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1.  Human papillomavirus serology and tobacco smoking in a community control group 
Background
HPV infection is an established risk factor for oropharyngeal cancer, and it has been proposed that cigarette smoking may potentiate HPV infection in the oral epithelium. We sought to test the hypothesis that cigarette smoking increases HPV infection in an HPV16 serology study of cancer-free individuals.
Methods
Subjects were participants in a risk factor study for head and neck cancer, and were required to have no prior history of either HNSCC or any other cancer. Tobacco use and other risk factor data were gathered through interviewer-assisted questionnaires, while serology was conducted in a blinded fashion using a glutathione S-transferase capture enzyme-linked immunosorbent assay (ELISA) to detect antibodies against HPV16 L1, E1, E2, E4, E6 and E7 proteins. The differences in tobacco use by HPV serology were evaluated by ANOVA; and the reported odds ratios and 95% confidence intervals were determined by using unconditional logistic regression.
Results
We found no overall association of HPV16 serological markers with smoking. However, when the data were stratified by median age, smoking was positively associated with seropositivity for the HPV16 L1 capsid antigen in the younger controls while the older controls were less likely to be HPV16 L1 positive if they smoked (pinteraction < 0.002). There was no similar association of smoking and age with serological response to the early proteins (i.e E6, E7).
Conclusions
Exposure to HPV16 capsid protein (L1) is increased among relatively younger adults who smoke and diminished among older smokers. However, this pattern is not accompanied by a differential susceptibility for active infection (as determined by the early gene proteins such as E6 and E7) among young and older smokers.
doi:10.1186/s12879-014-0737-3
PMCID: PMC4296688  PMID: 25572638
HPV; Smoking; Serology
2.  Occupational asbestos exposure is associated with pharyngeal squamous cell carcinoma in men from the greater Boston area 
Objectives
Asbestos describes a group of naturally occurring silicate mineral fibers that were widely used in industry during the 20th century due to their desirable physical properties. Although use in the United States has fallen over the last three decades, significant exposure in the developing world continues and the burden of disease is considerable. Asbestos is a known risk factor for several malignant diseases, including lung cancer and mesothelioma, and has more recently been implicated in pharyngeal and laryngeal cancer. However, studies of asbestos and cancers of the larynx or pharynx with adequate sample-size that control for major head and neck squamous cell carcinoma (HNSCC) risk factors remain relatively sparse.
Methods
We report findings from a case-control study of 674 incident male HNSCC cases from the greater Boston region and 857 population-based male controls, matched on age (+/− 3 years), sex, and town or neighborhood of residence. Multivariable logistic regression was used to assess the association between occupational asbestos exposure and HNSCC by primary tumor site.
Results
A total of 190 cases (28.2%) and 203 controls (23.7%) reported an occupational exposure to asbestos. Occupational asbestos exposure was associated with an elevated risk of pharyngeal carcinoma in men (OR = 1.41, 95% CI: 1.01–1.97), adjusted for age, race, smoking, alcohol consumption, education, income, and HPV16 serology, with borderline increasing risk for each decade at the exposed occupation (OR = 1.10, 95% CI: 0.99–1.23).
Conclusion
These observations are consistent with the mounting evidence that asbestos is a risk factor for pharyngeal cancer.
doi:10.1136/oemed-2013-101528
PMCID: PMC4227396  PMID: 24142981
HNSCC; head and neck cancer; epidemiology; RERI
3.  Proximity of US Schools to Major Roadways: a Nationwide Assessment 
Long-term exposure to traffic pollution has been associated with adverse health outcomes in children and adolescents. A significant number of schools may be located near major roadways, potentially exposing millions of children to high levels of traffic pollution, but this hypothesis has not been evaluated nationally. We obtained data on the location and characteristics of 114,644 US public and private schools, grades pre-kindergarten through 12, and calculated their distance to nearest major roadway. In 2005–2006, 3.2 million students (6.2%) attended 8,424 schools (7.3%) located within 100 meters of a major roadway, and an additional 3.2 million (6.3%) students attended 8,555 (7.5%) schools located 100 to 250 m from a major roadway. Schools serving predominantly black students were 18% (95% CI, 13% – 23%) more likely to be located within 250 m of a major roadway. Public schools eligible for Title I programs and those with a majority of students eligible for free/reduced price meals were also more likely to be near major roadways. In conclusion, 6.4 million US children attended schools within 250 m of a major roadway and were likely exposed to high levels of traffic pollution. Minority and underprivileged children were disproportionately affected, although some results varied regionally.
doi:10.1038/jes.2014.5
PMCID: PMC4179205  PMID: 24496217
air pollution; children; schools; socioeconomic status; traffic
4.  Short‐term Changes in Ambient Particulate Matter and Risk of Stroke: A Systematic Review and Meta‐analysis 
Background
Stroke is a leading cause of death and long‐term disability in the United States. There is a well‐documented association between ambient particulate matter air pollution (PM) and cardiovascular disease morbidity and mortality. Given the pathophysiologic mechanisms of these effects, short‐term elevations in PM may also increase the risk of ischemic and/or hemorrhagic stroke morbidity and mortality, but the evidence has not been systematically reviewed.
Methods and Results
We provide a comprehensive review of all observational human studies (January 1966 to January 2014) on the association between short‐term changes in ambient PM levels and cerebrovascular events. We also performed meta‐analyses to evaluate the evidence for an association between each PM size fraction (PM2.5, PM10, PM2.5‐10) and each outcome (total cerebrovascular disease, ischemic stroke/transient ischemic attack, hemorrhagic stroke) separately for mortality and hospital admission. We used a random‐effects model to estimate the summary percent change in relative risk of the outcome per 10‐μg/m3 increase in PM.
Conclusions
We found that PM2.5 and PM10 are associated with a 1.4% (95% CI 0.9% to 1.9%) and 0.5% (95% CI 0.3% to 0.7%) higher total cerebrovascular disease mortality, respectively, with evidence of inconsistent, nonsignificant associations for hospital admission for total cerebrovascular disease or ischemic or hemorrhagic stroke. Current limited evidence does not suggest an association between PM2.5‐10 and cerebrovascular mortality or morbidity. We discuss the potential sources of variability in results across studies, highlight some observations, and identify gaps in literature and make recommendations for future studies.
doi:10.1161/JAHA.114.000983
PMCID: PMC4310387  PMID: 25103204
air pollution; cerebrovascular disease; meta‐analysis; particulate matter; stroke
5.  Periodontal disease and mouthwash use are risk factors for head and neck squamous cell carcinoma 
Cancer causes & control : CCC  2013;24(7):1315-1322.
Purpose
The purpose of this study was to examine associations between oral hygiene, including history of periodontal disease and mouthwash use, and risk of head and neck squamous cell carcinoma (HNSCC).
Methods
We measured history of oral hygiene and dental care on 513 HNSCC cases and 567 controls from a population-based study of HNSCC. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI).
Results
Periodontal disease was associated with a slightly elevated risk of HNSCC (OR = 1.09, 95% CI: 1.02, 1.16). Using any type of mouthwash at least once per day was associated with increased risk compared to never using mouthwash (OR = 1.11, 95% CI: 1.02, 1.20). HNSCC was associated with frequent use of nonalcoholic mouthwash compared to using any kind of mouthwash rarely or never (OR = 1.24, 95% CI: 1.05, 1.47).
Conclusions
Our results support an association between periodontal disease and HNSCC. Our data suggest that mouthwash use is associated with HNSCC, but we noted no difference between the effects of alcohol-containing and nonalcoholic mouthwashes.
doi:10.1007/s10552-013-0209-x
PMCID: PMC3677056  PMID: 23568534
Periodontal disease; mouthwash use; oral hygiene; head and neck cancer
6.  Gastric reflux is an independent risk factor for laryngopharyngeal carcinoma 
Background
Gastric reflux can reach into the upper airway, inducing cellular damage in the epithelial lining. This condition is believed to be a risk factor for development of laryngopharyngeal squamous cell carcinoma (LPSCC), although the literature is conflicting.
Methods
To better clarify this relationship, we assessed the association of self-reported heartburn history and medication use among 631 LPSCC patients and 1234 control subjects (frequency-matched on age, gender and town of residence) enrolled as part of a population-based case-control study of head and neck squamous cell carcinoma in the greater Boston area.
Results
After adjusting for age, gender, race, smoking, alcohol consumption, HPV16 seropositivity, education and body mass index, subjects reporting a history of frequent heartburn and who were neither a heavy smoker nor heavy drinker had a significantly elevated risk of LPSCC (OR = 1.78, 95% CI: 1.00–3.16). Among those with a history of heartburn, there was an inverse association between antacid use and LPSCC relative to those never taking heartburn medication (OR = 0.59, 95% CI: 0.38–0.93) that remained consistent when analyzed by smoking/drinking status, HPV16 status, or by primary tumor site.
Conclusions
Our data show that gastric reflux is an independent risk factor for squamous cancers of the pharynx and larynx. Further studies are needed to clarify the possible chemopreventive role of antacid use for patients with gastric reflux.
Impact
Elucidation of additional risk factors for head and neck cancer can allow for risk stratification and inform surveillance of high-risk patients.
doi:10.1158/1055-9965.EPI-13-0183
PMCID: PMC3681904  PMID: 23703970
Heartburn; antacids; proton pump inhibitor; histamine H2 receptor antagonist; head and neck cancer
7.  Ambient Air Pollution and Depressive Symptoms in Older Adults: Results from the MOBILIZE Boston Study 
Environmental Health Perspectives  2014;122(6):553-558.
Background: Exposure to ambient air pollution, particularly from traffic, has been associated with adverse cognitive outcomes, but the association with depressive symptoms remains unclear.
Objectives: We investigated the association between exposure to ambient air and traffic pollution and the presence of depressive symptoms among 732 Boston-area adults ≥ 65 years of age (78.1 ± 5.5 years, mean ± SD).
Methods: We assessed depressive symptoms during home interviews using the Revised Center for Epidemiological Studies Depression Scale (CESD-R). We estimated residential distance to the nearest major roadway as a marker of long-term exposure to traffic pollution and assessed short-term exposure to ambient fine particulate matter (PM2.5), sulfates, black carbon (BC), ultrafine particles, and gaseous pollutants, averaged over the 2 weeks preceding each assessment. We used generalized estimating equations to estimate the odds ratio (OR) of a CESD-R score ≥ 16 associated with exposure, adjusting for potential confounders. In sensitivity analyses, we considered CESD-R score as a continuous outcome and mean annual residential BC as an alternate marker of long-term exposure to traffic pollution.
Results: We found no evidence of a positive association between depressive symptoms and long-term exposure to traffic pollution or short-term changes in pollutant levels. For example, we found an OR of CESD-R score ≥ 16 of 0.67 (95% CI: 0.46, 0.98) per interquartile range (3.4 μg/m3) increase in PM2.5 over the 2 weeks preceding assessment.
Conclusions: We found no evidence suggesting that ambient air pollution is associated with depressive symptoms among older adults living in a metropolitan area in attainment of current U.S. regulatory standards.
Citation: Wang Y, Eliot MN, Koutrakis P, Gryparis A, Schwartz JD, Coull BA, Mittleman MA, Milberg WP, Lipsitz LA, Wellenius GA. 2014. Ambient air pollution and depressive symptoms in older adults: results from the MOBILIZE Boston Study. Environ Health Perspect 122:553–558; http://dx.doi.org/10.1289/ehp.1205909
doi:10.1289/ehp.1205909
PMCID: PMC4050499  PMID: 24610154
8.  SMOKELESS TOBACCO AND RISK OF HEAD AND NECK CANCER: EVIDENCE FROM A CASE-CONTROL STUDY IN NEW ENGLAND 
Current studies suggesting that smokeless tobacco use increases the risk of head and neck cancer are hampered by small numbers. Consequently, there remains uncertainty in the magnitude and significance of this risk. We examined the relationship between smokeless tobacco use and head and neck squamous cell carcinoma (HNSCC) in a population-based case-control study with 1,046 cases and 1,239 frequency-matched controls. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI), adjusting for age, gender, race, education level, cigarette smoking, and alcohol consumption. A non-significant elevated association between having ever used smokeless tobacco and HNSCC risk (OR = 1.20, 95% CI: 0.67, 2.16) was observed. Individuals who reported 10 or more years of smokeless tobacco use had a significantly elevated risk of HNSCC (OR = 4.06, 95% CI: 1.31, 12.64), compared to never users. In an analysis restricted to never cigarette smokers, a statistically significant association was observed between ever use of smokeless tobacco and the risk of HNSCC (OR = 4.21, 95% CI: 1.01, 17.57). These findings suggest that long term use of smokeless tobacco increases the risk of HNSCC.
doi:10.1002/ijc.27839
PMCID: PMC3552089  PMID: 22987222
smokeless tobacco; head and neck cancer; case-control
9.  Occupational dust exposure and head and neck squamous cell carcinoma risk in a population-based case–control study conducted in the greater Boston area 
Cancer Medicine  2013;2(6):978-986.
Head and neck cancers account for an estimated 549,000 global cancer diagnoses each year. While tobacco use, alcohol consumption, and HPV16 infection are considered to be the major risk factors for this disease, occupational risk factors, including exposure to asbestos, have also been described, although dust exposures other than asbestos have been historically understudied. We have investigated the relationship between occupational exposures to five types of dusts, including sawdust, concrete dust, leather dust, metal dust, and chimney soot, and head and neck squamous cell carcinomas (HNSCC) in the greater Boston area. We report findings from a population-based case–control study involving 951 incident HNSCC cases and 1193 controls, frequency matched on age (±3 years), sex, and town/neighborhood of residence. Multivariable logistic regression was used to assess the association between occupational exposure to each type of dust and HNSCC, overall and by primary tumor site. After adjusting for age, sex, race, smoking, alcohol consumption, education, and HPV16 serology, laryngeal carcinoma risk increased for each decade of occupational exposure to sawdust (OR = 1.2, 95% CI: 1.0, 1.3) and metal dust (OR = 1.2, 95% CI: 1.0, 1.4); and HNSCC risk increased for each decade of occupational leather dust exposure (OR = 1.5, 95% CI: 1.2, 1.9). We have provided evidence for an association between occupational sawdust and metal dust and laryngeal squamous cell carcinoma, and leather dust and HNSCC, with increasing risk with longer duration at the exposed occupation.
doi:10.1002/cam4.155
PMCID: PMC3892403  PMID: 24403272
Concrete dust; epidemiology; HNSCC; leather dust; metal dust; sawdust; soot
10.  Regular dental visits are associated with earlier stage at diagnosis for oral and pharyngeal cancer 
Cancer causes & control : CCC  2012;23(11):1821-1829.
Purpose
Oral and pharyngeal cancer patients diagnosed at an advanced stage experience increased morbidity and mortality relative to those with localized disease. The aim of this study was to assess the impact of dental insurance status and regularity of dental visits on early detection of oral and pharyngeal cancer.
Methods
We examined the relationship of dental insurance and frequency of dental visits with stage at diagnosis among 441 oral and pharyngeal cancer cases from a population-based study of head and neck cancer. Ordinal logistic regression models were used to assess the association with stage, and tumor (T) and nodal (N) classification.
Results
Never or rarely going to the dentist was associated with being diagnosed at higher stage for oral and pharyngeal cancer (cumulative OR = 2.28, 95% CI: 1.02–5.10) and oral cancer (cumulative OR = 9.17, 95% CI: 2.70–31.15) compared to those going to the dentist at least annually. Oral and pharyngeal cancer patients who went to the dentist infrequently (cumulative OR = 1.82, 95% CI: 1.09–3.05) or rarely/never (cumulative OR = 3.24, 95% CI: 1.59–6.57) were diagnosed with a higher T classification compared with those who went at least annually.
Conclusions
Receipt of regular dental examinations at least annually may reduce the public health burden of oral and pharyngeal cancer by facilitating earlier detection of the disease.
doi:10.1007/s10552-012-0061-4
PMCID: PMC3469776  PMID: 22961100
Dental coverage; oral examination; oral cancer screening; head and neck cancer; early detection
11.  Allergies and risk of head and neck cancer 
Cancer causes & control : CCC  2012;23(8):1317-1322.
Background
Individuals with allergies have a heightened Th2 (T helper 2) immunity which may provide advantages in controlling tumor growth. Inverse associations have been reported among individuals with allergies and risk of brain and pancreatic cancers.
Methods
We examined the relationship between allergies and risk of head and neck squamous cell carcinoma (HNSCC) in a population-based case-control study with 1014 cases and 1193 frequency-matched controls. Logistic regression models were used to estimate odds ratio (OR) and 95% confidence intervals (95% CI) controlling for age, sex, race, smoking history, alcohol consumption, and education. In addition, in a subset of the population, models were adjusted for HPV16 status.
Results
Individuals with allergies had a 19% lower risk of HNSCC (OR = 0.81, 95% CI = 0.67-0.98). Associations with allergies were stronger for laryngeal (OR = 0.66, 95% CI = 0.45-0.97) and oropharyngeal (OR =0.73, 95% CI=0.57-0.92) cancers, while no association was observed for oral cavity cancers (OR = 0.98, 95% CI = 0.76-1.26). History of asthma was not associated with overall HNSCC, but the association was statistically significant for oropharyngeal cancer (OR = 0.67, 95% CI = 0.44-0.99). HPV16 status did not confound or modify the associations with allergies.
Conclusions
Elevated Th2 immunity in individuals with history of allergies and asthma may reduce the risk of HNSCC. Additional research into related mechanisms may provide new insights into how to treat HNSCC.
Impact
These findings may provide new insight into biological pathways that could lead to a better understanding of the etiology of this disease.
doi:10.1007/s10552-012-0009-8
PMCID: PMC3598569  PMID: 22710748
allergies; atopy; head and neck cancer
12.  Ridge Regression for Longitudinal Biomarker Data 
Technological advances facilitating the acquisition of large arrays of biomarker data have led to new opportunities to understand and characterize disease progression over time. This creates an analytical challenge, however, due to the large numbers of potentially informative markers, the high degrees of correlation among them, and the time-dependent trajectories of association. We propose a mixed ridge estimator, which integrates ridge regression into the mixed effects modeling framework in order to account for both the correlation induced by repeatedly measuring an outcome on each individual over time, as well as the potentially high degree of correlation among possible predictor variables. An expectation-maximization algorithm is described to account for unknown variance and covariance parameters. Model performance is demonstrated through a simulation study and an application of the mixed ridge approach to data arising from a study of cardiometabolic biomarker responses to evoked inflammation induced by experimental low-dose endotoxemia.
doi:10.2202/1557-4679.1353
PMCID: PMC3202941  PMID: 22049265
biomarkers; cardiovascular disease (CVD); mixed effects; repeated measures; ridge regression
13.  Low-Cost HIV-1 Diagnosis and Quantification in Dried Blood Spots by Real Time PCR 
PLoS ONE  2009;4(6):e5819.
Background
Rapid and cost-effective methods for HIV-1 diagnosis and viral load monitoring would greatly enhance the clinical management of HIV-1 infected adults and children in limited-resource settings. Recent recommendations to treat perinatally infected infants within the first year of life are feasible only if early diagnosis is routinely available. Dried blood spots (DBS) on filter paper are an easy and convenient way to collect and transport blood samples. A rapid and cost effective method to diagnose and quantify HIV-1 from DBS is urgently needed to facilitate early diagnosis of HIV-1 infection and monitoring of antiretroviral therapy.
Methods and Findings
We have developed a real-time LightCycler (rtLC) PCR assay to detect and quantify HIV-1 from DBS. HIV-1 RNA extracted from DBS was amplified in a one-step, single-tube system using primers specific for long-terminal repeat sequences that are conserved across all HIV-1 clades. SYBR Green dye was used to quantify PCR amplicons and HIV-1 RNA copy numbers were determined from a standard curve generated using serially diluted known copies of HIV-1 RNA. This assay detected samples across clades, has a dynamic range of 5 log10, and %CV <8% up to 4 log10 dilution. Plasma HIV-1 RNA copy numbers obtained using this method correlated well with the Roche Ultrasensitive (r = 0.91) and branched DNA (r = 0.89) assays. The lower limit of detection (95%) was estimated to be 136 copies. The rtLC DBS assay was 2.5 fold rapid as well as 40-fold cheaper when compared to commercial assays. Adaptation of the assay into other real-time systems demonstrated similar performance.
Conclusions
The accuracy, reliability, genotype inclusivity and affordability, along with the small volumes of blood required for the assay suggest that the rtLC DBS assay will be useful for early diagnosis and monitoring of pediatric HIV-1 infection in resource-limited settings.
doi:10.1371/journal.pone.0005819
PMCID: PMC2688035  PMID: 19503790

Results 1-13 (13)