Vulnérabilité à la chaleur dans le contexte des changements climatiques.

Thèse réalisée en cotutelle avec Université Paris 11 (Ecole Doctorale 420)

Case-Crossover Analysis of Air Pollution Health Effects: A Systematic Review of Methodology and Application

Case-crossover is one of the most used designs for analyzing the health-related effects of air pollution. Nevertheless, no one has reviewed its application and methodology in this context. Objective: We conducted a systematic review of case-crossover (CCO) designs used to study the relationship between air pollution and morbidity and mortality, from the standpoint of methodology and application.Data sources and extraction: A search was made of the MEDLINE and EMBASE databases.Reports were classified as methodologic or applied. From the latter, the following information was extracted: author, study location, year, type of population (general or patients), dependent variable(s), independent variable(s), type of CCO design, and whether effect modification was analyzed for variables at the individual level. Data synthesis: The review covered 105 reports that fulfilled the inclusion criteria. Of these, 24 addressed methodological aspects, and the remainder involved the design’s application. In the methodological reports, the designs that yielded the best results in simulation were symmetric bidirectional CCO and time-stratified CCO. Furthermore, we observed an increase across time in the use of certain CCO designs, mainly symmetric bidirectional and time-stratified CCO. The dependent variables most frequently analyzed were those relating to hospital morbidity; the pollutants most often studied were those linked to particulate matter. Among the CCO-application reports, 13.6% studied effect modification for variables at the individual level.Conclusions: The use of CCO designs has undergone considerable growth; the most widely used designs were those that yielded better results in simulation studies: symmetric bidirectional and time-stratified CCO. However, the advantages of CCO as a method of analysis of variables at the individual level are put to little use

Solar ultraviolet-B radiation and vitamin D: a cross-sectional population-based study using data from the 2007 to 2009 Canadian Health Measures Survey

Background: Exposure to solar ultraviolet-B (UV-B) radiation is a major source of vitamin D3. Chemistry climate models project decreases in ground-level solar erythemal UV over the current century. It is unclear what impact this will have on vitamin D status at the population level. The purpose of this study was to measure the association between ground-level solar UV-B and serum concentrations of 25-hydroxyvitamin D (25(OH)D) using a secondary analysis of the 2007 to 2009 Canadian Health Measures Survey (CHMS). Methods: Blood samples collected from individuals aged 12 to 79 years sampled across Canada were analyzed for 25(OH)D (n=4,398). Solar UV-B irradiance was calculated for the 15 CHMS collection sites using the Tropospheric Ultraviolet and Visible Radiation Model. Multivariable linear regression was used to evaluate the association between 25(OH)D and solar UV-B adjusted for other predictors and to explore effect modification. Results: Cumulative solar UV-B irradiance averaged over 91 days (91-day UV-B) prior to blood draw correlated significantly with 25(OH)D. Independent of other predictors, a 1 kJ/m 2 increase in 91-day UV-B was associated with a significant 0.5 nmol/L (95% CI 0.3-0.8) increase in mean 25(OH)D (P =0.0001). The relationship was stronger among younger individuals and those spending more time outdoors. Based on current projections of decreases in ground-level solar UV-B, we predict less than a 1 nmol/L decrease in mean 25(OH)D for the population. Conclusions: In Canada, cumulative exposure to ambient solar UV-B has a small but significant association with 25(OH)D concentrations. Public health messages to improve vitamin D status should target safe sun exposure with sunscreen use, and also enhanced dietary and supplemental intake and maintenance of a healthy body weight.

Genetic polymorphisms in the hypothalamic pathway in relation to subsequent weight change--the DiOGenes study

BACKGROUND: Single nucleotide polymorphisms (SNPs) in genes encoding the components involved in the hypothalamic pathway may influence weight gain and dietary factors may modify their effects. AIM: We conducted a case-cohort study to investigate the associations of SNPs in candidate genes with weight change during an average of 6.8 years of follow-up and to examine the potential effect modification by glycemic index (GI) and protein intake. METHODS AND FINDINGS: Participants, aged 20-60 years at baseline, came from five European countries. Cases ('weight gainers') were selected from the total eligible cohort (n = 50,293) as those with the greatest unexplained annual weight gain (n = 5,584). A random subcohort (n = 6,566) was drawn with the intention to obtain an equal number of cases and noncases (n = 5,507). We genotyped 134 SNPs that captured all common genetic variation across the 15 candidate genes; 123 met the quality control criteria. Each SNP was tested for association with the risk of being a 'weight gainer' (logistic regression models) in the case-noncase data and with weight gain (linear regression models) in the random subcohort data. After accounting for multiple testing, none of the SNPs was significantly associated with weight change. Furthermore, we observed no significant effect modification by dietary factors, except for SNP rs7180849 in the neuromedin β gene (NMB). Carriers of the minor allele had a more pronounced weight gain at a higher GI (P = 2 x 10⁻⁷). CONCLUSIONS: We found no evidence of association between SNPs in the studied hypothalamic genes with weight change. The interaction between GI and NMB SNP rs7180849 needs further confirmation.

The Gly482Ser genotype at the PPARGC1A gene and elevated blood pressure: a meta-analysis involving 13,949 individuals.

The protein encoded by the PPARGC1A gene is expressed at high levels in metabolically active tissues and is involved in the control of oxidative stress via reactive oxygen species detoxification. Several recent reports suggest that the PPARGC1A Gly482Ser (rs8192678) missense polymorphism may relate inversely with blood pressure. We used conventional meta-analysis methods to assess the association between Gly482Ser and systolic (SBP) or diastolic blood pressures (DBP) or hypertension in 13,949 individuals from 17 studies, of which 6,042 were previously unpublished observations. The studies comprised cohorts of white European, Asian, and American Indian adults, and adolescents from South America. Stratified analyses were conducted to control for population stratification. Pooled genotype frequencies were 0.47 (Gly482Gly), 0.42 (Gly482Ser), and 0.11 (Ser482Ser). We found no evidence of association between Gly482Ser and SBP [Gly482Gly: mean = 131.0 mmHg, 95% confidence interval (CI) = 130.5-131.5 mmHg; Gly482Ser mean = 133.1 mmHg, 95% CI = 132.6-133.6 mmHg; Ser482Ser: mean = 133.5 mmHg, 95% CI = 132.5-134.5 mmHg; P = 0.409] or DBP (Gly482Gly: mean = 80.3 mmHg, 95% CI = 80.0-80.6 mmHg; Gly482Ser mean = 81.5 mmHg, 95% CI = 81.2-81.8 mmHg; Ser482Ser: mean = 82.1 mmHg, 95% CI = 81.5-82.7 mmHg; P = 0.651). Contrary to previous reports, we did not observe significant effect modification by sex (SBP, P = 0.966; DBP, P = 0.715). We were also unable to confirm the previously reported association between the Ser482 allele and hypertension [odds ratio: 0.97, 95% CI = 0.87-1.08, P = 0.585]. These results were materially unchanged when analyses were focused on whites only. However, statistical evidence of gene-age interaction was apparent for DBP [Gly482Gly: 73.5 (72.8, 74.2), Gly482Ser: 77.0 (76.2, 77.8), Ser482Ser: 79.1 (77.4, 80.9), P = 4.20 x 10(-12)] and SBP [Gly482Gly: 121.4 (120.4, 122.5), Gly482Ser: 125.9 (124.6, 127.1), Ser482Ser: 129.2 (126.5, 131.9), P = 7.20 x 10(-12)] in individuals <50 yr (n = 2,511); these genetic effects were absent in those older than 50 yr (n = 5,088) (SBP, P = 0.41; DBP, P = 0.51). Our findings suggest that the PPARGC1A Ser482 allele may be associated with higher blood pressure, but this is only apparent in younger adults.

Variation in genes related to hepatic lipid metabolism and changes in waist circumference and body weight.

We analysed single nucleotide polymorphisms (SNPs) tagging the genetic variability of six candidate genes (ATF6, FABP1, LPIN2, LPIN3, MLXIPL and MTTP) involved in the regulation of hepatic lipid metabolism, an important regulatory site of energy balance for associations with body mass index (BMI) and changes in weight and waist circumference. We also investigated effect modification by sex and dietary intake. Data of 6,287 individuals participating in the European prospective investigation into cancer and nutrition were included in the analyses. Data on weight and waist circumference were followed up for 6.9 ± 2.5 years. Association of 69 tagSNPs with baseline BMI and annual changes in weight as well as waist circumference were investigated using linear regression analysis. Interactions with sex, GI and intake of carbohydrates, fat as well as saturated, monounsaturated and polyunsaturated fatty acids were examined by including multiplicative SNP-covariate terms into the regression model. Neither baseline BMI nor annual weight or waist circumference changes were significantly associated with variation in the selected genes in the entire study population after correction for multiple testing. One SNP (rs1164) in LPIN2 appeared to be significantly interacting with sex (p = 0.0003) and was associated with greater annual weight gain in men (56.8 ± 23.7 g/year per allele, p = 0.02) than in women (-25.5 ± 19.8 g/year per allele, p = 0.2). With respect to gene-nutrient interaction, we could not detect any significant interactions when accounting for multiple testing. Therefore, out of our six candidate genes, LPIN2 may be considered as a candidate for further studies.

Neighborhood and individual socio-economic variations in the contribution of occupational physical activity to total physical activity

Background: There is an inverse relationship between individual socio-economic status (SES) and amount of occupational physical activity. The role of the socio-economic environment is, however, less clear. This study examined the independent influences of neighborhood and individual SES on absolute and relative amount of occupational physical activity. It also examined the moderating effects of neighborhood SES on the relationship between individual SES and occupational physical activity.

Methods: Employees (n = 1236) resident in high or low SES neighborhoods were assessed on socio-demographic factors, including educational attainment and household income, and physical activity.

Results: Neighborhood SES and individual SES were independently inversely related to absolute and relative amount of occupational physical activity. Significant interactions between neighborhood SES and level of educational attainment in the contribution of total and vigorous occupational physical activity to total physical activity were found.

Conclusions: Neighborhood SES can function as a moderator in the relationship between individual SES and occupational physical activity.

Does workplace social capital buffer the effects of job stress? A cross-sectional, multilevel analysis of cigarette smoking among U.S. manufacturing workers

Objective: To investigate whether workplace social capital buffers the association between job stress and smoking status. Methods: As part of the Harvard Cancer Prevention Project's Healthy Directions—Small Business Study, interviewer-administered questionnaires were completed by 1740 workers and 288 managers in 26 manufacturing firms (84% and 85% response). Social capital was assessed by multiple items measured at the individual level among workers and contextual level among managers. Job stress was operationalized by the demand-control model. Multilevel logistic regression was used to estimate associations between job stressors and smoking and test for effect modification by social capital measures. Results: Workplace social capital (both summary measures) buffered associations between high job demands and smoking. One compositional item—worker trust in managers—buffered associations between job strain and smoking. Conclusion: Workplace social capital may modify the effects of psychosocial working conditions on health behaviors.

Duration of unemployment and suicide in Australia over the period 1985–2006: an ecological investigation by sex and age during rising versus declining national unemployment rates

Background The relationship between unemployment and suicide may be sensitive to demographic factors, national unemployment rates, and length of time without employment. This study investigated these factors in relation to suicide in Australia for the period 1985–2006, in an ecological study. Methods The outcome variable was annual suicide rate by age group, sex and the eight states and territories over 22 years of observation (total observations=1760). The main predictor variable was the average duration of unemployment in the population, categorised into three time periods (<2 weeks, 2–4 weeks, >4 weeks). Poisson regression models were used to investigate the relationship between duration of unemployment and suicide over the years 1985–2006 in a series of cross-sectional analyses. Interaction analyses indicated significant differences during periods of declining or increasing labour market opportunity and by age group. Results During periods of declining unemployment rates in the country, longer durations of unemployment were associated with higher male suicide rates. During periods of increasing unemployment in the country, longer unemployment duration was associated with lower male suicide rates. Effect modification was also apparent by age-group, with stronger associations between unemployment duration and male suicide evident in those aged 25–34 and 55–64, and weaker associations in those aged 15–24 and 44–54 years. Longer length of unemployment was not associated with an increase in female suicide rates. Conclusions The labour market opportunities in Australia modified the effect of duration of unemployment on suicide, and the effect was more prominent in men and older age groups. This may reflect social norms and acceptability about unemployment, as well as life-stage influences associated with transitions into and out of the labour market.

Employment status and mental health among persons with and without a disability: Evidence from an Australian cohort study

Background: Unemployment and economic inactivity are associated with worse mental health in the general population, but there is limited understanding of whether these relationships are different for those persons with mental or physical disabilities. The aim of this study was to assess whether there were differences in mental health by labour force status among persons with and without disabilities. Method: Over eight annual waves of the Household, Income and Labour Dynamics in Australia (HILDA) survey, a total of 2379 people with disabilities and 11 417 people without disabilities were identified. Mental health using the Mental Component Summary (MCS) from the Short Form 36 was modelled as a function of labour force status using fixed-effects regression models to control for time invariant confounding. Differences between those with and without disabilities were assessed by including an interaction term in regression models. Results: After finding evidence of effect modification, regression models were stratified by disability status. After adjustment, unemployment and economic inactivity were associated with a -1.85 (95% CI -2.96 to -0.73, p<0.001) and -2.66 (95% CI -3.46 to -1.86, p<0.001) reduction in scores of the MCS among those with a disability. For those without a disability, there were smaller declines associated with unemployment (-0.57, 95% CI -1.02 to -0.12, p=0.013) and economic inactivity (-0.34, 95% CI -0.64 to 0.05, p=0.022). Conclusions: These results suggest a greater reduction in mental health for those persons with disabilities who were unemployed or economically inactive than those who were employed. This highlights the value of employment for people with disabilities.

The Dutch Obesity Intervention in Teenagers (DOiT) cluster controlled implementation trial: intervention effects and mediators and moderators of adiposity and energy balance-related behaviours

 Background: The Dutch Obesity Intervention in Teenagers (DOiT) programme is an evidence-based obesity prevention programme tailored to adolescents attending the first two years of prevocational education in the Netherlands. The initial programme showed promising results during an effectiveness trial. The programme was adapted and prepared for nationwide dissemination. To gain more insight into the process of translating evidence-based approaches into ‘real world’ (i.e., ‘natural’) conditions, our research aims were to evaluate the impact of the DOiT-implementation programme on adolescents’ adiposity and energy balance-related behaviours during natural dissemination and to explore the mediating and moderating factors underlying the DOiT intervention effects.
Methods: We conducted a cluster-controlled implementation trial with 20 voluntary intervention schools (n=1002 adolescents) and 9 comparable control schools (n = 484 adolescents). We measured adolescents’ body height and weight, skinfold thicknesses, and waist circumference. We assessed adolescents’ dietary and physical activity behaviours by means of self-report. Data were collected at baseline and at 20-months follow-up. We used multivariable multilevel linear or logistic regression analyses to evaluate the intervention effects and to test the hypothesised behavioural mediating factors. We checked for potential effect modification by gender, ethnicity and education level.
Results: We found no significant intervention effects on any of the adiposity measures or behavioural outcomes. Furthermore, we found no mediating effects by any of the hypothesised behavioural mediators. Stratified analyses for gender showed that the intervention was effective in reducing sugar-containing beverage consumption in girls (B = -188.2 ml/day; 95% CI = -344.0; -32.3). In boys, we found a significant positive intervention effect on breakfast frequency (B = 0.29 days/week; 95% CI = 0.01; 0.58). Stratified analyses for education level showed an adverse intervention effect (B = 0.09; 95% CI = 0.02; 0.16) on BMI z-scores for adolescents attending the vocational education track.
Conclusions: Although not successful in changing adolescents’ adiposity, the DOiT-implementation programme had some beneficial effects on specific obesity-related behaviours in subgroups. This study underlines the difficulty of translating intervention effectiveness in controlled settings to real world contexts. Adaptations to the implementation strategy are needed in order to promote implementation as intended by the teachers.

Association between variants of the leptin receptor gene (LEPR) and overweight: a systematic review and an analysis of the CoLaus study

Background Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N) of the leptin receptor gene (LEPR) have been tested for association with obesity-related outcomes in multiple studies, showing inconclusive results. We performed a systematic review and meta-analysis on the association of the three LEPR variants with BMI. In addition, we analysed 15 SNPs within the LEPR gene in the CoLaus study, assessing the interaction of the variants with sex. Methodology/Principal Findings We searched electronic databases, including population-based studies that investigated the association between LEPR variants Q223R, K109R and K656N and obesity- related phenotypes in healthy, unrelated subjects. We furthermore performed meta-analyses of the genotype and allele frequencies in case-control studies. Results were stratified by SNP and by potential effect modifiers. CoLaus data were analysed by logistic and linear regressions and tested for interaction with sex. The meta-analysis of published data did not show an overall association between any of the tested LEPR variants and overweight. However, the choice of a BMI cut-off value to distinguish cases from controls was crucial to explain heterogeneity in Q223R. Differences in allele frequencies across ethnic groups are compatible with natural selection of derived alleles in Q223R and K109R and of the ancient allele in K656N in Asians. In CoLaus, the rs10128072, rs3790438 and rs3790437 variants showed interaction with sex for their association with overweight, waist circumference and fat mass in linear regressions. Conclusions Our systematic review and analysis of primary data from the CoLaus study did not show an overall association between LEPR SNPs and overweight. Most studies were underpowered to detect small effect sizes. A potential effect modification by sex, population stratification, as well as the role of natural selection should be addressed in future genetic association studies.

Surgical glove perforation and the risk of surgical site infection

HYPOTHESIS: Clinically apparent surgical glove perforation increases the risk of surgical site infection (SSI). DESIGN: Prospective observational cohort study. SETTING: University Hospital Basel, with an average of 28,000 surgical interventions per year. PARTICIPANTS: Consecutive series of 4147 surgical procedures performed in the Visceral Surgery, Vascular Surgery, and Traumatology divisions of the Department of General Surgery. MAIN OUTCOME MEASURES: The outcome of interest was SSI occurrence as assessed pursuant to the Centers of Disease Control and Prevention standards. The primary predictor variable was compromised asepsis due to glove perforation. RESULTS: The overall SSI rate was 4.5% (188 of 4147 procedures). Univariate logistic regression analysis showed a higher likelihood of SSI in procedures in which gloves were perforated compared with interventions with maintained asepsis (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.4-2.8; P < .001). However, multivariate logistic regression analyses showed that the increase in SSI risk with perforated gloves was different for procedures with vs those without surgical antimicrobial prophylaxis (test for effect modification, P = .005). Without antimicrobial prophylaxis, glove perforation entailed significantly higher odds of SSI compared with the reference group with no breach of asepsis (adjusted OR, 4.2; 95% CI, 1.7-10.8; P = .003). On the contrary, when surgical antimicrobial prophylaxis was applied, the likelihood of SSI was not significantly higher for operations in which gloves were punctured (adjusted OR, 1.3; 95% CI, 0.9-1.9; P = .26). CONCLUSION: Without surgical antimicrobial prophylaxis, glove perforation increases the risk of SSI.

Electrocardiographic PR interval and adverse outcomes in older adults: the Health, Aging, and Body Composition study

BACKGROUND The electrocardiographic PR interval increases with aging, differs by race, and is associated with atrial fibrillation (AF), pacemaker implantation, and all-cause mortality. We sought to determine the associations between PR interval and heart failure, AF, and mortality in a biracial cohort of older adults. METHODS AND RESULTS The Health, Aging, and Body Composition (Health ABC) Study is a prospective, biracial cohort. We used multivariable Cox proportional hazards models to examine PR interval (hazard ratios expressed per SD increase) and 10-year risks of heart failure, AF, and all-cause mortality. Multivariable models included demographic, anthropometric, and clinical variables in addition to established cardiovascular risk factors. We examined 2722 Health ABC participants (aged 74±3 years, 51.9% women, and 41% black). We did not identify significant effect modification by race for the outcomes studied. After multivariable adjustment, every SD increase (29 ms) in PR interval was associated with a 13% greater 10-year risk of heart failure (95% confidence interval, 1.02-1.25) and a 13% increased risk of incident AF (95% confidence interval, 1.04-1.23). PR interval >200 ms was associated with a 46% increased risk of incident heart failure (95% confidence interval, 1.11-1.93). PR interval was not associated with increased all-cause mortality. CONCLUSIONS We identified significant relationships of PR interval to heart failure and AF in older adults. Our findings extend prior investigations by examining PR interval and associations with adverse outcomes in a biracial cohort of older men and women.

Factorial designs: an overview with applications to orthodontic clinical trials.

Factorial designs for clinical trials are often encountered in medical, dental, and orthodontic research. Factorial designs assess two or more interventions simultaneously and the main advantage of this design is its efficiency in terms of sample size as more than one intervention may be assessed on the same participants. However, the factorial design is efficient only under the assumption of no interaction (no effect modification) between the treatments under investigation and, therefore, this should be considered at the design stage. Conversely, the factorial study design may also be used for the purpose of detecting an interaction between two interventions if the study is powered accordingly. However, a factorial design powered to detect an interaction has no advantage in terms of the required sample size compared to a multi-arm parallel trial for assessing more than one intervention. It is the purpose of this article to highlight the methodological issues that should be considered when planning, analysing, and reporting the simplest form of this design, which is the 2 × 2 factorial design. An example from the field of orthodontics using two parameters (bracket type and wire type) on maxillary incisor torque loss will be utilized in order to explain the design requirements, the advantages and disadvantages of this design, and its application in orthodontic research.