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1.  Oral contraceptive use and mortality after 36 years of follow-up in the Nurses’ Health Study: prospective cohort study 
Objective To determine whether use of oral contraceptives is associated with all cause and cause specific mortality.
Design Prospective cohort study.
Setting Nurses’ Health Study, data collected between 1976 and 2012.
Population 121 701 participants were prospectively followed for 36 years; lifetime oral contraceptive use was recorded biennially from 1976 to 1982.
Main outcome measures Overall and cause specific mortality, assessed throughout follow-up until 2012. Cox proportional hazards models were used to calculate the relative risks of all cause and cause specific mortality associated with use of oral contraceptives.
Results In our population of 121 577 women with information on oral contraceptive use, 63 626 were never users (52%) and 57 951 were ever users (48%). After 3.6 million person years, we recorded 31 286 deaths. No association was observed between ever use of oral contraceptives and all cause mortality. However, violent or accidental deaths were more common among ever users (hazard ratio 1.20, 95% confidence interval 1.04 to 1.37). Longer duration of use was more strongly associated with certain causes of death, including premature mortality due to breast cancer (test for trend P<0.0001) and decreased mortality rates of ovarian cancer (P=0.002). Longer time since last use was also associated with certain outcomes, including a positive association with violent or accidental deaths (P=0.005).
Conclusions All cause mortality did not differ significantly between women who had ever used oral contraceptives and never users. Oral contraceptive use was associated with certain causes of death, including increased rates of violent or accidental death and deaths due to breast cancer, whereas deaths due to ovarian cancer were less common among women who used oral contraceptives. These results pertain to earlier oral contraceptive formulations with higher hormone doses rather than the now more commonly used third and fourth generation formulations with lower estrogen doses.
PMCID: PMC4216099  PMID: 25361731
2.  Are operating room nurses at higher risk of severe persistent asthma? 
To assess the associations between operating room (OR) nursing, a category of health care workers at high risk of exposure to various inhaled agents, and asthma severity/control among women with asthma.
The level of severity/control in nurses with prevalent doctor-diagnosed asthma in 1998/2000 was compared, using nominal logistic regression, in OR nursing (n=69) and administrative nursing (n=546) from the US Nurses’ Health Study for whom detailed information on asthma and nursing employment status was available.
We observed a significant association between OR nursing, compared to administrative nursing, and severe persistent asthma (adjusted odds ratio 2.48, 95%CI 1.06–5.77).
Our findings suggest that nurses working in the operating room are at a higher risk of severe persistent asthma. Further studies with detailed estimates of occupational exposures, especially to disinfectant/cleaning agents, are warranted.
PMCID: PMC3740047  PMID: 23887704
operating room nurse; occupation; asthma severity; epidemiology
3.  Asia: Changing Times and Changing Problems 
Environmental Health Perspectives  2008;116(9):A370-A371.
PMCID: PMC2535635  PMID: 18795176
4.  Pooled analyses of 13 prospective cohort studies on folate intake and colon cancer 
Cancer causes & control : CCC  2010;21(11):1919-1930.
Studies of folate intake and colorectal cancer risk have been inconsistent. We examined the relation with colon cancer risk in a series of 13 prospective studies.
Study- and sex-specific relative risks (RRs) were estimated from the primary data using Cox proportional hazards models and then pooled using a random-effects model.
Among 725,134 participants, 5,720 incident colon cancers were diagnosed during follow-up. The pooled multivariate RRs (95% confidence interval [CI]) comparing the highest vs. lowest quintile of intake were 0.92 (95% CI 0.84–1.00, p-value, test for between-studies heterogeneity = 0.85) for dietary folate and 0.85 (95% CI 0.77–0.95, p-value, test for between-studies heterogeneity = 0.42) for total folate. Results for total folate intake were similar in analyses using absolute intake cutpoints (pooled multivariate RR = 0.87, 95% CI 0.78–0.98, comparing ≥560 mcg/days vs. <240 mcg/days, p-value, test for trend = 0.009). When analyzed as a continuous variable, a 2% risk reduction (95% CI 0–3%) was estimated for every 100 μg/day increase in total folate intake.
These data support the hypothesis that higher folate intake is modestly associated with reduced risk of colon cancer.
PMCID: PMC3082430  PMID: 20820900
Colon cancer; Folate; Cohort studies; Meta-analysis; Pooled analysis
5.  Reproductive factors, hormone use and risk of lung cancer in postmenopausal women, the Nurses’ Health Study 
There is increasing evidence suggesting that female hormones may play a significant role in lung cancer (LC) development. We evaluated the associations between reproductive factors, exogeneous hormone use, and LC incidence in the Nurses’ Health Study (NHS).
We assessed age at menopause, age at menarche, type of menopause, parity, age at first birth, postmenopausal hormone (PMH) use and past oral contraceptive use in 107,171 postmenopausal women. Cox models were used to estimate the hazard ratios (HR) for each exposure, adjusted for smoking and other covariates.
We identified 1,729 LC cases during follow up from 1984 to 2006. Menopause onset before 44 years of age (HR=1.39, 95%CI 1.14-1.70) and past oral contraceptive use for greater than 5 years (HR=1.22, 95%CI 1.05-1.42) were associated with increased LC risk. These associations were strongest in current smokers and small cell histology. In never smokers, increased parity was associated with decreased risk among parous women (p-trend=0.03), whereas in current smokers, older age at first birth was associated with increased risk (p-trend=0.02). PMH use was not associated with overall LC incidence. However, nonsignificant results of increased risk in adenocarcinoma were seen with current PMH use.
Our findings suggest female hormones may influence lung carcinogenesis though the effect is likely modest, varied by histologic subtype and altered by smoking.
Further investigation of the pathophysiology of female hormones in LC subtypes and their interaction with smoking will lead to better understanding of lung carcinogenesis.
PMCID: PMC2952036  PMID: 20739629
lung cancer; reproductive factors; hormone replacement therapy; epidemiology
6.  T-wave Alternans, Air Pollution and Traffic in High-risk Subjects 
The American journal of cardiology  2009;104(5):665-670.
Particulate pollution has been linked to risk of cardiac death; possible mechanisms include pollution-related increases in cardiac electrical instability. T-wave alternans (TWA) is a marker of cardiac electrical instability measured as differences in the magnitude between adjacent T waves. In a repeated-measures study of 48 patients aged 43-75 years, we investigated associations of ambient and home indoor particulate pollution including black carbon (BC) and report of traffic exposure, with changes in half-hourly maximum TWA (TWA-MAX), measured by 24 hour Holter electrocardiogram monitoring. Each patient was observed up to 4 times within one year after percutaneous intervention for myocardial infarction, acute coronary syndrome without infarction, or stable coronary artery disease for a total of 5,830 half-hour observations. Diary data for each half-hour period defined whether the patient was home or not home, or in traffic. Increases in TWA-MAX were independently associated both with the previous 2-h mean ambient BC (2.1%; 95% C.I.: 0.9-3.3) and with being in traffic in the previous 2 hours (6.1%; 95% C.I.: 3.4-8.8). When subjects were home, indoor home BC effects were largest and most precise; when subjects were away from home, ambient central site BC effects were strongest. Increases in pollution increased the odds of TWA-MAX ≥ 75th percentile (OR 1.4; 95% CI: 1.2-1.6 for 1 μg/m3 increase in 6-h mean BC). In conclusion, following hospitalization for coronary artery disease, being in traffic, and short-term ambient or indoor BC exposures increase TWA, a marker of cardiac electrical instability.
PMCID: PMC3139397  PMID: 19699342
Air pollution; coronary disease; myocardial infarction; T-wave alternans; circadian rhythm
7.  Reduction in Heart Rate Variability with Traffic and Air Pollution in Patients with Coronary Artery Disease 
Environmental Health Perspectives  2009;118(3):324-330.
Ambient particulate pollution and traffic have been linked to myocardial infarction and cardiac death risk. Possible mechanisms include autonomic cardiac dysfunction.
In a repeated-measures study of 46 patients 43–75 years of age, we investigated associations of central-site ambient particulate pollution, including black carbon (BC) (a marker for regional and local traffic), and report of traffic exposure with changes in half-hourly averaged heart rate variability (HRV), a marker of autonomic function measured by 24-hr Holter electrocardiogram monitoring. Each patient was observed up to four times within 1 year after a percutaneous intervention for myocardial infarction, acute coronary syndrome without infarction, or stable coronary artery disease (4,955 half-hour observations). For each half-hour period, diary data defined whether the patient was home or not home, or in traffic.
A decrease in high frequency (HF; an HRV marker of vagal tone) of −16.4% [95% confidence interval (CI), −20.7 to −11.8%] was associated with an interquartile range of 0.3-μg/m3 increase in prior 5-day averaged ambient BC. Decreases in HF were independently associated both with the previous 2-hr averaged BC (−10.4%; 95% CI, −15.4 to −5.2%) and with being in traffic in the previous 2 hr (−38.5%; 95% CI, −57.4 to −11.1%). We also observed independent responses for particulate air matter with aerodynamic diameter ≤ 2.5 μm and for gases (ozone or nitrogen dioxide).
After hospitalization for coronary artery disease, both particulate pollution and being in traffic, a marker of stress and pollution, were associated with decreased HRV.
PMCID: PMC2854758  PMID: 20064780
air pollution; cardiac event; heart rate variability; myocardial infarction; traffic
8.  Chronic Particulate Exposure, Mortality, and Coronary Heart Disease in the Nurses’ Health Study 
American Journal of Epidemiology  2008;168(10):1161-1168.
Adverse health effects of exposures to acute air pollution have been well studied. Fewer studies have examined effects of chronic exposure. Previous studies used exposure estimates for narrow time periods and were limited by the geographic distribution of pollution monitors. This study examined the association of chronic particulate exposures with all-cause mortality, incident nonfatal myocardial infarction, and fatal coronary heart disease (CHD) in a prospective cohort of 66,250 women from the Nurses’ Health Study in northeastern US metropolitan areas. Nonfatal outcomes were assessed through self-report and medical record review and fatalities through death certificates and medical record review. During follow-up (1992–2002), 3,785 deaths and 1,348 incident fatal CHD and nonfatal myocardial infarctions occurred. In age- and calendar-time-adjusted models, 10-μg/m3 increases in 12-month average exposures to particulate matter <10 μm in diameter were associated with increased all-cause mortality (16%, 95% confidence interval: 5, 28) and fatal CHD (43%, 95% confidence interval: 10, 86). Adjustment for body mass index and physical activity weakened these associations. Body mass index and smoking modified the association between exposure to particulate matter <10 μm in diameter and fatal CHD. In this population, increases in such exposures were associated with increases in all-cause and CHD mortality. Never smokers with higher body mass indexes were at greatest risk of fatal CHD.
PMCID: PMC2732957  PMID: 18835862
air pollution; cohort studies; coronary disease; environmental exposure; incidence; particulate matter; risk factors
9.  Chronic Fine and Coarse Particulate Exposure, Mortality, and Coronary Heart Disease in the Nurses’ Health Study 
Environmental Health Perspectives  2009;117(11):1697-1701.
The relationship of fine particulate matter < 2.5 μm in diameter (PM2.5) air pollution with mortality and cardiovascular disease is well established, with more recent long-term studies reporting larger effect sizes than earlier long-term studies. Some studies have suggested the coarse fraction, particles between 2.5 and 10 μm (PM10–2.5), may also be important. With respect to mortality and cardiovascular events, questions remain regarding the relative strength of effect sizes for chronic exposure to fine and coarse particles.
We examined the relationship of chronic PM2.5 and PM10–2.5 exposures with all-cause mortality and fatal and nonfatal incident coronary heart disease (CHD), adjusting for time-varying covariates.
The current study included women from the Nurses’ Health Study living in metropolitan areas of the northeastern and midwestern United States. Follow-up was from 1992 to 2002. We used geographic information systems–based spatial smoothing models to estimate monthly exposures at each participant’s residence.
We found increased risk of all-cause mortality [hazard ratio (HR), 1.26; 95% confidence interval (CI), 1.02–1.54] and fatal CHD (HR = 2.02; 95% CI, 1.07–3.78) associated with each 10-μg/m3 increase in annual PM2.5 exposure. The association between fatal CHD and PM10–2.5 was weaker.
Our findings contribute to growing evidence that chronic PM2.5 exposure is associated with risk of all-cause and cardiovascular mortality.
PMCID: PMC2801178  PMID: 20049120
air pollution; cardiovascular disease; mortality; particulate matter
10.  Particulate Air Pollution as a Risk Factor for ST-segment Depression in Patients with Coronary Artery Disease 
Circulation  2008;118(13):1314-1320.
The association of particulate matter (PM) with cardiovascular morbidity and mortality is well documented. PM-induced ischemia is considered a potential mechanism linking PM to adverse cardiovascular outcomes.
Methods and Results
In a repeated-measures study including 5,979 observations on 48 patients aged 43–75 years, we investigated associations of ambient pollution with ST-segment level changes averaged over half-hour periods, measured in the modified V5 position by 24-hr Holter electrocardiogram monitoring. Each patient was observed up to 4 times within one year after a percutaneous intervention for myocardial infarction, acute coronary syndrome without infarction, or stable coronary artery disease without acute coronary syndrome. Elevation in fine particles (PM2.5) and black carbon (BC) levels predicted depression of half-hour averaged ST-segment levels. An interquartile increase in the previous 24-h mean BC level was associated with a 1.50-fold increased in risk of ST-segment depression ≥0.1 mm (95% CI: 1.19, 1.89) and a −0.031 mm (95% CI: −0.042, −0.019) decrease in half-hour averaged ST-segment level (continuous outcome). Effects were greatest within the first month after hospitalization, and for patients with myocardial infarction during hospitalization or with diabetes.
ST-segment depression is associated with increased exposure to PM2.5 and BC in cardiac patients. The risk of pollution-associated ST-segment depression may be greatest in those with myocardial injury in the first month after the cardiac event.
PMCID: PMC2751595  PMID: 18779445
air pollution; particles; cardiovascular diseases; myocardial infarction; ST-segment depression
11.  Prospective Study of Inhaled Corticosteroid Use, Cardiovascular Mortality, and All-Cause Mortality in Asthmatic Women* 
Chest  2008;134(3):546-551.
Therapy with inhaled corticosteroids (ICSs) decreases the risk of asthma exacerbations. Recent studies have suggested that ICS therapy also may decrease the risk of cardiovascular disease, and perhaps of all-cause mortality. We examined this hypothesis in a large, well-characterized cohort of asthmatic women.
In 1976, the Nurses’ Health Study enrolled 121,700 registered nurses, who were 30 to 55 years of age. Participants were asked about “physician-diagnosed asthma” on biennial questionnaires. In 1998, asthmatic participants were sent a supplementary questionnaire on asthma diagnosis and management, including ICS use. Mortality was assessed through 2003, without knowledge of the 1998 (baseline) ICS status. The odds ratios (ORs) for death were adjusted for age, asthma severity, smoking, heart disease, cancer, stroke, aspirin, and statin use.
Among 2,671 eligible women (ie, those who responded to the 1998 supplement [85%], met criteria for persistent asthma, and had not received a prior diagnosis of COPD), 54% reported ICS use. Over the next 5 years, 87 women (3.3%) died (cardiovascular deaths, 22; cancer deaths, 31; other, 34 [including 4 from asthma]). Compared to asthmatic women who did not use ICSs, those receiving therapy with ICSs had lower all-cause mortality (OR, 0.58; 95% confidence interval [CI], 0.36 to 0.92). ICS users were at significantly lower risk of cardiovascular death (OR, 0.35; 95% CI, 0.13 to 0.93), but not of death from cancer (OR, 0.66; 95% CI, 0.32 to 1.38) or other causes (OR, 0.62; 95% CI, 0.30 to 1.27).
ICS use was associated with significantly lower cardiovascular and all-cause mortality in women with asthma. These observational data suggest that ICSs may indeed have antiinflammatory benefits beyond the airway, which is a possibility that merits further study.
PMCID: PMC2643337  PMID: 18641096
all-cause mortality; asthma; cardiovascular mortality; inhaled corticosteroids
12.  Reduction in Fine Particulate Air Pollution and Mortality 
Rationale: A large body of epidemiologic literature has found an association of increased fine particulate air pollution (PM2.5) with acute and chronic mortality. The effect of improvements in particle exposure is less clear.
Objectives: Earlier analysis of the Harvard Six Cities adult cohort study showed an association between long-term ambient PM2.5 and mortality between enrollment in the mid-1970s and follow-up until 1990. We extended mortality follow-up for 8 yr in a period of reduced air pollution concentrations.
Methods: Annual city-specific PM2.5 concentrations were measured between 1979 and 1988, and estimated for later years from publicly available data. Exposure was defined as (1) city-specific mean PM2.5 during the two follow-up periods, (2) mean PM2.5 in the first period and change between these periods, (3) overall mean PM2.5 across the entire follow-up, and (4) year-specific mean PM2.5. Mortality rate ratios were estimated with Cox proportional hazards regression controlling for individual risk factors.
Measurements and Main Results: We found an increase in overall mortality associated with each 10 μg/m3 increase in PM2.5 modeled either as the overall mean (rate ratio [RR], 1.16; 95% confidence interval [CI], 1.07–1.26) or as exposure in the year of death (RR, 1.14; 95% CI, 1.06–1.22). PM2.5 exposure was associated with lung cancer (RR, 1.27; 95% CI, 0.96–1.69) and cardiovascular deaths (RR, 1.28; 95% CI, 1.13–1.44). Improved overall mortality was associated with decreased mean PM2.5 (10 μg/m3) between periods (RR, 0.73; 95% CI, 0.57–0.95).
Conclusion: Total, cardiovascular, and lung cancer mortality were each positively associated with ambient PM2.5 concentrations. Reduced PM2.5 concentrations were associated with reduced mortality risk.
PMCID: PMC2662950  PMID: 16424447
air pollution; cohort studies; follow-up studies; mortality
13.  Impact of Extended-Duration Shifts on Medical Errors, Adverse Events, and Attentional Failures 
PLoS Medicine  2006;3(12):e487.
A recent randomized controlled trial in critical-care units revealed that the elimination of extended-duration work shifts (≥24 h) reduces the rates of significant medical errors and polysomnographically recorded attentional failures. This raised the concern that the extended-duration shifts commonly worked by interns may contribute to the risk of medical errors being made, and perhaps to the risk of adverse events more generally. Our current study assessed whether extended-duration shifts worked by interns are associated with significant medical errors, adverse events, and attentional failures in a diverse population of interns across the United States.
Methods and Findings
We conducted a Web-based survey, across the United States, in which 2,737 residents in their first postgraduate year (interns) completed 17,003 monthly reports. The association between the number of extended-duration shifts worked in the month and the reporting of significant medical errors, preventable adverse events, and attentional failures was assessed using a case-crossover analysis in which each intern acted as his/her own control. Compared to months in which no extended-duration shifts were worked, during months in which between one and four extended-duration shifts and five or more extended-duration shifts were worked, the odds ratios of reporting at least one fatigue-related significant medical error were 3.5 (95% confidence interval [CI], 3.3–3.7) and 7.5 (95% CI, 7.2–7.8), respectively. The respective odds ratios for fatigue-related preventable adverse events, 8.7 (95% CI, 3.4–22) and 7.0 (95% CI, 4.3–11), were also increased. Interns working five or more extended-duration shifts per month reported more attentional failures during lectures, rounds, and clinical activities, including surgery and reported 300% more fatigue-related preventable adverse events resulting in a fatality.
In our survey, extended-duration work shifts were associated with an increased risk of significant medical errors, adverse events, and attentional failures in interns across the United States. These results have important public policy implications for postgraduate medical education.
During months in which medical interns worked extended shifts, the chances of their reporting at least one fatigue-related significant medical error increased more than 3-fold compared to months with no extended shifts.
Editors' Summary
In the United States, medical students who are doing their internship (first year of postgraduate clinical training) regularly work in the clinic for longer than 24 h at a time. It is already known that doctors or students who work for long shifts make more medical errors and are less able to pay attention to what they are doing. Many thousands of adverse medical events per year including, in the extreme, deaths of patients, are thought to result from medical errors, but it is not clear whether doctors or students working long shifts—as opposed to, for example, an increase in total number of hours worked—are the cause of many or any of these errors.
Why Was This Study Done?
This research group wanted to find out whether long shifts worked by interns had an effect on reported medical errors, and hence patient safety, and specifically whether any harm that happened to patients might otherwise have been preventable.
What Did the Researchers Do and Find?
The researchers contacted all US medical school graduates beginning their internships from one particular year-group by email, and asked each person whether they wanted to take part in a confidential survey. Individuals who agreed to participate were directed to a secure website to enter basic information about themselves and then to complete a form each month. On that form the interns gave information about their working hours, hours of sleep, and number of extended-duration shifts worked, and completed questions about medical errors in the past month. Then, for each intern in the study, researchers compared month by month the number of medical errors and the number of extended-duration shifts that had been worked. A total of 2,737 interns took part in the survey.
  Compared to months in which no extended-duration shifts were worked, in those months in which between one and four, and more than five extended-duration shifts were worked, the doctors were, respectively, three and seven times more likely to report at least one fatigue-related significant medical error. Similarly, fatigue-related adverse events increased by around seven and eight times, respectively, compared with months in which no extended-duration shifts were worked. Fatigue-related preventable adverse events associated with the death of the patient increased by ∼300% in interns working more than five extended-duration shifts per month; they were also more likely to fall asleep during lectures, rounds, and clinical activities, including surgery.
What Do These Findings Mean?
Guidelines for graduate medical education in the United States still allow up to nine marathon shifts (30 h at a stretch) per month, even though the total number of hours worked is capped. This study shows that the long shifts worked by interns are bad for patient safety, as they are more likely to cause harm that would not otherwise happen.
Additional Information.
Please access these Web sites via the online version of this summary at
The US Food and Drug Administration has resources on its website about medication errors
The National Sleep Foundation aims to improve public health and safety by achieving understanding of sleep and sleep disorders
Wikipedia (an internet encyclopedia anyone can edit) has a page about residency training in the United States
PMCID: PMC1705824  PMID: 17194188
14.  A Functional Mutation in the Terminal Exon of Elastin in Severe, Early-Onset Chronic Obstructive Pulmonary Disease 
We describe a novel variant in the terminal exon of human elastin, c.2318 G>A, resulting in an amino acid substitution of glycine 773 to aspartate (G773D) in a pedigree with severe early-onset chronic obstructive pulmonary disease (COPD). Transfection studies with elastin cDNAs demonstrate that the glycine to aspartate change compromises the ability of the mutant protein to undergo normal elastin assembly. Other functional consequences of this amino acid substitution include altered proteolytic susceptibility of the C-terminal region of elastin and reduced interaction of the exon 36 sequence with matrix receptors on cells. These results suggest that the G773D variant confers structural and functional consequences relevant to the pathogenesis of COPD.
PMCID: PMC2715343  PMID: 16081882
chronic obstructive pulmonary disease; elastin; extracellular matrix; genetics; mutation
15.  Attempted Replication of Reported Chronic Obstructive Pulmonary Disease Candidate Gene Associations 
Case-control studies have successfully identified many significant genetic associations for complex diseases, but lack of replication has been a criticism of case-control genetic association studies in general. We selected 12 candidate genes with reported associations to chronic obstructive pulmonary disease (COPD) and genotyped 29 polymorphisms in a family-based study and in a case-control study. In the Boston Early-Onset COPD Study families, significant associations with quantitative and/or qualitative COPD-related phenotypes were found for the tumor necrosis factor (TNF)-α −308G>A promoter polymorphism (P < 0.02), a coding variant in surfactant protein B (SFTPB Thr131Ile) (P = 0.03), and the (GT)31 allele of the heme oxygenase (HMOX1) promoter short tandem repeat (P = 0.02). In the case-control study, the SFTPB Thr131Ile polymorphism was associated with COPD, but only in the presence of a gene-by-environment interaction term (P = 0.01 for both main effect and interaction). The 30-repeat, but not the 31-repeat, allele of HMOX1 was associated (P = 0.04). The TNF −308G>A polymorphism was not significant. In addition, the microsomal epoxide hydrolase “fast” allele (EPHX1 His139Arg) was significantly associated in the case-control study (P = 0.03). Although some evidence for replication was found for SFTPB and HMOX1, none of the previously published COPD genetic associations was convincingly replicated across both study designs.
PMCID: PMC2715305  PMID: 15817713
association studies; case-control studies; emphysema; genetics; single nucleotide polymorphism
16.  Increased Risk of Paroxysmal Atrial Fibrillation Episodes Associated with Acute Increases in Ambient Air Pollution 
Environmental Health Perspectives  2005;114(1):120-123.
Objectives: We reported previously that 24-hr moving average ambient air pollution concentrations were positively associated with ventricular arrhythmias detected by implantable cardioverter defibrillators (ICDs). ICDs also detect paroxysmal atrial fibrillation episodes (PAF) that result in rapid ventricular rates. In this same cohort of ICD patients, we assessed the association between ambient air pollution and episodes of PAF.
Design: We performed a case–crossover study.
Participants: Patients who lived in the Boston, Massachusetts, metropolitan area and who had ICDs implanted between June 1995 and December 1999 (n = 203) were followed until July 2002.
Evaluations/Measurements: We used conditional logistic regression to explore the association between community air pollution and 91 electrophysiologist-confirmed episodes of PAF among 29 subjects.
Results: We found a statistically significant positive association between episodes of PAF and increased ozone concentration (22 ppb) in the hour before the arrhythmia (odds ratio = 2.08; 95% confidence interval = 1.22, 3.54; p = 0.001). The risk estimate for a longer (24-hr) moving average was smaller, thus suggesting an immediate effect. Positive but not statistically significant risks were associated with fine particles, nitrogen dioxide, and black carbon.
Conclusions: Increased ambient O3 pollution was associated with increased risk of episodes of rapid ventricular response due to PAF, thereby suggesting that community air pollution may be a precipitant of these events.
PMCID: PMC1332666  PMID: 16393668
air pollution; arrhythmias; fibrillation; epidemiology; case—crossover; ozone
17.  Lung Cancer in Railroad Workers Exposed to Diesel Exhaust 
Environmental Health Perspectives  2004;112(15):1539-1543.
Diesel exhaust has been suspected to be a lung carcinogen. The assessment of this lung cancer risk has been limited by lack of studies of exposed workers followed for many years. In this study, we assessed lung cancer mortality in 54,973 U.S. railroad workers between 1959 and 1996 (38 years). By 1959, the U.S. railroad industry had largely converted from coal-fired to diesel-powered locomotives. We obtained work histories from the U.S. Railroad Retirement Board, and ascertained mortality using Railroad Retirement Board, Social Security, and Health Care Financing Administration records. Cause of death was obtained from the National Death Index and death certificates. There were 43,593 total deaths including 4,351 lung cancer deaths. Adjusting for a healthy worker survivor effect and age, railroad workers in jobs associated with operating trains had a relative risk of lung cancer mortality of 1.40 (95% confidence interval, 1.30–1.51). Lung cancer mortality did not increase with increasing years of work in these jobs. Lung cancer mortality was elevated in jobs associated with work on trains powered by diesel locomotives. Although a contribution from exposure to coal combustion products before 1959 cannot be excluded, these results suggest that exposure to diesel exhaust contributed to lung cancer mortality in this cohort.
PMCID: PMC1247618  PMID: 15531439
diesel exhaust; lung cancer; occupational exposure
18.  Polymorphic repeat in AIB1 does not alter breast cancer risk 
Breast Cancer Research : BCR  2000;2(5):378-385.
We assessed the association between a glutamine repeat polymorphism in AIB1 and breast cancer risk in a case-control study (464 cases, 624 controls) nested within the Nurses' Health Study cohort. We observed no association between AIB1 genotype and breast cancer incidence, or specific tumor characteristics. These findings suggest that AIB1 repeat genotype does not influence postmenopausal breast cancer risk among Caucasian women in the general population.
A causal association between endogenous and exogenous estrogens and breast cancer has been established. Steroid hormones regulate the expression of proteins that are involved in breast cell proliferation and development after binding to their respective steroid hormone receptors. Coactivator and corepressor proteins have recently been identified that interact with steroid hormone receptors and modulate transcriptional activation [1]. AIB1 (amplified in breast 1) is a member of the steroid receptor coactivator (SRC) family that interacts with estrogen receptor (ER)α in a ligand-dependent manner, and increases estrogen-dependent transcription [2]. Amplification and overexpression of AIB1 has been observed in breast and ovarian cancer cell lines and in breast tumors [2,3]. A polymorphic stretch of glutamine amino acids, with unknown biologic function, has recently been described in the carboxyl-terminal region of AIB1 [4]. Among women with germline BRCA1 mutations, significant positive associations were observed between AIB1 alleles with 26 or fewer glutamine repeats and breast cancer risk [5]
To establish whether AIB1 repeat alleles are associated with breast cancer risk and specific tumor characteristics among Caucasian women.
Patients and methods:
We evaluated associations prospectively between AIB1 alleles and breast cancer risk in the Nurses' Health Study using a nested case-control design. The Nurses' Health Study was initiated in 1976, when 121 700 US-registered nurses between the ages of 30 and 55 years returned an initial questionnaire reporting medical histories and baseline health-related exposures. Between 1989 and 1990 blood samples were collected from 32 826 women. Eligible cases in this study consisted of women with pathologically confirmed incident breast cancer from the subcohort who gave a blood specimen. Cases with a diagnosis anytime after blood collection up to June 1, 1994, with no previously diagnosed cancer except for nonmelanoma skin cancer were included. Controls were randomly selected participants who gave a blood sample and were free of diagnosed cancer (except nonmelanoma skin cancer) up to and including the interval in which the cases were diagnosed, and were matched to cases on year of birth, menopausal status, postmenopausal hormone use, and time of day, month and fasting status at blood sampling. The nested case-control study consisted of 464 incident breast cancer cases and 624 matched controls. The protocol was approved by the Committee on Human Subjects, Brigham and Womens' Hospital, Boston, Massachusetts USA. Information regarding breast cancer risk factors was obtained from the 1976 baseline questionnaire, subsequent biennial questionnaires, and a questionnaire that was completed at the time of blood sampling. Histopathologic characteristics, such as stage, tumor size and ER and progesterone receptor (PR) status, were ascertained from medical records when available and used in case subgroup analyses.
AIB1 repeat alleles were determined by automated fluorescence-based fragment detection from polymerase chain reaction (PCR)-amplified DNA extracted from peripheral blood lymphocytes. Fluorescent 5' -labeled primers were utilized for PCR amplification, and glutamine repeat number discrimination was performed using the ABI Prism 377 DNA Sequencer (Perkin-Elmer, Foster City, CA, USA). Genotyping was performed by laboratory personnel who were blinded to case-control status, and blinded quality control samples were inserted to validate genotyping identification procedures (n = 110); concordance for the blinded samples was 100%. Methods regarding plasma hormone assays have previously been reported [6]. Conditional and unconditional logistic regression models, including terms for the matching variables and other potential confounders, were used to assess the association of AIB1 alleles and breast cancer characterized by histologic subtype, stage of disease, and ER and PR status. We also evaluated whether breast cancer risk associated with AIB1 genotype differed within strata of established breast cancer risk factors, and whether repeat length in AIB1 indirectly influenced plasma hormone levels.
The case-control comparisons of established breast cancer risk factors among these women have previously been reported [7], and are generally consistent with expectation. The mean age of the women was 58.3 (standard deviation [SD] 7.1) years, ranging from 43 to 69 years at blood sampling. There were 188 premenopausal and 810 postmenopausal women, with mean ages of 48.1 (SD 2.8) years and 61.4 (SD 5.0) years, respectively, at blood sampling. Women in this study were primarily white; Asians, African-Americans and Hispanics comprised less than 1% of cases or controls.
The distribution of AIB1 glutamine repeat alleles and AIB1 genotypes for cases and controls are presented in Table 1. Women with AIB1 alleles of 26 glutamine repeats or fewer were not at increased risk for breast cancer (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.75-1.36; Table 2). Results were also similar by menopausal status and in analyses additionally adjusting for established breast cancer risk factors. Among premenopausal women, the OR for women with at least one allele with 26 glutamine repeats or fewer was 0.82 (95% Cl 0.37-1.81), and among postmenopausal women the OR was 1.09 (95% Cl 0.78-1.52; Table 2). We did not observe evidence of a positive association between shorter repeat length and advanced breast cancer, defined as women with breast cancer having one or more involved nodes (OR 1.07, 95% Cl 0.64-1.78), or with cancers with a hormone-dependent phenotype (ER-positive: OR 1.16, 95% Cl 0.81-1.65; Table 3). No associations were observed among women who had one or more alleles with 26 glutamine repeats or fewer, with or without a family history of breast cancer (family history: OR 1.09; 95% Cl 0.46-2.58; no family history: OR 0.94; 95% Cl 0.68-1.31; test for interaction P = 0.65). We also did not observe associations with breast cancer risk to be modified by other established breast cancer risk factors. Among postmenopausal controls not using postmenopausal hormones, geometric least-squared mean plasma levels of estrone sulfate and estrone were similar among carriers and noncarriers of AIB1 alleles with 26 glutamine repeats or fewer (both differences: ≤ +3.5%; P >0.50). Mean levels of estradiol were slightly, but nonsignificantly elevated among carriers of alleles with 26 glutamine repeats or fewer (+11.6%; P = 0.08).
In this population-based nested case-control study, women with at most 26 repeating glutamine codons (CAG/CAA) within the carboxyl terminus of AIB1 were not at increased risk for breast cancer. We did not observe shorter repeat alleles to be positively associated with breast cancer grouped by histologic subtype, stage of disease, or by ER and PR status. These data suggest that AIB1 repeat length is not a strong independent risk factor for postmenopausal breast cancer, and does not modify the clinical presentation of the tumor among Caucasian women in the general population.
PMCID: PMC13920  PMID: 11056690
AIB1 polymorphism; breast cancer; genetic susceptibility; molecular epidemiology
19.  Frequent nut consumption and risk of coronary heart disease in women: prospective cohort study 
BMJ : British Medical Journal  1998;317(7169):1341-1345.
To examine the relation between nut consumption and risk of coronary heart disease in a cohort of women from the Nurses’ Health Study.
Prospective cohort study.
Nurses’ Health Study.
86 016 women from 34 to 59 years of age without previously diagnosed coronary heart disease, stroke, or cancer at baseline in 1980.
Main outcome measures
Major coronary heart disease including non-fatal myocardial infarction and fatal coronary heart disease.
1255 major coronary disease events (861 cases of non-fatal myocardial infarction and 394 cases of fatal coronary heart disease) occurred during 14 years of follow up. After adjusting for age, smoking, and other known risk factors for coronary heart disease, women who ate more than five units of nuts (one unit equivalent to 1 oz of nuts) a week (frequent consumption) had a significantly lower risk of total coronary heart disease (relative risk 0.65, 95% confidence interval 0.47 to 0.89, P for trend=0.0009) than women who never ate nuts or who ate less than one unit a month (rare consumption). The magnitude of risk reduction was similar for both fatal coronary heart disease (0.61, 0.35 to 1.05, P for trend=0.007) and non-fatal myocardial infarction (0.68, 0.47 to 1.00, P for trend=0.04). Further adjustment for intakes of dietary fats, fibre, vegetables, and fruits did not alter these results. The inverse association persisted in subgroups stratified by levels of smoking, use of alcohol, use of multivitamin and vitamin E supplements, body mass index, exercise, and intake of vegetables or fruits.
Frequent nut consumption was associated with a reduced risk of both fatal coronary heart disease and non-fatal myocardial infarction. These data, and those from other epidemiological and clinical studies, support a role for nuts in reducing the risk of coronary heart disease.
Key messagesNuts are high in fat, but most of the fatty acids are unsaturatedThis study suggests that frequent consumption of nuts, including peanuts, may reduce the risk of coronary heart diseaseThis protective effect may be partly mediated through serum lipids because unsaturated fats have benefical effects on serum lipids. Other potentially protective constituents include vegetable protein, magnesium, vitamin E, fibre, and potassiumNuts can be included as part of a healthy diet
PMCID: PMC28714  PMID: 9812929

Results 1-19 (19)