Disposables used cumulatively in routine IVF procedures could display toxicity.

STUDY QUESTION: Is there a cumulative toxicity of disposables used in IVF procedures? SUMMARY ANSWER: A toxicity may be detected when consumables are used cumulatively, while no toxicity is detected when the same consumables are used and tested individually. WHAT IS KNOWN ALREADY: Many components of items used in IVF laboratories may impair human embryonic development. Consequently, it is necessary to screen all reagents and materials which could be in contact with gametes and embryos. Toxicity tests, such as the mouse embryo assay and the human sperm motility assay (HSMA), are used by manufacturers as quality control tools to demonstrate the safety of their products. This evaluation is currently individually performed for each single consumable. However, during an IVF cycle, several devices are used sequentially, potentially creating a cumulative exposure to chemical contaminants, which could not be detected for individually tested consumables. STUDY DESIGN, SIZE, DURATION: The objective of this observational study conducted from March 2021 to October 2022 was to evaluate with the HSMA methodology if there was a cumulative toxicity when several disposables are sequentially used. Fourteen categories of consumables currently used in routine IVF procedures were studied, which included devices used for sperm and oocyte collection (cups, condoms, and oocyte aspiration needles), manipulation (flasks, tubes, tips, pipettes, embryo transfer catheters, syringes, and gloves), culture (dishes), and storage (straws). PARTICIPANTS/MATERIALS, SETTING, METHODS: After obtaining patient consent, the surplus semen assessed as having normal parameters according to the World Health Organization 2010 criteria were used to perform the HSMAs. First, each consumable was tested individually. Then, associations of three, four, and five consumables, previously validated as non-toxic when tested individually, were analyzed. HSMAs were conducted three times to ensure reproducibility, with a defined toxicity threshold of a sperm motility index (SMI) below 0.85 in at least two of three tests. MAIN RESULTS AND THE ROLE OF CHANCE: Thirty-six references of disposables were first individually tested across 53 lots. Forty-nine (92%) demonstrated compliance. However, four (8%) devices revealed toxicity: one lot of 1 ml syringes, two lots of sperm cups, and one lot of 25 cm2 flasks. These four references were excluded from the IVF routine procedures. A total of 48 combinations of consumables were assessed, involving 41 lots from 32 references that were previously individually tested. Among the evaluated combinations, 17 out of 48 (35%) associations exhibited toxicity with a SMI below 0.85 for two of the three tests (n = 8) or all the three tests (n = 9). Notably, three out of 17 (18%) of the three-consumable associations, five out of 16 (31%) of the four-consumable associations, and nine out of 15 (60%) of the five-consumable associations were found not compliant. The toxicity did not originate from a single consumable, because only consumables that were individually pre-validated as non-toxic were included in the combinations, but the toxicity had a cumulative origin. The risk of cumulative toxicity increased with the number of consumables included in the association (Cochran-Mantel-Haenszel statistic, P = 0.013). LIMITATIONS, REASONS FOR CAUTION: The high proportion of non-compliant combinations of disposables can be attributed directly to the extreme rigorous extraction conditions employed during the tests, which could deviate from the conditions encountered in routine clinical use. Also, the methodology employed in the HSMAs (e.g. toxicity extraction duration, sperm concentrations, and protein supplementation of the medium) can influence the sensitivity of the tests. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the significance of performing toxicity testing on devices before introducing them into clinical practice. Disposables should be tested individually to detect immediate toxicities and also in combination. Our results advocate rationalizing the number of consumables used in each IVF procedure and re-evaluating the use of glass consumables. STUDY FUNDING/COMPETING INTEREST(S): This study received fundings from GCS Ramsay Santé pour l'Enseignement et la Recherche (Paris, France) and the Centre de Biologie Médicale BIOGROUP (Le Chesnay-Rocquencourt, France). The authors declare that they have no conflict of interest that could be perceived as prejudicing the impartiality of the reported research. TRIAL REGISTRATION NUMBER: N/A.

Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy.

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

Estimates of epidemiology, mortality and disease burden associated with progressive fibrosing interstitial lung disease in France (the PROGRESS study).

BACKGROUND: There is a paucity of data on the epidemiology, survival estimates and healthcare resource utilisation and associated costs of patients with progressive fibrosing interstitial lung disease (PF-ILD) in France. An algorithm for extracting claims data was developed to indirectly identify and describe patients with PF-ILD in the French national administrative healthcare database. METHODS: The French healthcare database, the Système National des Données de Santé (SNDS), includes data related to ambulatory care, hospitalisations and death for 98.8% of the population. In this study, algorithms based on age, diagnosis and healthcare consumption were created to identify adult patients with PF-ILD other than idiopathic pulmonary fibrosis between 2010 and 2017. Incidence, prevalence, survival estimates, clinical features and healthcare resource usage and costs were described among patients with PF-ILD. RESULTS: We identified a total of 14,413 patients with PF-ILD. Almost half of them (48.1%) were female and the mean (± standard deviation) age was 68.4 (± 15.0) years. Between 2010 and 2017, the estimated incidence of PF-ILD ranged from 4.0 to 4.7/100,000 person-years and the estimated prevalence from 6.6 to 19.4/100,000 persons. The main diagnostic categories represented were exposure-related ILD other than hypersensitivity pneumonitis (n = 3486; 24.2%), idiopathic interstitial pneumonia (n = 3113; 21.6%) and rheumatoid arthritis-associated ILD (n = 2521; 17.5%). Median overall survival using Kaplan-Meier estimation was 3.7 years from the start of progression. During the study, 95.2% of patients had ≥ 1 hospitalisation for respiratory care and 34.3% were hospitalised in an intensive care unit. The median (interquartile range) total specific cost per patient during the follow-up period was €25,613 (10,622-54,287) and the median annual cost per patient was €18,362 (6856-52,026), of which €11,784 (3003-42,097) was related to hospitalisations. Limitations included the retrospective design and identification of cases through an algorithm in the absence of chest high-resolution computed tomography scans and pulmonary function tests. CONCLUSIONS: This large, real-world, longitudinal study provides important insights into the characteristics, epidemiology and healthcare resource utilisation and costs associated with PF-ILD in France using a comprehensive and exhaustive database, and provides vital evidence that PF-ILD represents a high burden on both patients and healthcare services. Trial registration ClinicalTrials.gov, NCT03858842. ISRCTN, ISRCTN12345678. Registered 3 January 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03858842.

Antipsychotics use: 2006-2013 trends in prevalence and incidence and characterization of users.

PURPOSE: The present study was conducted to describe antipsychotic (AP) prevalent and incident use, characteristics of AP users, and their trends in the French population. METHODS: A cross-sectional study was repeated yearly from January 1, 2007 to December 31, 2013 (for prevalence analysis) or to December 31, 2012 (for incidence analysis) using the French Health Insurance reimbursement database (Echantillon Généraliste de Bénéficiaires, EGB). For each year studied, prevalent and incident AP users were described in terms of age and gender overall, and according to the type of AP (FGAPs or SGAPs) used at index date. In addition, concurrent medications and comorbidities that a priori contraindicate the use of drugs having atropinic properties were researched. RESULTS: Prevalence and incidence remained relatively stable along the 2007-2013 period. Trends slightly decreased, from 2.07% (n = 10,252) to 2.05% (n = 11,015) for prevalence, and from 0.73% (n = 3461) to 0.66% (n = 3363) for incidence, especially in elderly, in contrast of children and adolescents (+ 39% for prevalence, from 184 to 271). The number of coprescribed drugs was found high (median = 5) and remained constant over time. In 2013, about 7% of prevalent AP users presented with a comorbidity increasing the risk of atropinic ADRs, and 36% used at least one concurrent atropinic drug. In incident AP users, these numbers were of 8 and 29%, respectively. CONCLUSIONS: The present study highlighted a marked shift from FGAPs toward SGAPs, as well as an increase in AP use in children and adolescents in France.

Trends in incident use of benzodiazepines and Z-drugs in France from 2006 to 2012: a population-based study.

PURPOSE: To study trends in incident use of benzodiazepines in France between 2006 and 2012. METHODS: A cross-sectional study repeated yearly was conducted using data from the French national healthcare insurance system. New benzodiazepine users were defined as users without any benzodiazepine dispensing in the year prior to the first dispensing of benzodiazepine in each year. Relative changes in incidence of use were calculated with the year 2006 as reference; confidence intervals for changes were estimated using the bootstrap method. RESULTS: Over the study period, the incident use of benzodiazepines decreased from 6.2% to 5.9%; this corresponded to a 5.1% decrease (95%CI: -6.8% to -4.2%) for 2012 compared to 2006. The decrease mainly concerned hypnotics (-15.5%; -21.2% to -15.3%) and appeared more pronounced in people aged 18-44 years. Incident use of anxiolytics remained stable overall during the period (4.0% of the population). Within anxiolytics, incident use of long half-life benzodiazepines (bromazepam, prazepam) decreased in favor of short half-life benzodiazepines (alprazolam, oxazepam). This change concerned patients aged 65-79 and patients aged 80 years and over. Nevertheless, in 2012, nearly one third of incident users aged 65 years and over started a treatment with a long half-life benzodiazepine, mostly bromazepam. CONCLUSIONS: A limited decrease in incident benzodiazepine use was observed in France between 2006 and 2012 that concerned only hypnotics. Although congruent with recommendations, this improvement appears insufficient with regard to the level of exposure to these drugs in France. New actions especially targeting anxiolytic benzodiazepine use should be undertaken to consolidate these results. Copyright © 2016 John Wiley & Sons, Ltd.

Comorbidities and concurrent medications increasing the risk of adverse drug reactions: prevalence in French benzodiazepine users.

PURPOSE: To estimate benzodiazepine prevalence of use and to quantify, in benzodiazepine users, the prevalence of comorbidities and concurrent medications increasing the risk of adverse drug reactions (ADRs). METHODS: Cross-sectional study performed using data from the French national healthcare insurance system. The prevalence of use was estimated by considering as users, patients who had at least one benzodiazepine reimbursement during the year 2013. Patients at increased risk for benzodiazepine ADRs were those who had (i) drug-drug interactions at risk for central nervous system and respiratory depression and (ii) comorbidities at risk for adverse respiratory effects, or for falls or fractures. RESULTS: Overall, the prevalence of benzodiazepine use in 2013 was estimated to be 13.8 %; it was higher among women and increased with age. This prevalence was 10.6 % for anxiolytic benzodiazepines, and 6.1 % for hypnotic benzodiazepines. Approximately half of the benzodiazepine users (48.1 %) were at increased risk for benzodiazepine ADRs; this proportion increased with age. Drug-drug interactions represented the most prevalent condition (39.3 % of benzodiazepine users). The drugs most frequently involved were opioids: analgesics (15.9 %) and antitussives (6.8 %). Overall, 11.3 % of benzodiazepine users had comorbidities at increased risk for adverse respiratory effects (13.9 % in those aged 65-79), and 7.0 % comorbidities at increased risk for falls or fractures (13.4 % in those aged ≥80). CONCLUSIONS: This study found that benzodiazepine use remained high in France, and that roughly half of the users presented with comorbidities and concurrent medications increasing the risk of ADRs. These findings are of concern, given that benzodiazepines are frequently used, and especially among the elderly.

Engagement in leisure activities and benzodiazepine use in a French community-dwelling elderly population.

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 65 years 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.

Epidemiology, Mortality and Healthcare Resource Utilization Associated With Systemic Sclerosis-Associated Interstitial Lung Disease in France.

Objectives: To investigate the clinical characteristics, epidemiology, survival estimates and healthcare resource utilization and associated costs in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in France. Methods: The French national administrative healthcare database, the Système National des Données de Santé (SNDS), includes data on 98.8% of the French population, including data relating to ambulatory care, hospitalizations and death. In our study, claims data from the SNDS were used to identify adult patients with SSc-ILD between 2010 and 2017. We collected data on clinical features, incidence, prevalence, survival estimates, healthcare resource use and costs. Results: In total, 3,333 patients with SSc-ILD were identified, 76% of whom were female. Patients had a mean age [standard deviation (SD)] of 60.6 (14.4) years and a mean (SD) individual study duration of 3.9 (2.7) years. In 2016, the estimated overall incidence and prevalence were 0.69/100,000 individuals and 5.70/100,000 individuals, respectively. The overall survival estimates of patients using Kaplan-Meier estimation were 93, 82, and 55% at 1, 3, and 8 years, respectively. During the study, 98.7% of patients had ≥1 hospitalization and 22.3% of patients were hospitalized in an intensive care unit. The total annual mean healthcare cost per patient with SSc-ILD was €25,753, of which €21,539 was related to hospitalizations. Conclusions: This large, real-world longitudinal study provides important insights into the epidemiology of SSc-ILD in France and shows that the disease is associated with high mortality, healthcare resource utilization and costs. SSc-ILD represents a high burden on both patients and healthcare services. Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03858842.

Comparison of health insurance claims and patient interviews in assessing drug use: data from the Three-City (3C) Study.

PURPOSE: Precise determination of drug exposure is fundamental in pharmacoepidemiology. Drug exposure is often presumed from health insurance claims but this may not correspond exactly to what subjects actually take. This study was designed to investigate French reimbursement databases in assessing drug use. METHODS: Between 1999 and 2001, 9294 subjects were included in the Three-City (3C) Study, a French cohort studying the relationship between vascular risk factors and dementia. Of these, 4112 subjects had data available from both clinical interviews and the reimbursement databases of the French national health insurance system. Agreement between drugs reported as used at interview and drugs reimbursed during the previous 30 or 60 days was measured with kappa coefficients. Using calculations of sensitivity (Se), specificity (Sp), positive predictive values (PPVs) and negative predictive values (NPVs), the validity of reimbursement data for the 30 or 60 days preceding the interview was investigated taking drugs reported at interview as the 'gold standard'. RESULTS: Declared drug use at interview was less well predicted by 30-day than by 60-day reimbursement data. Agreement between reimbursement data and interviews as well as validity of reimbursement data with reference to interviews were substantial for drugs used in cardiovascular diseases, diabetes, rheumatic disorders or neuropsychiatric conditions and were poor for laxatives, vitamins, vasculoprotectives, first and second line analgesics, anti-infective products or dermatologicals. CONCLUSIONS: Reimbursement data with an appropriate time frame and interviews estimate exposure to chronically used drugs similarly. Self-medication was better described with interviews whereas reimbursement data seem more useful for drugs used topically or intermittently.

A Multicenter, Prospective, Observational Study of Conversion from Twice-Daily Immediate-Release to Once-Daily Prolonged-Release Tacrolimus in Liver Transplant Recipients in France: The COBALT Study.

BACKGROUND In adult liver transplant patients, the use of prolonged-release tacrolimus may have treatment adherence benefits over the immediate-release formulation. The aim of this study was to characterise real-world practice data on conversion of liver transplant recipients from immediate- to prolonged-release tacrolimus in France. MATERIAL AND METHODS A prospective, observational study (NCT02143479) was conducted in 18 transplant centers in France between June 2014 and March 2016. Liver transplant recipients (n=398) included patients who changed from immediate-release to prolonged-release tacrolimus within the first three months (early conversion group) (n=205) or between three and 12 months after transplantation (late conversion group) (n=184). Clinical data were collected at an initial baseline outpatient visit and six-month and 12-month follow-up visits. Endpoints included the dose conversion ratio from immediate-release to prolonged-release tacrolimus, number of and reasons for additional visits due to conversion, safety, and tolerability. RESULTS Baseline clinical and demographic characteristics were similar between the two cohorts. The mean ±SD ratio of conversion of tacrolimus dose was 1.04±0.28; 1.01±0.28 (early) and 1.08±0.28 (late) (p=0.0247). The mean ±SD time from conversion to the first tacrolimus trough blood concentration was 30.8±42.8 days; 24.8±45.4 days (early) and 37.5±38.7 days (late). Only one patient required an additional visit due to conversion. Reasons for conversion included the physician's preference (56.3%), center practice (38.6%), and the dosing frequency (36.0%). Conversion was associated with a low rate of graft rejection, and no new safety issues were reported. CONCLUSIONS Conversion of liver transplant recipients from immediate-release to prolonged-release tacrolimus within three to 12 months of transplantation was easy to manage and associated with favorable clinical outcomes and safety profiles.

The sustainable impact of an educational approach to improve the appropriateness of laboratory test orders in the ICU.

INTRODUCTION: Few studies described strategies to improve the use of diagnostic tests in intensive care units (ICU). No study assessed whether their impact was sustained or not. In this study, we assessed whether a multi-faceted intervention for more appropriate use of laboratory testing can decrease the number of tests, is sustainable, is not associated with additional morbidity and represents a potential cost saving. MATERIAL AND METHODS: An open-label prospective cohort study in two separated units of the same medical intensive care unit (ICU) including respectively 3315 and 2392 consecutive patients. After the observation period (2010), a reduction in ICU A of unnecessary diagnostics tests as part of a program including senior supervisory of juniors' orders, encouragements for orders containment at each everyday round discussions (period 2; 2011). Period 3 (2012) consisted in the prolongation of the protocol as a routine care without supervision; Period 4 (2013) was a new period of observation without intervention. No modification was implemented in ICU B in periods 2-4. RESULTS: After the intervention, a decrease in the overall number of tests per ICU-patient-days (37.3±5.5 (baseline) to 15.2±3.2 (- 59%); p<0.0001) was observed. The total cost of the tests decreased from 239±41 to 104±28 euros per ICU-patient days; p<0.0001. The effect on laboratory test orders was sustainable in period 3 (-49%) and 4 (-30%). No significant secondary effect of the intervention was observed in period 2. In ICU B, there was no significant change in the overall laboratory test orders in between the periods. CONCLUSIONS: Laboratory test containment is effective, likely safe and sustainable provided that an educational program is repeatedly promoted, that it makes sense for the whole team, that senior and junior physicians are both committed in the program, and that encouragements for laboratory orders containment at each everyday round discussions.

Vitamin K Antagonists and Cognitive Function in Older Adults: The Three-City Cohort Study.

BACKGROUND: A growing body of evidence supports a beneficial role for vitamin K in brain and cognition, notably in studies where animals are rendered vitamin K deficient by warfarin, a potent vitamin K antagonist (VKA). Given VKAs are commonly used oral anticoagulants in older persons, we investigated the relationship between VKA therapy and cognitive performances over 10 years in participants of the Three-City study. METHODS: The Three-City cohort included 7,133 nondemented community dwellers, aged 65 years or older at baseline. Exposures to VKAs and platelet aggregation inhibitors, another antithrombotic agent, were determined at baseline. Participants underwent cognitive assessment at baseline and every 2 years over 10 years. Associations were analyzed with mixed linear models adjusting for many covariates including VKA and platelet aggregation inhibitor indications. RESULTS: About 239 (3.4%) and 1,192 (16.7%) of the participants were treated with VKAs and platelet aggregation inhibitors at baseline, respectively. VKA treatment was significantly associated with worse performances on Benton Visual Retention Test assessing visual memory (adjusted mean difference -0.29; p = .02 in multivariate models) and Isaacs Set Test assessing verbal fluency (adjusted mean difference -1.37; p = .0009) at baseline. Treatment with VKAs was not associated with global cognitive functioning on the Mini Mental State Examination, neither with rate of subsequent decline in scores on all three cognitive tests. No associations were found between platelet aggregation inhibitors and cognitive performances or rate of decline. CONCLUSION: These findings do not indicate a long-term detrimental effect of VKAs on cognition, but the risk-benefit balance of VKA treatment still deserves further research.

Fibrates and risk of cancer in tissues with high PPAR-α concentration: a nested case-control study.

BACKGROUND: Fibrates are lipid-lowering agents that act as peroxisome proliferator-activated receptor (PPAR)-α agonists. They have been associated with cancers in experimental models, but data in humans are rare, and among published studies none has investigated cancers in tissues with high PPAR-α concentrations. METHODS: A nested case-control study was performed in a French population-based healthcare database. Adults aged ≥45 years, and free of cancer for 3 years, were followed for 5 years for incident cases of melanoma, non-melanoma skin cancers, thyroid, pancreas, bladder, and kidney cancers. Cases were matched with up to ten controls for age, sex, and diseases that could increase the risk of cancers. Conditional logistic models, adjusted for drug-use as potential confounders, were used to estimate the risk (odds ratio [OR]) of cancers of interest (and individual cancers) associated with cumulative exposure to fibrates (defined daily doses [DDD]). RESULTS: Among the 147,338 eligible subjects, 3,331 (2.3 %) cases of studied cancers were identified. Only use of fibrates >550 DDDs was associated with an increased risk (OR 1.26; 95 % CI 1.12-1.42), and similar results were found for statins (≥1,460 DDDs; OR 1.15; 95 % CI 1.03-1.28). When considering cancers individually, the association was significant for non-melanoma skin-cancer (OR 1.35; 95 % CI 1.14-1.60), and close to significance for bladder cancer (OR 1.26; 95 % CI 0.96-1.64); similar associations with the use of statins were found. CONCLUSIONS: The associations found between fibrate exposure and cancers of tissues with high PPAR-α concentrations were most likely related to residual confounding as similar associations were found for statins.

Cardiovascular events associated with the long-term use of NSAIDs: a review of randomized controlled trials and observational studies.

INTRODUCTION: An increased risk of cardiovascular thrombotic events in users of NSAIDs was first demonstrated for rofecoxib. This risk seems to be related to the COX-2 inhibitory potency and has been found with most NSAIDs except naproxen. Two main hypotheses have been advanced: an imbalance between COX-1-dependent platelet production of thromboxane and partly COX-2-dependent endothelial production of prostacyclin, and a COX-2-dependent increase in blood pressure. AREAS COVERED: Clinical trials and observational studies providing information about cardiovascular risk associated with long-term use of NSAIDs were retrieved; 14 clinical trials and 16 observational studies mentioned a follow-up of at least 6 months. EXPERT OPINION: Results are ambiguous: long-term exposure seemed associated with an increased risk of myocardial infarction or stroke with high-dose rofecoxib, and perhaps diclofenac, but less with other NSAIDs. In other studies, little or no increase in risk was associated with exposures shorter than 30 days. Since most NSAIDs are rarely used long term, there is little information on risks associated with long-term use. The relative risks or odds ratios associated with most drugs are mostly well below 2.

Validity of chronic drug exposure presumed from repeated patient interviews varied according to drug class.

OBJECTIVE: To evaluate the validity of chronic drug exposure presumed from cross-sectional interviews taking reimbursement data as reference. STUDY DESIGN AND SETTING: The study concerned 2,985 elderly persons of the French Three-City cohort (1) who were interviewed on current drug use 2 and 4 years after inclusion and (2) whose reimbursement data were obtained from the main health care insurance system. Validity (sensitivity, Se; specificity, Sp; positive predictive value, PPV; negative predictive value, NPV) of chronic exposure presumed from follow-up interviews was investigated taking two exposure definitions from reimbursements as reference for the period between interviews: at least 80% coverage with and without a maximal time between reimbursements of 60 days. RESULTS: Using 80% coverage as reference, validity of interview data was substantial for cardiovascular and antithrombotic drugs (Se, 85.3-95.4%; Sp, 67.1-97.6%; PPV, 65.9-86.6%; NPV, 93.3-99.3%). For benzodiazepines, nonsteroidal anti-inflammatory drugs, or analgesics, validity was low especially owing to PPVs (15.8-51.4%). CONCLUSION: Using reported use at cross-sectional interviews as a proxy for chronic exposure between interviews was valid for drugs used regularly but not so for drugs used more irregularly.

Benzodiazepine use and risk of dementia: prospective population based study.

OBJECTIVE: To evaluate the association between use of benzodiazepines and incident dementia. DESIGN: Prospective, population based study. SETTING: PAQUID study, France. PARTICIPANTS: 1063 men and women (mean age 78.2 years) who were free of dementia and did not start taking benzodiazepines until at least the third year of follow-up. MAIN OUTCOME MEASURES: Incident dementia, confirmed by a neurologist. RESULTS: During a 15 year follow-up, 253 incident cases of dementia were confirmed. New use of benzodiazepines was associated with an increased risk of dementia (multivariable adjusted hazard ratio 1.60, 95% confidence interval 1.08 to 2.38). Sensitivity analysis considering the existence of depressive symptoms showed a similar association (hazard ratio 1.62, 1.08 to 2.43). A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia. The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46 (1.10 to 1.94). Results of a complementary nested case-control study showed that ever use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia (adjusted odds ratio 1.55, 1.24 to 1.95) compared with never users. The results were similar in past users (odds ratio 1.56, 1.23 to 1.98) and recent users (1.48, 0.83 to 2.63) but reached significance only for past users. CONCLUSIONS: In this prospective population based study, new use of benzodiazepines was associated with increased risk of dementia. The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study. Considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects of this drug class in the general population, indiscriminate widespread use should be cautioned against.

Original approach to the individual characteristics associated with forgone healthcare: a study in underprivileged areas, Paris region, France, 2001-2003.

BACKGROUND: The social inequalities in health have endured or even worsened comparatively throughout different social groups since the 1990s. Our objective was to identify the individual characteristics (socio-economic status, living conditions, individuals' social integration, health beliefs, expectations and representation and psychological characteristics) statistically associated with the fact of stating (or not) that healthcare had been forgone because of cost. METHODS: In this cross-sectional, multi-centre study we randomly selected a study sample from five underprivileged areas in the Paris region. A multiple logistic regression model was used to calculate the odds ratios (OR) and 95% confidence interval (CI). The validity of the model was assessed by goodness-of-fit tests (Pearson and deviance) and by the study of 100 bootstrap samples. RESULTS: After making adjustments for numerous individual socio-economic and health characteristics, we observed a higher occurrence of reported forgone healthcare among people who have had financial worries during adulthood [ORyes/no=5.47 (1.44-20.75)], a life-course experience of physical, sexual or psychological abuse [ORyes/no=2.86 (1.40-5.84)]; who have experienced childhood difficulties [OR1/never difficulties=5.28 (1.81-15.39), OR2-4/never=7.62 (2.69-21.57), OR>4/never=8.57 (2.39-30.80)]; who have expressed a low degree of sickness orientation [OR(low/high)=2.62 (1.33-5.14)], a high worry/concern about health [ORhigh/low=2.71 (1.33-5.50)] and a low self-esteem [ORmedium/high=8.28 (1.44-47.64), ORlow/high=16.44 (2.81-96.24)]. CONCLUSION: Aside from purely financial hurdles, other factors play a role in the non-use of healthcare services. Health policies mainly promoting equal financial access to healthcare have little chance of abating health inequalities.