Using LASSO Regression to Estimate the Population-Level Impact of Pneumococcal Conjugate Vaccines.

Pneumococcal conjugate vaccines (PCVs) protect against diseases caused by Streptococcus pneumoniae, such as meningitis, bacteremia, and pneumonia. It is challenging to estimate their population-level impact due to the lack of a perfect control population and the subtleness of signals when the endpoint-such as all-cause pneumonia-is nonspecific. Here we present a new approach for estimating the impact of PCVs: using least absolute shrinkage and selection operator (LASSO) regression to select variables in a synthetic control model to predict the counterfactual outcome for vaccine impact inference. We first used a simulation study based on hospitalization data from Mexico (2000-2013) to test the performance of LASSO and established methods, including the synthetic control model with Bayesian variable selection (SC). We found that LASSO achieved accurate and precise estimation, even in complex simulation scenarios where the association between the outcome and all control variables was noncausal. We then applied LASSO to real-world hospitalization data from Chile (2001-2012), Ecuador (2001-2012), Mexico (2000-2013), and the United States (1996-2005), and found that it yielded estimates of vaccine impact similar to SC. The LASSO method is accurate and easily implementable and can be applied to study the impact of PCVs and other vaccines.

Statin Use and Incidence of Parkinson's Disease in Women from the French E3N Cohort Study.

BACKGROUND: Statins represent candidates for drug repurposing in Parkinson's disease (PD). Few studies examined the role of reverse causation, statin subgroups, and dose-response relations based on time-varying exposures. OBJECTIVES: We examined whether statin use is associated with PD incidence while attempting to overcome the limitations described previously, especially reverse causation. METHOD: We used data from the E3N cohort study of French women (follow-up, 2004-2018). Incident PD was ascertained using multiple sources and validated by experts. New statin users were identified through linked drug claims. We set up a nested case-control study to describe trajectories of statin prescriptions and medical consultations before diagnosis. We used time-varying multivariable Cox proportional hazards regression models to examine the statins-PD association. Exposure indexes included ever use, cumulative duration/dose, and mean daily dose and were lagged by 5 years to address reverse causation. RESULTS: The case-control study (693 cases, 13,784 controls) showed differences in case-control trajectories, with changes in the 5 years before diagnosis in cases. Of 73,925 women (aged 54-79 years), 524 developed PD and 11,552 started using statins in lagged analyses. Ever use of any statin was not associated with PD (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.67-1.11). Alternatively, ever use of lipophilic statins was significantly associated with lower PD incidence (HR = 0.70, 95% CI = 0.51-0.98), with a dose-response relation for the mean daily dose (P-linear trend = 0.02). There was no association for hydrophilic statins. CONCLUSION: Use of lipophilic statins at least 5 years earlier was associated with reduced PD incidence in women, with a dose-response relation for the mean daily dose. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Identifying Protective Drugs for Parkinson's Disease in Health-Care Databases Using Machine Learning.

BACKGROUND: Available treatments for Parkinson's disease (PD) are only partially or transiently effective. Identifying existing molecules that may present a therapeutic or preventive benefit for PD (drug repositioning) is thus of utmost interest. OBJECTIVE: We aimed at detecting potentially protective associations between marketed drugs and PD through a large-scale automated screening strategy. METHODS: We implemented a machine learning (ML) algorithm combining subsampling and lasso logistic regression in a case-control study nested in the French national health data system. Our study population comprised 40,760 incident PD patients identified by a validated algorithm during 2016 to 2018 and 176,395 controls of similar age, sex, and region of residence, all followed since 2006. Drug exposure was defined at the chemical subgroup level, then at the substance level of the Anatomical Therapeutic Chemical (ATC) classification considering the frequency of prescriptions over a 2-year period starting 10 years before the index date to limit reverse causation bias. Sensitivity analyses were conducted using a more specific definition of PD status. RESULTS: Six drug subgroups were detected by our algorithm among the 374 screened. Sulfonamide diuretics (ATC-C03CA), in particular furosemide (C03CA01), showed the most robust signal. Other signals included adrenergics in combination with anticholinergics (R03AL) and insulins and analogues (A10AD). CONCLUSIONS: We identified several signals that deserve to be confirmed in large studies with appropriate consideration of the potential for reverse causation. Our results illustrate the value of ML-based signal detection algorithms for identifying drugs inversely associated with PD risk in health-care databases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

High-Dimensional Propensity Score-Adjusted Case-Crossover for Discovering Adverse Drug Reactions from Computerized Administrative Healthcare Databases.

INTRODUCTION: Increasing availability of medico-administrative databases has prompted the development of automated pharmacovigilance signal detection methodologies. Self-controlled approaches have recently been proposed. They account for time-independent confounding factors that may not be recorded. So far, large numbers of drugs have been screened either univariately or with LASSO penalized regressions. OBJECTIVE: We propose and assess a new method that combines the case-crossover self-controlled design with propensity scores (propensity score-adjusted case-crossover) built from high-dimensional data-driven variable selection, to account for co-medications or possibly other measured confounders. METHODS: Comparison with the univariate and LASSO case-crossover was performed from simulations and a real-data study. Multiple regressions (LASSO, propensity score-adjusted case-crossover) accounted for co-medications and no other covariates. For the univariate and propensity score-adjusted case-crossover methods, the detection threshold was based on a false discovery rate procedure, while for LASSO, it relied on the Akaike Information Criterion. For the real-data study, two drug safety experts evaluated the signals generated from the analysis of 4099 patients with acute myocardial infarction from the French national health database. RESULTS: On simulations, our approach ranked the signals similarly to the LASSO and better than the univariate method while controlling the false discovery rate at the prespecified level, contrary to the univariate method. The LASSO provided the best sensitivity at the cost of larger false discovery rate estimates. On the application, our approach showed similar performances to the LASSO and better performances than the univariate method. It highlighted 43 signals out of 609 drug candidates: 22 (51%) were considered as potentially pharmacologically relevant, including seven (16%) regarded as highly relevant. CONCLUSIONS: Our findings show the interest of a propensity score combined with a case-crossover for pharmacovigilance. They also confirm that indication bias remains a challenge when mining medico-administrative databases.

Estimation of mid-and long-term benefits and hypothetical risk of Guillain-Barre syndrome after human papillomavirus vaccination among boys in France: A simulation study.

BACKGROUND: The burden of human papillomavirus (HPV) infection can be substantially reduced through vaccination of girls, and gender-neutral policies are being adopted in many countries to accelerate disease control among women and expand direct benefits to men. Clinical direct benefit of boys HPV vaccination has been established for ano-genital warts and anal cancer. HPV vaccines are considered safe, but an association with Guillain-Barre syndrome has been found in French reimbursement and hospital discharge data. METHODS: We conducted a Monte-Carlo simulation assuming a stable French population of 11- to 14-year-old boys, adult men and men having sex with men. We modelled and quantified the mid-term benefits as the annually prevented ano-genital warts among the 8.72 M men aged 15-35 years and the long-term benefits as the annually prevented anal cancer cases among the 17.4 M men aged 25-65 years. We also estimated the number of Guillain-Barre syndrome cases hypothetically induced by vaccination. RESULTS: With a vaccine coverage of 30%, an annual number of 9310 (95% uncertainty interval [7050-11,200]) first ano-genital warts episodes among the 8.72 M men aged 15-35 years are prevented. According to more or less optimistic hypotheses on the proportion of HPV cancers covered by the vaccine, between 15.1 [11.7-17.7] and 19.2 [15.0-22.6] cases of anal cancer among the 17.4 M men aged 25-65 years would be annually avoided. Among men having sex with men, the corresponding figures were 1907 (1944-2291) for ano-genital warts and between 2.0 [0.23-4.5] and 2.6 [0.29-5.7] for anal cancer. Among 11- to 14-year-old boys, 0.82 (0.15-2.3) Guillain-Barre syndrome cases would be induced annually. INTERPRETATION: A long-term program of HPV vaccination among boys in France would avoid substantially more cancer cases than hypothetically induce Guillain-Barre syndrome cases, in the general and specifically the homosexual population. Additional benefits may arise with the possible vaccine protection against oro-laryngeal and -pharyngeal cancer.

Accounting for indirect protection in the benefit-risk ratio estimation of rotavirus vaccination in children under the age of 5 years, France, 2018.

Background Rotavirus is a major cause of severe gastroenteritis in children worldwide. The disease burden has been substantially reduced in countries where rotavirus vaccines are used. Given the risk of vaccine-induced intussusception, the benefit­risk balance of rotavirus vaccination has been assessed in several countries, however mostly without considering indirect protection effects. Aim We performed a benefit­risk analysis of rotavirus vaccination accounting for indirect protection in France among the 2018 population of children under the age of 5 years. Methods To incorporate indirect protection effects in the benefit formula, we adopted a pseudo-vaccine approach involving mathematical approximation and used a simulation design to provide uncertainty intervals. We derived background incidence distributions from quasi-exhaustive health claim data. We examined different coverage levels and assumptions regarding the waning effects and intussusception case fatality rate. Results With the current vaccination coverage of < 10%, the indirect effectiveness was estimated at 6.4% (+/− 0.4). For each hospitalisation for intussusception, 277.0 (95% uncertainty interval: (165.0­462.1)) hospitalisations for rotavirus gastroenteritis were prevented. Should 90% of infants be vaccinated, indirect effectiveness would reach 57.9% (+/− 3.7) and the benefit­risk ratio would be 192.4 (95% uncertainty interval: 116.4­321.3). At a coverage level of 50%, indirect protection accounted for 27% of the prevented rotavirus gastroenteritis cases. The balance remained in favour of the vaccine even in a scenario with a high assumption for intussusception case fatality. Conclusions These findings contribute to a better assessment of the rotavirus vaccine benefit­risk balance.

Identifying Drugs Inducing Prematurity by Mining Claims Data with High-Dimensional Confounder Score Strategies.

BACKGROUND: Pregnant women are largely exposed to medications. However, knowledge is lacking about their effects on pregnancy and the fetus. OBJECTIVE: This study sought to evaluate the potential of high-dimensional propensity scores and high-dimensional disease risk scores for automated signal detection in pregnant women from medico-administrative databases in the context of drug-induced prematurity. METHODS: We used healthcare claims and hospitalization discharges of a 1/97th representative sample of the French population. We tested the association between prematurity and drug exposure during the trimester before delivery, for all drugs prescribed to at least five pregnancies. We compared different strategies (1) for building the two scores, including two machine-learning methods and (2) to account for these scores in the final logistic regression models: adjustment, weighting, and matching. We also proposed a new signal detection criterion derived from these scores: the p value relative decrease. Evaluation was performed by assessing the relevance of the signals using a literature review and clinical expertise. RESULTS: Screening 400 drugs from a cohort of 57,407 pregnancies, we observed that choosing between the two machine-learning methods had little impact on the generated signals. Score adjustment performed better than weighting and matching. Using the p value relative decrease efficiently filtered out spurious signals while maintaining a number of relevant signals similar to score adjustment. Most of the relevant signals belonged to the psychotropic class with benzodiazepines, antidepressants, and antipsychotics. CONCLUSIONS: Mining complex healthcare databases with statistical methods from the high-dimensional inference field may improve signal detection in pregnant women.

Seasonal influenza vaccine and Guillain-Barré syndrome: A self-controlled case series study.

OBJECTIVE: To evaluate the risk of Guillain-Barré syndrome (GBS) following seasonal influenza vaccination based on French nationwide data. METHODS: All cases of GBS occurring in metropolitan France between September 1 and March 31 from 2010 to 2014 were identified from the French national health data system. Data were analyzed according to the self-controlled case series method. The risk period started 1 day after the patient received vaccine (D1) until 42 days after vaccination (D42). The incidence of GBS during this risk period was compared to that of the control period (D43-March 31). The incidence rate ratio (IRR) was estimated after adjusting for seasonality and presence or not of acute infections. RESULTS: Between September and March, of the 2010/2011 to 2013/2014 influenza vaccination seasons, 3,523 cases of GBS occurred in metropolitan France and were included in the study. Among them, 15% (527 patients) had received influenza vaccination. A total of 140 patients developed GBS during the 42 days following influenza vaccination. The crude risk of developing GBS was not significantly increased during the 42 days following influenza vaccination (IRR, 1.02; 95% confidence interval [CI], 0.83-1.25; p = 0.85). This result remained nonsignificant after adjustment for calendar months and the incidence of acute gastrointestinal and respiratory tract infections (IRR, 1.10; 95% CI, 0.89-1.37; p = 0.38). In contrast, the risk of GBS was fourfold higher after acute respiratory tract infection (IRR, 3.89; 95% CI, 3.52-4.30; p < 0.0001) or gastrointestinal infection (IRR, 3.64; 95% CI, 3.01-4.40; p < 0.0001). CONCLUSIONS: No association between seasonal influenza vaccination and GBS was shown during the 42 days following vaccination.

Instrumental variable analysis in the context of dichotomous outcome and exposure with a numerical experiment in pharmacoepidemiology.

BACKGROUND: In pharmacoepidemiology, the prescription preference-based instrumental variables (IV) are often used with linear models to solve the endogeneity due to unobserved confounders even when the outcome and the endogenous treatment are dichotomous variables. Using this instrumental variable, we proceed by Monte-Carlo simulations to compare the IV-based generalized method of moment (IV-GMM) and the two-stage residual inclusion (2SRI) method in this context. METHODS: We established the formula allowing us to compute the instrument's strength and the confounding level in the context of logistic regression models. We then varied the instrument's strength and the confounding level to cover a large range of scenarios in the simulation study. We also explore two prescription preference-based instruments. RESULTS: We found that the 2SRI is less biased than the other methods and yields satisfactory confidence intervals. The proportion of previous patients of the same physician who were prescribed the treatment of interest displayed a good performance as a proxy of the physician's preference instrument. CONCLUSIONS: This work shows that when analysing real data with dichotomous outcome and exposure, appropriate 2SRI estimation could be used in presence of unmeasured confounding.

A benefit-risk analysis of rotavirus vaccination, France, 2015.

IntroductionTwo vaccines available for protection against rotavirus gastroenteritis (RVGE), Rotarix and RotaTeq, have contributed to a large decrease in the incidence of paediatric diarrhoea in countries where they have been used. However, they have also led to a small increase in the risk of intussusception. Methods: We compare the number of prevented hospitalisations for RVGE to the number of vaccine-induced hospitalised intussusceptions in France. Results: With 9.5% coverage (French 2015 estimation), vaccination was estimated to prevent, annually, a median of 1,074 hospitalisations (2.5th and 97.5th percentiles (2.5th-97.5th): 810-1,378) and 1.4 deaths (2.5th-97.5th: 1.2-1.6) from RVGE. It was also estimated to cause, annually, 5.0 hospitalisations (2.5th-97.5th: 3.2-7.7) and 0.005 deaths (2.5th-97.5th: 0.001-0.015) from intussusception. The benefit-risk ratio is therefore 214 (2.5th-97.5th: 128-362) for hospitalisations and 273 (2.5th-97.5th: 89-1,228) for deaths. Under a hypothetical 92% coverage, rotavirus vaccination with Rotarix would avoid 10,459 (2.5th-97.5th: 7,702-13,498) hospitalisations for RVGE and induce 47.0 (2.5th-97.5th: 25.1-81.4) hospitalisations for intussusception annually, thereby preventing 13.7 (2.5th-97.5th: 11.1-15.2) deaths and inducing 0.05 (2.5th-97.5th: 0.01-0.15) deaths. Conclusion: The benefit-risk ratio in France is similar to that of other European countries.

Prescription drug use during pregnancy in France: a study from the national health insurance permanent sample.

PURPOSE: To provide an up-to-date account of drug prescription during pregnancy in France from 2011 to 2014 using the permanent sample of the French national computerized healthcare database and with a focus on recommended supplementations, fetotoxic drugs and teratogenic drugs. METHODS: All pregnancies identified by the International Classification of Diseases, 10th Revision codes list in the hospitalization database, lasting more than 9 weeks of amenorrhea and whose delivery occurred between 01/01/2011 and 12/31/2014, were included. Drugs delivered between the trimester before and until the end of the pregnancy were included. Drug exposure prevalence was calculated for each year and according to pregnancy trimesters. RESULTS: The study included 28,491 pregnancies with a median number of 9 [5-13] (median [IQ range]) drugs delivered. The most prescribed drug class was antianemia (in 72.5% of exposed). The prescription rate of recommended vitamins (B9 and D) increased over the study period (+10%). Influenza vaccination also increased but remained at a low rate (1%). Exposure to fetotoxic drugs decreased as pregnancy advanced. Exposure to the main teratogenic antiepileptics was stable over the study period. Low-income pregnant women had a higher average drug consumption except for recommended vitamins. CONCLUSION: Pregnant French women are among the largest consumers of prescription medications worldwide. Overall, the dispensation trends observed in this study are in line with the recommendations of the French National College of Gynecologists and Obstetricians. Nevertheless, while being low, exposure to fetotoxic drugs, teratogenic drugs or those under safety alerts still occurred. Supplementations and vaccines in low-income pregnant women should also be increased.

Executive function after severe childhood traumatic brain injury - Age-at-injury vulnerability periods: The TGE prospective longitudinal study.

BACKGROUND: Executive function (EF) impairment is a major predictor of overall outcome after traumatic brain injury (TBI). TBI severity is a factor of poor outcome, but most studies include a majority of children with mild and moderate TBI. The aims of this study were to estimate EF impairment after severe childhood TBI and to explore factors predicting EF outcome. The secondary aim was to compare recovery trajectories by age-at-injury groups. METHODS: This was a prospective longitudinal study of children with severe TBI who were tested for EFs by performance-based tests and questionnaires at 3, 12 and 24 months. RESULTS: Children with TBI (n=65) showed significant impairment in working memory, inhibition, attention and global EF, with little or no recovery at 24 months. For flexibility and performance-based EF score, children were impaired at 3 months only and showed normal scores by 12 months. No impairment was found in planning. At 3 and 24 months, Glasgow Coma Scale score and parental education predicted global EF. Coma length was not a significant predictor of outcome. Age at injury predicted progress in EF, but the relationship was not linear; children 10-12 years old at injury showed better outcome than older and younger children. CONCLUSIONS: EFs are impaired after severe TBI in childhood. The relationship between age at injury and outcome is not linear. Relying on only performance-based EF tests can underestimate EF impairment.

Mefloquine Versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment in Pregnancy: A Joint Analysis on Efficacy and Tolerability.

Since there is no ideal candidate to replace sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment (IPTp), alternatives need to be evaluated on basis of their benefit-risk ratio. We reanalyzed the first Beninese trial on mefloquine (MQ) versus SP for IPTp using a multiple outcome approach, which allowed the joint assessment of efficacy and tolerability. Overall superiority of MQ to SP was defined as superiority on at least one efficacy outcome (low birth weight [LBW], placental malaria, or maternal anemia), non-inferiority on all of them as well as on tolerability defined as cutaneous or neuropsychiatric adverse events (AEs) or low compliance with the treatment. The analysis included 1,601 women. MQ was found to be overall superior to SP (P = 0.004). Performing several sensitivity analyses to handle both missing data and stillbirths provided similar results. Using MQ for IPTp as an example, we show that a multiple outcome analysis is a pragmatic way to assess the benefits/disadvantages of one drug compared with another. In the current context of a lack of antimalarials that could be used for IPTp, such a statistical approach could be widely used by institutional policy makers for future recommendations regarding the prevention of malaria in pregnancy (MiP).

Short-term exposure to environmental parameters and onset of ST elevation myocardial infarction. The CARDIO-ARSIF registry.

BACKGROUND: Environmental parameters have been reported to be triggers of acute myocardial infarction (MI). However, the individual role of each parameter is unknown. We quantified the respective association of climate parameters, influenza epidemics and air pollutants with the onset of ST elevation MI (STEMI) in Paris and the surrounding small ring. METHODS: Data from the CARDIO-ARSIF registry (Paris and small ring STEMI population), Météo France (Climate), GROG (Influenza epidemic) and AIRPARIF (Air Pollution) were analyzed. The association between short-term exposure (1 day lag time) to environmental parameters and STEMI occurrence was quantified by time series modeling of daily STEMI count data, using Poisson regression with generalized additive models. RESULTS: Between 2003 and 2008, 11,987 <24H STEMI confirmed by angiography were adjudicated. There was a 5.0% excess relative risk (ERR) of STEMI per 10°C decrease in maximal temperature (95% CI 2.1% to 7.8%: p=0.001) and an 8.9% ERR (95% CI 3.2% to 14.9%: p=0.002) during an influenza epidemic after adjustment on week-days and holidays. Associations were consistent when short-term exposure varied from 2 to 7 days. Associations between lower temperatures and STEMI were stronger in magnitude when influenza epidemic was present. Short-term exposure to climatic parameters or pollutants was not associated with STEMI. CONCLUSIONS: The present population based registry of STEMI suggests that short-term exposure to lower temperature and influenza epidemic is associated with a significant excess relative risk of STEMI. Subjects at risk for MI may benefit from specific protections against cold temperature and influenza infection.

Intussusception risk after RotaTeq vaccination: evaluation from worldwide spontaneous reporting data using a self-controlled case series approach.

The increased risk of intussusception after vaccination with the rhesus-human reassortant rotavirus vaccine Rotashield led to its withdrawal in 2005. We assess the risk of intussusception following the pentavalent rotavirus vaccine (RV5) on the basis of worldwide reports to the manufacturer up to May 2014, using a self-controlled case series. The method had to be modified to account for the under-reporting, a specific feature of pharmacovigilance spontaneous reports. The risk of intussusception occurring in either of the 0- to 2-day, 3- to 7-day or 8- to 14-day risk periods, was compared to the risk in the 15- to 30-day period. A total of 502 cases occurring 0-30 days after a vaccine dose were studied, including 188 cases after the first dose, 190 cases after the second dose, and 124 cases after the third dose. The incidence risk ratio relative to the control period was highest for the 3- to 7-day period and equal to 3.45 (95% CI 1.84-6.55), 1.63 (0.86-3.13) and 1.73 (0.86-3.51) after the first, second and third dose, respectively. Rotavirus vaccination with RV5 increases the risk of intussusception 3-7 days following vaccination, mainly after the first dose and marginally after the second and third doses. The risk is small and restricted to a short time window. It does not outweigh the benefit of the vaccination, but parents of vaccinated infants should be informed in order to react appropriately to the first symptoms. With appropriate assumptions about the reporting rate, spontaneous reports of adverse events after vaccination can be studied to evaluate vaccine safety.

Resistance of M. leprae to quinolones: a question of relativity?

UNLABELLED: Multidrug resistant leprosy, defined as resistance to rifampin, dapsone and fluoroquinolones (FQ), has been described in Mycobacterium leprae. However, the in vivo impact of fluoroquinolone resistance, mainly mediated by mutations in DNA gyrase (GyrA2GyrB2), has not been precisely assessed. Our objective was to measure the impact of a DNA gyrase mutation whose implication in fluoroquinolone resistance has been previously demonstrated through biochemical studies, on the in vivo activity of 3 fluoroquinolones: ofloxacin, moxifloxacin and garenoxacin. METHODOLOGY/PRINCIPAL FINDINGS: We used the proportional bactericidal method. 210 four-week-old immunodeficient female Nude mice (NMRI-Foxn1(nu) /Foxn1(nu) ) were inoculated in the left hind footpad with 0.03 ml of bacterial suspension containing 5 × 10(3), 5 × 10(2), 5 × 10(1), and 5 × 10(0) M. leprae AFB organisms of strain Hoshizuka-4 which is a multidrug resistant strain harboring a GyrA A91V substitution. An additional subgroup of 10 mice was inoculated with 5 × 10(-1) bacilli in the untreated control group. The day after inoculation, subgroups of mice were treated with a single dose of ofloxacin, moxifloxacin, garenoxacin or clarithromycin at 150 mg/kg dosing. 12 months later mice were sacrificed and M. leprae bacilli were numbered in the footpad. The results from the untreated control group indicated that the infective inoculum contained 23% of viable M. leprae. The results from the moxifloxacin and garenoxacin groups indicated that a single dose of these drugs reduced the percentage of viable M. leprae by 90%, similarly to the reduction observed after a single dose of the positive control drug clarithromycin. Conversely, ofloxacin was less active than clarithromycin. CONCLUSION/SIGNIFICANCE: DNA gyrase mutation is not always synonymous of lack of in vivo fluoroquinolone activity in M. leprae. As for M. tuberculosis, in vivo studies allow to measure residual antibiotic activity in case of target mutations in M. leprae.

Validation of the French national health insurance information system as a tool in vaccine safety assessment: application to febrile convulsions after pediatric measles/mumps/rubella immunization.

In the French national health insurance information system (SNIIR-AM), routine records of health claimed reimbursements are linked to hospital admissions for the whole French population. The main focus of this work is the usability of this system for vaccine safety assessment programme. Self-controlled case series analyses were performed using an exhaustive SNIIR-AM extraction of French children aged less than 3 years, to investigate the relationship between MMR immunization and children hospitalizations for febrile convulsions, a well-documented rare adverse event, over 2009-2010. The results suggest a significant increase of febrile convulsions during the 6-11 days period following any MMR immunization (IRR=1.49, 95% CI=1.22, 1.83; p=0.0001) and no increase 15-35 days post any MMR immunization (IRR=1.03, 95% CI=0.89, 1.18; p=0.72). These results are in accordance with other results obtained from large epidemiologic studies, which suggest the usability of the SNIIR-AM as a relevant database to study the occurrence of adverse events associated with immunization. For future use, results associated with risk of convulsion during the day of vaccination should nevertheless be considered with particular caution.

Changes in reperfusion strategy over time for ST segment elevation myocardial infarction in the Greater Paris Area: results from the e-MUST Registry.

BACKGROUND: ESC guidelines recommend a shorter (90 min) delay for the use of primary percutaneous intervention (pPCI) in patients presenting within the first 2h of pain onset. Using registry data on STEMI patients in the Greater Paris Area, we assessed changes between 2003 and 2008 in the rates of pPCI, pre-hospital fibrinolytic therapy (PHF) and time delays in patients presenting within 2h of STEMI pain onset. METHODS: The Greater Paris Area was divided in 3 regions: Paris, the small and large rings. Patients were divided in three groups according to their reperfusion strategy: a) PHF, b) timely pPCI (FMC to balloon inflation time < 90 min), and c) late pPCI (FMC to balloon inflation time > 90 min). RESULTS: Among the 5592 patients included, 1695 (39%) had PHF, 1266 (29%) had timely pPCI, and 1415 (32%) had late pPCI. Over the 6 years, there was a sharp increase in timely pPCI in all regions, balanced by a decrease in PHF. The rate of late pPCI remained globally stable, with a decrease in Paris, stabilization in the small ring, and an increase in the large ring, where the density of catheterization laboratories was the lowest. By multivariate analysis, using on-time pPCI as a reference group, mortality was higher in the PHF and late pPCI groups. CONCLUSIONS: In areas with a low density of pPCI centers, efforts should be made to improve the timeliness of pPCI. Otherwise, PHF followed by an immediate transfer to a pPCI capable hospital may be considered.

Main air pollutants and myocardial infarction: a systematic review and meta-analysis.

CONTEXT: Short-term exposure to high levels of air pollution may trigger myocardial infarction (MI), but this association remains unclear. OBJECTIVE: To assess and quantify the association between short-term exposure to major air pollutants (ozone, carbon monoxide, nitrogen dioxide, sulfur dioxide, and particulate matter ≤10 µm [PM(10)] and ≤2.5 µm [PM(2.5)] in diameter) on MI risk. DATA SOURCES: EMBASE, Ovid MEDLINE in-process and other nonindexed citations, and Ovid MEDLINE (between 1948 and November 28, 2011), and EBM Reviews-Cochrane Central Register of Controlled Trials and EBM Reviews-Cochrane Database of Systematic Reviews (between 2005 and November 28, 2011) were searched for a combination of keywords related to the type of exposure (air pollution, ozone, carbon monoxide, nitrogen dioxide, sulfur dioxide, PM(10), and PM(2.5)) and to the type of outcome (MI, heart attack, acute coronary syndrome). STUDY SELECTION: Two independent reviewers selected studies of any study design and in any language, using original data and investigating the association between short-term exposure (for up to 7 days) to 1 or more air pollutants and subsequent MI risk. Selection was performed from abstracts and titles and pursued by reviewing the full text of potentially eligible studies. DATA EXTRACTION: Descriptive and quantitative information was extracted from each selected study. Using a random effects model, relative risks (RRs) and 95% CIs were calculated for each increment of 10 µg/m(3) in pollutant concentration, with the exception of carbon monoxide, for which an increase of 1 mg/m(3) was considered. DATA SYNTHESIS: After a detailed screening of 117 studies, 34 studies were identified. All the main air pollutants, with the exception of ozone, were significantly associated with an increase in MI risk (carbon monoxide: 1.048; 95% CI, 1.026-1.070; nitrogen dioxide: 1.011; 95% CI, 1.006-1.016; sulfur dioxide: 1.010; 95% CI, 1.003-1.017; PM(10): 1.006; 95% CI, 1.002-1.009; and PM(2.5): 1.025; 95% CI, 1.015-1.036). For ozone, the RR was 1.003 (95% CI, 0.997-1.010; P = .36). Subgroup analyses provided results comparable with those of the overall analyses. Population attributable fractions ranged between 0.6% and 4.5%, depending on the air pollutant. CONCLUSION: All the main air pollutants, with the exception of ozone, were significantly associated with a near-term increase in MI risk.

Behavioral problems, cognitive difficulties and quality of life in children with epilepsy: an analysis of parental concerns.

In cognitively impaired or young children with epilepsy, only proxy-report can be used for the assessment of Quality of Life (QOL) and behavior. The present study aims to propose proxy QOL tools applicable in all children with epilepsy and to examine the impact of epilepsy characteristics (e.g., age of onset of epilepsy, epilepsy syndrome) and child's age and situation (in mainstream school or in special institution). We studied 219 children with various types of epilepsy with and without cognitive impairment. The study adapted published QOL scales and used a new parental QOL questionnaire. Selected items concerned 6 "domains" of QOL: global QOL, illness impact, depression/anxiety, hyperactivity/disrupting behavior, sociability, and parental QOL. School situation, epilepsy syndrome, and age were significantly and differentially related to the QOL domains. The proposed QOL tools are applicable to all children with epilepsy independently of comorbid conditions and can be used in a clinical context and for research studies of QOL in children with epilepsy. Epilepsy syndromes in children and their associated factors have a crucial impact on parental concerns and QOL.