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Objectives Bilateral oophorectomy permanently reduces endogenous estrogen exposure and may increase cardiovascular mortality in women. This study aimed to investigate the association between bilateral oophorectomy and cardiovascular mortality and whether this association was conditional on hysterectomy or on the use of hormone therapy at the time of study entry. Methods A prospective cohort study of 25,338 female nurses aged ≥ 45 years within the Danish Nurse Cohort. Nurses were enrolled in 1993 or 1999 and followed until death, emigration, or end of follow-up on December 31, 2018, whichever came first. Exposure was bilateral oophorectomy. Outcome was cardiovascular mortality. Associations were estimated using Poisson regression models with log person-years as the offset. Results A total of 2,040 (8.1%) participants underwent bilateral oophorectomy. During a mean follow-up of 21.2 (SD: 5.6) years, 772 (3.0%) nurses died from cardiovascular disease. In adjusted analyses, a 31% higher rate of cardiovascular mortality was observed after bilateral oophorectomy (aMRR 1.31; 95% CI, 0.88-1.96) compared with women who retained their ovaries. No evidence of effect modification by use of hormone therapy at baseline or by hysterectomy on the association between bilateral oophorectomy and cardiovascular mortality was observed. Conclusion Bilateral oophorectomy may be associated with cardiovascular mortality in women, but the estimate was not statistically significant. Additionally, we were unable to make firm conclusions regarding the possible modifying role of hormone therapy and hysterectomy on this potential association. Additional studies are needed to replicate this work.

Worldwide, colorectal cancer is the second most common cancer and third cause of cancer death in women. Estrogen exposure has been inversely associated with colorectal cancer. Oophorectomy reduces circulating estrogen, but the effect on colorectal cancer remains uncertain. The aim of this study was to examine the association between unilateral and bilateral oophorectomy and subsequent risk of colorectal cancer, and whether this association varied by menopausal status at time of oophorectomy, use of hormone replacement therapy (HRT) at baseline, hysterectomy and baseline body mass index (BMI). The study included 25 698 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from baseline until date of colorectal cancer, death, emigration or end of follow-up at December 31, 2018, whichever came first. We examined the association between oophorectomy and colorectal cancer (all ages and stratified by menopausal status). The potential modifying effects of hysterectomy, HRT use at baseline and BMI were investigated. During 542 140 person-years of follow-up, 863 (3.4%) nurses were diagnosed with colorectal cancer. Bilateral oophorectomy was associated with a 79% increased colorectal cancer rate, adjusted rate ratio (aRR) (95% confidence interval [CI]): 1.79 (1.33-2.42). Effect estimates following unilateral oophorectomy also showed higher rate of colorectal cancer, although less pronounced and nonstatistically significant (aRR) (95% CI): 1.25 (0.86-1.82). Similar results were seen when stratifying by menopausal status. The association was not modified by baseline HRT use, hysterectomy or BMI. Oophorectomy was associated with increased rate of colorectal cancer, with highest rates among women with bilateral oophorectomy.

The association between oophorectomy and risk of breast cancer in the general population is uncertain. The aim of this study was to determine the breast cancer rate in women from the general population after oophorectomy (performed before/after menopause), and whether this varies by use of hormone replacement therapy (HRT), hysterectomy, body mass index (BMI) and shift work. The study included 24,409 female nurses (aged ≥45 years) participating in the Danish Nurse Cohort. Nurses were followed from cohort entry until date of breast cancer, death, disappearance, emigration or end of follow-up at 31st December 2018, whichever came first. Poisson regression with log-transformed person-years as the offset examined the association between oophorectomy and breast cancer (all ages and stratified by menopausal status at time of oophorectomy). The potential modifying effect of HRT use, hysterectomy, BMI and shift work on the associations was estimated. During 502,463 person-years of follow-up, 1,975 (8.1%) nurses were diagnosed with breast cancer. Bilateral oophorectomy was associated with reduced breast cancer rate compared to nurses with preserved ovaries, adjusted rate ratio (aRR) (95% confidence interval, CI): 0.79 (0.64; 0.99). Similar associations (magnitude and direction) were detected for unilateral oophorectomy and when stratifying according to menopausal status at time of oophorectomy, but without statistical significance. Unilateral and bilateral oophorectomy is associated with a reduced breast cancer rate in women from the general population. This association is not modified by use of HRT, hysterectomy, BMI or shift-work. This article is protected by copyright. All rights reserved.

Context Gynecomastia, the proliferation of mammary glandular tissue in the male, is a frequent but little-studied condition. Available prevalence data are based on selected patient populations or autopsy cases with their inherent bias. Objective The objective of this work is to evaluate the age-related incidence and secular trends in gynecomastia in the general population. Design An observational, 20-year national registry study was conducted. Setting This population-based study used nationwide registry data. Participants Participants included all Danish males (age 0-80 years) with a first-time diagnosis of gynecomastia. Main Outcome Measures All Danish males (age 0-80 years) were followed up for incident diagnosis of gynecomastia in the Danish National Patient Registry from 1998 to 2017 using the International Codes of Diseases, 10th revision, and the Danish Health Care Classification System. Age-specific incidence rates were estimated. The hypothesis tested in this study was formulated prior to data collection. Results Overall, a total 17 601 males (age 0-80 years) were registered with an incident diagnosis of gynecomastia within the 20-year study period, corresponding to 880 new cases per year and an average 20-year incidence of 3.4 per 10 000 men (age 0-80 years). The average annual incidence was 6.5/10 000 in postpubertal males age 16 to 20 years and 4.6/10 000 in males age 61 to 80 years, with a respective 5- and 11-fold overall increase in these 2 age groups over the 20-year period. Conclusions The incidence of gynecomastia has dramatically increased over the last 20 years, implying that the endogenous or exogenous sex-steroid environment has changed, which is associated with other adverse health consequences in men such as an increased risk of prostate cancer, metabolic syndrome, type 2 diabetes, or cardiovascular disorders.

Background Anogenital distance (AGD), the distance between the anus and genitals, is in rodents a well-established marker of early androgen action and has been suggested to be so in humans as well. Thus, a link between human AGD and semen quality and potentially fecundity may exist. Objective The aim of this study was to assess the association between AGD and male factor infertility and among proven fertile men also time to pregnancy (TTP). Material and methods All included men were recruited from and examined at Copenhagen University Hospital - Rigshospitalet, Denmark (N = 388). Men with impaired semen quality were included from infertile couples (N = 128), and men with naturally conceived pregnant partners were invited to participate when their partners had their routine second trimester examination (N = 260). All men underwent a physical examination, completed a questionnaire (including TTP for the fertile men), delivered a semen sample and had a blood sample drawn. The primary exposure was AGD(AS) measured from the centre of the anus to the posterior base of the scrotum. Associations between AGD and fertility status as well as between AGD and TTP among the fertile men were calculated using multiple logistic regression adjusted for covariates. Results AGD did not show a statistically significant association with fertility status. In adjusted logistic regression models, the odds of infertility per 1 cm increase in AGD(AS) were 1.02 (95% confidence interval [CI]: 0.88; 1.19). Among fertile men, a 1-cm increase in AGD(AS) was associated with an 8% non-statistically significantly reduced odds of having a longer (>3months) TTP (adjusted odds ratio (OR) = 0.92, 95% CI: 0.76-1.11). Conclusion Our study showed that the clinical application of AGD as a predictor of fertility and fecundity seems to be limited as no associations were observed between AGD and fertility status, nor was the decreased risk of experiencing a longer TTP with longer AGD(AS) statistically significant.

BackgroundRoad traffic noise has been linked to increased risk of ischemic heart disease, yet evidence on stroke shows mixed results. We examine the association between long-term exposure to road traffic noise and incidence of stroke, overall and by subtype (ischemic or hemorrhagic), after adjustment for air pollution.MethodsTwenty-five thousand six hundred and sixty female nurses from the Danish Nurse Cohort recruited in 1993 or 1999 were followed for stroke-related first-ever hospital contact until December 31st, 2014. Full residential address histories since 1970 were obtained and annual means of road traffic noise (Lden[dB]) and air pollutants (particulate matter with diameter 2.5and PM10], nitrogen dioxide [NO2], nitrogen oxides [NOx]) were determined using validated models. Time-varying Cox regression models were used to estimate hazard ratios (HR) (95% confidence intervals [CI]) for the associations of one-, three-, and 23-year running means of Ldenpreceding stroke (all, ischemic or hemorrhagic), adjusting for stroke risk factors and air pollutants. The World Health Organization and the Danish government’s maximum exposure recommendations of 53 and 58 dB, respectively, were explored as potential Ldenthresholds.ResultsOf 25,660 nurses, 1237 developed their first stroke (1089 ischemic, 148 hemorrhagic) during 16 years mean follow-up. For associations between a 1-year mean of Ldenand overall stroke incidence, the estimated HR (95% CI) in the fully adjusted model was 1.06 (0.98–1.14) per 10 dB, which attenuated to 1.01 (0.93–1.09) and 1.00 (0.91–1.09) in models further adjusted for PM2.5or NO2, respectively. Associations for other exposure periods or separately for ischemic or hemorrhagic stroke were similar. There was no evidence of a threshold association between Ldenand stroke.ConclusionsLong-term exposure to road traffic noise was suggestively positively associated with the risk of overall stroke, although not after adjusting for air pollution.

STUDY QUESTION Is there an association between prenatal exposure to stressful life events and age at menarche, and does childhood BMI mediate this association? SUMMARY ANSWER Girls exposed to prenatal stress had a slightly earlier age at menarche, but this association did not show a dose-response effect and was not mediated by childhood offspring BMI. WHAT IS ALREADY KNOWN Prenatal stress may impact on reproductive function in females including age at menarche, but human data are very limited. High childhood BMI is known to be associated with earlier age at menarche. Only one small study has measured the association between maternal stress and age at menarche and reported that childhood BMI mediated the association between maternal stress and earlier age at menarche. However, neither maternal stress nor age at menarche was prospectively recorded and the study was limited to 31 mother-daughter pairs. STUDY DESIGN, SIZE, DURATION The Raine Study is a large prospective population-based pregnancy cohort study (n = 1414 mother-daughter pairs) continuously followed from prenatal life through to adolescence. In the present study, we examined the association between exposure to maternal stressful life events during early, late and total gestation and age at menarche in offspring using 753 mother-daughter pairs with complete case information. PARTICIPANTS/MATERIALS, SETTING, METHODS Mothers prospectively reported stressful life events during pregnancy at 18 and 34 weeks using a standardized 10-point questionnaire. Exact date of menarche was assessed using a purpose-designed questionnaire at 8, 10, 14 and 17 years of age. Complete information on exposure, outcome and confounding variables was obtained from 753 mothers-daughter pairs. Multivariate linear regression complete case analysis was used to examine associations between maternal stressful life event exposure and age at menarche. Potential selection bias was evaluated using multiple imputations (50 datasets). The mediating effects of offspring childhood BMI (ages 5, 8, or 10 years) on these associations were measured in separate sub-analyses. MAIN RESULTS AND ROLE OF CHANCE Most (580/753, 77%) daughters were exposed to at least one prenatal stressful life event. Exposure to maternal stressful life events during the entire pregnancy was associated with a non-linear earlier age at menarche. Exposure to one event and two or more psychological stressful events was associated with a 3.5 and 1.7-month earlier onset of puberty, respectively when compared to the reference group with no exposure maternal stressful life events. The estimates from multiple imputation with 50 datasets were comparable with complete case analysis confirming the existence of an underlying effect. No separate significant effects were observed for exposure during early or late gestation. The association between prenatal stressful events and age at menarche was not mediated by childhood BMI in the offspring. LIMITATIONS, REASONS FOR CAUTION Stressful life events may have affected pregnant women in different ways and self-perceived maternal stress severity may have provided a more precise estimate of gestational psychological stress. The observed non-linear U-shape of the association between maternal psychological stress and age at menarche did not reflect a dose-response. This suggests that the first exposure to prenatal stress exerts a greater effect on fetal reproductive development. A potential mechanism is via dramatic initial activation of the hypothalamic-pituitary-adrenal (HPA) axis following the first stressful life event which is greater than that observed following subsequent exposure to two or more maternal stressful life events. Whilst we adjusted for a priori chosen confounders, we cannot exclude residual confounding or confounding by factors we did not include. Maternal age at menarche was not available so the effects of familial history/genetics could not be assessed. There was a large loss due to the number of girls with no information on date of menarche and missing confounder information implying risk of selection bias and multiple imputation analyses did not fully exclude this risk (similar direction but slightly weaker estimate magnitude). WIDER IMPLICATIONS OF THE FINDINGS Menarche is a sentinel reproductive event and earlier age at menarche carries implications for psychological, social and reproductive health and for long-term risk of common non-communicable diseases. Understanding the factors regulating age at menarche has extensive health implications. This is the first population-based cohort study in humans to demonstrate that prenatal psychological stress might directly modify age at menarche. STUDY FUNDING/COMPETING INTEREST(S) Dr. Brauner and Trine Koch's salaries were supported by Doctor Sofus Carl Emil Friis and spouse Olga Doris Friis foundation, The Danish Cancer Society (Kraeftens Bekaempelse, RP15468, R204-A12636, Denmark) and The Danish Health Foundation (Helsefonden, F-22181-23, Denmark). Martha Hickey was funded by NHMRC Practitioner Fellowships. The funding bodies played no role in the design, collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Dr. Hart has received personal fees in his function as the Medical Director of Fertility Specialists of Western Australia and received educational sponsorship grants from MSD, Merck-Serono and from Ferring Pharmaceuticals. Dr Hart has also received personal fees from Shareholders in Western IVF outside the submitted work. TRIAL REGISTRATION NUMBER NA.

BACKGROUND: Associations between long-term exposure to air pollution and road traffic noise have been established for ischemic heart disease, but findings have been mixed for atrial fibrillation (AF). OBJECTIVES: The goal of the study was to examine associations of long-term exposure to road traffic noise and air pollution with AF. METHODS: Time-varying Cox regression models were used to estimate associations of 1-, 3-, and 23-y mean road traffic noise and air pollution exposures with AF incidence in 23,528 women enrolled in the Danish Nurse Cohort (age >44 y at baseline in 1993 or 1999). AF diagnoses were ascer-tained via the Danish National Patient Register. Annual mean weighted 24-h average road traffic noise levels (L den) at the nurses’ residences, since 1970, were estimated using the Nord2000 model, and annual mean levels of particulate matter with a diameter 2:5) and nitrogen dioxide (NO 2) were estimated using the DEHM/UBM/AirGIS model. RESULTS: Of 23,528 nurses with no prior AF diagnosis at the cohort baseline, 1,522 developed AF during follow-up. In a fully adjusted model (including PM 2:5), the estimated risk of AF was 18% higher [hazard ratio (HR); 95% confidence interval (CI): 1.18; 1.02, 1.36] in nurses with residential 3-y mean L den levels >58 dB vs. 3 increase in 3-y mean PM 2:5 was associated with incident AF before and after adjustment for concurrent exposure to road traffic noise (HR 1.09; 95% CI: 1.00, 1.20 and 1.08; 95% CI: 0.97, 1.19, respectively). Associations with 1-y mean PM 2:5 exposures were positive but closer to the null and not significant. Associations with NO 2 were null for all time periods before and after adjustment for road traffic noise and inverse when adjusted for concurrent PM 2:5. CONCLUSION: Our analysis of prospective data from a cohort of Danish female nurses followed for up to 14 y provided suggestive evidence of independent associations between incident AF and 1-and 3-y exposures to road traffic noise and PM 2:5. https://doi.org/10.1289/EHP8090.

Background Experimental studies suggest that prenatal stress affects reproductive function in female offspring, but human evidence is sparse and inconsistent. In this present study, we aim to investigate whether maternal psychological stress, quantified as stressful life events during pregnancy, affect reproductive function in the female offspring. Method In a large population-based pregnancy cohort study (The Raine Study) continuously followed from prenatal life through to adolescence we examined the association between the number of maternal stressful life events in both early and late gestation and subsequent ovarian and uterine function in 228 female adolescent offspring. Mothers prospectively reported stressful life events during pregnancy at 18 and 34 weeks using a standardized 10-point questionnaire. Female offspring (n ​= ​228) age 14–16 years underwent gynecological examination including transabdominal abdominal ultrasound (TAUS) to measure uterine volume and ovarian AFC. Plasma samples on day 2–6 of the spontaneous menstrual cycle measured circulating AMH and inhibin B. Multivariate linear regression analysis was used to examine the associations between maternal stressful life events and reproductive function in female offspring. Adolescents taking hormonal contraception were excluded. Results Most adolescents (145/228, 64%) were exposed to at least one stressful life event in early gestation and around half (125/228, 55%) were exposed to at least one in later gestation. Exposure to one or more maternal stressful life events in late gestation was associated with a greater uterine volume (β ​= ​0.13, 95% CI 0.04; 0.23) and higher ovarian AFC (β ​= ​0.19, 95% CI 0.02; 0.35) at age 14–16 years. No associations between maternal stressful events in late gestation and reproductive function were identified. No associations between stressful life events in early or late gestation and circulating AMH or Inhibin B were observed. Conclusion Maternal psychological stress in late, but not early gestation was associated with a significantly greater uterine volume and ovarian antral follicle count (AFC) in adolescent offspring but did not affect ovarian production of antimullerian hormone (AMH) or Inhibin B. These findings suggest that female reproductive function is influenced by prenatal exposure to stress.

Background: There is a high and growing prevalence of childhood obesity which increases the risk of adult obesity and adverse physical and mental health outcomes in adulthood. Experimental and clinical data suggest that the early life environment, particularly prenatal stress, may program development of obesity in the offspring. But few studies have assessed the associations between prenatal maternal stress and rapid (ascending) weight gain, which is the strongest predictor of adult obesity and metabolic disease. Experimental data indicate that the associations may be sex dependent, but the sex-dependent association between prenatal stress and growth in the human offspring during childhood and adolescence is largely unexplored. The aim of this study is to investigate the association between prenatal exposure to stressful life events and childhood obesity in the offspring and whether maternal smoking during pregnancy and breastfeeding mediate this.Method: Participants from a large prospective population-based Australian pregnancy cohort study (The Raine Study, n=2868) were closely and frequently followed from prenatal life (18 weeks gestation) through to adolescence. Maternal stressful life events were prospectively recorded at 18 and 34 weeks and childhood BMI (categorized into six z-score trajectories) was measured from 3 to age 14 years. We studied the prospective association between maternal exposure to stressful life events and BMI z-score trajectories in 2056 offspring (1082 boys). Mothers prospectively reported stressful life events at 18- and 34-weeks' gestation using a standardized and validated 10-point questionnaire. Age- and gender-specific z-scores for BMI were obtained from height and weight at age 3, 5, 8, 10 and 14 years using standardized methods. Latent class group analysis identified six distinct trajectory classes of BMI z-score. Multinomial logistic regression was used to examine the associations between maternal stressful life events and gender-specific BMI z-score trajectories as well as risk of overweight/obesity at each age point. Mediation analyses were also conducted to model the indirect associations through maternal smoking during pregnancy and breastfeeding. Results: Of the 2056-included offspring, 1322 (64.3%) were exposed to at least one maternal stressful life event during early gestation and 1203 (58.5%) were exposed in late gestation. In boys, exposure to stressful life events in early but not late gestation was significantly associated with ascending (accelerated) weight-gain (ages 3-14 years) (adjusted odds ratio (aOR): 1.25, 95% CI: 1.02, 1.52) and increased risk of overweight (aOR: 1.18, 95% CI: 1.00, 1.39) aged 10 years. No similar associations were observed in girls. We observed that 29.2% of the association between more maternal stressful life events and obesity in male offspring was mediated by breastfeeding for less than 6 months. Likewise, up to 35% of the association between more maternal stressful life events and obesity in male offspring was mediated by maternal smoking during the index pregnancy.Conclusion: Prenatal stress in early gestation is directly associated with accelerated childhood weight gain (assessed by childhood BMI z-score trajectories) and risk of obesity in adolescent boys, but not girls and breastfeeding and maternal smoking significantly mediates this association.

Background: Long-term road traffic noise exposure is linked to cardio-metabolic disease morbidity, whereas evidence on mortality remains limited. Objectives: We investigated association of long-term exposure to road traffic noise with all-cause and cause-specific mortality. Methods: We linked 22,858 females from the Danish Nurse Cohort (DNC), recruited into the Danish Register of Causes of Death up to 2014. Road traffic noise levels since 1970 were modelled by Nord2000 as the annual mean of a weighted 24 h average (Lden). Cox regression models examined the associations between Lden (5-year and 23-year means) and all-cause and cause-specific mortalities, adjusting for lifestyle and exposure to PM2.5 (particulate matter with diameter < 2.5 μm) and NO2 (nitrogen dioxide). Results: During follow-up (mean 17.4 years), 3902 nurses died: 1622 from cancer, 922 from CVDs (289 from stroke), 338 from respiratory diseases (186 from chronic obstructive pulmonary disease, 114 from lower respiratory tract infections [ALRIs]), 234 from dementia, 95 from psychiatric disorders, and 79 from diabetes. Hazard ratios (95% confidence intervals) for all-cause mortality from fully-adjusted models were 1.06 (1.01, 1.11) and 1.09 (1.03, 1.15) per 10 dB of 5-year and 23-year mean Lden, respectively, which attenuated slightly in our main model (fully-adjusted plus PM2.5: 1.04 [1.00, 1.10]; 1.08 [1.02, 1.13]). Main model estimates suggested the strongest associations between 5-year mean Lden and diabetes (1.14: 0.81, 1.61), ALRIs (1.13: 0.84, 1.54), dementia (1.12: 0.90, 1.38), and stroke (1.10: 0.91, 1.31), whereas associations with 23-year mean Lden were suggested for respiratory diseases (1.15: 0.95, 1.39), psychiatric disorders (1.11: 0.78, 1.59), and all cancers (1.08: 0.99, 1.17). Discussion: Among the female nurses from the DNC, we observed that long-term exposure to road traffic noise led to premature mortality, independently of air pollution, and its adverse effects may extend well beyond those on the cardio-metabolic system to include respiratory diseases, cancer, neurodegenerative and psychiatric disorders.

BackgroundWhile air pollution has been linked to the development of chronic obstructive pulmonary disease (COPD), evidence on the role of environmental noise is just emerging. We examined the associations of long-term exposure to air pollution and road traffic noise with COPD incidence.MethodsWe defined COPD incidence for 24 538 female nurses from the Danish Nurse Cohort (age >44 years) as the first hospital contact between baseline (1993 or 1999) and 2015. We estimated residential annual mean concentrations of particulate matter with an aerodynamic diameter 2.5) since 1990 and nitrogen dioxide (NO2) since 1970 using the Danish Eulerian Hemispheric Model/Urban Background Model/Air Geographic Information System modelling system, and road traffic noise (Lden) since 1970 using the Nord2000 model. Time-varying Cox regression models were applied to assess the associations of air pollution and road traffic noise with COPD incidence.Results977 nurses developed COPD during a mean of 18.6 years’ follow-up. We observed associations with COPD for all three exposures with HRs and 95% CIs of 1.19 (1.01–1.41) per 6.26 µg·m−3 for PM2.5, 1.13 (1.05–1.20) per 8.19 µg·m−3 for NO2 and 1.15 (1.06–1.25) per 10 dB for Lden. Associations with NO2 and Lden attenuated slightly after mutual adjustment, but were robust to adjustment for PM2.5. Associations with PM2.5 were attenuated to null after adjustment for either NO2 or Lden. No potential interaction effect was observed between air pollutants and noise.ConclusionLong-term exposure to air pollution, especially traffic-related NO2, and to road traffic noise were independently associated with COPD.

Background: Ambient air pollution is likely a risk factor for asthma, and recent evidence suggests the possible relevance of road traffic noise. Objectives: We examined the associations of long-term exposure to air pollution and road traffic noise with adult-asthma incidence. Methods: We followed 28,731 female nurses (age > 44 years) from the Danish Nurse Cohort, recruited in 1993 and 1999, for first hospital contact for asthma from 1977 until 2015. We estimated residential annual mean concentrations of particulate matter with diameter < 2.5 µm (PM2.5) since 1990 and nitrogen dioxide (NO2) since 1970 with the Danish DEHM/UBM/AirGIS modeling system, and road traffic noise (Lden) since 1970 with the Nord2000 model. Time-varying Cox regression models were used to associate air pollution and road traffic noise exposure with asthma incidence. Results: During 18.6 years’ mean follow-up, 528 out of 23,093 participants had hospital contact for asthma. The hazard ratios (HR) and 95% confidence intervals for asthma incidence associated with 3-year moving average exposures were 1.29 (1.03, 1.61) per 6.3 µg/m3 for PM2.5, 1.16 (1.07, 1.27) per 8.2 µg/m3 for NO2, and 1.12 (1.00, 1.25) per 10 dB for Lden. The HR for NO2 remained unchanged after adjustment for either PM2.5 or Lden, while the HRs for PM2.5 and Lden attenuated to unity after adjustment for NO2. Conclusions: Long-term exposure to air pollution was associated with adult-asthma incidence independently of road traffic noise, with NO2 most relevant. Road traffic noise was not independently associated with adult-asthma incidence.

Background: The association between air pollution and mortality is well established, yet some uncertainties remain: there are few studies that account for road traffic noise exposure or that consider in detail the shape of the exposure–response function for cause-specific mortality outcomes, especially at low-levels of exposure. Objectives: We examined the association between long-term exposure to particulate matter [(PM) with a diameter of 2.5), 10)], and nitrogen dioxide (NO2) and total and cause-specific mortality, accounting for road traffic noise. Methods: We used data on 24,541 females (age > 44 years) from the Danish Nurse Cohort, who were recruited in 1993 or 1999, and linked to the Danish Causes of Death Register for follow-up on date of death and its cause, until the end of 2013. Annual mean concentrations of PM2.5, PM10, and NO2 at the participants’ residences since 1990 were estimated using the Danish DEHM/UBM/AirGIS dispersion model, and annual mean road traffic noise levels (Lden) were estimated using the Nord2000 model. We examined associations between the three-year running mean of PM2.5, PM10, and NO2 with total and cause-specific mortality by using time-varying Cox Regression models, adjusting for individual characteristics and residential road traffic noise. Results: During the study period, 3,708 nurses died: 843 from cardiovascular disease (CVD), 310 from respiratory disease (RD), and 64 from diabetes. In the fully adjusted models, including road traffic noise, we detected associations of three-year running mean of PM2.5 with total (hazard ratio; 95% confidence interval: 1.06; 1.01–1.11), CVD (1.14; 1.03–1.26), and diabetes mortality (1.41; 1.05–1.90), per interquartile range of 4.39 μg/m3. In a subset of the cohort exposed to PM2.5 < 20 µg/m3, we found even stronger association with total (1.19; 1.11–1.27), CVD (1.27; 1.01–1.46), RD (1.27; 1.00–1.60), and diabetes mortality (1.44; 0.83–2.48). We found similar associations with PM10 and none with NO2. All associations were robust to adjustment for road traffic noise. Discussion: Long-term exposure to low-levels of PM2.5 and PM10 is associated with total mortality, and mortality from CVD, RD, and diabetes. Associations were even stronger at the PM2.5 levels below EU limit values and were independent of road traffic noise.

Background: Long-term exposure to air pollution was linked with adult asthma onset and a study suggested relevance of road traffic noise. We linked long-term exposures to air pollution and road traffic noise to asthma incidence in adults. Methods: We followed 23,093 female nurses (age ≥44 years) from the Danish Nurse cohort, recruited in 1993 or 1999, in the National Patient Register for first-ever hospital contact for asthma until 2015. Particulate matter with diameter Results: During 18.6 years mean follow-up 528 nurses developed asthma. The mean concentrations of PM2.5, NO2 and Lden at baseline were 18.9μg/m3, 12.8μg/m3 and 52.7dB. We found associations of asthma with PM2.5 (hazard ratio; 95% confidence interval 1.29; 1.03-1.61 per 6.33µg/m3) and NO2 (1.16; 1.07-1.27 per 8.19µg/m3) in the fully adjusted model, which changed to 1.21 (0.95-1.54) and 1.16 (1.04-1.29), respectively, after adjustment for Lden, and to 0.99 (0.74-1.35) and 1.17 (1.02-1.32), in the two-pollutant model with PM2.5 and NO2. Association of asthma with Lden (1.12; 1.00-1.25 per 10dB) attenuated after adjustment for PM2.5 (1.08; 0.96-1.22) or NO2 (1.01; 0.88-1.15). Conclusion: Long-term exposure to traffic-related NO2 was associated with new-onset asthma in Danish nurses; while neither PM2.5 nor road traffic noise inferred risk of asthma.

Background PCOS is the most common endocrine disorder in reproductive age women. The origins of PCOS are unknown but experimental and limited human evidence suggests that greater prenatal exposure to androgens may predispose to PCOS. Experimental evidence suggests that maternal stressors may affect reproductive function in the offspring via changes in prenatal androgen exposure. In this present study, we aim to investigate whether maternal stressful life events during pregnancy are associated with polycystic ovary morphology (PCOM) or polycystic ovary syndrome (PCOS) in adolescent offspring. Method In a large population-based pregnancy cohort study (The Raine Study) continuously followed from prenatal life through to adolescence we examined the association between maternal stressful life events during pregnancy in both early and late gestation, and subsequent circulating concentrations of ovarian and adrenal androgens, PCOM and PCOS in the normal menstrual cycle of offspring age 14–16 years. Maternal stressful life events were prospectively recorded during pregnancy at 18 and 34 weeks using a 10-point questionnaire. Female offspring (n = 223) completed a questionnaire about their menstrual cycles, underwent a clinical examination for hirsutism (Ferriman-Gallwey score) and transabdominal pelvic ultrasound examination to determine ovarian morphology according to standardized criteria for classification of PCOM. Plasma samples were obtained at day 2–6 of the normal menstrual cycle for measurement of androgens. PCOM was defined according to the international consensus definition, 2003 and the evidence-based guideline for the assessment and management of PCOS, 2018. PCOS was diagnosed according to Rotterdam criteria and National Institute of Health (NIH) criteria. Multivariate linear and logistic regression analyses were used to examine the associations between maternal stressful life event exposure and ovarian morphology (PCOM), circulating ovarian and adrenal androgens (clinical and biochemical hyperandrogenism (hirsutism)) and presence of PCOS. Results Of 223 recruited adolescent girls, 78 (35.9%) and 68 (31.3%) had PCOM by the 2003 and 2018 criteria respectively, while 66 (29.6%) and 37 (16.6%) had PCOS, using Rotterdam and NIH criteria, respectively. Most girls (141/223, 63.2%) were exposed to at least one stressful life event in early gestation and around half (121/223, 54.3%) were exposed to at least one stressful life event in late gestation. Maternal stressful life events in early gestation were associated with a statistically significant lower prevalence of PCOM when applying the 2003 criteria [adjusted odds ratio [aOR] and 95% confidence intervals (CI): 0.74 (95% CI: 0.55; 0.99)], and a similar association was detected when applying the 2018 PCOM criteria (aOR, 0.69, 95% CI: 0.50; 0.95)]. Maternal stressful life events in early gestation were also associated with lower circulating concentrations of testosterone (β = −0.05, 95% CI: −0.09; −0.004) and androstenedione (β = −0.05, 95% CI: −0.10; −0.002) in the offspring. No similar effects for PCOM or circulating androgens were detected in late gestation. No statistically significant associations between maternal stressful life events in early or late gestation with PCOS (neither Rotterdam nor NIH criteria) in adolescence were detected. The prospective collection of maternal stressful life events during both early and late gestation and direct measurement of PCOM, PCOS and circulating androgens in adolescence and key co-variates implies minimal possibility of recall, information bias and selection bias. Conclusion Maternal exposure to stressful life events in early gestation is associated with significantly reduced circulating ovarian and adrenal androgen concentrations in adolescence (testosterone and androstenedione), and an indication of fewer cases of polycystic ovary morphology (PCOM) defined by the 2003 international consensus definition and by the 2018 international evidence-based guideline, but has no effect on polycystic ovary syndrome (PCOS), diagnosed using either Rotterdam or NIH criteria.

Ambient air pollution has been linked to stroke, but few studies have examined in detail stroke subtypes and confounding by road traffic noise, which was recently associated with stroke. Here we examined the association between long-term exposure to air pollution and incidence of stroke (overall, ischemic, hemorrhagic), adjusting for road traffic noise. In a nationwide Danish Nurse Cohort consisting of 23,423 nurses, recruited in 1993 or 1999, we identified 1,078 incident cases of stroke (944 ischemic and 134 hemorrhagic) up to December 31, 2014, defined as first-ever hospital contact. The full residential address histories since 1970 were obtained for each participant and the annual means of air pollutants (particulate matter with diameter < 2.5 µm and < 10 µm (PM2.5 and PM10), nitrogen dioxide (NO2), nitrogen oxides (NOx)) and road traffic noise were determined using validated models. Time-varying Cox regression models were used to estimate hazard ratios (HR) (95% confidence intervals (CI)) for the associations of one-, three, and 23-year running mean of air pollutants with stroke adjusting for potential confounders and noise. In fully adjusted models, the HRs (95% CI) per interquartile range increase in one-year running mean of PM2.5 and overall, ischemic, and hemorrhagic stroke were 1.12 (1.01–1.25), 1.13 (1.01–1.26), and 1.07 (0.80–1.44), respectively, and remained unchanged after adjustment for noise. Long-term exposure to ambient PM2.5 was associated with the risk of stroke independent of road traffic noise.

STUDY QUESTION Is there an association between prenatal exposure to stressful life events and age at menarche, and does childhood BMI mediate this association? SUMMARY ANSWER Girls exposed to prenatal stress had a slightly earlier age at menarche, but this association did not show a dose-response effect and was not mediated by childhood offspring BMI. WHAT IS ALREADY KNOWN Prenatal stress may impact on reproductive function in females including age at menarche, but human data are very limited. High childhood BMI is known to be associated with earlier age at menarche. Only one small study has measured the association between maternal stress and age at menarche and reported that childhood BMI mediated the association between maternal stress and earlier age at menarche. However, neither maternal stress nor age at menarche was prospectively recorded and the study was limited to 31 mother–daughter pairs. STUDY DESIGN, SIZE, DURATION The Raine Study is a large prospective population-based pregnancy cohort study (n = 1414 mother–daughter pairs) continuously followed from prenatal life through to adolescence. In the present study, we examined the association between exposure to maternal stressful life events during early, late and total gestation and age at menarche in offspring using 753 mother–daughter pairs with complete case information. PARTICIPANTS/MATERIALS, SETTING, METHODS Mothers prospectively reported stressful life events during pregnancy at 18 and 34 weeks using a standardized 10-point questionnaire. Exact date of menarche was assessed using a purpose-designed questionnaire at 8, 10, 14 and 17 years of age. Complete information on exposure, outcome and confounding variables was obtained from 753 mothers–daughter pairs. Multivariate linear regression complete case analysis was used to examine associations between maternal stressful life event exposure and age at menarche. Potential selection bias was evaluated using multiple imputations (50 datasets). The mediating effects of offspring childhood BMI (ages 5, 8, or 10 years) on these associations were measured in separate sub-analyses. MAIN RESULTS AND ROLE OF CHANCE Most (580/753, 77%) daughters were exposed to at least one prenatal stressful life event. Exposure to maternal stressful life events during the entire pregnancy was associated with a non-linear earlier age at menarche. Exposure to one event and two or more psychological stressful events was associated with a 3.5 and 1.7-month earlier onset of puberty, respectively when compared to the reference group with no exposure maternal stressful life events. The estimates from multiple imputation with 50 datasets were comparable with complete case analysis confirming the existence of an underlying effect. No separate significant effects were observed for exposure during early or late gestation. The association between prenatal stressful events and age at menarche was not mediated by childhood BMI in the offspring. LIMITATIONS, REASONS FOR CAUTION Stressful life events may have affected pregnant women in different ways and self-perceived maternal stress severity may have provided a more precise estimate of gestational psychological stress. The observed non-linear U-shape of the association between maternal psychological stress and age at menarche did not reflect a dose-response. This suggests that the first exposure to prenatal stress exerts a greater effect on fetal reproductive development. A potential mechanism is via dramatic initial activation of the hypothalamic–pituitary–adrenal (HPA) axis following the first stressful life event which is greater than that observed following subsequent exposure to two or more maternal stressful life events. Whilst we adjusted for a priori chosen confounders, we cannot exclude residual confounding or confounding by factors we did not include. Maternal age at menarche was not available so the effects of familial history/genetics could not be assessed. There was a large loss due to the number of girls with no information on date of menarche and missing confounder information implying risk of selection bias and multiple imputation analyses did not fully exclude this risk (similar direction but slightly weaker estimate magnitude). WIDER IMPLICATIONS OF THE FINDINGS Menarche is a sentinel reproductive event and earlier age at menarche carries implications for psychological, social and reproductive health and for long-term risk of common non-communicable diseases. Understanding the factors regulating age at menarche has extensive health implications. This is the first population-based cohort study in humans to demonstrate that prenatal psychological stress might directly modify age at menarche. STUDY FUNDING/COMPETING INTEREST(S) Dr. Bräuner and Trine Koch’s salaries were supported by Doctor Sofus Carl Emil Friis and spouse Olga Doris Friis foundation, The Danish Cancer Society (Kræftens Bekæmpelse, RP15468, R204-A12636, Denmark) and The Danish Health Foundation (Helsefonden, F-22181-23, Denmark). Martha Hickey was funded by NHMRC Practitioner Fellowships. The funding bodies played no role in the design, collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication. Dr. Hart has received personal fees in his function as the Medical Director of Fertility Specialists of Western Australia and received educational sponsorship grants from MSD, Merck-Serono and from Ferring Pharmaceuticals. Dr Hart has also received personal fees from Shareholders in Western IVF outside the submitted work. TRIAL REGISTRATION NUMBER NA.

BACKGROUND: Air pollution exposure has been linked to coronary heart disease, although evidence on PM2:5 and myocardial infarction (MI) incidence is mixed. OBJECTIVES: This prospective cohort study aimed to investigate associations between long-term exposure to air pollution and MI incidence, adjusting for road traffic noise. METHODS: We used data from the nationwide Danish Nurse Cohort on 22,882 female nurses (>44 years of age) who, at recruitment in 1993 or 1999, reported information on cardiovascular disease risk factors. Data on MI incidence was collected from the Danish National Patient Register until the end of 2014. Annual mean concentrations of particulate matter (PM) with a diameter 3 (PM2:5), PM10, nitrogen dioxide (NO2), and nitrogen oxides (NOx) at the nurses’ residences since 1990 (PM10 and PM2:5) or 1970 (NO2 and NOx) were estimated using the Danish Eulerian Hemispheric Model/Urban Background Model/AirGIS (DEHM/UBM/AirGIS) dispersion model. We used time-varying Cox regression models to examine the association between 1-and 3-y running means of these pollutants, as well as 23-y running means of NO2 and NOx, with both overall and fatal incident MI. Associations were explored in three progressively adjusted models: Model 1, adjusted for age and baseline year; Model 2, with further adjustment for potential confounding by lifestyle and cardiovascular disease risk factors; and Model 3, with further adjustment for road traffic noise, modeled as the annual mean of a weighted 24-h average (Lden). RESULTS: Of the 22,882 women, 641 developed MI during a mean follow-up of 18.6 y, 121 (18.9%) of which were fatal. Reported hazard ratios (HRs) were based on interquartile range increases of 5.3, 5.5, 8.1, and 11:5 lg=m3 for PM2:5, PM10, NO2, and NOX, respectively. In Model 1, we observed a positive association between a 3-y running mean of PM2:5 and an overall incident MI with an HR = 1.20 (95% CI: 1.07, 1.35), which attenuated to HR = 1.06 (95% CI: 0.92, 1.23) in Model 2. In Model 1 for incident fatal MI, we observed a strong association with a 3-y running mean of PM2:5, with an HR = 1.69 (95% CI: 1.33, 2.13), which attenuated to HR = 1.35 (95% CI: 1.01, 1.81) in Model 2. Similar associations were seen for PM10, with 3-y, Model 2 estimates for overall and fatal incident MI of HR = 1.06 (95% CI: 0.91, 1.23) and HR = 1.35 (95% CI: 1.01, 1.81), respec-tively. No evidence of an association was observed for NO2 or NOx. For all pollutants, associations in Model 2 were robust to further adjustment for road traffic noise in Model 3 and were similar for a 1-y running mean exposure. CONCLUSIONS: We found no association between long-term exposure to PM2:5, PM10, NO2, or NOx and overall MI incidence, but we observed positive associations for PM2:5 and PM10 with fatal MI. We present novel findings that the association between PM and MI incidence is robust to adjustment for road traffic noise. https://doi.org/10.1289/EHP5818.

Background: Studies have reported associations between psychological stress and semen quality, but most have been performed on selected populations using different stress measures. Thus, it is uncertain which stress scale best quantifies the effects of stress on testicular function. Objective: To study the association between three different measures of stress and testicular function in young men. Material and Methods: In total, 1362 men (median age 19 years) delivered semen and blood samples. They also answered a questionnaire including information from three stress scales: Stress Symptoms, Stressful Life Events and Perceived Stress. Various statistical analyses for associations between stress and testicular function (semen quality and reproductive hormones) were performed. Results: Perceived Stress was negatively associated with sperm concentration, total count and motility and positively associated with serum FSH. Men with the highest scores (>30 points) had 38% (95% CI 3-84%) lower sperm concentration, 42% (95% CI 5-91%) lower total count and 22% (95% CI 2-32%) lower proportion of motile spermatozoa than men with the lowest scores (0-10 points). For the stress symptoms score, men with highest scores (>95th percentile vs. lower) had lower sperm concentration, total sperm count, motility and serum Inhibin-B/FSH-ratio. Although men with highest stress levels were characterized by an unhealthier lifestyle, adjusting for lifestyle factors did not attenuate results suggesting that the associations between stress and testicular function were not mediated by lifestyle. Stressful Life Events were not associated with testicular function. Discussion and Conclusion: The linear association between Perceived Stress and semen parameters and lack of dose-response association for the other two stress scales indicated that perceived stress was the most sensitive marker of stress affecting semen quality in young men. The lack of associations between Stressful Life Events and testis function confirmed that the perception of stressful events rather than the stressful event per se matters.

Importance The initial clinical sign of pubertal onset in girls is breast gland development (thelarche). Although numerous studies have used recalled age at menarche (first menstruation) to assess secular trends of pubertal timing, no systematic review has been conducted of secular trends of thelarche. Objectives To systematically evaluate published data on pubertal timing based on age at thelarche and evaluate the change in pubertal onset in healthy girls around the world. Data Sources A systematic literature search was performed in PubMed and Embase of all original peer-reviewed articles published in English before June 20, 2019. Study Selection Included studies used clinical assessment of breast development in healthy girls and used adequate statistical methods, including the reporting of SEs or CIs. The quality of the articles was evaluated by assessing study design, potential sources of bias, main characteristics of the study population, and methods of statistical analysis. Data Extraction and Synthesis In accordance with PRISMA guidelines, all articles were assessed for eligibility independently by 2 authors. Weighted regression analysis was performed using a random-effects model. Main Outcomes and Measures Studies examining age at thelarche (development of Tanner breast stage 2) in healthy girls. Results The literature search resulted in a total of 3602 studies, of which 30 studies fulfilled the eligibility criteria. There was a secular trend in ages at thelarche according to race/ethnicity and geography. Overall, the age at thelarche decreased 0.24 years (95% CI, −0.44 to −0.04) (almost 3 months) per decade from 1977 to 2013 (P = .02). Conclusions and Relevance The age at thelarche has decreased a mean of almost 3 months per decade from 1977 to 2013. A younger age at pubertal onset may change current diagnostic decision-making. The medical community needs current and relevant data to redefine “precocious puberty,” because the traditional definition may be outdated, at least in some regions of the world.

Background: While air pollution has been linked to the development of chronic obstructive pulmonary disease (COPD), evidence on the role of environmental noise is just emerging. We examined the association of long-term exposure to air pollution and road traffic noise with COPD incidence. Methods: We defined COPD incidence for 24,538 female nurses from the Danish Nurse Cohort (age > 44 years) as the first hospital contact between baseline (1993 or 1999) and 2015. We estimated residential annual mean concentrations of particulate matter with diameter < 2·5 µm (PM2·5) since 1990 and nitrogen dioxide (NO2) since 1970 by the Danish DEHM/UBM/AirGIS modeling system, and road traffic noise (Lden) since 1970 by the Nord2000 model. Time-varying Cox regression models were applied to assess the associations of air pollution and noise with COPD incidence. Findings: 977 nurses developed COPD during 18·6 years’ mean follow-up. We observed associations with COPD for all three exposures with hazard ratios (HRs) and 95% confidence intervals (CIs) of 1·19 (1·01, 1·41) per 6·26 µg/m3 for PM2·5, 1·13 (1·05, 1·20) per 8·19 µg/m3 for NO2, and 1·15 (1·06, 1·25) per 10 dB for Lden. Associations with NO2 and Lden attenuated slightly after adjustment for each other, but were robust to adjustment for PM2·5. Associations with PM2·5 were attenuated to null after adjustment for either NO2 or Lden. Interpretation: Long-term exposures to traffic-related NO2 and road traffic noise were associated with COPD, independent of each other. Funding Statement: Danish Council for Independent Research, Novo Nordisk Foundation, and China Scholarship Council. Funding Statement: This work was supported by the Danish Council for Independent Research [DFF-4183-00353], the Novo Nordisk Foundation Challenge Programme [NNF17OC0027812], and the China Scholarship Council [No. 201806010406]. Declaration of Interests: We declare that we have no conflicts of interest. Ethics Approval Statement: The establishment of the cohort was approved by the Scientific and Ethical Committee of Copenhagen and Frederiksberg Municipalities, and the Danish Data Protection Agency.

Background: Growing evidence supports the concept that traffic noise exposure leads to long-term health complications other than annoyance, including cardiovascular disease. Similar effects may be expected from wind turbine noise exposure, but evidence is sparse. Here, we examined the association between long-term exposure to wind turbine noise and incidence of myocardial infarction (MI). Methods: We used the Danish Nurse Cohort with 28,731 female nurses and obtained data on incidence of MI in the Danish National Patient and Causes of Death Registries until ultimo 2013. Wind turbine noise levels at residential addresses between 1982 and 2013 were estimated using the Nord2000 noise propagation model, as the annual means of a weighted 24-hour average (Lden) at the most exposed façade. Time-varying Cox proportional hazard regression was used to examine the association between the 11-, 5- and 1-year rolling means prior to MI diagnosis of wind turbine noise levels and MI incidence. Results: Of 23,994 nurses free of MI at cohort baseline, 686 developed MI by end of follow-up in 2013. At the cohort baseline (1993 or 1999), 10.4% nurses were exposed to wind turbine noise (≥1 turbine within a 6000-m radius of the residence) and 13.3% in 2013. Mean baseline residential noise levels among exposed nurses were 26.3 dB, higher in those who developed MI (26.6 dB) than among those who didn't develop MI (26.3 dB). We found no association between wind turbine noise and MI incidence: adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) comparing nurses with 11-years mean residential noise levels of 29.9 dB, to non-exposed nurses were 0.89 (0.64–1.25), 1.20 (0.82–1.77), 1.38 (0.95–2.01), and 0.88 (0.53–1.28), respectively. Corresponding HR (95% CI) for the linear association between 11-year mean levels of wind turbine noise (per 10 dB increase) with MI incidence was 0.99 (0.77–1.28). Similar associations were observed when considering the 5- and 1-year running means, and with no evidence of dose-response. Conclusions: The results of this comprehensive cohort study lend little support to a causal association between outdoor long-term wind-turbine noise exposure and MI. However, there were only few cases in the highest exposure groups and our findings need reproduction.

Background and purpose - Obesity is a rising issue worldwide and growing evidence supports poor outcome amongst obese patients following total knee arthroplasty (TKA). Using nationwide registries we investigated the association between bodyweight and risk of revision of primary TKA. Patients and methods - All primary TKA performed during 1997-2015, weight at time of primary TKA and subsequent TKA revisions were identified in the Danish Knee Arthroplasty Register (DKR). Data on comorbidities and a priori selected confounding variables were collected from nationwide registries. The association between weight and 1st time TKA revision was calculated as both crude and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) using Cox regression. Results - Of 67,810 identified primary TKAs, 4.8% were revised within a median follow-up time of 5.4 years. No association between weight and risk of any revision in patients aged 18-54 and 55-70 years was found. Increased risk of any revision was seen in patients >70 years, 80-89 kg (aHR =1.5, CI 1.2-1.8), 90-99 kg (aHR =1.7, CI 1.3-2.1) and patients >99 kg (aHR =1.6, CI 1.3-2.1), as well as those weighing 45-60 kg (aHR =1.4, CI 1.1-1.9) compared with same aged patients weighing 70-79 kg. Interpretation - We found a complex association between weight and knee arthroplasty survival. There was an increased risk of any revision in patients older than 70 years of age weighing 80 kg. Patients aged 18-55 years weighing 60-69 kg had a lower risk of revision compared with all other weight groups, whereas weight was not found to affect risk of any revision in patients aged 55-70 years.

Background: Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world. Involvement of organochlorines has been proposed in disease etiology. No study has investigated organochlorine exposure in relation to survival after a NHL diagnosis. Methods: In a survivor cohort consisting of 232 NHL cases from the Danish Diet, Cancer and Health cohort, we examined the association between adipose tissue organochlorine concentrations [polychlorinated biphenyls (PCBs) and pesticides] and subsequent survival, using Cox proportional hazards models. Results: We found no statistically significant association between organochlorine concentrations and subsequent survival. If anything, there was a nonsignificant tendency toward an inverse association with PCBs, but not pesticides. Conclusions: In conclusion, the current study does not support an increased risk of death among NHL patients with high tissue concentrations of organochlorines. Impact: This is the first study to investigate adipose organochlorine concentrations and survival after a NHL diagnosis. Cancer Epidemiol Biomarkers Prev; 27(2); 224–6. ©2017 AACR.

Background Epidemiological studies suggest that road traffic noise increases the risk of stroke. Similar effects may be expected from wind turbine noise ( WTN ) exposure, but epidemiological evidence is lacking. The present study investigated the association between long‐term exposure to WTN and the risk for stroke. Methods and Results First‐ever stroke in 28 731 female nurses in the Danish Nurse Cohort was identified in the Danish National Patient register until the end of 2013. WTN , traffic noise, and air pollution exposures were estimated for all historic and present residential addresses between 1982 and 2013. Time‐varying Cox proportional hazard regression was used to examine the associations between the 11‐, 5‐, and 1‐year rolling means of WTN levels and stroke incidence. Of 23 912 nurses free of stroke at the cohort baseline, 1097 nurses developed stroke by the end of follow‐up. At the cohort baseline, 10.3% of nurses were exposed to WTN (≥1 turbine within a 6000‐meter radius of the residence) and 13.3% in 2013. Mean baseline residential noise levels among exposed nurses were 26.3 dB (A). No association between long‐term WTN exposure and stroke incidence was found. The adjusted hazard ratios and 95% CIs for the 11‐, 5‐, and 1‐year running mean residential WTN exposures preceding stroke diagnosis, comparing nurses with residential WTN levels above and below 20 dB (A) were 1.09 (0.90–1.31), 1.08 (0.89–1.31) and 1.08 (0.89–1.32), respectively. Conclusions This comprehensive cohort study lends no support to an association between long‐term WTN exposure and stroke risk.

STUDY QUESTION What is the risk of death among men with oligospermia, unspecified male factor and azoospermia in the years following fertility treatment? SUMMARY ANSWER No significantly elevated risk was observed among men with oligospermia and unspecified male factor, while an increased risk was found among men with azoospermia. WHAT IS KNOWN ALREADY Previous studies have shown associations between male factor infertility and risk of death, but these studies have relied on internal reference groups and the risk of death according to type of male infertility is not well characterized. STUDY DESIGN, SIZE, DURATION In this prospective record-linkage cohort study, we identified men who had undergone medically assisted reproduction (MAR) between 1994 and 2015. Data was linked to the Danish causes of death register and sociodemographic registers through personal identification numbers assigned to all Danish citizens at birth. PARTICIPANTS/MATERIALS, SETTING, METHODS Men that had undergone MAR in Denmark (MAR Cohort; n = 64 563) were identified from the Danish IVF register, which includes data on whether infertility was due to male factor. For each man in the MAR cohort, five age-matched men who became fathers without fertility treatment were selected from the general population (non-MAR fathers; n = 322 108). Men that could not adequately be tracked in the Danish CPR register (n = 1259) and those that were censored prior to study entry (n = 993) were excluded, leaving a final population of 384 419 men. Risk of death was calculated by Cox regression analysis with age as an underlying timeline and adjustments for educational attainment, civil status and year of study entry. The risk of death was compared among men with and without male factor infertility identified from the IVF register (internal comparisons) as well as to the non-MAR fathers (external comparison). MAIN RESULTS AND THE ROLE OF CHANCE The risk of death between the MAR cohort (all men, regardless of infertility) and the non-MAR fathers was comparable [hazard ratio (HR), 1.07; 95% CI, 0.98–1.15]. When the MAR cohort was limited to infertile men, these men were at increased risk of death [HR, 1.27; 95% CI, 1.12–1.44]. However, when stratified by type of male factor infertility, men with azoospermia had the highest risk of death, which persisted when in both the internal [HR, 2.30; 95% CI, 1.54–3.41] and external comparison [HR, 3.32; 95% CI, 2.02–5.40]. No significantly elevated risk of death was observed among men with oligospermia [HR, 1.14; 95% CI, 0.87–1.50] and unspecified male factor [HR, 1.10; 95% CI, 0.75–1.61] compared with the non-MAR fathers. The same trends were observed for the internal comparison. LIMITATIONS, REASONS FOR CAUTION Duration of the follow-up was limited and there is limited generalizability to infertile men who do not seek fertility treatment. WIDER IMPLICATIONS OF THE FINDINGS Using national health registers, we found an increased risk of death among azoospermic men while no increased risk was found among men with other types of infertility. For the azoospermic men, further insight into causal pathways is needed to identify options for monitoring and prevention. STUDY FUNDING/COMPETING INTEREST(S) This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. C.G.’s research stay at Stanford was funded by grants from the University of Copenhagen, Kong Christian den Tiendes Fond, Torben og Alice Frimodt Fond and Julie Von Müllen Fond. M.E. is an advisor for Sandstone and Dadi. All other authors declare no conflict of interests. TRIAL REGISTRATION NUMBER Not relevant.

Evidence on the association between road traffic noise and diabetes risk is sparse and inconsistent with respect to how confounding by air pollution was treated.In this study, we aimed to examine whether long-term exposure to road traffic noise over 25 years is associated with incidence of diabetes, independent of air pollution.A total of 28,731 female nurses from the Danish Nurse cohort ([Formula: see text] at recruitment in 1993 or 1999) were linked to the Danish National Diabetes Register with information on incidence of diabetes from 1995 until 2013. The annual mean weighted levels of 24-h average road traffic noise ([Formula: see text]) at nurses' residences from 1970 until 2013 were estimated with the Nord2000 method and annual mean levels of particulate matter (PM) with diameter [Formula: see text] and [Formula: see text] ([Formula: see text] and [Formula: see text]), nitrogen dioxide ([Formula: see text]), and nitrogen oxide ([Formula: see text]) with the Danish AirGIS modeling system. Cox proportional hazards regression models were used to examine the association between residential [Formula: see text] in four different exposure windows (1-, 5-, 10-, and 25-years) and the incidence of diabetes, adjusted for lifestyle factors and air pollutants.Of 23,762 nurses free of diabetes at the cohort baseline, 1,158 developed diabetes during a mean follow-up of 15.2 years. We found weak positive associations between 5-y mean exposure to [Formula: see text] (per [Formula: see text] increase) and diabetes incidence in a crude model [hazard ratio (HR): 1.07; 95% confidence interval (CI): 0.99, 1.12], which attenuated in a model adjusted for lifestyle factors (HR:1.04; 95% CI: 0.97, 1.12), and reached unity after additional adjustment for [Formula: see text] (HR: 0.99; 0.91, 1.08). In analyses by level of urbanization, we found a positive association between noise and diabetes in urban areas (HR:1.27; 95% CI: 0.98, 1.63) that was unchanged after adjusting for [Formula: see text] (HR: 1.25; 95% CI: 0.97, 1.62), but we found no apparent association in provincial (HR: 1.02; 95% CI: 0.88, 1.18) or rural areas (HR: 0.97; 95% CI: 0.87, 1.08).In the nationwide cohort of Danish nurses 44 years of age and older, we found no association between long-term exposure to road traffic noise and diabetes incidence after adjustment for [Formula: see text] but found suggestive evidence of an association limited to urban areas. https://doi.org/10.1289/EHP4389.

Background: The potential health effects related to wind turbine noise (WTN) have received increased focus during the past decades, but evidence is sparse. We examined the association between long-term exposure to wind turbine noise and incidence of atrial fibrillation (AF). Methods: First ever hospital admission of AF amongst 28,731 female nurses in the Danish Nurse Cohort were identified in the Danish National Patient register until ultimo 2013. WTN levels at residential addresses between 1982 and 2013 were estimated using the Nord2000 noise propagation model, as the annual means of Lden, Lday, Levening and Lnight at the most exposed façade. Time-varying Cox proportional hazard regression models were used to examine the association between the 11-, 5- and 1-year rolling means of WTN levels and AF incidence. Results: 1430 nurses developed AF by end of follow-up in 2013. Mean (standard deviation) baseline residential noise levels amongst exposed nurses were 26.3 (6.7) dB and slightly higher in those who developed AF (27.3 (7.31) dB), than those who didn't (26.2 (6.6)). We observed a 30% statistically significant increased risk (95% CI: 1.05–1.61) of AF amongst nurses exposed to long-term (11-year running mean) WTN levels ≥20 dB(A) at night compared to nurses exposed to levels

Background: Studies have suggested that traffic noise is associated with markers of obesity. We investigated the association of exposure to road traffic noise with body mass index (BMI) and waist circumference in the Danish Nurse Cohort. Methods: We used data on 15,501 female nurses (aged >44 years) from the nationwide Danish Nurse Cohort who, in 1999, reported information on self-measured height, weight and waist circumference, together with information on socioeconomic status, lifestyle, work and health. Road traffic noise at the most exposed façade of the residence was estimated using Nord2000 as the annual mean of a weighted 24 h average (L den ). We used multiple linear regression models to examine associations of road traffic noise levels in 1999 (1-year mean) with BMI and waist circumference, adjusting for potential confounders, and evaluated effect-modification by degree of urbanization, air pollution levels, night shift work, job strain, sedative use, sleep aid use, and family history of obesity. Results: We did not observe associations between road traffic noise (per 10 dB increase in the 1-year mean L den ) and BMI (kg/m 2 ) (beta: 0.00; 95% confidence interval CI: −0.07, 0.07) or waist circumference (cm) (−0.09; −0.31, 0.13) in the fully adjusted model. We found significant effect modification of job strain and degree of urbanization on the associations between L den and both BMI and waist circumference. Job strained nurses were associated with a 0.41 BMI-point increase, (0.06–0.76) and a 1.00 cm increase in waist circumference (0.00–2.00). Nurses living in urban areas had a statistically significant positive association of L den with BMI (0.26; 0.11–0.42), whilst no association was found for nurses living in suburban and rural areas. Conclusion: Our results suggest that road traffic noise exposure in nurses with particular susceptibilities, such as those with job strain, or living in urban areas may lead to increased BMI, a marker of adiposity.

Study question Is exposure to gestational stress in the critical time window for the normal differentiation and growth of male reproductive tissue associated with male reproductive function in offspring in later life? Summary answer Exposure to stressful life events (SLEs) in early, but not late gestation, are associated with reduced adult male reproductive function, consistent with the hypothesis that events during early prenatal life programme adult male reproductive function. What is already known Animal studies suggest that gestational stress may impact on the reproductive function of male offspring, but human evidence is sparse. Study design, size, duration Using a prospective longitudinal cohort, we examined the association between number and type of maternal stressors during pregnancy in both early and late gestation and reproductive function in 643 male Generation 2 (offspring) at age 20 years. Mothers and their male Generation 2 (offspring) from The Raine Study participated. Mothers prospectively reported SLEs during pregnancy recorded at gestational weeks 18 and 34 using a standardized 10-point questionnaire. Participants/materials, setting, methods The 643 male Generation 2 (offspring) underwent testicular ultrasound examination and semen analysis and provided serum for reproductive hormone analysis. Multivariate linear regression analysis was used to examine associations. Main results and role of chance Of 643 recruited males, 407 (63%) were exposed to at least one SLE in early gestation. Fewer SLEs were reported in late gestation (n = 343, 53%). Maternal SLE exposure in early gestation was negatively associated with total sperm count (β = -0.31, 95% CI -0.58; -0.03), number of progressive motile sperm (β = -0.15, 95% CI -0.31; 0.00) and morning serum testosterone concentration (β = -0.04, 95% CI -0.09; -0.00). No similar effects of maternal SLE exposure in late pregnancy were detected. The large sample size and an objective detailed direct assessment of adult male reproductive function with strict external quality control for sperm quality, as well as detailed prospectively collected information on prenatal SLEs in two distinct time windows of pregnancy reported by the women in early and late gestation along with other risk factors, imply minimal possibility of recall, information bias and selection bias. When assessing our results, we adjusted for a priori chosen confounders, but residual confounding or confounding by factors unbeknown to us cannot be ruled out. Limitations, reasons for caution It is not possible to measure how SLEs impacted differently on the mother's experience or perception of stress. Resilience (coping) gradients may alter cortisol levels and thus modify the associations we observed and the mothers' own perception of stress severity may have provided a more precise estimate of her exposure. Wider implications of the findings Our findings suggest that exposure to SLEs in early, but not late gestation, are associated with reduced adult male reproductive function. Improved support for women with exposure to SLEs during pregnancy, particularly during the first trimester, may improve the reproductive health of their male offspring in later life. Intervention studies of improved pregnancy support could provide more insight into this association and more information is needed about the potential specific epigenetic mechanisms underlying this association. Study funding/competing interest(s) The male fertility sub-study was funded by NHMRC Grant 634 457. The core management of the Raine Study is funded by University of Western Australia, Curtin University, Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, The University of Notre Dame Australia and Raine Medical Research foundation. Dr Brauner's salary was supported by Laege Sofus Carl Emil Friis og Hustru Olga Doris Friis foundation in Denmark. All authors declare no competing interests. Trial registration number N/A.

Early studies suggesting physiological responses (increased blood pressure and altered heart muscle) to noise in animal experiments1,2 have set the scene for a surge in epidemiological studies investigating the effects of noise in humans,3 particularly with a focus on coronary syndrome including myocardial infarction (MI). The World Health Organization (WHO) has concluded that there is convincing evidence of increased risk of MI associated with road traffic noise in Europe4 based on recent reviews,5,6 yet several uncertainties remain. While the majority of prospective cohort studies observed an increased risk of MI associated with long-term exposure to road traffic noise,7–10 some reported no associations11,12 (Supplementary Material, Table S1; http://links.lww.com/EE/A134). Furthermore, the WHO report concluded that the association between road traffic noise and MI is observed only above a threshold of 53 dB, with no adverse effects below this value.4,13,14 However, the literature on road traffic noise and MI generally lacks systematic investigation of the shape of the dose-response curve and identification of possible threshold, and presents effect estimates for the number of different thresholds for categorized noise exposure, which seem to be arbitrarily selected by authors. For example, the following thresholds or reference levels have been suggested as associated with symptoms, incidence, or mortality in the literature: 40 dB,15 45 dB,7,11 49-50 dB,16,17 55 dB,10,12 or 60 dB18,19 (Supplementary Material, Table S1; http://links.lww.com/EE/A134). While the WHO and Danish Environment Protection Agency provided guidelines for road traffic noise to prevent noise-induced diseases, regulation on road traffic noise is absent. Road traffic is a major emission source of both air pollution and road traffic noise. Therefore, traffic-related air pollutants, including nitrogen dioxide (NO2) and nitrogen oxides, have been assessed in some studies as confounding factors or effect modifiers of the association between road traffic noise and MI.8–12,16,17,20 Particulate matter with a diameter

Key Points Question Have the annual incidence rates of central precocious puberty (CPP) and normal variant puberty (ie, premature thelarche and premature adrenarche) increased during the past 20 years in Denmark? Findings This cohort study of 8596 children in Denmark who were diagnosed with CPP, premature thelarche, or premature adrenarche between 1998 and 2017 found that the annual incidence of CPP and normal variant puberty has increased substantially in Denmark during the last 20 years. Meaning The findings of this study have implications for short-term and long-term health and potentially for the international classification of the reference age at puberty., This cohort study provides epidemiological data on the 20-year secular trend in the incidence rates of central precocious puberty and normal variant puberty among children in Denmark., Importance There has been a worldwide secular trend toward earlier onset of puberty in the general population. However, it remains uncertain if these changes are paralleled with increased incidence of central precocious puberty (CPP) and normal variant puberty (ie, premature thelarche [PT] and premature adrenarche [PA]) because epidemiological evidence on the time trends in the incidence of these puberty disorders is scarce. Objective To provide valid epidemiological data on the 20-year secular trend in the incidence rates of CPP and normal variant puberty. Design, Setting, and Participants This population-based, 20-year cohort study used national registry data for all youth in Denmark registered with an incident diagnosis of CPP, PT, or PA in the Danish National Patient Registry from 1998 to 2017 (N = 8596) using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). We applied the maximum diagnostic age limit for precocious puberty (ie, onset of puberty before age 8 years for girls and age 9 years for boys) with and without a 12-month lag to address time from first contact to final registration in the Danish National Patient Registry. Data analysis was conducted in 2019. Exposures Diagnosis of CPP, PT, or PA. Main Outcomes and Measures The age-specific and sex-specific incidence rates of first-time diagnosis of CPP, PT, and PA were estimated using data from the Danish National Patient Registry from 1998 to 2017, and information about the total number of children at risk within the same age groups and sex from Statistics Denmark. Incidences were stratified according to immigration group (Danish origin, first-generation immigrant, second-generation immigrant). Results Overall a total 8596 children (7770 [90.4%] girls; median [interquartile] age at diagnosis for boys, 8.0 [7.1-9.0] years; for girls, 8.0 [7.6-8.5] years) were registered with an incident diagnosis of CPP, PT, or PA, of whom 7391 (86.0%) had Danish origin (6671 [90.3%] girls), corresponding to 370 new cases in children with Danish origin per year. The 20-year mean annual incidence rates of CPP, PT, PA, and all 3 conditions per 10 000 girls with Danish origin were 9.2 (95% CI, 8.0 to 10.3), 1.1 (95% CI, 0.7 to 1.5), 1.3 (95% CI, 0.9 to 1.7), and 11.5 (95% CI, 10.3 to 12.8), respectively. For boys with Danish origin, the 20-year mean annual incidence rates per 10 000 boys were lower: 0.9 (95% CI, 0.6 to 1.2), 0.2 (95% CI, 0.1 to 0.4), and 1.1 (95% CI, 0.7 to 1.4) for CPP, PA, and the sum, respectively. There was a 6-fold increase in incidence for girls with Danish origin (from 2.6 per 10 000 to 14.6 per 10 000) and a 15-fold increase for boys with Danish origin (from 0.1 per 10 000 to 2.1 per 10 000). The 20-year mean incidence of CPP and PA among girls in the first-generation and second-generation immigrant groups were greater than that of girls with Danish origin. The incidence rate for CPP per 10 000 girls in the first-generation and second-generation groups were 13.7 (95% CI, 9.3 to 18.2) and 14.2 (95% CI, 4.6 to 23.9), respectively; the incidence rate for PA per 10 000 girls in the first-generation and second-generation groups were 2.0 (95% CI, 0.3 to 3.6) and 1.5 (95% CI, −1.6 to 4.7), respectively. No differences associated with immigration status were observed among boys. Conclusions and Relevance Our findings suggest that the annual incidence of CPP and normal variant puberty has substantially increased in Denmark during the last 20 years. These findings have implications for short-term and long-term health and potentially for the international classification of the reference age of puberty.

Background Exposure to road traffic noise was associated with increased risk of estrogen receptor (ER)-negative (ER-) breast cancer in a previous cohort study, but not with overall or ER-positive (ER+) breast cancer, or breast cancer prognosis. We examined the association between long-term exposure to road traffic noise and incidence of breast cancer, overall and by ER and progesterone receptor (PR) status. Methods We used the data from a nationwide Danish Nurse Cohort on 22,466 female nurses (age > 44 years) who at recruitment in 1993 or 1999 reported information on breast cancer risk factors. We obtained data on the incidence of breast cancer from the Danish Cancer Registry, and on breast cancer subtypes by ER and PR status from the Danish Breast Cancer Cooperative Group, up to 31 December 2012. Road traffic noise levels at the nurses’ residences were estimated by the Nord2000 method between 1970 and 2013 as annual means of a weighted 24 h average (Lden) at the most exposed facade. We used time-varying Cox regression to analyze the associations between the 24-year, 10-year, and 1-year mean of Lden and breast cancer, separately for total breast cancer and by ER and PR status. Results Of the 22,466 women, 1193 developed breast cancer in total during 353,775 person-years of follow up, of whom 611 had complete information on ER and PR status. For each 10 dB increase in 24-year mean noise levels at their residence, we found a statistically significant 10% (hazard ratio and 95% confidence interval 1.10; 1.00–1.20) increase in total breast cancer incidence and a 17% (1.17; 1.02–1.33) increase in analyses based on 611 breast cancer cases with complete ER and PR information. We found positive, statistically significant association between noise levels and ER+ (1.23; 1.06–1.43, N = 494) but not ER- (0.93; 0.70–1.25, N = 117) breast cancers, and a stronger association between noise levels and PR+ (1.21; 1.02–1.42, N = 393) than between noise levels and PR- (1.10; 0.89–1.37, N = 218) breast cancers. Association between noise and ER+ breast cancer was statistically significantly stronger in nurses working night shifts (3.36; 1.48–7.63) than in those not working at night (1.21; 1.02–1.43) (p value for interaction = 0.05). Conclusion Long-term exposure to road traffic noise may increase risk of ER+ breast cancer. Electronic supplementary material The online version of this article (10.1186/s13058-018-1047-2) contains supplementary material, which is available to authorized users.

Background: Exposure to air pollution has been linked to coronary heart disease, yet still evidence on PM2.5 and myocardial infarction (MI) incidence has been mixed. Here, we examined the associati...

Background/aim Exposure to road traffic noise has been linked to adverse health effects, including cardiovascular diseases (CVD), however, evidence is inconsistent. In this study we examined the association between long-term exposure to road traffic noise and incidence of myocardial infarction (MI). Methods We used the data from a nationwide Danish Nurse Cohort on 22 438 female nurses (age >44 years) who at recruitment in 1993 or 1999 reported information on CVD risk factors. We obtained data on incidence of MI from the Danish National Patient Register until end of 2014. Road traffic noise levels at the nurses’ residences between 1970 and 2014 were estimated using The Nord2000 as the annual mean of a weighted 24 hour average (Lden). We used time-varying Cox regression models to examine the association between 24-, 10-, and 1 year running mean of Lden and MI incidence, in a crude model (adjusted for age and time of cohort enrolment) and in a fully adjusted model (adjusted for age, enrolment year, physical activity, alcohol, smoking, marital status, fruit consumption and use of hormone therapy). Results Of the 22 438 women, 590 developed MI during a mean follow-up of 18.3 years. Residential road traffic noise levels ranged from 5–82.7 dB at the year of cohort baseline. We found no association between exposure to road traffic noise and MI in crude (hazard ratio; 95% confidence interval: 0.94; 0.83–1.05) or fully (0.92; 0.82–1.04) adjusted model, for each 10 dB increase in 24 year mean road traffic noise levels. Similar results were found with 10 year and 1 year exposure windows. We observed a possible trend of increased risk, although statistically non-significant, in nurses living in urban areas (1.29; 0.84–2.00), and none in those living in provincial (0.98; 0.77–1.23) or rural (0.91; 0.77–1.07) areas (p for interaction 0.38). Conclusion We found no association between long-term exposure to road traffic noise and MI in the total population of Danish nurses. We present novel finding that nurses living in urban areas may be more susceptible to the effects of exposure to road traffic noise with respect to MI.

Background/Aim: Well-established risk factors for diabetes include diet, body mass index and physical activity, all of which are individually modifiable factors. However, recent evidence suggests t...

Background. Epidemiological evidence on the association between ambient air pollution and brain tumor risk is sparse and inconsistent. Methods. In 12 cohorts from 6 European countries, individual estimates of annual mean air pollution levels at the baseline residence were estimated by standardized land-use regression models developed within the ESCAPE and TRANSPHORM projects: Particulate matter (PM) ≥2.5,≥10, and 2.5-10 FÊm in diameter (PM2.5, PM10, and PMcoarse), PM2.5 absorbance, nitrogen oxides (NO2 and NOx) and elemental composition of PM. We estimated cohort-specific associations of air pollutant concentrations and traffic intensity with total, malignant, and nonmalignant brain tumor, in separate Cox regression models, adjusting for risk factors, and pooled cohort-specific estimates using random-effects meta-analyses. Results. Of 282 194 subjects from 12 cohorts, 466 developed malignant brain tumors during 12 years of follow-up. Six of the cohorts also had data on nonmalignant brain tumor, where among 106 786 subjects, 366 developed brain tumor: 176 nonmalignant and 190 malignant. We found a positive, statistically nonsignificant association between malignant brain tumor and PM2.5 absorbance (hazard ratio and 95% CI: 1.67; 0.89.3.14 per 10.5/m3), and weak positive or null associations with the other pollutants. Hazard ratio for PM2.5 absorbance (1.01; 0.38.2.71 per 10-5/m3) and all other pollutants were lower for nonmalignant than for malignant brain tumors. Conclusion. We found suggestive evidence of an association between long-term exposure to PM2.5 absorbance indicating traffic-related air pollution and malignant brain tumors, and no association with overall or nonmalignant brain tumors. © 2018 The Author(s). Chemicals/CAS: nitric oxide, 10102-43-9; nitrogen dioxide, 10102-44-0

Background: Gender, possibly due to the influence of gonadal hormones, is presumed to play a role in the pathogenesis of multiple sclerosis (MS), but no studies have evaluated whether male infertility is associated with MS. Objective: To study the association between male factor infertility and prevalent as well as incident MS. Method: Our cohort was established by linkage of the Danish National in vitro fertilization (IVF) registry to The Danish Multiple Sclerosis Registry and consisted of 51,063 men whose partners had undergone fertility treatment in all public and private fertility clinics in Denmark between 1994 and 2015. Results: With a median age of 34 years at baseline, 24,011 men were diagnosed with male factor infertility and 27,052 did not have male factor infertility and made up the reference group. Men diagnosed with male factor infertility had a higher risk of prevalent (odds ratio (OR) = 1.61, 95% confidence interval (95% CI) 1.04–2.51) and incident MS (hazard ratio (HR) = 1.28, 95% CI 0.76–2.17) when compared to the reference group. Conclusion: This nationwide cohort study has shown, for the first time, an association between male infertility and MS which may be due to underlying common etiologies such as hypogonadism, shared genetics, or a joint autoimmune component.

Introduction: Adult-onset asthma may be caused or aggravated by occupational exposures.. Two new nationwide databases provide an opportunity to access asthma prevalence and incidence across jobs. Objectives: The objective of the study is to map the nationwide yearly prevalence and incidence of asthma between 2000 and 2016 according to job title and specific exposures. Emphasis will be on last held job before debut of asthma as well as on effects of job change on asthma prognosis. Methods: The Danish National Database for Asthma include all asthma patients in Denmark based on the prescription of medicine for obstructive lung diseases (ATC code R03) or a diagnostic code for asthma in the Danish Hospital Register, while DOC-X provides the occupational code (ISCO-88) for every year between 1970 and 2015. Other national registries provides demographic and social data. Age is restricted to 15-45 years. ISCO-codes will be collapsed into relevant groups, in which the prevalence and incidence of asthma are assessed. Job Exposure matrices (JEMs) relevant for asthma as well as exposure to dust in general will be applied. Results: The two databases are documented and active. Merging of the bases as well as the application of JEM is ongoing. In 2014 87,714 asthma cases (prevalence rate 3.9%) and 8,036 incident cases (361 per 100,000 persons) were included in the asthma database. More than 80% in this age group are economically active. Conclusion: The combination of nationwide high quality public databases about occupational activity and of asthma provides a unique opportunity to investigate the influence of work on the occurrence and worsening of the disease.

BACKGROUND: No scientific consensus has been reached on whether active tobacco smoking causes breast cancer. We examine the association between active smoking and breast cancer risk in Denmark, which has some of the highest smoking and breast cancer rates in women worldwide.METHODS: We used the data from a nationwide Danish Nurse Cohort on 21,867 female nurses (age > 44 years) who at recruitment in 1993 or 1999 reported information on smoking status, onset, duration, and intensity, as well as breast cancer risk factors. We obtained data on incidence of breast cancer from Danish Cancer Registry until 2013, and used Cox regression models to analyze the association between smoking and breast cancer.RESULTS: Of 21,831 women (mean age 53.2 years) 1162 developed breast cancer during 15.7 years of follow-up. 33.7% of nurses were current and 30.0% former smokers at cohort baseline. Compared to never smokers, we found increased risk of breast cancer of 18% in ever (hazard ratio and 95% confidence interval: 1.18; 1.04-1.34) and 27% in current (1.27; 1.11-1.46) smokers. We detected a dose-response relationship with smoking intensity with the highest breast cancer risk in women smoking >15 g/day (1.31; 1.11-1.56) or >20 pack-years (1.32; 1.12-1.55). Parous women who smoked heavily (>10 pack-years) before first childbirth had the highest risk of breast cancer (1.58; 1.20-2.10). Association between smoking and breast cancer was not modified by menopausal status, obesity, alcohol or hormone therapy use, and seemed to be limited to the estrogen receptor positive breast cancer subtype.CONCLUSIONS: Active smoking increases risk of breast cancer, with smoking before first birth being the most relevant exposure window.

The association between male infertility and increased risk of certain cancers is well studied. Less is known about the long-term risk of nonmalignant diseases in men with decreased fertility. A systemic literature review was performed on the epidemiologic evidence of male infertility as a precursor for increased risk of diabetes, cardiovascular diseases, and all-cause mortality. PubMed and Embase were searched from January 1, 1980, to September 1, 2016, to identify epidemiological studies reporting associations between male infertility and the outcomes of interest. Animal studies, case reports, reviews, studies not providing an accurate reference group, and studies including infertility due to vasectomy or malignancy were excluded. The literature search resulted in 2,485 references among which we identified seven articles fulfilling the eligibility criteria. Of these, four articles were prospective (three on risk of mortality, one on risk of chronic diseases) and three were cross-sectional relating male infertility to the Charlson Comorbidity Index. The current epidemiological evidence is compatible with an association between male infertility and risk of chronic disease and mortality, but the small number of prospective studies and insufficient adjustment of confounders preclude strong statements about male infertility as precursor of these outcomes.

STUDY QUESTION: Is male factor infertility associated with an increased risk of developing diabetes?SUMMARY ANSWER: The study provides evidence that male factor infertility may predict later occurrence of diabetes mellitus with the risk being related to the severity of the underlying fertility problem.WHAT IS KNOWN ALREADY: Previous cross-sectional studies have shown an increased prevalence of comorbidities among infertile men when compared to controls.STUDY DESIGN, SIZE, DURATION: In this prospective cohort study, 39 516 men who had since 1994 undergone fertility treatment with their female partner were identified from the Danish national IVF register, which includes data on assumed cause of couple infertility (male/female factor, mixed and unexplained infertility) and type of fertility treatment. With a median follow-up time of 5.6 years, each man was followed for diabetes occurrence from enrollment until 31 December 2012 using the National Diabetes Register (NDR). Men with a history of diabetes prior to their fertility diagnosis were excluded. Hazard ratios (HR) were estimated by Cox proportional hazard models with age as the underlying time scale. In addition to analyzing the data for the entire IVF registration period (1994-2012), separate analyses were performed for men identified from the first (1994-2005) and second (2006-2012) IVF registration period owing to heterogeneity in the reporting of male factor infertility in these two time periods, because the reason for male factor infertility was not available from the first register.PARTICIPANTS/MATERIALS, SETTING, METHODS: Male factor infertility was identified from the variable 'yes' or 'no' from the first IVF register and through a diagnosis code (e.g. oligospermia, azoospermia) from the second IVF register. The reference group was men with male factor infertility (='no') and those with normal semen quality or sterilized men. Of the included men, 18 499 (46.8%) had male factor infertility and 21 017 (53.2%) made up the reference group.MAIN RESULTS AND THE ROLE OF CHANCE: A total of 651 (1.6%) diabetes cases were identified during the follow-up period. The adjusted HR's for diabetes risk among men with male factor infertility when compared to the reference group were HR = 1.08 (95% CI: 0.89, 1.31) and HR = 1.45 (95% CI: 1.06, 1.97) for the first and second IVF registration period, respectively. When assessing the effects of individual causes of male factor infertility, the adjusted HR's for men with oligospermia, azoospermia and aspermia were HR = 1.44 (95% CI: 1.01, 2.06), HR = 2.10 (95% 1.25, 3.56) and HR = 3.20 (95% CI 1.00, 10.31), respectively.LIMITATIONS, REASONS FOR CAUTION: We found no increased risk among men identified from the first IVF register, which may be related to exposure misclassification as the reason for male factor infertility was not available from this time period. The NDR does not distinguish between type 1 and type 2 diabetes.WIDER IMPLICATIONS OF THE FINDINGS: These findings support previous studies that a man's reproductive and somatic health are closely intertwined and highlight the importance for further monitoring of these men. Further, implementation of diabetes screening may be especially relevant among aspermic and azoospermic men.STUDY FUNDING/COMPETING INTERESTS: This article is part of the ReproUnion collaborative study, co-financed by the European Union, Intereg V Öresund-Kattegat-Skagerrak. None of the authors declare any conflict of interest.TRIAL REGISTRATION NUMBER: None.

The use of biological agents against enemies has persisted throughout centuries and the use of Anthrax spores on civilians in USA in 2001, suggests a growing worldwide threat. Safeguarding spaces under attack requires rapid detection and identification. Bio-protect is a project supported by the European Commission, with the concept of developing a fast-alert, mobile, easy-to-use device to detect and identify airborne pathogens. It is important that biosensors are both selective and sensitive as interference with or response to benign indoor aerosols in their typical concentrations can create panic. The purpose of this paper is to provide background information on typical levels of benign indoor aerosols. We performed a literature search to identify relevant original studies reporting indoor aerosol concentrations in areas we considered could be targeted by malicious attacks of bioterrorism including assembly spaces as well as the transport sector. We identified 95 eligible studies representing different seasons and geographical and climatic regions. Levels of indoor aerosols ranged over several orders of magnitude and were mostly affected by indoor human activities and population density, outdoor air levels and ventilation type. Outdoor variables most important for non-bioaerosols were proximity to major roads and composition of the vehicle fleet, whilst for bioaerosols season and geography were the most important. Selectivity and sensitivity issues are very important in designing and manufacturing biosensors. The ranges of the typical indoor aerosols presented in this study can be used as a reference in designing biosensors used for improvement of public security.