Subanesthetic S-ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats.

Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast-acting antidepressant S-ketamine, an N-methyl-D-aspartate receptor antagonist, provides a new approach for treatment-resistant patients. However, knowledge of S-ketamine's mechanism of action is still being established. Depressed human subjects have lower striatal dopamine transporter (DAT) availability compared to healthy controls. Rodent studies report increased striatal dopamine concentration in response to acute ketamine administration. In vivo [18F]FE-PE2I ([18F]-(E)-N-(3-iodoprop-2-enyl)-2ß-carbofluoroethoxy-3ß-(4'-methyl-phenyl) nortropane) positron emission tomography (PET) imaging of the DAT has not previously been applied to assess the effect of acute subanesthetic S-ketamine administration on DAT availability. We applied translational in vivo [18F]FE-PE2I PET imaging of the DAT in healthy female rats to evaluate whether an acute subanesthetic intraperitoneal dose of 15 mg/kg S-ketamine alters DAT availability. We also performed [3H]GBR-12935 autoradiography on postmortem brain sections. We found no effect of acute S-ketamine administration on striatal DAT binding using [18F]FE-PE2I PET or [3H]GBR-12935 autoradiography. This negative result does not support the hypothesis that DAT changes are associated with S-ketamine's rapid antidepressant effects, but additional studies are warranted.

Exposure to long-term source-specific transportation noise and incident breast cancer: A pooled study of eight Nordic cohorts.

BACKGROUND: Environmental noise is an important environmental exposure that can affect health. An association between transportation noise and breast cancer incidence has been suggested, although current evidence is limited. We investigated the pooled association between long-term exposure to transportation noise and breast cancer incidence. METHODS: Pooled data from eight Nordic cohorts provided a study population of 111,492 women. Road, railway, and aircraft noise were modelled at residential addresses. Breast cancer incidence (all, estrogen receptor (ER) positive, and ER negative) was derived from cancer registries. Hazard ratios (HR) were estimated using Cox Proportional Hazards Models, adjusting main models for sociodemographic and lifestyle variables together with long-term exposure to air pollution. RESULTS: A total of 93,859 women were included in the analyses, of whom 5,875 developed breast cancer. The median (5th-95th percentile) 5-year residential road traffic noise was 54.8 (40.0-67.8) dB Lden, and among those exposed, the median railway noise was 51.0 (41.2-65.8) dB Lden. We observed a pooled HR for breast cancer (95 % confidence interval (CI)) of 1.03 (0.99-1.06) per 10 dB increase in 5-year mean exposure to road traffic noise, and 1.03 (95 % CI: 0.96-1.11) for railway noise, after adjustment for lifestyle and sociodemographic covariates. HRs remained unchanged in analyses with further adjustment for PM2.5 and attenuated when adjusted for NO2 (HRs from 1.02 to 1.01), in analyses using the same sample. For aircraft noise, no association was observed. The associations did not vary by ER status for any noise source. In analyses using <60 dB as a cutoff, we found HRs of 1.08 (0.99-1.18) for road traffic and 1.19 (0.95-1.49) for railway noise. CONCLUSIONS: We found weak associations between road and railway noise and breast cancer risk. More high-quality prospective studies are needed, particularly among those exposed to railway and aircraft noise before conclusions regarding noise as a risk factor for breast cancer can be made.

Preclinical Imaging Studies: Protocols, Preparation, Anesthesia, and Animal Care.

Today preclinical PET imaging connects laboratory research with clinical applications. Here PET clearly bridges the gap, as nearly identical imaging protocols can be applied to both animal and humans. However, some hurdles exist and researchers must be careful, partly because the animals are usually anesthetized during the scans, while human volunteers are awake. This review is based on our own experiences of some of the most important pitfalls and how to overcome them. This includes how studies should be designed, how to select the right anesthesia and monitoring. The choice of anesthesia is quite crucial, as it may have a greater influence on the results than the effect of the tested procedures. Monitoring is necessary, as the animals cannot fully maintain homeostasis during anesthesia, and reliable results are dependent on a stable physiology. Additionally, it is important to note that rodents, in particular, are prone to rapidly becoming hypothermic. Thus, the selection of an appropriate anesthetic and monitoring protocol is crucial for both obtaining accurate results and ensuring animal welfare. Prior to imaging, catheters for tracer administration and, if necessary, blood sampling should be implanted. The administration of tracers should be done in a manner that minimizes interference with the scans, and the same applies to any serial blood sampling. The limited blood volume and organ size of rodents should also be taken into consideration when planning experiments. Finally, if the animal needs to be awakened after the scan, proper care must be taken to ensure their welfare.

Long-term exposure to traffic noise and risk of incident colon cancer: A pooled study of eleven Nordic cohorts.

Background Colon cancer incidence is rising globally, and factors pertaining to urbanization have been proposed involved in this development. Traffic noise may increase colon cancer risk by causing sleep disturbance and stress, thereby inducing known colon cancer risk-factors, e.g. obesity, diabetes, physical inactivity, and alcohol consumption, but few studies have examined this. Objectives The objective of this study was to investigate the association between traffic noise and colon cancer (all, proximal, distal) in a pooled population of 11 Nordic cohorts, totaling 155,203 persons. Methods We identified residential address history and estimated road, railway, and aircraft noise, as well as air pollution, for all addresses, using similar exposure models across cohorts. Colon cancer cases were identified through national registries. We analyzed data using Cox Proportional Hazards Models, adjusting main models for harmonized sociodemographic and lifestyle data. Results During follow-up (median 18.8 years), 2757 colon cancer cases developed. We found a hazard ratio (HR) of 1.05 (95% confidence interval (CI): 0.99-1.10) per 10-dB higher 5-year mean time-weighted road traffic noise. In sub-type analyses, the association seemed confined to distal colon cancer: HR 1.06 (95% CI: 0.98-1.14). Railway and aircraft noise was not associated with colon cancer, albeit there was some indication in sub-type analyses that railway noise may also be associated with distal colon cancer. In interaction-analyses, the association between road traffic noise and colon cancer was strongest among obese persons and those with high NO2-exposure. Discussion A prominent study strength is the large population with harmonized data across eleven cohorts, and the complete address-history during follow-up. However, each cohort estimated noise independently, and only at the most exposed façade, which may introduce exposure misclassification. Despite this, the results of this pooled study suggest that traffic noise may be a risk factor for colon cancer, especially of distal origin.

Long-Term Exposure to Transportation Noise and Ischemic Heart Disease: A Pooled Analysis of Nine Scandinavian Cohorts.

BACKGROUND: Transportation noise may induce cardiovascular disease, but the public health implications are unclear. OBJECTIVES: The study aimed to assess exposure-response relationships for different transportation noise sources and ischemic heart disease (IHD), including subtypes. METHODS: Pooled analyses were performed of nine cohorts from Denmark and Sweden, together including 132,801 subjects. Time-weighted long-term exposure to road, railway, and aircraft noise, as well as air pollution, was estimated based on residential histories. Hazard ratios (HRs) were calculated using Cox proportional hazards models following adjustment for lifestyle and socioeconomic risk factors. RESULTS: A total of 22,459 incident cases of IHD were identified during follow-up from national patient and mortality registers, including 7,682 cases of myocardial infarction. The adjusted HR for IHD was 1.03 [95% confidence interval (CI) 1.00, 1.05] per 10 dB Lden for both road and railway noise exposure during 5 y prior to the event. Higher risks were indicated for IHD excluding angina pectoris cases, with HRs of 1.06 (95% CI: 1.03, 1.08) and 1.05 (95% CI: 1.01, 1.08) per 10 dB Lden for road and railway noise, respectively. Corresponding HRs for myocardial infarction were 1.02 (95% CI: 0.99, 1.05) and 1.04 (95% CI: 0.99, 1.08). Increased risks were observed for aircraft noise but without clear exposure-response relations. A threshold at around 55 dB Lden was suggested in the exposure-response relation for road traffic noise and IHD. DISCUSSION: Exposure to road, railway, and aircraft noise in the prior 5 y was associated with an increased risk of IHD, particularly after exclusion of angina pectoris cases, which are less well identified in the registries. https://doi.org/10.1289/EHP10745.

How do reproductive history and anthropometry in midlife relate to later risk of pelvic organ prolapse? A prospective cohort study.

INTRODUCTION AND HYPOTHESIS: The objective was to examine the association between reproductive and anthropometric factors and later risk of pelvic organ prolapse (POP). METHODS: We carried out a prospective cohort study including 11,114 female nurses > 44 years from the Danish Nurse Cohort. In 1993, the study population was recruited through the Danish Nurse Organization and self-reported data on age, height, weight, age at menarche, age at first birth and number of childbirths were obtained. POP diagnosis was obtained from the National Patient Registry. Risk of POP was estimated using COX regression and presented as hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Overall, 10% of the women received a diagnosis of POP within a median follow-up of 22 years. A 4% increase in risk of POP was seen for each increasing BMI (kg/m2) unit at baseline. Compared to women of normal weight, higher risks of POP were seen in overweight (HR 1.18: 1.02-1.36) and obese women (HR 1.33: 1.02-1.74), while underweight had a lower risk (HR 0.51: 0.27-0.95). Compared to women with one childbirth, women with no childbirths had a reduced risk of 57% while increased risks of 46%, 78% and 137% were observed in women with two, three and four childbirths. Women with menarche before the age of 12 tended to have a higher risk of POP as did women who were 30-33 years at their first childbirth. CONCLUSIONS: POP is a common health problem in women, and BMI and number of childbirths are strong predictors.

The long-term association between bilateral oophorectomy and depression: a prospective cohort study.

OBJECTIVE: Depression is a leading cause of disability globally and affects more women than men. Ovarian sex steroids are thought to modify depression risk in women and interventions such as bilateral oophorectomy that permanently change the sex steroid milieu may increase the risk of depression. This study aimed to investigate the associations between unilateral and bilateral oophorectomy and depression over a 25-year period (1993-2018) and whether this varied by age at oophorectomy or use of menopausal hormone therapy. METHODS: Twenty-five thousand one hundred eighty-eight nurses aged ≥45 years from the Danish Nurse Cohort were included. Nurses with depression prior to baseline were excluded. Poisson regression models, with log-transformed person-years as offset, were used to assess the associations between oophorectomy and incident depression. Nurses who retained their ovaries were the reference group. RESULTS: Compared with nurses with retained ovaries, bilateral oophorectomy was associated with a slightly higher rate of depression (rate ratio [RR], 1.08; 95% confidence interval [CI], 0.95-1.23), but without statistical significance. However, when stratified by age at oophorectomy, compared with nurses with retained ovaries, bilateral oophorectomy at age ≥51 years was associated with higher rates of depression (RR 1.16; 95% CI, 1.00-1.34), but not bilateral oophorectomy at age <51 years (RR 0.86; 95% CI, 0.69-1.07); P value for difference in estimates = 0.02. No association between unilateral oophorectomy and depression was observed. CONCLUSIONS: In this cohort of Danish female nurses, bilateral oophorectomy at age ≥51 years, but not at younger ages, was associated with a slightly higher rate of depression compared with those who retained their ovaries.

Oophorectomy and rate of dementia: a prospective cohort study.

OBJECTIVE: Globally, dementia disproportionally affects women, which is not fully explained by higher female longevity. Oophorectomy at any age leads to the permanent loss of ovarian sex steroids, potentially increasing the risk of dementia. We aimed to investigate the association between oophorectomy and dementia and whether this was conditional on age at oophorectomy, hysterectomy or use of hormone therapy (HT). METHODS: A prospective study of 24,851 female nurses from the Danish Nurse Cohort. Nurses were followed from age 60 years or entry into the cohort, whichever came last, until date of dementia, death, emigration or end of follow-up (December 31, 2018), whichever came first. Poisson regression models with log-transformed person-years as offset were used to estimate the associations. RESULTS: During 334,420 person-years of follow-up, 1,238 (5.0%) nurses developed dementia and 1,969 (7.9%)/ 1,016 (4.1%) contributed person-time after bilateral-/unilateral oophorectomy. In adjusted analyses, an 18% higher rate of dementia was observed following bilateral oophorectomy (aRR 1.18: 95% CI, 0.89-1.56) and 13% lower rate (aRR 0.87: 95% CI, 0.59-1.23) following unilateral oophorectomy compared to nurses who retained their ovaries. Similar effects were detected after stratification according to age at oophorectomy. No statistically significant modifying effects of hysterectomy or HT were detected (Pinteraction≥0.60). CONCLUSIONS: Bilateral, but not unilateral, oophorectomy was associated with an increased rate of incident dementia. We were unable to establish whether this association was conditional on hysterectomy or HT use. Although an increase in dementia after bilateral oophorectomy is biologically plausible, limited statistical power hampers the precision of the estimates.

Long-term exposure to road traffic noise and all-cause and cause-specific mortality: a Danish Nurse Cohort study.

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.

The association between general and central obesity and the risks of coronary heart disease in women with and without a familial predisposition to obesity: findings from the Danish Nurse Cohort.

Several studies show an increased risk of coronary heart disease (CHD) among people with obesity, but it is largely unknown whether this association also depends on a familial predisposition to obesity. This study examined if associations between Body Mass Index (BMI) or waist circumference (WC) and incident CHD differed among Danish female nurses with and without familial overweight and obesity. Analyses were based on data from the Danish Nurse Cohort (n = 20,701). Self-reported height, weight and self-measured WC were assessed in 1999, as was information on familial overweight/obesity, defined as having one or both parents with overweight/obesity. Information on the development of or death from CHD was collected from nationwide Danish registries in 2015. Analyses were based on Cox proportional hazard regression models adjusted for potential confounding factors. Both BMI and WC were directly associated with CHD risk, but we found no evidence of effect modification from familial predisposition to obesity. Hence a familial predisposition to obesity does not seem to influence the risk of CHD associated with general or central obesity.

Bilateral oophorectomy and rate of colorectal cancer: A prospective cohort study.

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.

Long-term exposure to road traffic noise and stroke incidence: a Danish Nurse Cohort study.

BACKGROUND: Road 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. METHODS: Twenty-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 < 2.5 µm and < 10 µm [PM2.5 and 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 Lden preceding 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 Lden thresholds. RESULTS: Of 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 Lden and 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 PM2.5 or 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 Lden and stroke. CONCLUSIONS: Long-term exposure to road traffic noise was suggestively positively associated with the risk of overall stroke, although not after adjusting for air pollution.

Effect of PEP flute self-care versus usual care in early covid-19: non-drug, open label, randomised controlled trial in a Danish community setting.

OBJECTIVE: To determine whether positive expiratory pressure (PEP) by PEP flute self-care is effective in reducing respiratory symptoms among community dwelling adults with SARS-CoV-2 infection and early stage covid-19. DESIGN: Non-drug, open label, randomised controlled trial. SETTING: Capital Region and Region Zealand in Denmark from 6 October 2020 to 26 February 2021. PARTICIPANTS: Community dwelling adults, able to perform self-care, with a new SARS-CoV-2 infection (verified by reverse transcription polymerase chain reaction tests) and symptoms of covid-19. INTERVENTION: Participants were randomised to use PEP flute self-care in addition to usual care or have usual care only. Randomisation was based on permuted random blocks in a 1:1 ratio, stratified for sex and age (<60 or ≥60 years). The PEP self-care group was instructed to use a PEP flute three times per day during the 30 day intervention. MAIN OUTCOME MEASURES: Primary outcome was a change in symptom severity from baseline to day 30, as assessed by the self-reported COPD (chronic obstructive pulmonary disease) assessment test (CAT), which was adjusted for baseline values and stratification factors. Participants completed the CAT test questionnaire every day online. Secondary outcomes were self-reported urgent care visits due to covid-19, number of covid-19 related symptoms, and change in self-rated health, all within 30-days' follow-up. RESULTS: 378 participants were assigned to the PEP flute self-care intervention (n=190) or usual care only (n=188). In the PEP self-care group, the median number of days with PEP flute use was 21 days (interquartile range 13-25). For the intention-to-treat population, a group difference was observed in changes from baseline in CAT scores of -1.2 points (95% confidence interval -2.1 to -0.2; P=0.017) in favour of the PEP flute self-care group. At day 30, the PEP flute self-care group also reported less chest tightness, less dyspnoea, more vigour, and higher level of daily activities, but these differences were small, and no consistent effects were seen on the secondary outcomes. No serious adverse events were reported. CONCLUSIONS: In community dwelling adults with early covid-19, PEP flute self-care had a significant, yet marginal and uncertain clinical effect on respiratory symptom severity, as measured by CAT scores. TRIAL REGISTRATION: ClinicalTrials.gov NCT04530435.

Long-Term Exposure to Transportation Noise and Risk of Incident Stroke: A Pooled Study of Nine Scandinavian Cohorts.

BACKGROUND: Transportation noise is increasingly acknowledged as a cardiovascular risk factor, but the evidence base for an association with stroke is sparse. OBJECTIVE: We aimed to investigate the association between transportation noise and stroke incidence in a large Scandinavian population. METHODS: We harmonized and pooled data from nine Scandinavian cohorts (seven Swedish, two Danish), totaling 135,951 participants. We identified residential address history and estimated road, railway, and aircraft noise for all addresses. Information on stroke incidence was acquired through linkage to national patient and mortality registries. We analyzed data using Cox proportional hazards models, including socioeconomic and lifestyle confounders, and air pollution. RESULTS: During follow-up (median=19.5y), 11,056 stroke cases were identified. Road traffic noise (Lden) was associated with risk of stroke, with a hazard ratio (HR) of 1.06 [95% confidence interval (CI): 1.03, 1.08] per 10-dB higher 5-y mean time-weighted exposure in analyses adjusted for individual- and area-level socioeconomic covariates. The association was approximately linear and persisted after adjustment for air pollution [particulate matter (PM) with an aerodynamic diameter of ≤2.5µm (PM2.5) and NO2]. Stroke was associated with moderate levels of 5-y aircraft noise exposure (40-50 vs. ≤40 dB) (HR=1.12; 95% CI: 0.99, 1.27), but not with higher exposure (≥50 dB, HR=0.94; 95% CI: 0.79, 1.11). Railway noise was not associated with stroke. DISCUSSION: In this pooled study, road traffic noise was associated with a higher risk of stroke. This finding supports road traffic noise as an important cardiovascular risk factor that should be included when estimating the burden of disease due to traffic noise. https://doi.org/10.1289/EHP8949.

Long-Term Exposure to Air Pollution, Road Traffic Noise, and Heart Failure Incidence: The Danish Nurse Cohort.

Background We examined the association of long-term exposure to air pollution and road traffic noise with incident heart failure (HF). Methods And Results Using data on female nurses from the Danish Nurse Cohort (aged >44 years), we investigated associations between 3-year mean exposures to air pollution and road traffic noise and incident HF using Cox regression models, adjusting for relevant confounders. Incidence of HF was defined as the first hospital contact (inpatient, outpatient, or emergency) between cohort baseline (1993 or 1999) and December 31, 2014, based on the Danish National Patient Register. Annual mean levels of particulate matter with a diameter <2.5 µm since 1990 and NO2 and road traffic noise since 1970 were estimated at participants' residences. Of the 22 189 nurses, 484 developed HF. We detected associations with all 3 pollutants, with hazard ratios (HRs) of 1.17 (95% CI, 1.01-1.36), 1.10 (95% CI, 0.99-1.22), and 1.12 (95% CI, 0.99-1.26) per increase of 5.1 µg/m3 in particulate matter with a diameter <2.5 µm, 8.6 µg/m3 in NO2, and 9.3 dB in road traffic noise, respectively. We observed an enhanced risk of HF incidence for those exposed to high levels of the 3 pollutants; however, the effect modification of coexposure was not statistically significant. Former smokers and nurses with hypertension showed the strongest associations with particulate matter with a diameter <2.5 µm (Peffect modification<0.05). Conclusions We found that long-term exposures to air pollution and road traffic noise were independently associated with HF.

Meta-analysis for individual participant data with a continuous exposure: A case study.

OBJECTIVE: Methods for meta-analysis of studies with individual participant data and continuous exposure variables are well described in the statistical literature but are not widely used in clinical and epidemiological research. The purpose of this case study is to make the methods more accessible. STUDY DESIGN AND SETTING: A two-stage process is demonstrated. Response curves are estimated separately for each study using fractional polynomials. The study-specific curves are then averaged pointwise over all studies at each value of the exposure. The averaging can be implemented using fixed effects or random effects methods. RESULTS: The methodology is illustrated using samples of real data with continuous outcome and exposure data and several covariates. The sample data set, segments of Stata and R code, and outputs are provided to enable replication of the results. CONCLUSION: These methods and tools can be adapted to other situations, including for time-to-event or categorical outcomes, different ways of modelling exposure-outcome curves, and different strategies for covariate adjustment.

Long-Term Exposure to Road Traffic Noise and Air Pollution, and Incident Atrial Fibrillation in the Danish Nurse Cohort.

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 >44y at baseline in 1993 or 1999). AF diagnoses were ascertained via the Danish National Patient Register. Annual mean weighted 24-h average road traffic noise levels (Lden) at the nurses' residences, since 1970, were estimated using the Nord2000 model, and annual mean levels of particulate matter with a diameter <2.5µm (PM2.5) and nitrogen dioxide (NO2) 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 PM2.5), 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 Lden levels >58 dB vs. <48 dB, with similar findings for 1-y mean exposures. A 3.9-µg/m3 increase in 3-y mean PM2.5 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 PM2.5 exposures were positive but closer to the null and not significant. Associations with NO2 were null for all time periods before and after adjustment for road traffic noise and inverse when adjusted for concurrent PM2.5. 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 PM2.5. https://doi.org/10.1289/EHP8090.

Long-term exposure to air pollution and liver cancer incidence in six European cohorts.

Particulate matter air pollution and diesel engine exhaust have been classified as carcinogenic for lung cancer, yet few studies have explored associations with liver cancer. We used six European adult cohorts which were recruited between 1985 and 2005, pooled within the "Effects of low-level air pollution: A study in Europe" (ELAPSE) project, and followed for the incidence of liver cancer until 2011 to 2015. The annual average exposure to nitrogen dioxide (NO2 ), particulate matter with diameter <2.5 µm (PM2.5 ), black carbon (BC), warm-season ozone (O3 ), and eight elemental components of PM2.5 (copper, iron, zinc, sulfur, nickel, vanadium, silicon, and potassium) were estimated by European-wide hybrid land-use regression models at participants' residential addresses. We analyzed the association between air pollution and liver cancer incidence by Cox proportional hazards models adjusting for potential confounders. Of 330 064 cancer-free adults at baseline, 512 developed liver cancer during a mean follow-up of 18.1 years. We observed positive linear associations between NO2 (hazard ratio, 95% confidence interval: 1.17, 1.02-1.35 per 10 µg/m3 ), PM2.5 (1.12, 0.92-1.36 per 5 µg/m3 ), and BC (1.15, 1.00-1.33 per 0.5 10-5 /m) and liver cancer incidence. Associations with NO2 and BC persisted in two-pollutant models with PM2.5 . Most components of PM2.5 were associated with the risk of liver cancer, with the strongest associations for sulfur and vanadium, which were robust to adjustment for PM2.5 or NO2 . Our study suggests that ambient air pollution may increase the risk of liver cancer, even at concentrations below current EU standards.