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.

Ability of epidemiological studies to monitor HPV post-vaccination dynamics: a simulation study.

Genital human papillomavirus (HPV) infections are caused by a broad diversity of genotypes. As available vaccines target a subgroup of these genotypes, monitoring transmission dynamics of nonvaccine genotypes is essential. After reviewing the epidemiological literature on study designs aiming to monitor those dynamics, we evaluated their abilities to detect HPV-prevalence changes following vaccine introduction. We developed an agent-based model to simulate HPV transmission in a heterosexual population under various scenarios of vaccine coverage and genotypic interaction, and reproduced two study designs: post-vs.-prevaccine and vaccinated-vs.-unvaccinated comparisons. We calculated the total sample size required to detect statistically significant prevalence differences at the 5% significance level and 80% power. Although a decrease in vaccine-genotype prevalence was detectable as early as 1 year after vaccine introduction, simulations indicated that the indirect impact on nonvaccine-genotype prevalence (a decrease under synergistic interaction or an increase under competitive interaction) would only be measurable after >10 years whatever the vaccine coverage. Sample sizes required for nonvaccine genotypes were >5 times greater than for vaccine genotypes and tended to be smaller in the post-vs.-prevaccine than in the vaccinated-vs.-unvaccinated design. These results highlight that previously published epidemiological studies were not powerful enough to efficiently detect changes in nonvaccine-genotype prevalence.

Comparison of cohort and nested case-control designs for estimating the effect of time-varying drug exposure on the risk of adverse event in the presence of ties.

Cohort and nested case-control (NCC) designs are frequently used in pharmacoepidemiology to assess the associations of drug exposure that can vary over time with the risk of an adverse event. Although it is typically expected that estimates from NCC analyses are similar to those from the full cohort analysis, with moderate loss of precision, only few studies have actually compared their respective performance for estimating the effects of time-varying exposures (TVE). We used simulations to compare the properties of the resulting estimators of these designs for both time-invariant exposure and TVE. We varied exposure prevalence, proportion of subjects experiencing the event, hazard ratio, and control-to-case ratio and considered matching on confounders. Using both designs, we also estimated the real-world associations of time-invariant ever use of menopausal hormone therapy (MHT) at baseline and updated, time-varying MHT use with breast cancer incidence. In all simulated scenarios, the cohort-based estimates had small relative bias and greater precision than the NCC design. NCC estimates displayed bias to the null that decreased with a greater number of controls per case. This bias markedly increased with higher proportion of events. Bias was seen with Breslow's and Efron's approximations for handling tied event times but was greatly reduced with the exact method or when NCC analyses were matched on confounders. When analyzing the MHT-breast cancer association, differences between the two designs were consistent with simulated data. Once ties were taken correctly into account, NCC estimates were very similar to those of the full cohort analysis.

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.

Contact patterns and HPV-genotype interactions yield heterogeneous HPV-vaccine impacts depending on sexual behaviors: An individual-based model.

Human papillomaviruses are common sexually transmitted infections, caused by a large diversity of genotypes. In the context of vaccination against a subgroup of genotypes, better understanding the role of genotype interactions and human sexual behavior on genotype dynamics is essential. Herein, we present an individual-based model that integrates realistic heterosexual partnership behaviors and simulates interactions between vaccine and non-vaccine genotypes. Genotype interactions were considered, assuming a previous vaccine-genotype infection shortened (competition) or extended (synergy) the duration of a secondary non-vaccine-genotype infection. Sexual behavior determined papillomavirus acquisition and transmission: only 19.5% of active individuals at most 1 partner r during the year, but > 80% of those with ≥ 2 partners, were infected before vaccine introduction. The pre-vaccination situation was consistent with all genotype interaction scenarios. These genotype interactions, despite being undetectable during the pre-vaccination era, markedly impacted genotype prevalence after vaccination started, with a significant increase/decrease of non-vaccine genotypes prevalence for respectively competitive/synergistic interactions. These prevalence changes were more pronounced in individuals with ≤ 3 partners per year (up to 30% of prevalence modification assuming 65% vaccine coverage) but barely visible for individuals with > 3 partners per year (at most 0.30%). Results suggest the presence of genotype interaction, which is consistent with the pre-vaccine situation, may impact the dynamics of non-vaccine genotypes, particularly in less active individuals.

Nonoptimal Vaginal Microbiota After Azithromycin Treatment for Chlamydia trachomatis Infection.

We characterized the composition and structure of the vaginal microbiota in a cohort of 149 women with genital Chlamydia trachomatis infection at baseline who were followed quarterly for 9 months after antibiotic treatment. At time of diagnosis, the vaginal microbiota was dominated by Lactobacillus iners or a diverse array of bacterial vaginosis-associated bacteria including Gardnerella vaginalis. Interestingly, L. iners-dominated communities were most common after azithromycin treatment (1 g monodose), consistent with the observed relative resistance of L. iners to azithromycin. Lactobacillus iners-dominated communities have been associated with increased risk of C. trachomatis infection, suggesting that the impact of antibiotic treatment on the vaginal microbiota could favor reinfections. These results provide support for the dual need to account for the potential perturbing effect(s) of antibiotic treatment on the vaginal microbiota, and to develop strategies to protect and restore optimal vaginal microbiota.

Early screening for Chlamydia trachomatis in young women for primary prevention of pelvic inflammatory disease (i-Predict): study protocol for a randomised controlled trial.

BACKGROUND: Genital infection with Chlamydia trachomatis (Ct) is the most common bacterial sexually transmitted infection, especially among young women. Mostly asymptomatic, it can lead, if untreated, to pelvic inflammatory disease (PID), tubal factor infertility and ectopic pregnancy. Recent data suggest that Ct infections are not controlled in France and in Europe. The effectiveness of a systematic strategy for Ct screening in under-25 women remains controversial. The main objective of the i-Predict trial (Prevention of Diseases Induced by Chlamydia trachomatis) is to determine whether early screening and treatment of 18- to-24-year-old women for genital Ct infection reduces the incidence of PID over 24 months. METHODS/DESIGN: This is a randomised prevention trial including 4000 eighteen- to twenty-four-year-old sexually active female students enrolled at five universities. The participants will provide a self-collected vaginal swab sample and fill in an electronic questionnaire at baseline and at 6, 12 and 18 months after recruitment. Vaginal swabs in the intervention arm will be analysed immediately for Ct positivity, and participants will be referred for treatment if they have a positive test result. Vaginal swabs from the control arm will be analysed at the end of the study. All visits to general practitioners, gynaecologists or gynaecology emergency departments for pelvic pain or other gynaecological symptoms will be recorded to evaluate the incidence of PID, and all participants will attend a final visit in a hospital gynaecology department. The primary endpoint measure will be the incidence of PID over 24 months. The outcome status (confirmed, probable or no PID) will be assessed by two independent experts blinded to group assignment and Ct status. DISCUSSION: This trial is expected to largely contribute to the development of recommendations for Ct screening in young women in France to prevent PID and related complications. It is part of a comprehensive approach to gathering data to facilitate decision-making regarding optimal strategies for Ct infection control. The control group of this randomised trial, following current recommendations, will allow better documentation of the natural history of Ct infection, a prerequisite to evaluating the impact of Ct screening. Characterisation of host immunogenetics will also allow identification of women at risk for complications. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02904811 . Registered on September 14, 2016. World Health Organisation International Clinical Trials Registry, NCT02904811. AOM, 15-0063 and P150950. Registered on September 26, 2016. A completed Standard Protocol Items : Recommendations for International Trials (SPIRIT) Checklist is available in additional file 1.

A Cohort Study of Adolescent and Midlife Diet and Pancreatic Cancer Risk in the NIH-AARP Diet and Health Study.

Given the long latency period of pancreatic cancer, exploring the influence of early and midlife exposures will further advance our understanding of the disease. We assessed associations between diet and pancreatic cancer incidence in the National Institutes of Health (NIH)-AARP (formerly American Association of Retired Persons) Diet and Health Study. In 1996, a total of 303,094 participants completed 2 food frequency questionnaires that assessed diet at ages 12-13 years and 10 years previously. We used Cox proportional hazards regression to estimate adjusted hazard ratios and 95% confidence intervals. Through the end of 2006, a total of 1,322 pancreatic cancer cases occurred (average follow up time = 10.1 years). When comparing the highest tertiles with the lowest, carbohydrate intake during adolescence (hazard ratio (HR) = 0.87, 95% confidence interval (CI): 0.76, 0.99), but not 10 years before baseline, was inversely associated with pancreatic cancer risk. Total fat intake 10 years before baseline was significantly associated with increased risk (HR = 1.17, 95% CI: 1.02, 1.34), while risk was higher for high fat intake during both adolescence and midlife. Calcium intake 10 years before baseline was associated with reduced risk (HR = 0.87, 95% CI: 0.76, 0.99), as was a change from low intake in adolescence to high intake in midlife (HR = 0.71, 95% CI: 0.54, 0.93). Our study found a number of dietary factors present during adolescence and midlife to be associated with pancreatic cancer.

Comparison of methods for estimating the attributable risk in the context of survival analysis.

BACKGROUND: The attributable risk (AR) measures the proportion of disease cases that can be attributed to an exposure in the population. Several definitions and estimation methods have been proposed for survival data. METHODS: Using simulations, we compared four methods for estimating AR defined in terms of survival functions: two nonparametric methods based on Kaplan-Meier's estimator, one semiparametric based on Cox's model, and one parametric based on the piecewise constant hazards model, as well as one simpler method based on estimated exposure prevalence at baseline and Cox's model hazard ratio. We considered a fixed binary exposure with varying exposure probabilities and strengths of association, and generated event times from a proportional hazards model with constant or monotonic (decreasing or increasing) Weibull baseline hazard, as well as from a nonproportional hazards model. We simulated 1,000 independent samples of size 1,000 or 10,000. The methods were compared in terms of mean bias, mean estimated standard error, empirical standard deviation and 95% confidence interval coverage probability at four equally spaced time points. RESULTS: Under proportional hazards, all five methods yielded unbiased results regardless of sample size. Nonparametric methods displayed greater variability than other approaches. All methods showed satisfactory coverage except for nonparametric methods at the end of follow-up for a sample size of 1,000 especially. With nonproportional hazards, nonparametric methods yielded similar results to those under proportional hazards, whereas semiparametric and parametric approaches that both relied on the proportional hazards assumption performed poorly. These methods were applied to estimate the AR of breast cancer due to menopausal hormone therapy in 38,359 women of the E3N cohort. CONCLUSION: In practice, our study suggests to use the semiparametric or parametric approaches to estimate AR as a function of time in cohort studies if the proportional hazards assumption appears appropriate.

Fluoroquinolone Impact on Nasal Methicillin-Resistant and Methicillin-Sensitive Staphylococcus aureus Colonization Durations in Neurologic Long-Term-Care Facilities.

Staphylococcus aureus nasal carriage is a risk factor for subsequent infection. Estimates of colonization duration vary widely among studies, and factors influencing the time to loss of colonization, especially the impact of antibiotics, remain unclear. We conducted a prospective study on patients naive for S. aureus colonization in 4 French long-term-care facilities. Data on nasal colonization status and potential factors for loss of colonization were collected weekly. We estimated methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) colonization durations using the Kaplan-Meier method and investigated factors for loss of colonization using shared-frailty Cox proportional hazards models. A total of 285 S. aureus colonization episodes were identified in 149 patients. The median time to loss of MRSA or MSSA colonization was 3 weeks (95% confidence interval, 2 to 8 weeks) or 2 weeks (95% confidence interval, 2 to 3 weeks), respectively. In multivariable analyses, the methicillin resistance phenotype was not associated with S. aureus colonization duration (P = 0.21); the use of fluoroquinolones (hazard ratio, 3.37; 95% confidence interval, 1.31 to 8.71) and having a wound positive for a nonnasal strain (hazard ratio, 2.17; 95% confidence interval, 1.15 to 4.07) were associated with earlier loss of MSSA colonization, while no factor was associated with loss of MRSA colonization. These results suggest that the methicillin resistance phenotype does not influence the S. aureus colonization duration and that fluoroquinolones are associated with loss of MSSA colonization but not with loss of MRSA colonization.

Detailed contact data and the dissemination of Staphylococcus aureus in hospitals.

Close proximity interactions (CPIs) measured by wireless electronic devices are increasingly used in epidemiological models. However, no evidence supports that electronically collected CPIs inform on the contacts leading to transmission. Here, we analyzed Staphylococcus aureus carriage and CPIs recorded simultaneously in a long-term care facility for 4 months in 329 patients and 261 healthcare workers to test this hypothesis. In the broad diversity of isolated S. aureus strains, 173 transmission events were observed between participants. The joint analysis of carriage and CPIs showed that CPI paths linking incident cases to other individuals carrying the same strain (i.e. possible infectors) had fewer intermediaries than predicted by chance (P < 0.001), a feature that simulations showed to be the signature of transmission along CPIs. Additional analyses revealed a higher dissemination risk between patients via healthcare workers than via other patients. In conclusion, S. aureus transmission was consistent with contacts defined by electronically collected CPIs, illustrating their potential as a tool to control hospital-acquired infections and help direct surveillance.

Fluoroquinolone use is a risk factor for methicillin-resistant Staphylococcus aureus acquisition in long-term care facilities: a nested case-case-control study.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization is a well-established risk factor for subsequent infection and a key event in interindividual transmission. Some studies have showed an association between fluoroquinolones and MRSA colonization or infection. The present study was performed to identify specific risk factors for MRSA acquisition in long-term care facilities (LTCFs). METHODS: A prospective cohort of patients naive for S. aureus colonization was established and followed (January 2008 through October 2010) in 4 French LTCFs. Nasal colonization status and potential risk factors were assessed weekly for 13 weeks after inclusion. Variables associated with S. aureus acquisition were identified in a nested-matched case-case-control study using conditional logistic regression models. Cases were patients who acquired MRSA (or methicillin-sensitive S. aureus [MSSA]). Patients whose nasal swab samples were always negative served as controls. Matching criteria were center, date of first nasal swab sample, and exposure time. RESULTS: Among 451 included patients, 76 MRSA cases were matched to 207 controls and 112 MSSA cases to 208 controls. Multivariable analysis retained fluoroquinolones (odds ratio, 2.17; 95% confidence interval, 1.01-4.67), male sex (2.09; 1.10-3.98), and more intensive care at admission (3.24; 1.74-6.04) as significantly associated with MRSA acquisition, and body-washing assistance (2.85; 1.27-6.42) and use of a urination device (1.79; 1.01-3.18) as significantly associated with MSSA acquisition. CONCLUSIONS: Our results suggest that fluoroquinolones are a risk factor for MRSA acquisition. Control measures to limit MRSA spread in LTCFs should also be based on optimization of fluoroquinolone use.

Comparing human papillomavirus prevalences in women with normal cytology or invasive cervical cancer to rank genotypes according to their oncogenic potential: a meta-analysis of observational studies.

BACKGROUND: Mucosal human papillomavirus (HPV) infection is a necessary cause of cervical cancer. Vaccine and non-vaccine genotype prevalences may change after vaccine introduction. Therefore, it appears essential to rank HPV genotypes according to their oncogenic potential for invasive cervical cancer, independently of their respective prevalences. METHODS: We performed meta-analyses of published observational studies and estimated pooled odds ratios with random-effects models for 32 HPV genotypes, using HPV-16 as the reference. RESULTS: Twenty-seven studies yielded 9,252 HPV-infected women: 2,902 diagnosed with invasive cervical cancer and 6,350 with normal cytology. Expressed as (odds ratio [95% confidence interval]), HPV-18 (0.63 [0.51, 0.78]) ranked closest to HPV-16, while other genotypes showed continuously decreasing relative oncogenic potentials: HPV-45 (0.35 [0.22, 0.55]), HPV-69 (0.28 [0.09, 0.92]), HPV-58 (0.24 [0.15, 0.38]), HPV-31 (0.22 [0.14, 0.35]), HPV-33 (0.22 [0.12, 0.38]), HPV-34 (0.21 [0.06, 0.80]), HPV-67 (0.21 [0.06, 0.67]), HPV-39 (0.17 [0.09, 0.30]), HPV-59 (0.17 [0.09, 0.31]), HPV-73 (0.16 [0.06, 0.41]), and HPV-52 (0.16 [0.11, 0.23]). CONCLUSIONS: Our results support the markedly higher oncogenic potentials of HPV-16 and -18, followed by HPV-31, -33, -39, -45, -52, -58 and -59, and highlight the need for further investigation of HPV-34, -67, -69 and -73. Overall, these findings could have important implications for the prevention of cervical cancer.

The performance of functional methods for correcting non-Gaussian measurement error within Poisson regression: corrected excess risk of lung cancer mortality in relation to radon exposure among French uranium miners.

A broad variety of methods for measurement error (ME) correction have been developed, but these methods have rarely been applied possibly because their ability to correct ME is poorly understood. We carried out a simulation study to assess the performance of three error-correction methods: two variants of regression calibration (the substitution method and the estimation calibration method) and the simulation extrapolation (SIMEX) method. Features of the simulated cohorts were borrowed from the French Uranium Miners' Cohort in which exposure to radon had been documented from 1946 to 1999. In the absence of ME correction, we observed a severe attenuation of the true effect of radon exposure, with a negative relative bias of the order of 60% on the excess relative risk of lung cancer death. In the main scenario considered, that is, when ME characteristics previously determined as most plausible from the French Uranium Miners' Cohort were used both to generate exposure data and to correct for ME at the analysis stage, all three error-correction methods showed a noticeable but partial reduction of the attenuation bias, with a slight advantage for the SIMEX method. However, the performance of the three correction methods highly depended on the accurate determination of the characteristics of ME. In particular, we encountered severe overestimation in some scenarios with the SIMEX method, and we observed lack of correction with the three methods in some other scenarios. For illustration, we also applied and compared the proposed methods on the real data set from the French Uranium Miners' Cohort study.

Variability of intestinal colonization with third-generation cephalosporin-resistant Enterobacteriaceae and antibiotic use in intensive care units.

OBJECTIVES: Healthcare-associated infections due to third-generation cephalosporin-resistant Enterobacteriaceae (CRE) have become a major public health threat, especially in intensive care units (ICUs). We assessed and compared ß-lactam use, the prevalence of colonization with CRE at admission and the incidence of CRE acquisition across ICUs. PATIENTS AND METHODS: A cohort study was conducted in 10 ICUs of the Paris (France) metropolitan area between November 2005 and February 2006. Antibiotic use was recorded prospectively in all patients admitted during the study period. Rectal swabs were collected at admission, twice weekly thereafter, before ß-lactam prescription and before discharge. RESULTS: A total of 893 patients provided 3453 rectal swabs; 793 of the patients were newly admitted, mostly for medical reasons (80.7%). On admission, 74 patients (9.6%) were colonized with CRE, including 32 with an extended-spectrum ß-lactamase (ESBL)-producing strain. Among the remaining 694 naive patients, 94 acquired CRE during their follow-up, including 31 with an ESBL-producing strain. Incidence rates of colonization ranged from 8.8 to 21.0/1000 patient-days for all CRE, and from 1.4 to 10.9/1000 patient-days for ESBL producers. A majority of patients (68.3%) were prescribed ß-lactams during their ICU stay, with defined daily doses ranging from 428 to 985/1000 patient-days. Across ICUs, prescriptions of all antibiotics, ß-lactams and carbapenems were significantly correlated to incidence rates of colonization with ESBL-producing CRE. CONCLUSIONS: The standardized and systematic follow-up of patients in 10 ICUs revealed great heterogeneity in the rates of colonization with ESBL- and non-ESBL-producing CRE, as well as in antimicrobial prescription practices.

Impact of measurement error in radon exposure on the estimated excess relative risk of lung cancer death in a simulated study based on the French Uranium Miners' Cohort.

Measurement error (ME) can lead to bias in the analysis of epidemiologic studies. Here a simulation study is described that is based on data from the French Uranium Miners' Cohort and that was conducted to assess the effect of ME on the estimated excess relative risk (ERR) of lung cancer death associated with radon exposure. Starting from a scenario without any ME, data were generated containing successively Berkson or classical ME depending on time periods, to reflect changes in the measurement of exposure to radon ((222)Rn) and its decay products over time in this cohort. Results indicate that ME attenuated the level of association with radon exposure, with a negative bias percentage on the order of 60% on the ERR estimate. Sensitivity analyses showed the consequences of specific ME characteristics (type, size, structure, and distribution) on the ERR estimates. In the future, it appears important to correct for ME upon analyzing cohorts such as this one to decrease bias in estimates of the ERR of adverse events associated with exposure to ionizing radiation.

Influence of the drug exposure definition on the assessment of the antipsychotic metabolic impact in patients initially treated with mood-stabilizers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Metabolic disturbances represent a well-known side effect of second generation antipsychotics. However, studies comparing second generation antipsychotic drugs (SGAPs) and first generation antipsychotic drugs (FGAPs) through administrative databases have shown contrasting findings, which may be attributable to methodological differences. WHAT THIS PAPER ADDS: • The definition of antipsychotic exposure impacts on the association between antipsychotics and metabolic risk in studies carried out through administrative databases. • Considering cumulative exposure to antipsychotics or including patients exposed to an antipsychotic drug for months or years is likely to over-represent patients who tolerate the drug well with a depletion of susceptible effects. • Antipsychotic drug exposure is a time-varying determinant and episodes of no use, past use and current use should be distinguished over the study period to avoid any misclassification bias that might lead to misleading findings. AIMS: To assess the influence of three definitions of antipsychotic exposure on the comparison between first generation (FGAP) and second generation (SGAP) antipsychotic drugs and 'conventional' mood stabilizers towards the risk of metabolic events using (i) a dichotomous measure (exposed/non-exposed over the follow-up), (ii) a categorical measure taking into account the chronology of exposure at the time of the metabolic event (current, recent and no use) and (iii) a continuous measure (cumulative duration). METHODS: A historical fixed cohort was identified from the 2004-2006 claims database of the French health insurance programme for self-employed workers, including 3172 patients aged 18 years and over who used conventional mood stabilizers over a 3 month period. A metabolic event was defined as an incident dispensing of an anti-diabetic or lipid-lowering drug. RESULTS: A metabolic event occurred in 367 patients (11.6%). At least one FGAP had been prescribed in 29% of patients who did not develop a metabolic event and in 22% of patients who developed a metabolic event. In addition, at least one SGAP had been prescribed in 12% of patients who did not develop a metabolic event and in 7% of patients who developed a metabolic event. Compared with conventional mood stabilizers, the risk of a metabolic event was negatively associated with exposure to SGAPs over the follow-up period (HR 0.53, 95% CI 0.34, 0.82, P= 0.004), positively associated with recent, but not current, exposure to SGAPs (HR 2.1, 95% CI 1.2, 3.7, P= 0.006) and not associated with cumulative duration of SGAPs (HR 1.001, 95% CI 0.999, 1.003, P= 0.20). CONCLUSIONS: The definition of exposure to antipsychotics in epidemiological studies exploring their metabolic impact is of paramount importance in understanding this association. Different definitions can lead to opposite and seemingly nonsensical results. Not taking into account past exposure, in order to minimize the depletion of susceptible effects, may lead to absurd results.

Adolescent and mid-life diet: risk of colorectal cancer in the NIH-AARP Diet and Health Study.

BACKGROUND: Colorectal cancer has a natural history of several decades; therefore, the diet consumed decades before diagnosis may aid in understanding this malignancy. OBJECTIVE: The objective was to investigate diet during adolescence and 10 y before baseline (ages 40-61 y) in relation to colorectal cancer. DESIGN: Participants in the NIH-AARP Diet and Health Study (n = 292,797) completed a 124-item food-frequency questionnaire (FFQ) about diet in the past 12 mo and two 37-item FFQs about diet at ages 12-13 y and 10 y previously. Cox regression was used to estimate multivariate HRs and 95% CIs for colon (n = 2794) and rectal (n = 979) cancers within quintiles of exposures. RESULTS: Colon cancer risk was lower in the highest than in the lowest quintile of vitamin A (HR: 0.82; 95% CI: 0.72, 0.92) and vegetable (HR: 0.81, 0.70, 0.92) intakes during adolescence. Those in the highest intake category 10 y previously for calcium (HR: 0.83; 95% CI: 0.73, 0.94), vitamin A (HR: 0.81; 95% CI: 0.71, 0.92), vitamin C (HR: 0.83; 95% CI: 0.72, 0.95), fruit (HR: 0.84; 95% CI: 0.73, 0.97), and milk (HR: 0.78; 95% CI: 0.67, 0.90) had a lower risk of colon cancer, but a higher risk was observed for total fat (HR: 1.15; 95% CI: 1.01, 1.30), red meat (HR: 1.31; 95% CI: 1.12, 1.53), and processed meat (HR: 1.24; 95% CI: 1.06, 1.45). For rectal cancer, milk was inversely associated (HR: 0.75; 95% CI: 0.58, 0.96) with risk. CONCLUSION: Adolescent and midlife diet may play a role in colorectal carcinogenesis.

Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome.

RATIONALE: Despite their controversial role, corticosteroids are often administered to patients with adult respiratory distress syndrome (ARDS) secondary to viral pneumonia. OBJECTIVES: To analyze the impact of corticosteroid therapy on outcomes of patients having ARDS associated with influenza A/H1N1 pneumonia. METHODS: Patients from the French registry of critically ill patients with influenza A/H1N1v 2009 infection were selected if fulfilling criteria for ARDS, excluding patients having other indication for corticosteroids, or decompensated underlying disease as the primary cause for intensive care unit admission. Survival to hospital discharge was analyzed using Cox regression, accounting for the time to administration of steroids, and after adjustment on the propensity for receiving steroid therapy. MEASUREMENTS AND MAIN RESULTS: Of 208 patients with ARDS, 83 (39.9%) received corticosteroids (median initial dose of 270 mg equivalent hydrocortisone per day for a median of 11 d). Steroid therapy was associated with death, both in crude analysis (33.7 vs. 16.8%; hazard ratio, 2.4; 95% CI, 1.3-4.3; P = 0.004) and after propensity score-adjusted analysis (adjusted hazard ratio, 2.82; 95% CI, 1.5-5.4; P = 0.002), controlling for an admission severity Simplified Acute Physiology Score, version 3, greater than 50, initial administration of vasopressors, and immunodepression. Early therapy (≤ 3 d of mechanical ventilation) appeared more strongly associated with mortality than late administration. Patients receiving steroids had more acquired pneumonia and a trend to a longer duration of ventilation. CONCLUSIONS: Our study provides no evidence of a beneficial effect of corticosteroids in patients with ARDS secondary to influenza pneumonia, but suggests that very early corticosteroid therapy may be harmful.