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Mutational signatures refer to patterns in the occurrence of somatic mutations that might be uniquely ascribed to particular mutational process. Tumour mutation catalogues can reveal mutational signatures but are often consistent with the mutation spectra produced by a variety of mutagens. To date, after the analysis of tens of thousands of exomes and genomes from about 40 different cancer types, tens of mutational signatures characterized by a unique probability profile across the 96 trinucleotide-based mutation types have been identified, validated and catalogued. At the same time, several concurrent methods have been developed for either the quantification of the contribution of catalogued signatures in a given cancer sequence or the identification of new signatures from a sample of cancer sequences. A review of existing computational tools has been recently published to guide researchers and practitioners through their mutational signature analyses, but other tools have been introduced since its publication and, a systematic evaluation and comparison of the performance of such tools is still lacking. In order to fill this gap, we have carried out an empirical evaluation of the main packages available to date, using both real and simulated data. Among other results, our empirical study shows that the identification of signatures is more difficult for cancers characterized by multiple signatures each having a small contribution. This work suggests that detection methods based on probabilistic models, especially EMu and bayesNMF, have in general better performance than NMF-based methods. [ABSTRACT FROM AUTHOR]

Objective: To identify individual and contextual socio-economic factors associated with an increase in fruit and vegetable (F&V) consumption over a 12-year period and evaluate if some socio-economic factors were differentially associated with the change in consumption of some types of F&V.Design: Associations between increased F&V consumption and socio-economic factors were studied with multivariate logistic regression.Setting: E3N, a French prospective cohort study of 98 995 women.Subjects: E3N participants (n 58 193) with information on diet in 1993 and 2005, and numerous individual and contextual socio-economic factors available.Results: Associations between some individual socio-economic factors and changes in F&V consumption were observed. For instance, women who lived in a large household (>3 children v. no child) had higher probability of increasing their vegetable consumption (OR=1·33; 95 % CI 1·24, 1·42). This association was driven by higher consumption of courgette and raw cucumber. Living with a partner was associated with higher odds of increasing consumption of fruits (OR=1·07; 95 % CI 1·02, 1·13) such as pear, peach and grape.Conclusions: Certain individual socio-economic factors, but none of the contextual socio-economic factors examined, were associated with an increase in F&V consumption. Factors associated with an increase in total F&V consumption were not necessarily associated with an increase in fruit or vegetable consumption separately, or with an increase in each subtype of fruit or vegetable. Magnitudes of the different associations observed also differed when F&V were considered together, separately or by subtype. Increases in F&V consumption were mostly observed in women with high socio-economic position. To develop effective nutritional interventions and policies that take the socio-economic environment of individuals into account, we recommend future research to further focus on (i) pathways through which population characteristics might influence changes in F&V consumption and (ii) existing interactions between individual and contextual socio-economic factors. [ABSTRACT FROM AUTHOR]

Objective: To identify individual and contextual socio-economic factors associated with a healthy diet.Design: Dietary data from a large cohort study were used to derive two mutually exclusive dietary patterns through a latent class analysis. Associations between dietary patterns and socio-economic factors were studied with logistic regression.Setting: E3N, a French prospective cohort study composed of women recruited from a national health insurance plan covering people working in the national education system.Subjects: E3N participants (n 73 031) with dietary and socio-economic data available.Results: The 'Healthy' pattern was characterized by a large consumption of fruits and vegetables and the 'Less Healthy' pattern by a large consumption of pizza and processed meat. When all socio-economic factors were analysed together, all of the individual factors considered were associated with a healthy diet (e.g. women with three or more children were less likely to follow a healthy diet v. women with no children, OR (95 % CI): 0·70 (0·66, 0·75)) while the contextual factors associated with a healthy diet included the size of the agglomeration of residence and the area of birth and residence (e.g. women living in the West of France were less likely to follow a healthy diet v. those living in the South of France: 0·78 (0·72, 0·83)).Conclusions: We demonstrated that individual and contextual factors are both associated with diet. Rather than focusing only on individual factors, we recommend future studies or public health and nutritional strategies on diet to consider both types of factors. [ABSTRACT FROM AUTHOR]

Only a minority of prostate cancers lead to death. Because no tissue biomarkers of aggressiveness other than Gleason score are available at diagnosis, many nonlethal cancers are treated aggressively. We evaluated whether a panel of biomarkers, associated with a range of disease outcomes in previous studies, could predict death from prostate cancer for men with localized disease. Using a case-only design, subjects were identified from three Australian epidemiological studies. Men who had died of their disease, 'cases' ( N = 83), were matched to 'referents' ( N = 232), those who had not died of prostate cancer, using incidence density sampling. Diagnostic tissue was retrieved to assess expression of AZGP1, MUC1, NKX3.1, p53, and PTEN by semiquantitative immunohistochemistry (IHC). Poisson regression was used to estimate mortality rate ratios ( MRRs) adjusted for age, Gleason score, and stage and to estimate survival probabilities. Expression of MUC1 and p53 was associated with increased mortality ( MRR 2.51, 95% CI 1.14-5.54, P = 0.02 and 3.08, 95% CI 1.41-6.95, P = 0.005, respectively), whereas AZGP1 expression was associated with decreased mortality ( MRR 0.44, 95% CI 0.20-0.96, P = 0.04). Analyzing all markers under a combined model indicated that the three markers were independent predictors of prostate cancer death and survival. For men with localized disease at diagnosis, assessment of AZGP1, MUC1, and p53 expression in diagnostic tissue by IHC could potentially improve estimates of risk of dying from prostate cancer based only on Gleason score and clinical stage. [ABSTRACT FROM AUTHOR]

Background Epidemiological studies have found that menopausal hormone therapy (MHT) use is associated with an increased ovarian cancer risk. However, whether different MHT types confer the same level of risk is unclear. We estimated the associations between different MHT types and the risk of ovarian cancer in a prospective cohort. Methods The study population included 75 606 postmenopausal women from the E3N cohort. Exposure to MHT was identified from self-reports in biennial questionnaires between 1992 and 2004 and from drug claim data matched to the cohort between 2004 and 2014. Hazard ratios and 95% confidence intervals (CIs) of ovarian cancer were estimated using multivariable Cox proportional hazards models with MHT as a time-varying exposure. Tests of statistical significance were 2-sided. Results Over an average 15.3 years follow-up, 416 ovarian cancers were diagnosed. Hazard ratios of ovarian cancer associated with ever use of estrogens combined with progesterone or dydrogesterone and ever use of estrogens combined with other progestagen were equal to 1.28 (95% CI = 1.04 to 1.57) and 0.81 (95% CI = 0.65 to 1.00), respectively (P homogeneity = .003), compared with never use. The hazard ratio for unopposed estrogen use was 1.09 (95% CI = 0.82 to 1.46). We found no trend according to duration of use or time since last use except for estrogens combined with progesterone or dydrogesterone, which showed decreasing risk with increasing time since last use. Conclusion Different MHT types may impact ovarian cancer risk differentially. The possibility that MHT containing progestagens other than progesterone or dydrogesterone may confer some protection should be evaluated in other epidemiological studies. [ABSTRACT FROM AUTHOR]

B vitamins are involved in 1-carbon metabolism, which is necessary for DNA replication, DNA repair, and regulation of gene expression. Recent studies suggest inverse associations between folate and vitamin B6 intakes and colorectal cancer risk but associations with other B vitamins and methionine have not been widely studied. After following 14,645 men and 22,467 women for 15 yr on average, we ascertained 910 incident colorectal cancers. Dietary intakes were estimated using a 121-item food frequency questionnaire. Hazard ratios (HRs) and 95% confidence intervals were estimated using Cox regression. We found some evidence of a U-shaped relationship between colon cancer risk and vitamin B6 and an inverse U-shaped relationship between rectal cancer risk and B12 (test for the quadratic trend,P= 0.005 andP= 0.0005 respectively). For colon cancer, we observed a reduced risk associated with low methionine/high folate, HR = 0.63 (0.49, 0.80) and an increased risk associated with high methionine/high folate, HR = 1.36 (1.06, 1.74) (Pinteraction < 0.0001). Our study suggests a U-shaped association between colon cancer risk and vitamin B6 intake and an inverse U-shaped association between rectal cancer risk and vitamin B12. Adequate folate intake might protect against colon cancer risk in those with low methionine intake. [ABSTRACT FROM AUTHOR]

The HOXB13 missense mutation G84E (rs138213197) is associated with increased risk of prostate cancer, but the current estimate of increased risk has a wide confidence interval (width of 95% confidence interval (CI) >200-fold) so the point estimate of 20-fold increased risk could be misleading. Population-based family studies can be more informative for estimating risks for rare variants, therefore, we screened for mutations in an Australian population-based series of early-onset prostate cancer cases (probands). We found that 19 of 1,384 (1.4%) probands carried the missense mutation, and of these, six (32%) had a family history of prostate cancer. We tested the 22 relatives of carriers diagnosed from 1998 to 2008 for whom we had a DNA sample, and found seven more carriers and one obligate carrier. The age-specific incidence for carriers was estimated to be, on average, 16.4 (95% CI 2.5–107.2) times that for the population over the time frame when the relatives were at risk prior to baseline. We then estimated the age and birth year- specific cumulative risk of prostate cancer (penetrance) for carriers. For example, the penetrance for an unaffected male carrier born in 1950 was 19% (95% CI 5–46%) at age 60 years, 44% (95% CI 18–74%) at age 70 years and 60% (95% CI 30–85%) at age 80 years. Our study has provided a population-based estimate of the average risk of prostate cancer for HOXB13 missense mutation G84E carriers that can be used to guide clinical practice and research. This study has also shown that the majority of hereditary prostate cancers due to the HOXB13 missense mutation are ‘sporadic’ in the sense that unselected cases with the missense mutation do not typically report having a family history of prostate cancer. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Cumulative Association of Five Genetic Variants With Prostate Cancer" by S. L. Zheng, J. Sun and F. Wilkund in the February 28, 2008 issue.

A letter to the editor is presented in response to the article "Sarcoidosis" by M. C. Iannuzzi, B. A. Rybicki and A. S. Teirstein in the November 22, 2007 issue.

OBJECTIVE To use a large population-based case-control study to test the association between the common genetic variant rs743572 (−34 T to C), prostate cancer risk and circulating levels of several hormones. SUBJECTS AND METHODS A previous meta-analysis concluded that reported associations between rs743572 in the promoter of CYP17A1 and prostate cancer risk might reflect publication bias, but a few recent studies reported associations with prostate cancer risk and data suggesting that rs743572 is functional. We genotyped 824 prostate cancer cases and 737 population-based controls, and applied unconditional logistic regression to estimate the association between rs743572 and prostate cancer risk. We also used linear regression of transformed testosterone, androstanediol glucuronide, dehydroepiandrosterone sulphate, androstenedione, sex hormone-binding globulin and oestradiol (circulating levels) measured for controls, to estimate the association between these levels and rs743572. The linear models were adjusted for age and laboratory batch. RESULTS Men with different genotypes had similar circulating levels of all the hormones measured (all P < 0.05). In the case-control comparison using unconditional unadjusted logistic regression, the odds ratios (95% confidence interval) for prostate cancer were 1.07 (0.87–1.32) and 0.94 (0.71–1.25) for the dominant and recessive models, respectively, and for the co-dominant model, 1.10 (0.88–1.36) and 0.99 (0.73–1.35) for carriers of one or two copies of the C allele, respectively. There was no evidence of heterogeneity in the odds ratios by tumour stage (all P > 0.3) and grade (all P > 0.3). CONCLUSION The results of the present study are consistent with the conclusions of the previous meta-analysis, and suggest that rs743572 has no role in the risk of prostate cancer for men of Caucasian origin. [ABSTRACT FROM AUTHOR]

Background: The ELAC2 gene has been proposed to be a prostate cancer susceptibility gene and is being referred to as HPC2, in part because three case-control studies suggested that two common polymorphisms (Ser217Leu and Ala541Thr) are associated with risk. However, four subsequent larger studies have not confirmed this association. In five of the seven total studies, subject selection was influenced by prostate-specific antigen (PSA) levels. We examined the association and possible effect of subject selection in a larger study and a meta-analysis.Methods: In a population-based study in Australia, 825 case patients and 732 control subjects were genotyped for the Ser217Leu and Ala541Thr polymorphisms of ELAC2. Odds ratios (ORs) for prostate cancer were estimated by unconditional logistic and polytomous regression. A meta-analysis was conducted combining our data with those from seven published studies. The association of genotype with the logarithm of plasma PSA levels in control subjects was analyzed by linear regression.Results: The ORs for prostate cancer were 0.74 (95% confidence interval [CI] = 0.50 to 1.09) for Leu217 homozygotes and 1.01 (95% CI = 0.68 to 1.50) for Thr541 heterozygotes and homozygotes compared with Ser217 and Ala541 homozygotes, respectively. ORs were not changed by excluding control subjects with elevated PSA levels. Among control subjects, there were no statistically significant associations between genotype frequencies and PSA level for either polymorphism (both P>.4). The meta-analysis gave pooled OR estimates of 1.04 (95% CI = 0.85 to 1.26) for Leu217 homozygotes and 1.18 (OR = 0.98 to 1.42) for Thr541 homozygotes and heterozygotes.Conclusion: There is no evidence that either ELAC2 polymorphism is associated with prostate cancer or PSA level. [ABSTRACT FROM AUTHOR]

Purpose: Recent evidence suggests that plant-based diets may reduce the risk of breast cancer (BC). However, the macronutrient composition of plant-based diets and its potential impact on BC risk has not been well explored. This analysis investigated the association of macronutrient composition with BC risk across a spectrum of plant-based diet indexes using a multidimensional approach. Design: This study followed 64,655 participants from the Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale (E3N) cohort from 1993 to 2014. Diets were evaluated using validated 208-item diet history questionnaires at baseline (1993) and follow-up (2005), to calculate adherence to the overall plant-based diet (PDI), healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI). The association of macronutrient composition with BC risk was assessed via generalized additive time-dependent Cox models across different levels of these indexes. Response surfaces were generated to visualize compositional associations at the 25th, 50th, and 75th percentile of each index (low, moderate, and high). Results: A total of 3,932 incident BC cases were identified during the 21-year follow-up. There was a significant association between macronutrient composition and BC risk for hPDI, uPDI, and PDI (all P < 0.001). Akaike information criterion favored the hPDI model for characterizing the association between macronutrients and BC. BC risk was highest for individuals with a lower hPDI score who also consumed a diet containing lower protein (10%), lower carbohydrate (35%), and higher fat (55%). The lowest risk of BC was observed in those with higher hPDI scores with the lowest intake of protein (10%). At higher PDI and uPDI, diets containing higher protein (30%) and fat (45%) had the highest BC risk. Conclusion: These results demonstrate a complex relationship between macronutrient composition, plant-based diet quality, and BC risk. Further research is needed to examine specific foods that may be driving these associations. Registry: The protocol is registered at clinicaltrials.gov as NCT03285230. [ABSTRACT FROM AUTHOR]

• Exposure to PM 2.5 was associated with higher risk of lung cancer. • Elevated risks persisted even at levels lower than the EU limit value of 25 µg/m3. • No association between NO 2 , BC or O 3 and lung cancer incidence was observed. Ambient air pollution has been associated with lung cancer, but the shape of the exposure-response function - especially at low exposure levels - is not well described. The aim of this study was to address the relationship between long-term low-level air pollution exposure and lung cancer incidence. The "Effects of Low-level Air Pollution: a Study in Europe" (ELAPSE) collaboration pools seven cohorts from across Europe. We developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates for nitrogen dioxide (NO 2), fine particulate matter (PM 2.5), black carbon (BC), and ozone (O 3) to assign exposure to cohort participants' residential addresses in 100 m by 100 m grids. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status). We fitted linear models, linear models in subsets, Shape-Constrained Health Impact Functions (SCHIF), and natural cubic spline models to assess the shape of the association between air pollution and lung cancer at concentrations below existing standards and guidelines. The analyses included 307,550 cohort participants. During a mean follow-up of 18.1 years, 3956 incident lung cancer cases occurred. Median (Q1, Q3) annual (2010) exposure levels of NO 2 , PM 2.5 , BC and O 3 (warm season) were 24.2 µg/m3 (19.5, 29.7), 15.4 µg/m3 (12.8, 17.3), 1.6 10−5m−1 (1.3, 1.8), and 86.6 µg/m3 (78.5, 92.9), respectively. We observed a higher risk for lung cancer with higher exposure to PM 2.5 (HR: 1.13, 95% CI: 1.05, 1.23 per 5 µg/m3). This association was robust to adjustment for other pollutants. The SCHIF, spline and subset analyses suggested a linear or supra-linear association with no evidence of a threshold. In subset analyses, risk estimates were clearly elevated for the subset of subjects with exposure below the EU limit value of 25 µg/m3. We did not observe associations between NO 2 , BC or O 3 and lung cancer incidence. Long-term ambient PM 2.5 exposure is associated with lung cancer incidence even at concentrations below current EU limit values and possibly WHO Air Quality Guidelines. [ABSTRACT FROM AUTHOR]

The individual results of SARS-CoV-2 serological tests measured after the first pandemic wave of 2020 cannot be directly interpreted as a probability of having been infected. Plus, these results are usually returned as a binary or ternary variable, relying on predefined cut-offs. We propose a Bayesian mixture model to estimate individual infection probabilities, based on 81,797 continuous anti-spike IgG tests from Euroimmun collected in France after the first wave. This approach used serological results as a continuous variable, and was therefore not based on diagnostic cut-offs. Cumulative incidence, which is necessary to compute infection probabilities, was estimated according to age and administrative region. In France, we found that a "negative" or a "positive" test, as classified by the manufacturer, could correspond to a probability of infection as high as 61.8% or as low as 67.7%, respectively. "Indeterminate" tests encompassed probabilities of infection ranging from 10.8 to 96.6%. Our model estimated tailored individual probabilities of SARS-CoV-2 infection based on age, region, and serological result. It can be applied in other contexts, if estimates of cumulative incidence are available. [ABSTRACT FROM AUTHOR]

Background: Our main objectives were to estimate the incidence of illnesses presumably caused by SARS-CoV-2 infection during the lockdown period and to identify the associated risk factors.Methods: Participants from 3 adult cohorts in the general population in France were invited to participate in a survey on COVID-19. The main outcome was COVID-19-Like Symptoms (CLS), defined as a sudden onset of cough, fever, dyspnea, ageusia and/or anosmia, that lasted more than 3 days and occurred during the 17 days before the survey. We used delayed-entry Cox models to identify associated factors.Results: Between April 2, 2020 and May 12, 2020, 279,478 participants were invited, 116,903 validated the questionnaire and 106,848 were included in the analysis. Three thousand thirty-five cases of CLS were reported during 62,099 person-months of follow-up. The cumulative incidences of CLS were 6.2% (95% Confidence Interval (95%CI): 5.7%; 6.6%) on day 15 and 8.8% (95%CI 8.3%; 9.2%) on day 45 of lockdown. The risk of CLS was lower in older age groups and higher in French regions with a high prevalence of SARS-CoV-2 infection, in participants living in cities > 100,000 inhabitants (vs rural areas), when at least one child or adolescent was living in the same household, in overweight or obese people, and in people with chronic respiratory diseases, anxiety or depression or chronic diseases other than diabetes, cancer, hypertension or cardiovascular diseases.Conclusion: The incidence of CLS in the general population remained high during the first 2 weeks of lockdown, and decreased significantly thereafter. Modifiable and non-modifiable risk factors were identified. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Consumption of soft drinks and juices and risk of liver and biliary tract cancers in a European cohort" published in a previous issue of the periodical.

A letter to the editor is presented in response to the article about prostate cancer.

Material conditions of lockdown and changes in regular functioning may have played a role on depressive manifestations. We aimed to examine the association between housing conditions and changes in professional activity and depression during the first COVID-19 outbreak in France. Participants of the CONSTANCES cohort were followed online. A first questionnaire covered the lockdown period (assessing housing conditions and changes in professional activity), and a second the post-lockdown period (assessing depression using the Center of Epidemiologic Studies Depression-Scale (CES-D)). Incident depression was also estimated (with a previous CES-D measure). Logistic regression models were applied. 22,042 participants (median age 46 years, 53.2 % women) were included and 20,534 had a previous CES-D measure. Depression was associated with female gender, lower household income and past history of depression. A negative gradient between the number of rooms and the likelihood of depression was consistently observed (OR = 1.55 95 % [1.19–2.00] for one room, OR = 0.76 [0.65–0.88] for seven rooms), while a U-shape relationship was observed with the number of people living together (OR = 1.62 [1.42–1.84] for living alone, OR = 1.44 [1.07–1.92] for six persons). These associations were also observed with incident depression. Changes in professional activity were associated with depression (Started distance working (OR = 1.33 [1.17–1.50]). Starting distance working was also associated with incident depression (OR = 1.27 [1.08–1.48]). A cross-sectional design was used. The consequences of lockdown on depression may vary depending on living conditions and changes in professional activity, including distance working. These results could help to better identify vulnerable people to promote mental health. • Housing conditions were associated with both prevalent and incident depression during the first COVID-19 related lockdown • A statistical gradient was observed between the number of rooms in the dwelling and the risk of depression • Changes in professional activity (such as starting distance working) were associated with prevalent and incident depression • Gender (women), lower household income and past history of depression were also associated with greater odds of depression [ABSTRACT FROM AUTHOR]

Background: Taste or smell disorders have been reported as strongly associated with COVID-19 diagnosis. We aimed to identify subject characteristics, symptom associations, and antibody response intensity associated with taste or smell disorders. Methods: We used data from SAPRIS, a study based on a consortium of five prospective cohorts gathering 279,478 participants in the French general population. In the analysis, we selected participants who were presumably infected by SARS-CoV-2 during the first epidemic wave. Results: The analysis included 3,439 patients with a positive ELISA-Spike. Sex (OR = 1.28 [95% CI 1.05–1.58] for women), smoking (OR = 1.54 [95% CI 1.13–2.07]), consumption of more than 2 drinks of alcohol a day (OR = 1.37 [95% CI 1.06–1.76]) were associated with a higher probability of taste or smell disorders. The relationship between age and taste or smell disorders was non-linear. Serological titers were associated with taste or smell disorders: OR = 1.31 [95% CI 1.26–1.36], OR = 1.37 [95% CI 1.33–1.42] and OR = 1.34 [95% CI 1.29–1.39] for ELISA-Spike, ELISA-Nucleocapsid and seroneutralization, respectively. Among participants with taste or smell disorders, 90% reported a wide variety of other symptoms whereas 10% reported no other symptom or only rhinorrhea. Conclusions: Among patients with a positive ELISA-Spike test, women, smokers and people drinking more than 2 drinks a day were more likely to develop taste or smell disorders. This symptom was strongly associated with an antibody response. The overwhelming majority of patients with taste or smell disorders experienced a wide variety of symptoms. [ABSTRACT FROM AUTHOR]

Despite experimental studies suggesting a disease-modifying role of oestrogens, results from epidemiological studies on the relation of reproductive characteristics and hormonal exposures with Parkinson disease in women are conflicting. We used the data from the E3N cohort study including 98,068 women aged 40-65y in 1990 followed until 2018. Parkinson disease was ascertained using a validation process based on drug claim databases and medical records. Reproductive characteristics and hormonal exposures were self-reported (11 questionnaires). Associations of exposures with Parkinson disease incidence were investigated using time-varying Cox proportional hazards regression with a 5-year exposure lag and age as the time scale adjusted for confounders. We identified 1165 incident Parkinson disease cases during a mean follow-up of 22.0 years (incidence rate = 54.7 per 100 000 person-years). Parkinson disease incidence was higher in women with early (<12y, hazard ratio [HR] = 1.21, 95% confidence interval [CI] = 1.04-1.40) or late age at menarche (≥14y, HR = 1.18, 95% CI = 1.03-1.35) than in women with menarche at 12-13y. Nulliparity was not associated with Parkinson disease, but Parkinson disease incidence increased with the number of children in parous women (P-trend = 0.009). Women with artificial (surgical, iatrogenic) menopause were at greater risk than women with natural menopause (HR = 1.28, 95% CI = 1.09-1.47), especially when artificial menopause occurred at an early age (≤45.0 years). Postmenopausal hormone therapy tended to mitigate greater risk associated with artificial or early menopause (≤45.0 years). While fertility treatments were not associated with Parkinson disease overall, ever users of clomiphene were at greater Parkinson disease risk than never users (HR = 1.81, 95% CI = 1.14-2.88). Other exposures (breastfeeding, oral contraceptives) were not associated with Parkinson disease. Our findings suggest that early and late age at menarche, higher parity, and artificial menopause, in particular at an early age, are associated with increased Parkinson disease incidence in women. In addition, there was some evidence that use of exogenous hormones may increase (fertility treatments) or decrease (postmenopausal hormone therapy) Parkinson disease incidence. These findings support the hypothesis that hormonal exposures play a role in the susceptibility to neurodegenerative diseases. If confirmed, they could help to identify subgroups at high risk for Parkinson disease. [ABSTRACT FROM AUTHOR]

Background: Taste or smell disorders have been reported as strongly associated with COVID-19 diagnosis. We aimed to identify subject characteristics, symptom associations, and antibody response intensity associated with taste or smell disorders. Methods: We used data from SAPRIS, a study based on a consortium of five prospective cohorts gathering 279,478 participants in the French general population. In the analysis, we selected participants who were presumably infected by SARS-CoV-2 during the first epidemic wave. Results: The analysis included 3,439 patients with a positive ELISA-Spike. Sex (OR = 1.28 [95% CI 1.05–1.58] for women), smoking (OR = 1.54 [95% CI 1.13–2.07]), consumption of more than 2 drinks of alcohol a day (OR = 1.37 [95% CI 1.06–1.76]) were associated with a higher probability of taste or smell disorders. The relationship between age and taste or smell disorders was non-linear. Serological titers were associated with taste or smell disorders: OR = 1.31 [95% CI 1.26–1.36], OR = 1.37 [95% CI 1.33–1.42] and OR = 1.34 [95% CI 1.29–1.39] for ELISA-Spike, ELISA-Nucleocapsid and seroneutralization, respectively. Among participants with taste or smell disorders, 90% reported a wide variety of other symptoms whereas 10% reported no other symptom or only rhinorrhea. Conclusions: Among patients with a positive ELISA-Spike test, women, smokers and people drinking more than 2 drinks a day were more likely to develop taste or smell disorders. This symptom was strongly associated with an antibody response. The overwhelming majority of patients with taste or smell disorders experienced a wide variety of symptoms. [ABSTRACT FROM AUTHOR]

Background: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive. Methods: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method. Results: Of 450,105 participants (318,680 women) followed for 14.2 ± 4.0 years, 6162 (3511 women) developed CRC. In men, total iron intake was not associated with CRC risk (highest vs. lowest quintile, HRQ5vs.Q1:0.88; 95%CI:0.73, 1.06). An inverse association was observed for non-heme iron (HRQ5vs.Q1:0.80, 95%CI:0.67, 0.96) whereas heme iron showed a non-significant association (HRQ5vs.Q1:1.10; 95%CI:0.96, 1.27). In women, CRC risk was not associated with intakes of total (HRQ5vs.Q1:1.11, 95%CI:0.94, 1.31), heme (HRQ5vs.Q1:0.95; 95%CI:0.84, 1.07) or non-heme iron (HRQ5vs.Q1:1.03, 95%CI:0.88, 1.20). Substitution of heme with non-heme iron demonstrated lower CRC risk in men (HR:0.94; 95%CI: 0.89, 0.99). Conclusions: Our findings suggest potential sex-specific CRC risk associations for higher iron consumption that may differ by dietary sources. [ABSTRACT FROM AUTHOR]

Purpose: Saturated fat has long been associated with cardiovascular disease in multiple prospective studies, and randomized controlled trials. Few studies have assessed the relative associations between saturated fat and other macronutrients with hypertension, a major risk factor for cardiovascular disease. The aim of this study was to assess the relative associations between saturated fat, other macronutrients such as monounsaturated and polyunsaturated fat, proteins, and carbohydrates, and incident hypertension in a large prospective cohort of French women. Methods: This study used data from the E3N cohort study, including participants free of hypertension at baseline. A food frequency questionnaire was used to determine dietary intakes of saturated fat (SFA), monounsaturated fat (MUFA), polyunsaturated fat (PUFA), animal protein (AP), vegetable protein (VP), carbohydrates (CH) and various foods. Cases of hypertension were based on self-report, validated by drug reimbursement data. Covariates were based on self-report. Cox proportional hazard models were used to estimate the relative associations between different macronutrients and hypertension risk, using the 'substitution' framework. Bootstrapping was used to generate 95% confidence intervals. Results: This study included 45,854 women free of hypertension at baseline. During 708,887 person-years of follow-up, 12,338 incident cases of hypertension were identified. Compared to saturated fat, higher consumption of all other macronutrients was associated with a lower risk of hypertension (HRMUFA = 0.74 [0.67: 0.81], HRPUFA = 0.84 [0.77: 0.92], HRCH = 0.83 [0.77: 0.88], HRAP = 0.91 [0.85: 0.97], HRVP = 0.93 [0.83: 1.03]). Conclusion: This study finds that relative to other macronutrients such as monounsaturated or polyunsaturated fat, higher intake of saturated fat is associated with a higher risk of hypertension among women. [ABSTRACT FROM AUTHOR]

Background: An infectious aetiology for prostate cancer has been conjectured for decades but the evidence gained from questionnaire-based and sero-epidemiological studies is weak and inconsistent, and a causal association with any infectious agent is not established. We describe and evaluate the application of new technology to detect bacterial and viral agents in high-grade prostate cancer tissues. The potential of targeted 16S rRNA gene sequencing and total RNA sequencing was evaluated in terms of its utility to characterise microbial communities within high-grade prostate tumours. Methods: Two different Massively Parallel Sequencing (MPS) approaches were applied. First, to capture and enrich for possible bacterial species, targeted-MPS of the V2-V3 hypervariable regions of the 16S rRNA gene was performed on DNA extracted from 20 snap-frozen prostate tissue cores from ten "aggressive" prostate cancer cases. Second, total RNA extracted from the same prostate tissue samples was also sequenced to capture the sequence profile of both bacterial and viral transcripts present. Results: Overall, 16S rRNA sequencing identified Enterobacteriaceae species common to all samples and P. acnes in 95% of analyzed samples. Total RNA sequencing detected endogenous retroviruses providing proof of concept but there was no evidence of bacterial or viral transcripts suggesting active infection, although it does not rule out a previous 'hit and run' scenario. Conclusions: As these new investigative methods and protocols become more refined, MPS approaches may be found to have significant utility in identifying potential pathogens involved in disease aetiology. Further studies, specifically designed to detect associations between the disease phenotype and aetiological agents, are required. [ABSTRACT FROM AUTHOR]

ABO blood type has been reported as a potential factor influencing SARS-CoV-2 infection, but so far mostly in studies that involved small samples, selected population and/or used PCR test results. In contrast our study aimed to assess the association between ABO blood types and SARS-CoV-2 infection using seroprevalence data (independent of whether or not individuals had symptoms or sought for testing) in a large population-based sample. Our study included 67,340 French participants to the SAPRIS-SERO multi-cohort project. Anti-SARS-CoV-2 antibodies were detected using ELISA (targeting the proteins spike (S) and nucleocapsid (NP)) and seroneutralisation (SN) tests on dried blood spots collected in May–November 2020. Non-O individuals (and especially types A and AB) were more likely to bear anti SARS-CoV-2 antibodies (ELISA-S, 2964 positive cases: ORnon-Ovs.O = 1.09[1.01–1.17], ORAvs.O = 1.08[1.00–1.17]; ELISA-S/ELISA-NP/SN, 678 triple positive cases: ORnon-Ovs.O = 1.19 [1.02–1.39], ORAvs.O = 1.19[1.01–1.41], ORABvs.O = 1.43[1.01–2.03]). Hence, our results provided additional insights into the dynamic of SARS-CoV-2 infection, highlighting a higher susceptibility of infection for individuals of blood types A and AB and a lesser risk for blood type O. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor commenting on M. Berwick and colleagues' study about sun exposure and mortality from melanoma.

Presents a letter to the editor in response to the article "Ejaculation frequency and subsequent risk of prostate cancer," by Michael Leitzmann and colleagues.

Background: Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations.Methods: We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty.Results: Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk.Conclusions: These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types. [ABSTRACT FROM AUTHOR]

[Display omitted] • We report the combined effect of eight air pollutants on breast cancer risk. • A Bayesian profile regression was used to identify correlated exposure profiles. • Out of 21 clusters identified, 3 showed significant evidence of breast cancer risk. • Greater risks were seen for clusters with high levels of NO 2 , PM 2.5 , PM 10 , & PCB153. • Women in these clusters were mainly located in high-density urban environments. Human exposure to air pollution involves complex mixtures of multiple correlated air pollutants. To date, very few studies have assessed the combined effects of exposure to multiple air pollutants on breast cancer (BC) risk. We aimed to assess the association between combined exposures to multiple air pollutants and breast cancer risk. The study was based on a case-control study nested within the French E3N cohort (5222 incident BC cases/5222 matched controls). For each woman, the average of the mean annual exposure to eight pollutants (benzo(a)oyrene, cadmium, dioxins, polychlorinated biphenyls (PCB153), nitrogen dioxide (NO 2), ozone, particulate matter and fine particles (PMs)) was estimated from cohort inclusion in 1990 to the index date. We used the Bayesian Profile Regression (BPR) model, which groups individuals according to their exposure and risk levels, and assigns a risk to each cluster identified. The model was adjusted on a combination of matching variables and confounders to better consider the design of the nested case-control study. Odds ratios (OR) and their 95 % credible intervals (CrI) were estimated. Among the 21 clusters identified, the cluster characterised by low exposures to all pollutants, except ozone, was taken as reference. A consistent increase in BC risk compared to the reference cluster was observed for 3 clusters: cluster 9 (OR=1.61; CrI=1.13,2.26), cluster 16 (OR=1.59; CrI=1.10,2.30) and cluster 15 (OR=1.38; CrI=1.00,1.88) characterised by high levels of NO 2 , PMs and PCB153. The other clusters showed no consistent association with BC. This is the first study assessing the effect of exposure to a mixture of eight air pollutants on BC risk, using the BPR approach. Overall, results showed evidence of a positive joint effect of exposure to high levels to most pollutants, particularly high for NO 2 , PMs and PCB153, on the risk of BC. [ABSTRACT FROM AUTHOR]

Assessment of the intensity, dynamics and determinants of the antibody response after SARS-CoV-2 infection or vaccination in the general population is critical to guide vaccination policies. This study characterized the anti-spike IgG titers in 13,971 participants included in a French multicohort population-based serological survey on COVID-19 between April and October 2020 and followed-up with serological testing between May and October 2021. Eight follow-up profiles were defined depending on SARS-CoV-2 infection (0, 1 or 2) and COVID-19 vaccination (0, 1, 2 or 3). The anti-spike titer was lower in adults with no vaccination even in case of infection or reinfection, while it was higher in adults with infection followed by vaccination. The anti-spike titer was negatively correlated with age in vaccinated but uninfected adults, whereas it was positively correlated with age in unvaccinated but infected adults. In adults with 2 vaccine injections and no infection, the vaccine protocol, age, gender, and time since the last vaccine injection were independently associated with the anti-spike titer. The decrease in anti-spike titer was much more rapid in vaccinated than in infected subjects. These results highlight the strong heterogeneity of the antibody response against SARS-CoV-2 in the general population depending on previous infection and vaccination. [ABSTRACT FROM AUTHOR]

Assessment of the intensity, dynamics and determinants of the antibody response after SARS-CoV-2 infection or vaccination in the general population is critical to guide vaccination policies. This study characterized the anti-spike IgG titers in 13,971 participants included in a French multicohort population-based serological survey on COVID-19 between April and October 2020 and followed-up with serological testing between May and October 2021. Eight follow-up profiles were defined depending on SARS-CoV-2 infection (0, 1 or 2) and COVID-19 vaccination (0, 1, 2 or 3). The anti-spike titer was lower in adults with no vaccination even in case of infection or reinfection, while it was higher in adults with infection followed by vaccination. The anti-spike titer was negatively correlated with age in vaccinated but uninfected adults, whereas it was positively correlated with age in unvaccinated but infected adults. In adults with 2 vaccine injections and no infection, the vaccine protocol, age, gender, and time since the last vaccine injection were independently associated with the anti-spike titer. The decrease in anti-spike titer was much more rapid in vaccinated than in infected subjects. These results highlight the strong heterogeneity of the antibody response against SARS-CoV-2 in the general population depending on previous infection and vaccination. [ABSTRACT FROM AUTHOR]

Background: Inflammation has been hypothesized to play a role in the development and progression of breast cancer and might differently impact breast cancer risk among pre and postmenopausal women. We performed a nested case-control study to examine whether pre-diagnostic circulating concentrations of adiponectin, leptin, c-reactive protein (CRP), tumour necrosis factor-α, interferon-γ and 6 interleukins were associated with breast cancer risk, overall and by menopausal status.Methods: Pre-diagnostic levels of inflammatory biomarkers were measured in plasma from 1558 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We used conditional logistic regression to estimate the odds ratios (ORs) of breast cancer at blood collection, per one standard deviation increase in biomarker concentration.Results: Cases were diagnosed at a mean age of 61.4 years on average 8.6 years after blood collection. No statistically significant association was observed between inflammatory markers and breast cancer risk overall. In premenopausal women, borderline significant inverse associations were observed for leptin, leptin-to-adiponectin ratio and CRP [OR= 0.89 (0.77-1.03), OR= 0.88 (0.76-1.01) and OR= 0.87 (0.75-1.01), respectively] while positive associations were observed among postmenopausal women [OR= 1.16 (1.05-1.29), OR= 1.11 (1.01-1.23), OR= 1.10 (0.99-1.22), respectively]. Adjustment for BMI strengthened the estimates in premenopausal women [leptin: OR = 0.83 (0.68-1.00), leptin-to-adiponectin ratio: OR = 0.80 (0.66-0.97), CRP: OR = 0.85 (0.72-1.00)] but attenuated the estimates in postmenopausal women [leptin: OR = 1.09 (0.96-1.24), leptin-to-adiponectin ratio: OR = 1.02 (0.89-1.16), CRP: OR = 1.04 (0.92-1.16)].Conclusions: Associations between CRP, leptin and leptin-to-adiponectin ratio with breast cancer risk may represent the dual effect of obesity by menopausal status although this deserves further investigation. [ABSTRACT FROM AUTHOR]

Background: Inflammation is a key feature of aging. We aimed to (i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality and (ii) develop a signature of "inflammaging."Methods: Thirty-four blood markers relating to inflammation, B vitamin status, and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age = 59 years) and follow-up (median age = 70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with 2 marker scores calculated across all markers associated with age and mortality, respectively.Results: The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5'-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, C-reactive protein, quinolinic acid, PAr index, and KTR. The inflammaging signature included 10 markers and was strongly associated with mortality (hazard ratio [HR] per SD = 1.40, 95% CI: 1.24-1.57, p = 2 × 10-8), similar to scores based on all age-associated (HR = 1.38, 95% CI: 1.23-1.55, p = 4 × 10-8) and mortality-associated markers (HR = 1.43, 95% CI: 1.28-1.60, p = 1 × 10-10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study.Conclusion: Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on 10 markers was strongly associated with mortality. [ABSTRACT FROM AUTHOR]

Background: Seroepidemiological studies have reported associations between exposure to sexually transmitted organisms and prostate cancer risk. This study sought DNA evidence of candidate organisms in archival prostate cancer tissues with the aim of assessing if a subset of these cancers show any association with common genital infections. Methods: 221 archival paraffin-embedded tissue blocks representing 128 histopathologically confirmed prostate cancers comprising 52 "aggressive" (Gleason score ≥ 7) and 76 "non-aggressive" (Gleason score ≤ 6) TURP or radical prostatectomy specimens were examined, as well as unaffected adjacent tissue when available. Representative tissue sections were subjected to DNA extraction, quality tested and screened by PCR for HSV-1, HSV-2, XMRV, BKV, HPV, Chlamydia trachomatis, Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma genitalium, and Trichomonas vaginalis. Results: 195 of 221 DNA samples representing 49 "aggressive" and 66 "non-aggressive" prostate cancer cases were suitable for analysis after DNA quality assessment. Overall, 12.2% (6/49) aggressive and 7.6% (5/66) non-aggressive cases were positive for any of the candidate organisms. Mycoplasma genitalium DNA was detected in 4/66 non-aggressive, 5/49 aggressive cancers and in one cancer-unaffected adjacent tissue block of an aggressive case. Ureaplasma urealyticum DNA was detected in 0/66 non-aggressive and 1/49 aggressive cancers and HSV DNA in 1/66 non-aggressive and 0/49 aggressive cancers. This study did not detect BKV, XMRV, T. vaginalis, U. parvum, C. trachomatis or HPV DNA. Conclusions: The low prevalence of detectable microbial DNA makes it unlikely that persistent infection by the selected candidate microorganisms contribute to prostate cancer risk, regardless of tumour phenotype. [ABSTRACT FROM AUTHOR]

Persistent organic pollutants (POPs) are a group of organic chemical compounds potentially toxic to human health. The objectives of this study were 1) to describe the levels of POPs biomarkers in blood samples from French women collected during the 1990s and to compare them with levels measured in two more recent French studies, 2) to identify POPs exposure profiles, and 3) to explore their main determinants. 73 POPs biomarkers were measured in the blood of 468 women from the French E3N cohort (aged 45–73 years), collected between 1994 and 1999: 28 per- and polyfluoroalkyl substances, 27 organochlorine pesticides, 14 polychlorinated biphenyls and 4 polybrominated diphenyl ethers. POPs biomarker levels were described and compared with levels measured in two more recent French studies conducted by the French National Public Health Agency, the ENNS and Esteban studies. Principal component analysis was performed on POPs quantified in at least 75% of samples to identify the main exposure profiles. Linear regression models were used to estimate the associations between anthropometric, socio-demographic and lifestyle characteristics and exposure to these profiles. Among the 73 biomarkers measured, 41 were quantified in more than 75% of samples. Levels of most pollutants that were also measured in the Esteban of ENNS studies have decreased over time. Six POPs exposure profiles were revealed, explaining 62.1% of the total variance. Most of the characteristics studied were associated with adherence to at least one of these profiles. This study highlighted that most of the pollutants for which a comparison was possible decreased over the 10 or 20 years following the E3N blood collection, and identified those which, on the contrary, tended to increase. The health effects of the profiles identified could be assessed in future studies. The determinants identified should be confirmed in larger populations. • Levels of 73 POPs were measured in blood samples from French E3N cohort women. • A decline in many POPs levels was observed over the 10–20 years since the 90's. • Six exposure profiles of POPs were identified. • Some individual and lifestyle characteristics were associated with these profiles. [ABSTRACT FROM AUTHOR]

Background: Brominated flame retardants (BFR) and per- and polyfluorinated alkylated substances (PFAS) are two groups of substances suspected to act as endocrine disruptors. Such substances could therefore be implicated in the occurrence of breast cancer, nevertheless, previous studies have led to inconstant results. Due to the large correlation between these substances, and the possibly non-linear effects they exert, evaluating their joint impact as mixtures on health remains challenging. This exploratory study aimed to generate hypotheses on the relationship between circulating levels of 7 BFR (6 polybrominated diphenyl ethers and 1 polybrominated biphenyls) and 11 PFAS and the risk of breast cancer in a case–control study nested in the E3N French prospective cohort by performing two methods: Principal Component Regression (PCR) models, and Bayesian Kernel Machine Regression (BKMR) models. Methods: 194 post-menopausal breast cancer cases and 194 controls were included in the present study. Circulating levels of BFR and PFAS were measured by gas chromatography coupled to high-resolution mass spectrometry and liquid chromatography coupled to tandem mass spectrometry, respectively. The first statistical approach was based on Principal Component Analysis (PCA) followed by logistic regression models that included the identified principal components as main exposure variables. The second approach used BKMR models with hierarchical variable selection, this latter being suitable for highly correlated exposures. Both approaches were also run separately for Estrogen Receptor positive (ER +) and Estrogen Receptor negative (ER-) breast cancer cases. Results: PCA identified four principal components accounting for 67% of the total variance. Component 3 showed a marginal association with ER + breast cancer risk. No clear association between BFR and PFAS mixtures and breast cancer was identified using BKMR models, and the credible intervals obtained were very wide. Finally, the BKMR models suggested a negative cumulative effect of BFR and PFAS on ER- breast cancer risk, and a positive cumulative effect on ER + breast cancer risk. Conclusion: Although globally no clear association was identified, both approaches suggested a differential effect of BFR and PFAS mixtures on ER + and ER- breast cancer risk. However, the results for ER- breast cancer should be interpreted carefully due to the small number of ER- cases included in the study. Further studies evaluating mixtures of substances on larger study populations are needed. [ABSTRACT FROM AUTHOR]

Background: Brominated flame retardants (BFR) and per- and polyfluorinated alkylated substances (PFAS) are two groups of substances suspected to act as endocrine disruptors. Such substances could therefore be implicated in the occurrence of breast cancer, nevertheless, previous studies have led to inconstant results. Due to the large correlation between these substances, and the possibly non-linear effects they exert, evaluating their joint impact as mixtures on health remains challenging. This exploratory study aimed to generate hypotheses on the relationship between circulating levels of 7 BFR (6 polybrominated diphenyl ethers and 1 polybrominated biphenyls) and 11 PFAS and the risk of breast cancer in a case-control study nested in the E3N French prospective cohort by performing two methods: Principal Component Regression (PCR) models, and Bayesian Kernel Machine Regression (BKMR) models.Methods: 194 post-menopausal breast cancer cases and 194 controls were included in the present study. Circulating levels of BFR and PFAS were measured by gas chromatography coupled to high-resolution mass spectrometry and liquid chromatography coupled to tandem mass spectrometry, respectively. The first statistical approach was based on Principal Component Analysis (PCA) followed by logistic regression models that included the identified principal components as main exposure variables. The second approach used BKMR models with hierarchical variable selection, this latter being suitable for highly correlated exposures. Both approaches were also run separately for Estrogen Receptor positive (ER +) and Estrogen Receptor negative (ER-) breast cancer cases.Results: PCA identified four principal components accounting for 67% of the total variance. Component 3 showed a marginal association with ER + breast cancer risk. No clear association between BFR and PFAS mixtures and breast cancer was identified using BKMR models, and the credible intervals obtained were very wide. Finally, the BKMR models suggested a negative cumulative effect of BFR and PFAS on ER- breast cancer risk, and a positive cumulative effect on ER + breast cancer risk.Conclusion: Although globally no clear association was identified, both approaches suggested a differential effect of BFR and PFAS mixtures on ER + and ER- breast cancer risk. However, the results for ER- breast cancer should be interpreted carefully due to the small number of ER- cases included in the study. Further studies evaluating mixtures of substances on larger study populations are needed. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Familial aggregation, a primary theme in genetic epidemiology, can be estimated from family studies based on an index person. The excess risk due to the presence of affected family members can be classified according to whether disease in the relatives is considered a risk factor for the index person (type I relative risk) or whether the disease status of the index person is considered a risk factor for the relatives (type II relative risk). Study Design and Setting: A meta-analysis of published colorectal cancer studies reporting a measure of familial association was performed and application of multilevel linear regression to model age-specific relative risks presented. Results: The pooled type I relative risk of colorectal cancer given any affected first-degree relative (based on 20 studies) was 2.26 (95% confidence interval CI = 1.86, 2.73) and decreased with the age of the consultand. The pooled type II estimate (based on seven studies) was 2.81 (95% CI = 2.05, 3.85). Conclusion: Type I relative risks are useful in clinical counseling settings when a consultand wants to know his/her disease risk given his or her family history. Type II relative risks can be used to quantify the risk of disease to relatives of an affected individual and then identify subjects eligible for screening. [Copyright &y& Elsevier]

Background: Metabolomics is a promising molecular tool for identifying novel etiological pathways leading to cancer. In an earlier prospective study among pre- and postmenopausal women not using exogenous hormones, we observed a higher risk of breast cancer associated with higher blood concentrations of one metabolite (acetylcarnitine) and a lower risk associated with higher blood concentrations of seven others (arginine, asparagine, phosphatidylcholines (PCs) aa C36:3, ae C34:2, ae C36:2, ae C36:3, and ae C38:2).Methods: To identify determinants of these breast cancer-related metabolites, we conducted a cross-sectional analysis to identify their lifestyle and anthropometric correlates in 2358 women, who were previously included as controls in case-control studies nested within the European Prospective Investigation into Cancer and Nutrition cohort and not using exogenous hormones at blood collection. Associations of each metabolite concentration with 42 variables were assessed using linear regression models in a discovery set of 1572 participants. Significant associations were evaluated in a validation set (n = 786).Results: For the metabolites previously associated with a lower risk of breast cancer, concentrations of PCs ae C34:2, C36:2, C36:3, and C38:2 were negatively associated with adiposity and positively associated with total and saturated fat intakes. PC ae C36:2 was also negatively associated with alcohol consumption and positively associated with two scores reflecting adherence to a healthy lifestyle. Asparagine concentration was negatively associated with adiposity. Arginine and PC aa C36:3 concentrations were not associated to any of the factors examined. For the metabolite previously associated with a higher risk of breast cancer, acetylcarnitine, a positive association with age was observed.Conclusions: These associations may indicate possible mechanisms underlying associations between lifestyle and anthropometric factors, and risk of breast cancer. Further research is needed to identify potential non-lifestyle correlates of the metabolites investigated. [ABSTRACT FROM AUTHOR]

Background: Nutritional factors are essential for the functioning of the immune system and could therefore play a role in COVID-19 but evidence is needed. Our objective was to study the associations between diet and the risk of SARS-CoV-2 infection in a large population-based sample. Methods: Our analyses were conducted in the French prospective NutriNet-Santé cohort study (2009--2020). Seroprevalence of anti-SARS-CoV-2 antibodies was assessed by ELISA on dried blood spots. Dietary intakes were derived from repeated 24 h dietary records (at least 6) in the two years preceding the start of the COVID-19 pandemic in France (February 2020). Multi-adjusted logistic regression models were computed. Results: A total of 7766 adults (70.3% women, mean age: 60.3 years) were included, among which 311 were positive for anti-SARS-CoV-2 antibodies. Dietary intakes of vitamin C (OR for 1 SD=0.86 (0.75--0.98), P=0.02), vitamin B9 (OR=0.84 (0.72--0.98), P=0.02), vitamin K (OR=0.86 (0.74--0.99), P=0.04), fibers (OR=0.84 (0.72--0.98), P=0.02), and fruit and vegetables (OR=0.85 (0.74--0.97), P=0.02) were associated to a decreased probability of SARS-CoV-2 infection while dietary intakes of calcium (OR=1.16 (1.01--1.35), P=0.04) and dairy products (OR=1.19 (1.06--1.33), P=0.002) associated to increased odds. No association was detected with other food groups or nutrients or with the overall diet quality. Conclusions: Higher dietary intakes of fruit and vegetables and, consistently, of vitamin C, folate, vitamin K and fibers were associated with a lower susceptibility to SARS-CoV-2 infection. Beyond its established role in the prevention of non-communicable diseases, diet could therefore also contribute to prevent some infectious diseases such as COVID-19. [ABSTRACT FROM AUTHOR]

Molecular studies suggest that cadmium due to its estrogenic properties, might play a role in breast cancer (BC) progression. However epidemiological evidence is limited. This study explored the association between long-term exposure to airborne cadmium and risk of BC by stage, grade of differentiation, and histological types at diagnosis. A nested case–control study of 4401 cases and 4401 matched controls was conducted within the French E3N cohort. A Geographic Information System (GIS)-based metric demonstrated to reliably characterize long-term environmental exposures was employed to evaluate airborne exposure to cadmium. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. There was no relationship between cadmium exposure and stage of BC. Also, no association between cadmium exposure and grade of differentiation of BC was observed. However, further analyses by histological type suggested a positive association between cadmium and risk of invasive tubular carcinoma (ITC) BC [ORQ5 vs Q1 = 3.4 (95% CI 1.1–10.7)]. The restricted cubic spline assessment suggested a dose–response relationship between cadmium and ITC BC subtype. Our results do not support the hypothesis that airborne cadmium exposure may play a role in advanced BC risk, but suggest that cadmium may be associated with an increased risk of ITC. [ABSTRACT FROM AUTHOR]

Purpose: Patterns of change from the traditional Palaeolithic lifestyle to the modern lifestyle may partly explain the epidemic proportions of non-communicable diseases (NCDs). We investigated to what extent adherence to the Palaeolithic diet (PD) and the Palaeolithic-like lifestyle was associated with type 2 diabetes (T2D) and hypertension risks. Methods: A study of 70,991 women from the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) cohort, followed up for nearly 20 years. There were 3292 incident T2D and 12,504 incident hypertension cases that were validated. Dietary data were collected at baseline in 1993 via a food frequency questionnaire. The PD score and the Palaeolithic-like lifestyle score (PD, physical activity, smoking status, and body mass index [BMI]) were derived and considered in quintiles. Multivariable Cox regression models were employed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for incident T2D and hypertension. Results: In the fully adjusted models, a 1-SD increase of the PD score was associated with 4% and 3% lower risks of T2D and hypertension, respectively. Those in the highest versus the lowest quintile of the score had HR (95% CI) of 0.88 (0.79, 0.98) and 0.91 (0.86, 0.96) for T2D and hypertension, respectively (P-trend < 0.0001). Associations were stronger for the Palaeolithic-like lifestyle score; in the fully adjusted model, a 1-SD increase of the score was associated with 19% and 6% lower risks of T2D and hypertension, respectively. Risks lowered successively with each increase in quintile; those in the highest versus the lowest quintile had HR (95% CI) of 0.58 (0.52, 0.65) and 0.85 (0.80, 0.90) for T2D and hypertension, respectively (P-trend < 0.0001). Conclusions: Our data suggest that adhering to a PD based on fruit, vegetables, lean meats, fish, and nuts, and incorporating a Palaeolithic-like lifestyle could be promising options to prevent T2D and hypertension. [ABSTRACT FROM AUTHOR]

Background: Nutritional epidemiology research using self-reported dietary intake is prone to measurement error. Objective methods are being explored to overcome this limitation.Objectives: We aimed to examine 1) the association between plasma markers related to inflammation and derive marker scores for dietary patterns [Mediterranean dietary score (MDS), energy-adjusted Dietary Inflammatory Index (E-DIITM), Alternative Healthy Eating Index 2010 (AHEI)] and 2) the associations of these marker scores with mortality.Methods: Weighted marker scores were derived from the cross-sectional association between 30 plasma markers and each dietary score (assessed using food-frequency questionnaires) using linear regression for 770 participants in the Melbourne Collaborative Cohort Study (aged 50-82 y). Prospective associations between marker scores and mortality (n = 249 deaths) were assessed using Cox regression (median follow-up: 14.4 y).Results: The MDS, E-DII, and AHEI were associated (P < 0.05) with 9, 14, and 11 plasma markers, respectively. Healthier diets (higher MDS and AHEI, and lower anti-inflammatory, E-DII) were associated with lower concentrations of kynurenines, neopterin, IFN-γ, cytokines, and C-reactive protein. Five of 6 markers common to the 3 dietary scores were components of the kynurenine pathway. The 3 dietary-based marker scores were highly correlated (Spearman ρ: -0.74, -0.82, and 0.93). Inverse associations (for 1-SD increment) were observed with all-cause mortality for the MDS marker score (HR: 0.84; 95% CI: 0.72-0.98) and the AHEI marker score (HR: 0.76; 95% CI: 0.66-0.89), whereas a positive association was observed with the E-DII marker score (HR: 1.18; 95% CI: 1.01-1.39). The same magnitude of effect was not observed for the respective dietary patterns.Conclusions: Markers involved in inflammation-related processes are associated with dietary quality, including a substantial overlap between markers associated with the MDS, the E-DII, and the AHEI, especially kynurenines. Unfavorable marker scores, reflecting poorer-quality diets, were associated with increased mortality. [ABSTRACT FROM AUTHOR]

Background: Glucocorticoids could theoretically decrease breast cancer risk through their anti-inflammatory effects or increase risk through immunosuppression. However, epidemiological evidence is limited regarding the associations between glucocorticoid use and breast cancer risk.Methods: We investigated the association between systemic glucocorticoid use and breast cancer incidence in the E3N cohort, which includes 98,995 women with information on various characteristics collected from repeated questionnaires complemented with drug reimbursement data available from 2004. Women with at least two reimbursements of systemic glucocorticoids in any previous 3-month period since January 1, 2004, were defined as exposed. We considered exposure as a time-varying parameter, and we used multivariable Cox regression models to estimate hazard ratios (HRs) of breast cancer. We performed a competing risk analysis using a cause-specific hazard approach to study the heterogeneity by tumour subtype/stage/grade.Results: Among 62,512 postmenopausal women (median age at inclusion of 63 years old), 2864 developed breast cancer during a median follow-up of 9 years (between years 2004 and 2014). Compared with non-exposure, glucocorticoid exposure was not associated with overall breast cancer risk [HR = 0.94 (0.85-1.05)]; however, it was associated with a higher risk of in situ breast cancer and a lower risk of invasive breast cancer [HRinsitu = 1.34 (1.01-1.78); HRinvasive = 0.86 (0.76-0.97); Phomogeneity = 0.01]. Regarding the risk of invasive breast cancer, glucocorticoid exposure was inversely associated with oestrogen receptor (ER)-positive breast cancer [HRER+ = 0.82 (0.72-0.94); HRER- = 1.21 (0.88-1.66); Phomogeneity = 0.03]; it was also inversely associated with the risk of stage 1 or stage 2 tumours but positively associated with the risk of stage 3/4 breast cancers [HRstage1 = 0.87 (0.75-1.01); HRstage2 = 0.67 (0.52-0.86); HRstage3/4 = 1.49 (1.02-2.20); Phomogeneity = 0.01].Conclusion: This study suggests that the association between systemic glucocorticoid use and breast cancer risk may differ by tumour subtype and stage. [ABSTRACT FROM AUTHOR]

Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR 1SD : 1.18, 95% CI: 1.05–1.33), and glycine, serine, and free carnitine (C0) were inversely (OR 1SD : 0.89, 95% CI: 0.80–0.99; OR 1SD : 0.89, 95% CI: 0.79–1.00 and OR 1SD : 0.91, 95% CI: 0.81–1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR 1SD : 1.14, 95% CI: 1.02–1.28) and that of short chain to free acylcarnitines (OR 1SD : 1.12, 95% CI: 1.00–1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention. • Endometrial cancer is the most common gynecological cancer in developed countries. • Metabolomics may uncover novel pathways linked to endometrial cancer. • 853 endometrial cancer case-control pairs from EPIC underwent metabolomic profiling. • Specific amino acids, sphingolipids & carnitine were linked to endometrial cancer. • If causal, these pathways may offer novel targets for endometrial cancer prevention. [ABSTRACT FROM AUTHOR]

Background: Perturbations in circulating metabolites prior to a breast cancer diagnosis are not well characterised. We aimed to gain more detailed knowledge to help understand and prevent the disease.Methods: Baseline plasma samples from 791 breast cancer cases and 791 matched controls from the E3N (EPIC-France) cohort were profiled by nuclear magnetic resonance (NMR)-based untargeted metabolomics. Partial least-squares discriminant analysis (PLS-DA) models were built from NMR profiles to predict disease outcome, and odds ratios and false discovery rate (FDR)-adjusted CIs were calculated for 43 identified metabolites by conditional logistic regression.Results: Breast cancer onset was predicted in the premenopausal subgroup with modest accuracy (AUC 0.61, 95% CI: 0.49-0.73), and 10 metabolites associated with risk, particularly histidine (OR = 1.70 per SD increase, FDR-adjusted CI 1.19-2.41), N-acetyl glycoproteins (OR = 1.53, FDR-adjusted CI 1.18-1.97), glycerol (OR = 1.55, FDR-adjusted CI 1.11-2.18) and ethanol (OR = 1.44, FDR-adjusted CI 1.05-1.97). No predictive capacity or significant metabolites were found overall or for postmenopausal women.Conclusions: Perturbed metabolism compared to controls was observed in premenopausal but not postmenopausal cases. Histidine and NAC have known involvement in inflammatory pathways, and the robust association of ethanol with risk suggests the involvement of alcohol intake. [ABSTRACT FROM AUTHOR]

Background: Significant differences in COVID-19 incidence by gender, class and race/ethnicity are recorded in many countries in the world. Lockdown measures, shown to be effective in reducing the number of new cases, may not have been effective in the same way for all, failing to protect the most vulnerable populations. This survey aims to assess social inequalities in the trends in COVID-19 infections following lockdown.Methods: A cross-sectional survey conducted among the general population in France in April 2020, during COVID-19 lockdown. Ten thousand one hundred one participants aged 18-64, from a national cohort who lived in the three metropolitan French regions most affected by the first wave of COVID-19. The main outcome was occurrence of possible COVID-19 symptoms, defined as the occurrence of sudden onset of cough, fever, dyspnea, ageusia and/or anosmia, that lasted more than 3 days in the 15 days before the survey. We used multinomial regression models to identify social and health factors related to possible COVID-19 before and during the lockdown.Results: In all, 1304 (13.0%; 95% CI: 12.0-14.0%) reported cases of possible COVID-19. The effect of lockdown on the occurrence of possible COVID-19 was different across social hierarchies. The most privileged class individuals saw a significant decline in possible COVID-19 infections between the period prior to lockdown and during the lockdown (from 8.8 to 4.3%, P = 0.0001) while the decline was less pronounced among working class individuals (6.9% before lockdown and 5.5% during lockdown, P = 0.03). This differential effect of lockdown remained significant after adjusting for other factors including history of chronic disease. The odds of being infected during lockdown as opposed to the prior period increased by 57% among working class individuals (OR = 1.57; 95% CI: 1.00-2.48). The same was true for those engaged in in-person professional activities during lockdown (OR = 1.53; 95% CI: 1.03-2.29).Conclusions: Lockdown was associated with social inequalities in the decline in COVID-19 infections, calling for the adoption of preventive policies to account for living and working conditions. Such adoptions are critical to reduce social inequalities related to COVID-19, as working-class individuals also have the highest COVID-19 related mortality, due to higher prevalence of comorbidities. [ABSTRACT FROM AUTHOR]