (OR = 1.9, 95% CI: 1.3–2.8, P = 0.001), independently from a large range of confounding factors. The risk of serious IDO was especially marked in subjects using LSD, buprenorphine or opiates. Conclusion: Systematic investigation of substance use could be important to adapt medical management of subjects with IDO in general hospital, but also in primary care and psychiatric settings.

Reviewing available data shows that most of antipsychotic drugs are associated with arrhythmia and sudden death. Experimental studies have shown a HERG channel blockade, a dose-dependent increase in duration of action potential or of QT interval, with various degrees of indicators of serious arrhythmogenicity. However, it seems difficult to relate these in vitro and in vivo preclinical models to clinical findings, in part, because the relationship between concentrations used and in vivo tissue concentrations during treatment in man is not known. Consequently, we established the myocardium to plasma concentration ratios for a series of antipsychotic drugs by intraperitoneal administration of different level doses to the guinea pig. Then, we compared these values to their ability to induce arrhythmia or torsade de pointes in clinical practice. The myocardium to plasma concentration ratios were 2.2 for clozapine, 2.7 for olanzapine, 3.1 for sertindole, 4.5 for risperidone, and 6.4 for haloperidol. These data suggest that when the ratio is higher than 4, arrhythmia and sudden death may be expected. On the contrary, when the ratio is less than 3, little effect may be predicted. These results underscore the importance of interpreting HERG channel data and electrophysiological data in the context of other pharmacokinetic parameters such as myocardium to plasma distribution.

Objective: To assess the accuracy of self-reported substance use and toxicological assays in subjects admitted for Intentional Drug Overdose (IDO), using as a reference diagnosis of substance use disorder. Method: Self-reported substance use was collected and toxicological assays were carried out in urine samples in 507 patients with IDO. A standardized psychiatric evaluation was performed in 100 randomly selected subjects. Results: In routine practice, the emergency department staff did not investigate substance use in nearly one of two patients. Patients’ statements and toxicological assays were more specific than sensitive, with lower scores for toxicological assays. Patients’ statements made it possible to detect nearly 80% of subjects with substance use disorder. Conclusion: Identification of substance use disorder in subjects with IDO has strong clinical consequences regarding treatment and prevention of suicidal behaviour. Thus, emergency department staff should be made aware of the value of more systematically exploring self-reported substance use.

The correct use of inhalation devices is an inclusion criterion in many comparative studies. However, patients can make errors, thus compromising the effectiveness of their own inhaler. The aim of the study is to evaluate inhaler use by patients with chronic obstructive pulmonary disease (COPD) [n = 984]. General practitioners assessed inhalation technique, using a specific checklist previously established for each inhaler model (Aerolizer, Autohaler, Diskus, a pressurised metered-dose inhaler (pMDI) or a Turbuhaler). A total of 24% of the patients using a pMDI did not make an error compared with 34-40% of those using breath-actuated devices. The frequency of critical errors varied according to the device: 11.5-14.9% of the subjects using an Aerolizer, Autohaler or Diskus versus 37.4% and 38.1% of the patients using a pMDI and a Turbuhaler, respectively. The proper use of the Turbuhaler is often overestimated (24.7%) compared with the pMDI (2.1%). The development of educational programmes for patients and prescribers is needed to improve the management of COPD.

Objectif Comparer les risques d’hemorragies, d’evenements arteriels thrombotiques, de syndromes coronaires aigus et de deces a un an chez les patients initiant un traitement anticoagulant pour une fibrillation auriculaire non valvulaire (FANV) : dabigatran (D) versus antivitamine K (AVK) et rivaroxaban (R) versus AVK. Methode Cohorte de patients avec une FANV debutant un premier traitement par D, R ou AVK en 2013 en France, identifies et suivis pendant un an dans le Sniiram. Deux populations FANV ont ete definies : – specifique : –patients avec un diagnostic de FA sans antecedent de pathologie valvulaire (ALD/hospitalisation) ; – sensible : –patients de la population specifique plus ceux avec une FANV probable basee sur un score de pathologie. Pour chaque comparaison, les patients etaient apparies 1:1 sur le sexe, l’âge, la date de premiere delivrance d’anticoagulant et un score de propension haute dimension incluant les facteurs de risque arteriel thrombotique et hemorragique. L’incidence cumulee a un an du premier evenement pendant l’exposition au traitement a ete estimee par la methode de Kaplan-Meier et les risques compares avec un modele de Cox pour le deces et de Fine et Gray pour les evenements cliniques, definis par un diagnostic principal d’hospitalisation. Resultats En 2013, 103 101 patients (27 060 D, 31 388 R, 44 653 AVK) ont ete identifies dans le Sniiram pour la population specifique et 144 220 (37 222 D, 46 882 R, 60 116 AVK) pour la population sensible. Pour la population specifique, les patients etaient âges en moyenne de 75 (± 12) ans avec 54 % d’hommes, un score CHA 2 DS 2 -VASc ≥ 2 pour 83 %, un score HAS-BLED > 3 pour 10 %, avec des differences standardisees importantes pour chacune des comparaisons et des differences standardisees normalisees ou nulles apres appariement. Le nombre de patients apparies de la population specifique pour chaque comparaison et leurs resultats sont presentes dans le Tableau S1 . La population sensible presentait des caracteristiques similaires et des resultats superposables. Conclusion Cette etude de plus de 100 000 patients montre un meilleur benefice–risque des anticoagulants oraux directs comparativement aux AVK dans la FANV, incluant moins de deces et d’hemorragies intracrâniennes, sans augmentation des hemorragies gastro-intestinales.

Objectif principal Evaluer le mesusage du Pylera® en France. Objectifs secondaires Decrire les caracteristiques des patients consommant du Pylera® ; decrire les nouvelles prescriptions d’un traitement specifique pour eradiquer Helicobacter pylori (H. pylori) (indicateur ou proxy pour evaluer l’echec au traitement). Methodes Etude de cohorte de patients avec une 1re delivrance de Pylera® (date index) entre le 1er avril 2013 et le 30 avril 2014 dans l’EGB (echantillon generaliste des beneficiaires), un echantillon permanent representatif au 1/97e de la base nationale de l’assurance maladie et du programme de medicalisation des systemes d’information (PMSI), avec un historique et un suivi de 12 mois a partir de la date index. Le critere de mesusage etait defini par la delivrance de plus d’une boite de Pylera® a la date index ou d’une delivrance de Pylera® sans test diagnostique specifique dans l’annee precedant la date index. Resultats Un total de 540 patients a eu au moins une delivrance de Pylera® dont les caracteristiques generales etaient : âge moyen de 53 ans (15 % de plus de 70 ans, 1 % d’adolescents entre 12 et 18 ans), 44 % d’hommes, 30 % avec au moins une affection longue-duree (ALD) et 18 % deja traites dans les 12 mois precedents pour une eradication de H. pylori. Les principaux prescripteurs de Pylera® etaient les gastro-enterologues ou medecins hospitaliers (61 %), suivis par les medecins generalistes (30 %). Un inhibiteur de la pompe a protons etait codelivre dans 93 % des cas, principalement l’omeprazole (65 %), suivi de l’esomeprazole (17 %). Neuf patients (2 %) avaient une insuffisance hepatique ou renale et une patiente etait enceinte. Cinquante-neuf patients (11 %) avaient au moins un critere de mesusage : 10 patients (2 %) avec une delivrance le meme jour de plus d’une boite de Pylera® (7 patients avec 2 boites, 2 avec 3 boites, et 1 avec 4 boites) et 49 patients (9 %) sans test a l’uree ou une endoscopie dans l’annee precedente. En tenant compte de la serologie comme test diagnostique, le nombre de patients avec un critere de mesusage diminue de 59 patients (11 %) a 51 patients (9 %). Pendant les 12 mois de suivi, 45 patients (8 %) ont eu une nouvelle delivrance de traitements pour eradiquer H. pylori, dont 17 patients dans les 3 mois suivant la date index. Conclusion Cette etude basee sur les donnees de remboursement de soins en France, montre un mesusage du Pylera® pour un peu plus de 10 % des patients, essentiellement une absence de test de diagnostic avant l’initiation du traitement, et la delivrance de plusieurs boites de Pylera® pour 2 % des patients. A cela s’ajoute quelques patients avec des contre-indications mentionnees dans le resume des caracteristiques du produit, insuffisance renale, insuffisance hepatique et grossesse. Les 8 % de patients qui ont eu une nouvelle delivrance dans l’annee d’un traitement pour eradiquer H. pylori sont dans la borne basse des 10 % et 30 % de taux d’echec d’eradication de l’infection a H. pylori decrit dans la litterature en France.

Background: The real-life benefits and risks of the direct oral anticoagulants (DOAC) for non-valvular atrial fibrillation (NVAF) have been disputed. This study aimed to compare the 1-year risk of major events for new users of dabigatran (D) or rivaroxaban (R) vs. vitamin K antagonists (VKA) in NVAF

Introduction Les scores de propension haute dimension (hdPS) ont ete developpes pour estimer l’effet d’une intervention en tenant compte d’un tres grand nombre de variables pour predire le fait de recevoir l’une ou l’autre des interventions, et egalement etre collectivement un proxy de facteurs de confusion non disponibles dans les donnees. L’objectif de cette analyse etait d’estimer l’impact d’un hdPS sur les differences initiales entre les patients initiant un traitement par anticoagulant oral direct (AOD) ou anti-vitamine K (AVK) pour une fibrillation auriculaire non-valvulaire (FANV) d’apres les donnees du Sniiram. Methodes Identification de tous les sujets initiant un AOD (dabigatran n = 27 060) ou un AVK ( n = 44 653) pour une FANV en 2013 dans le Sniiram. Definition d’un hdPS AOD versus AVK avec un modele de regression logistique prenant en compte des variables forcees (caracteristiques socio-demographiques, facteurs de risque thromboembolique et hemorragique) et 500 variables sur trois ans d’historique de soins reparties en quatre dimensions (ALD, diagnostics d’hospitalisation, medicaments, consultations medicales/paramedicales/biologie), selectionnees pour minimiser le biais entre exposition et evenement etudie (algorithme de Bross). L’impact du hdPS a ete evalue avec les differences standardisees (DS) entre AOD et AVK : brutes, ajustees sur le hdPS et apres appariement 1 : 1 sur le hdPS, ainsi que sur la courbe de distribution du hdPS brute et apres appariement. Resultats Les deux groupes presentaient des distributions de hdPS brutes nettement differentes, decalees a droite pour AOD et a gauche pour AVK (mediane hdPS 0,5 et 0,3 respectivement) avec une zone de recouvrement importante, et tout a fait superposables apres appariement, tout en conservant 76 % des patients du groupe le plus faible ( n = 20 489 par groupe). Une DS brute >10 % concernait 34 % des variables et aucune DS > 10 % apres ajustement ou appariement. Discussion/Conclusion Le hdPS permet de construire une variable d’ajustement ou d’appariement performante pour comparer l’effet et/ou le risque d’un traitement entre deux groupes dans le Sniiram.

Introduction Le paracetamol est le produit le plus prescrit en France mais presque rien n’est connu de son risque cardiovasculaire ou digestif eventuel en vie reelle. Nous avons donc mis en place une etude visant a mesurer le risque de survenue d’infarctus du myocarde, de syndrome coronaire aigu, d’accident vasculaire cerebral ou d’hemorragie digestive haute apres dispensation de paracetamol en France. Methode Il s’agit d’une etude de cohorte autocontrolee dans l’EGB, l’echantillon 1/97 permanent representatif du Sniiram, base couvrant plus de 98 % de la population francaise. Toutes les dispensations de paracetamol entre 2009 et 2012 ont ete identifiees dans l’EGB. Seuls ont ete conserves les episodes d’utilisation exclusive du paracetamol (sans AINS), chez les sujets âges de plus de 15 ans. Chaque episode comportant une periode a risque, de trois mois apres la dispensation, et une periode controle, symetrique avant la dispensation. Les evenements d’interet etaient les hospitalisations identifiees dans le PMSI, en rapport avec un infarctus du myocarde (I21, IdM), un angor instable (I20,0), les deux etant regroupes sous le terme de syndrome coronaire aigu (SCA) ; d’accident vasculaire cerebral (AVC, I63) ; d’hemorragie digestive haute (UGIB, K250, K254, K260, K270, K290, K920, K921 ou K922). Les analyses ont ete faites sur la population totale des episodes inclus, puis en stratifiant sur la presence d’aspirine a faible dose (AFD), selon l’âge, la quantite dispensee de paracetamol, le niveau de risque cardiovasculaire. Resultats Il y avait 1 025 877 episodes d’exposition au paracetamol chez 342 494 patients (âge moyen 47,2 ans ; 55,8 % feminins). Les risques relatifs globaux ajustes de survenue d’IDM, SCA, AVC et UGIB [IC 95 %] etaient de 1,01 [0,85–1,21], 0,91 [0,82–1,01], 0,85 [0,73–0,98] et 1,34 [1,08–1,66]. Chez les utilisateurs d’AFD (5 % des episodes), le risque d’IdM, de SCA ou d’AVC etaient reduits (0,29 [0,20–0,42], 0,39 [0,32–0,47], 0,35 [0,26–0,48]. Chez les non-utilisateurs d’AFD ayant plus de 60 ans, les risques etaient notablement eleves (IdM 1,91 [1,43–2,54], SCA 1,38 [1,19–161] ; AVC 1,13 [093–1,37], UGIB 1,45 [1,08–1,95]). Conclusions La prescription de paracetamol s’accompagne d’un risque diminue d’evenement cardiovasculaire chez les patients co-utilisateurs d’aspirine a faible dose. En revanche, chez les non-utilisateurs d’aspirine, l’accroissement notable des risques cardiovasculaires et digestifs devrait faire rediscuter de l’utilite reelle d’encourager l’utilisation de paracetamol, en particulier chez le sujet âge de plus de 60 ans.

The recommended pharmacotherapy for secondary prevention of acute coronary syndrome (ACS) is long-term treatment with a combination of four therapeutic classes: beta-blockers, antiplatelet agents (including aspirin), statins or other lipid-lowering agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The aim of this study was to describe use and persistence of the recommended drug combination after the first occurrence of ACS in France.This was a database cohort study of patients with first registration for ACS between 2004 and 2007 in a representative sample of the French healthcare insurance database (Echantillon Généraliste de Bénéficiaires, EGB). The drugs of interest were those recommended. Persistence was assessed for patients dispensed three or all four drug classes within 2 months following ACS. Discontinuation was defined by a gap of more than 6 weeks between two dispensations. The follow-up period was 24 months after ACS occurrence.Of 2,057 patients with incident ACS, 872 (42.4 %) had at least one dispensation of each of the four recommended drug classes, and 684 (33.3 %) had three of the four classes. Persistence to treatment at 24 months was 57.4 % (95 % CI [54.0-60.6]) for patients with four classes, and 55.5 % (95 % CI [51.6-59.1]) with three classes. Discontinuation of initial combination was higher in patients aged ≥ 65 years at ACS occurrence, those with associated ongoing chronic disease, and in those who did not suffer myocardial infarction.Post-ACS secondary prevention in France is not optimal, especially in patients who did not have myocardial infarction.