Levels and determinants of pesticide exposure in re-entry workers in vineyards: results of the PESTEXPO study.

Physical contact with branches, leaves, fruit or vegetables in previously treated crops is responsible for the transfer of pesticides to the worker's skin in agricultural tasks such as harvesting, pruning, thinning, cutting or sorting. Few studies have documented workers' exposure during re-entry in vineyards. In the PESTEXPO study, we described levels of exposure and analyzed their determinants during re-entry and harvesting in vineyards in the Bordeaux area, France. Between 2002 and 2007, volunteers performing re-entry tasks (N=46 days) or harvesting (N=48 days) after dithiocarbamate or folpet treatment were observed. Detailed information on the tasks was collected and dermal contamination was assessed using patches placed on the skin and hand-washing at the end of each working phase. Daily median contamination was 1 967.7 µl of mixture during re-entry (90(e) percentile: 5 045.3 µl) and 18.7 µl during harvesting (90(e) percentile: 911.4 µl). The type of task was the parameter found to be the most strongly associated with contamination. For re-entry, the highest contaminations were observed during raising of wires and cutting of branches. During the harvest, the contamination was maximal for grape-picking. The delay since the last treatment and the rate of active ingredient per hectare played a role, together with other factors such as meteorological factors, crop and farm characteristics, gloves and clothes. Our results underline the necessity to take into account exposures during re-entry and harvest when considering pesticide exposure, both for epidemiological research and preventive action.

Time to next treatment or death as a candidate surrogate endpoint for overall survival in advanced melanoma patients treated with immune checkpoint inhibitors: an insight from the phase III CheckMate 067 trial.

BACKGROUND: Time to next treatment or death (TNT-D) may be a patient-relevant endpoint in patients treated with immune checkpoint inhibitors. This study investigated TNT-D as a surrogate endpoint (SE) for overall survival (OS) in previously untreated advanced melanoma patients. METHODS: Patient-level data from the 60-month results of the CheckMate 067 randomised, controlled trial were used. Analyses were carried out for nivolumab monotherapy or nivolumab with ipilimumab versus ipilimumab monotherapy. The SE 1-step validation method based on a joint frailty-copula model was used where the country of enrolment was applied to define clusters. Kendall's τ and the coefficient of determination (R2trial) were estimated for respective measurements of association at the individual and cluster levels. The surrogate threshold effect, the maximum threshold hazard ratio for TNT-D that would translate into OS benefit, was estimated. A leave-one-out cross-validation analysis was carried out to evaluate model robustness. RESULTS: Fifteen clusters of data were generated from 945 patients. For both nivolumab-containing arms, the association between TNT-D and OS was deemed acceptable at the individual level (Kendall's τ > 0.60) and strong at the cluster level, with R2trial fairly close to 1, with narrow confidence intervals. The estimated surrogate threshold effects were 0.61 for nivolumab versus ipilimumab and 0.49 for nivolimub + ipilimumab versus ipilimumab. Cross-validation results showed minimum variation of the correlation measures and satisfactory predictive accuracy for the model. CONCLUSION: Results suggest that TNT-D may be a valuable SE in previously untreated advanced melanoma patients treated with immune checkpoint inhibitors. Surrogacy analyses considering multiple randomised controlled trials are warranted for confirming these findings.

Cervical preparation prior to surgical abortion in real-life conditions and factors driving the prescription: A national observational study.

INTRODUCTION: Few data exist to document the real-life practices regarding surgical abortion for first trimester abortion, in particular regarding the cervical preparation. Using a large national sample of French hospitals practicing surgical abortion, we explore actual practices and described drugs used for cervical preparation and factors that influence the prescription. METHODS: From December 2013 to July 2014, a longitudinal, prospective, multicenter, non-interventional study was undertaken with the main objective of assessing in real-life conditions the modalities of cervical preparation prior surgical abortion in women with less than 14 weeks of amenorrhea. RESULTS: A total of 542 patients agreed to participate and were included by 36 French private or public hospitals. Among 36 active centers, 31 (86.1%) implemented cervical preparation prior surgical abortion, in line with French and international clinical guidelines. For the 510 patients who underwent surgical abortions, the most frequent prescribed treatment was misoprostol only (224/510, 43.9% of patients), following by mifepristone only (167/510, 32.8%) and a combination of misoprostol and mifepristone (99/510, 19.4%). Finally, four factors were identified as independent contributor to guide the treatment prescribed for cervical preparation: woman work situation, gestational age intensity of center's activity regarding the number of abortions yearly and mode of anesthesia. CONCLUSIONS: Our study showed an almost systematic implementation of cervical preparation before surgical abortion in France. Misoprostol only was the most commonly prescribed treatment for the cervix preparation, followed by mifepristone only. Several factors may have a significant influence on the type of cervical preparation chosen by physicians.

Analysis of the effect of aluminum in drinking water and transferrin C2 allele on Alzheimer's disease.

Although highly controversial, the hypothesis of a link between aluminum (Al) in drinking water and Alzheimer's disease (AD) has been supported by several epidemiological studies. Transferrin (Tf) is a major transport protein for both iron and Al. Moreover, it has been demonstrated that defective binding of iron and Al to the Tf variant C2 could be present in AD. Individuals carrying the Tf C2 allele might therefore be at greater risk of developing AD. We investigated whether the Tf C2 allele might be responsible for susceptibility to AD in a sample of 292 subjects (with 55 AD) aged > or = 75 years from south-west France, some exposed to high levels of Al in tap water (n = 181 subjects) and others to low levels of Al (n = 111 subjects). We also examined the combined genetic effects of Tf C2 and epsilon4 allele of apolipoprotein E gene (ApoE). Logistic regression analysis showed that neither Tf C2 nor its interaction with Al or with the epsilon4 allele of the ApoE were significantly associated with the risk of AD.

Examining the influence of drop-outs in a follow-up of maintained opiate users.

INTRODUCTION: In most longitudinal studies of problem opiate users, drop-outs are frequent, but not taken into account. However, missing data can induce important bias in parameters estimates. OBJECTIVE: The aim of this study was to examine the influence of drop-outs in the statistical analysis of a follow-up of opiate users in maintenance treatment. METHODS: Participants were 519 patients who had sought maintenance treatment between 1994 and 2001. Drug use was studied using the drug composite score of the Addiction Severity Index. A classical data analysis (linear mixed effects model for repeated measurements) was compared with a selection model, which consists, in this case, of a joint modelling of the score and of the drop-out probability in order to reduce bias induced by drop-outs. RESULTS: At 18 months, 38% of the patients were available for evaluation. Drop-outs were associated with low drug use and were informative. Each model showed that the score decreased over time and that it was associated with psychiatric problems. Unlike the classical method, the joint model showed no significant association between the score and age or treatment setting. CONCLUSIONS: These results show the importance of accounting for informative drop-outs in data analysis before drawing conclusions from such studies.

Twenty five year mortality and air pollution: results from the French PAARC survey.

AIMS AND METHODS: Long term effects of air pollution on mortality were studied in 14,284 adults who resided in 24 areas from seven French cities when enrolled in the PAARC survey (air pollution and chronic respiratory diseases) in 1974. Daily measurements of sulphur dioxide, total suspended particles, black smoke, nitrogen dioxide, and nitric oxide were made in 24 areas for three years (1974-76). Cox proportional hazards models controlling for individual confounders (smoking, educational level, body mass index, occupational exposure) were applied, and frailty models used to take into account spatial correlation. Indicators of air pollution were the mean concentration. RESULTS: Models were run before and after exclusion of six area monitors influenced by local traffic (NO/NO2 >3 in ppb). After exclusion of these areas, analyses showed that adjusted risk ratios (95% CI) for TSP, BS, NO2, and NO for non-accidental mortality were 1.05 (1.02 to 1.08), 1.07 (1.03 to 1.10), 1.14 (1.03 to 1.25), and 1.11 (1.05 to 1.17) for 10 microg/m3 respectively. Consistent patterns for lung cancer and cardiopulmonary causes were observed. CONCLUSIONS: Urban air pollution assessed in the 1970s was associated with increased mortality over 25 years in France.

A multi-center trial of the effects of oral nutritional supplementation in critically ill older inpatients. GAGE Group. Groupe Aquitain Geriatrique d'Evaluation.

The purpose of this study was to assess the effect of nutritional supplementation on dietary intake and on pressure ulcer development in critically ill older patients. The multi-center trial involved 19 wards stratified according to specialty and recruitment for critically ill older patients; 9 wards were randomly selected for nutritional intervention (nutritional intervention group), consisting of the daily distribution of two oral supplements, with each supplement containg 200 kcal, for 15 d. Pressure ulcer incidence was prospectively recorded for grades I (erythema), II (superficial broken skin), and III (subcutaneous lesion) for 15 d. Nutritional intake was monitored by using estimates in units of quarters validated by comparison with weight measurement. There were 672 subjects older than 65 y, and 295 were in the nutritional intervention group versus 377 in the control group. The patients were similar for age, sex ratio, and C-reactive protein. In comparison with the control group, the nutritional intervention group included more patients with stroke, heart failure, and dyspnea and fewer with antecedent falls, delirium, lower limb fractures, and digestive disease. The nutritional intervention group had a lower risk of pressure ulcers according to the Norton score but was less dependent (Kuntzman score) and had a lower serum albumin level. During the trial, energy and protein intakes were higher in the nutritional intervention group (day 2: 1081 +/- 595 kcal versus 957 +/- 530 kcal, P = 0.006; 45.9 +/- 27.8 g protein versus 38.3 +/- 23.8 g protein in the control group, P < 0.001). At 15 d, the cumulative incidence of pressure ulcers was 40.6% in the nutritional intervention group versus 47.2% in the control group. The proportion of grade I cases relative to the total number of cases was 90%. Multivariate analysis, taking into account all diagnoses, potential risk factors, and the intra-ward correlation, indicated that the independent risk factors of developing a pressure ulcer during this period were: serum albumin level at baseline, for 1 g/L decrease: 1.05 (95% confidence interval: 1.02 to 1.07, P < 0.001); Kuntzmann score at baseline, for 1-point increase: 1.22 (0.32 to 4.58, P = 0.003); lower limb fracture: 2.68 (1.75 to 4.11, P < 0.001); Norton score < 10 versus > 14: 1.28 (1.01 to 1.62, P = 0.04); and belonging to the control group: 1.57 (1.03 to 2.38, P = 0.04). In conclusion, it was possible to increase the dietary intake of critically ill elderly subjects by systematic use of oral supplements. This intervention was associated with a decreased risk of pressure ulcer incidence.

[Analysis of a multicenter clinical trial on pressure ulcer development by a marginal approach in the Cox model]. / Etude multicentrique de la survenue d'escarres par un modèle de Cox basé sur une approche marginale.

BACKGROUND: We exemplify the use of a marginal approach with proportional hazards model when failure times are correlated. METHODS: The marginal distribution for each failure time is formulated by the Cox proportional hazards model, while the dependence structure is unspecified. However, a correct variance-covariance estimate of the regression coefficients that takes into account the intra-group correlation is proposed. The program MULCOX2 which implements this statistical methodology is used to assess the effect of a nutritional supplementation intervention on pressure ulcer development on critically ill older patients from a multicentric trial (involving 19 wards). We compare the results obtained with those of the usual Cox regression. RESULTS: The naive approach yields much smaller standard error estimates of the regression parameters than the robust approach. CONCLUSION: In our example, the results obtained with the marginal approach do not modify the conclusions: a nutritional supplementation intervention tends to decrease significantly the formation of pressure ulcers. However in other situations, ignoring the intra-cluster dependence could lead to invalid statistical inference. The variability of the estimated effects by MULCOX2 can be quite sensitive to the number of clusters in the sample and to the clusters size.

Risk factors for the presence and extent of Developmental Orthopaedic Disease in the limbs of young horses: Insights from a count model.

Developmental Orthopaedic Disease (DOD) in limb joints is frequent, can cause lameness and is a major cause of economic losses for the horse breeding industry. Studies on risk factors for DOD usually dichotomise the outcome to presence/absence without considering the extent of the disease, which can be appreciated by the number or the severity of the lesions. The aim of this study was to assess the effects of growth, exercise conditions and feeding practices on the number of radiographic findings (RF) of DOD in a cohort of horses, assuming that the risk factors associated with the presence of the disease and the number of RF may differ. We recruited broodmares on 21 stud farms in the Normandy region, France in 2002-2004. The stud farms were visited regularly to collect growth, exercise conditions, and feeding practices data from the end of the gestation to the weaning of the foal. The carpus, the front and hind digits, the tarsus and the stifle of the foals were radiographed at approximately six months of age. Each foal was classified according to the absence (no RF) or presence (≥1 RF) of DOD and to the number of RF. A zero-inflated Poisson model was used to simultaneously determine risk factors for presence/absence and for the number of RF of the disease. The convenience sample consisted of 378 foals, 53.1% of which did not have any RF. The mean number of RF per foal was 1.25 and the variance was 2.80. Comparing to the Poisson, negative binomial, and zero-inflated negative binomial regressions, the zero-inflated Poisson model was found to be best suited for these data. Of the 295 foals with complete data, three risk factors were significantly associated with a higher risk of being affected by DOD: high wither height increase, large group size in pasture and large pasture size. Seven risk factors were associated with the number of RF: wither height at 30 days of age, age of the mare, breed, regularity of exercise, Ca/P level in the mare and foal rations, group size in pasture, and the type and frequency of handling. This study shows that risk factors vary for the presence and extent of DOD, and that the use of a count model achieves a more detailed determination of risk factors for the presence of DOD and for the number of RF of DOD compared to the more conventional dichotomy presence/absence of the disease.

Investigating trial and treatment heterogeneity in an individual patient data meta-analysis of survival data by means of the penalized maximum likelihood approach.

In a meta-analysis combining survival data from different clinical trials, an important issue is the possible heterogeneity between trials. Such intertrial variation can not only be explained by heterogeneity of treatment effects across trials but also by heterogeneity of their baseline risk. In addition, one might examine the relationship between magnitude of the treatment effect and the underlying risk of the patients in the different trials. Such a scenario can be accounted for by using additive random effects in the Cox model, with a random trial effect and a random treatment-by-trial interaction. We propose to use this kind of model with a general correlation structure for the random effects and to estimate parameters and hazard function using a semi-parametric penalized marginal likelihood method (maximum penalized likelihood estimators). This approach gives smoothed estimates of the hazard function, which represents incidence in epidemiology. The idea for the approach in this paper comes from the study of heterogeneity in a large meta-analysis of randomized trials in patients with head and neck cancers (meta-analysis of chemotherapy in head and neck cancers) and the effect of adding chemotherapy to locoregional treatment. The simulation study and the application demonstrate that the proposed approach yields satisfactory results and they illustrate the need to use a flexible variance-covariance structure for the random effects.

Nested frailty models using maximum penalized likelihood estimation.

The frailty model is a random effect survival model, which allows for unobserved heterogeneity or for statistical dependence between observed survival data. The nested frailty model accounts for the hierarchical clustering of the data by including two nested random effects. Nested frailty models are particularly appropriate when data are clustered at several hierarchical levels naturally or by design. In such cases it is important to estimate the parameters of interest as accurately as possible by taking into account the hierarchical structure of the data. We present a maximum penalized likelihood estimation (MPnLE) to estimate non-parametrically a continuous hazard function in a nested gamma-frailty model with right-censored and left-truncated data. The estimators for the regression coefficients and the variance components of the random effects are obtained simultaneously. The simulation study demonstrates that this semi-parametric approach yields satisfactory results in this complex setting. In order to illustrate the MPnLE method and the nested frailty model, we present two applications. One is for modelling the effect of particulate air pollution on mortality in different areas with two levels of geographical regrouping. The other application is based on recurrent infection times of patients from different hospitals. We illustrate that using a shared frailty model instead of a nested frailty model with two levels of regrouping leads to inaccurate estimates, with an overestimation of the variance of the random effects. We show that even when the frailty effects are fairly small in magnitude, they are important since they alter the results in a systematic pattern.

Standardized martingale residuals applied to grouped left truncated observations of dementia cases.

The use of martingale residuals have been proposed for model checking and also to get a non-parametric estimate of the effect of an explanatory variable. We apply this approach to an epidemiological problem which presents two characteristics: the data are left truncated due to delayed entry in the cohort; the data are grouped into geographical units (parishes). This grouping suggests a natural way of smoothing the graph of residuals which is to compute the sum of the residuals for each parish. It is also natural to present a graph with standardized residuals. We derive the variances of the estimated residuals for left truncated data which allows computing the standardized residuals. This method is applied to the study of dementia in a cohort of old people, and to the possible effect of the concentration of aluminum and silica in drinking water on the risk of developing dementia.

Relation between aluminum concentrations in drinking water and Alzheimer's disease: an 8-year follow-up study.

To investigate the effect of aluminum and silica in drinking water on the risk of dementia and Alzheimer's disease, the authors analyzed data from a large prospective cohort (Paquid), including 3,777 subjects aged 65 years and over living at home in 75 civil parishes in Gironde and Dordogne in southwestern France in 1988-1989. The subjects were followed for up for 8 years with an active search for incident cases of dementia or Alzheimer's disease. Mean exposure to aluminum and silica in drinking water was estimated in each area. The sample studied included 2,698 nondemented subjects at baseline, for whom components of drinking water and covariates were available. A total of 253 incident cases of dementia (with 17 exposed to high levels of aluminum), including 182 Alzheimer's disease (with 13 exposed to high aluminum levels), were identified. The relative risk of dementia adjusted for age, gender, educational level, place of residence, and wine consumption was 1.99 (95 percent CI: 1.20, 3.28) for subjects exposed to an aluminum concentration greater than 0.1 mg/liter. This result was confirmed for Alzheimer's disease (adjusted relative risk = 2.14, 95 percent CI: 1.21, 3.80). However, no dose-response relation was found. Inversely, the adjusted relative risk of dementia for subjects exposed to silica (> or = 11.25 mg/liter) was 0.74 (95 percent CI: 0.58, 0.96). These findings support the hypothesis that a high concentration of aluminum in drinking water may be a risk factor for Alzheimer's disease.