Flortaucipir tau PET findings from former professional and college American football players in the DIAGNOSE CTE research project.

INTRODUCTION: Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD: We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS: Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. DISCUSSION: Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

White matter hyperintensities in former American football players.

INTRODUCTION: The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players. METHODS: A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60. RESULTS: In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function. DISCUSSION: In older former football players, WMH may have unique presentations, risk factors, and etiologies. HIGHLIGHTS: Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.

High prevalence of chronic kidney disease of unknown etiology among workers in the Mesoamerican Nephropathy Occupational Study.

BACKGROUND: Mortality from chronic kidney disease of unknown etiology (CKDu) is extremely high along the Pacific coast of Central America, particularly among sugarcane workers. The Mesoamerican Nephropathy Occupational Study (MANOS) is a prospective cohort study of CKDu among agricultural and non-agricultural workers in El Salvador and Nicaragua. The objective of this manuscript is to describe the MANOS cohort recruitment, baseline data collection, and CKDu prevalence after two rounds. METHODS: Workers with no known diabetes, hypertension, or CKD were recruited from sugarcane, corn, plantain, brickmaking, and road construction industries (n = 569). Investigators administered questionnaires, collected biological samples, and observed workers for three consecutive workdays at the worksite. Serum specimens were analyzed for kidney function parameters, and used to calculate estimated glomerular filtration rate (eGFR). At six months, serum was collected again prior to the work shift. CKD at baseline is defined as eGFR ≤ 60 ml/min/1.73m2 at both timepoints. Age-standardized prevalence was calculated by industry, country, and demographic measures. Kidney function parameters were compared by CKD status. RESULTS: Prevalence of CKD at baseline was 7.4% (n = 42). Age-standardized prevalence was highest in Salvadoran sugarcane (14.1%), followed by Salvadoran corn (11.6%), and Nicaraguan brickmaking (8.1%). Nicaraguan sugarcane had the lowest prevalence, likely due to kidney function screenings prior to employment. CONCLUSION: Despite efforts to enroll participants without CKD, our identification of prevalent CKD among agricultural and non-agricultural workers in the MANOS cohort indicates notable kidney disease in the region, particularly among sugarcane workers.

A Prospective Ultrasound Study of Plasma Polychlorinated Biphenyl Concentrations and Incidence of Uterine Leiomyomata.

BACKGROUND: Uterine leiomyomata, or fibroids, are hormone-dependent neoplasms of the myometrium that can cause severe gynecologic morbidity. In previous studies, incidence of these lesions has been positively associated with exposure to polychlorinated biphenyls (PCBs), a class of persistent endocrine-disrupting chemicals. However, previous studies have been retrospective in design and none has used ultrasound to reduce disease misclassification. METHODS: The Study of Environment, Lifestyle, and Fibroids is a prospective cohort of 1,693 reproductive-aged Black women residing in Detroit, Michigan (enrolled during 2010-2012). At baseline and every 20 months for 5 years, women completed questionnaires, provided blood samples, and underwent transvaginal ultrasound to detect incident fibroids. We analyzed 754 baseline plasma samples for concentrations of 24 PCB congeners using a case-cohort study design. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals for the association between plasma PCB concentrations and ultrasound-detected fibroid incidence over a 5-year period. RESULTS: We observed little association between PCB congener concentrations and fibroid incidence. The HR for a one-standard deviation increase in log-transformed total PCBs was 0.94 (95% CI = 0.78, 1.1). The PCB congener with the largest effect estimate was PCB 187 (HR for a one-standard deviation increase in log-transformed exposure = 0.88, 95% CI = 0.73, 1.1). Associations did not seem to vary strongly across PCB groupings based on hormonal activity. CONCLUSIONS: In this cohort of reproductive-aged Black women, plasma PCB concentrations typical of the contemporary general population were not appreciably associated with higher risk of fibroids.

Duration of American Football Play and Chronic Traumatic Encephalopathy.

OBJECTIVE: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to contact and collision sports, including American football. We hypothesized a dose-response relationship between duration of football played and CTE risk and severity. METHODS: In a convenience sample of 266 deceased American football players from the Veterans Affairs-Boston University-Concussion Legacy Foundation and Framingham Heart Study Brain Banks, we estimated the association of years of football played with CTE pathological status and severity. We evaluated the ability of years played to classify CTE status using receiver operating characteristic curve analysis. Simulation analyses quantified conditions that might lead to selection bias. RESULTS: In total, 223 of 266 participants met neuropathological diagnostic criteria for CTE. More years of football played were associated with having CTE (odds ratio [OR] = 1.30 per year played, 95% confidence interval [CI] = 1.19-1.41; p = 3.8 × 10-9 ) and with CTE severity (severe vs mild; OR = 1.14 per year played, 95% CI = 1.07-1.22; p = 3.1 × 10-4 ). Participants with CTE were 1/10th as likely to have played <4.5 years (negative likelihood ratio [LR] = 0.102, 95% CI = 0.100-0.105) and were 10 times as likely to have played >14.5 years (positive LR = 10.2, 95% CI = 9.8-10.7) compared with participants without CTE. Sensitivity and specificity were maximized at 11 years played. Simulation demonstrated that years played remained adversely associated with CTE status when years played and CTE status were both related to brain bank selection across widely ranging scenarios. INTERPRETATION: The odds of CTE double every 2.6 years of football played. After accounting for brain bank selection, the magnitude of the relationship between years played and CTE status remained consistent. ANN NEUROL 2020;87:116-131.

Chrysotile fibers in tissue adjacent to laryngeal squamous cell carcinoma in cases with a history of occupational asbestos exposure.

Asbestos describes a group of naturally occurring fibrous silicate mineral compounds that have been associated with a number of respiratory maladies, including mesothelioma and lung cancer. In addition, based primarily on epidemiologic studies, asbestos has been implicated as a risk factor for laryngeal and pharyngeal squamous cell carcinoma (SCC). The main objective of this work was to strengthen existing evidence via empirical demonstration of persistent asbestos fibers embedded in the tissue surrounding laryngeal and pharyngeal SCC, thus providing a more definitive biological link between exposure and disease. Six human papillomavirus (HPV)-negative laryngeal (n = 4) and pharyngeal (n = 2) SCC cases with a history working in an asbestos-exposed occupation were selected from a large population-based case-control study of head and neck cancer. A laryngeal SCC case with no history of occupational asbestos exposure was included as a control. Tissue cores were obtained from adjacent nonneoplastic tissue in tumor blocks from the initial primary tumor resection, and mineral fiber analysis was performed using a scanning electron microscope equipped with an energy dispersive X-ray analyzer (EDXA). Chrysotile asbestos fiber bundles were identified in 3/6 of evaluated cases with a history of occupational asbestos exposure. All three cases had tumors originating in the larynx. In addition, a wollastonite fiber of unclear significance was identified one of the HPV-negative pharyngeal SCC cases. No mineral fibers were identified in adjacent tissue of the case without occupational exposure. The presence of asbestos fibers in the epithelial tissue surrounding laryngeal SCC in cases with a history of occupational asbestos exposure adds a key line of physical evidence implicating asbestos as an etiologic factor.

Prevalence and Risk Factors for CKD Among Brickmaking Workers in La Paz Centro, Nicaragua.

RATIONALE & OBJECTIVE: In Central America, there is a high prevalence of chronic kidney disease (CKD) of nontraditional etiology often observed among agricultural workers. Few studies have assessed CKD prevalence among workers in nonagricultural occupations, which was the objective of this investigation. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Male and female workers (n = 224) employed by artisanal brickmaking facilities in La Paz Centro, Nicaragua. PREDICTORS: Age, sex, education, smoking status, body mass index, alcohol consumption, water consumption, first-degree relative(s) with CKD, years worked, hours worked per week, job category, study visit (baseline and follow-up), and self-reported hypertension and diabetes. OUTCOMES: CKD defined as estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2 at 2 time points 4 months apart and CKD stage. ANALYTICAL APPROACH: A linear mixed-effects model with an unstructured covariance matrix was used to evaluate the association between demographics, occupational risk factors, and eGFR at baseline. The interaction between risk factors and time with change in eGFR was also evaluated. Multivariable logistic regression models were used to evaluate predictors of CKD. RESULTS: The CKD prevalence was 12.1% (n = 27), 100% of cases were male, 30% had stage 5 CKD (eGFR < 15mL/min/1.73m2), and 22% were younger than 35 years. Proportions of participants with eGFRs < 60mL/min/1.73m2 at baseline and follow-up were 13.8% and 15.2%, respectively. Linear regression analysis demonstrated significant predictors of lower kidney function at baseline including oven work, older age, lack of education, and having an immediate family member with CKD. Predictors of CKD identified using logistic regression analysis included oven work and lack of education. LIMITATIONS: Crude job classification measures, loss to follow-up, self-reported exposures. CONCLUSIONS: The prevalence of CKD is high in this population of brick workers, suggesting that the epidemic of CKD affecting Mesoamerica is not limited to agricultural workers. These results are consistent with the hypothesis that occupational heat exposure is a risk factor for kidney disease in this region.

Age of first exposure to tackle football and chronic traumatic encephalopathy.

OBJECTIVE: To examine the effect of age of first exposure to tackle football on chronic traumatic encephalopathy (CTE) pathological severity and age of neurobehavioral symptom onset in tackle football players with neuropathologically confirmed CTE. METHODS: The sample included 246 tackle football players who donated their brains for neuropathological examination. Two hundred eleven were diagnosed with CTE (126 of 211 were without comorbid neurodegenerative diseases), and 35 were without CTE. Informant interviews ascertained age of first exposure and age of cognitive and behavioral/mood symptom onset. RESULTS: Analyses accounted for decade and duration of play. Age of exposure was not associated with CTE pathological severity, or Alzheimer's disease or Lewy body pathology. In the 211 participants with CTE, every 1 year younger participants began to play tackle football predicted earlier reported cognitive symptom onset by 2.44 years (p < 0.0001) and behavioral/mood symptoms by 2.50 years (p < 0.0001). Age of exposure before 12 predicted earlier cognitive (p < 0.0001) and behavioral/mood (p < 0.0001) symptom onset by 13.39 and 13.28 years, respectively. In participants with dementia, younger age of exposure corresponded to earlier functional impairment onset. Similar effects were observed in the 126 CTE-only participants. Effect sizes were comparable in participants without CTE. INTERPRETATION: In this sample of deceased tackle football players, younger age of exposure to tackle football was not associated with CTE pathological severity, but predicted earlier neurobehavioral symptom onset. Youth exposure to tackle football may reduce resiliency to late-life neuropathology. These findings may not generalize to the broader tackle football population, and informant-report may have affected the accuracy of the estimated effects. Ann Neurol 2018;83:886-901.

Acute Kidney Injury in Sugarcane Workers at Risk for Mesoamerican Nephropathy.

RATIONALE & OBJECTIVE: Mesoamerican nephropathy (MeN), a form of chronic kidney disease (CKD) of unknown cause in Central America, affects young individuals working in physically strenuous occupations. Repeated episodes of work-related kidney injury may lead to CKD in this setting. We aimed to better understand the burden and natural history of acute kidney injury (AKI) in workers at risk for MeN. STUDY DESIGN: Cross-sectional study of active sugarcane workers, followed by prospective follow-up of individuals with AKI. SETTING & PARTICIPANTS: 326 sugarcane workers with normal preharvest serum creatinine (Scr) values and no history of CKD in an MeN hotspot in Nicaragua near the end of the harvest, and prospective follow-up of workers with AKI. PREDICTOR: AKI during the harvest, as defined by Scr level increase ≥ 0.3mg/dL over baseline to a level ≥ 1.3mg/dL. OUTCOMES: Kidney function trajectory and development of CKD over 12 months. ANALYTICAL APPROACH: Linear regression models were used to analyze the association between job category and kidney function. For workers with AKI, the effect of time on Scr level was evaluated using linear mixed effects. RESULTS: 34 of 326 participants were found to have AKI, with a median late-harvest Scr level of 1.64mg/dL in the AKI group. Workers without AKI had a median Scr level of 0.88mg/dL. AKI was more common among cane cutters compared with other field workers. Participants with AKI had variable degrees of kidney function recovery, with median 6- and 12-month Scr values of 1.25 and 1.27mg/dL, respectively (P < 0.001 for each follow-up value compared to late-harvest Scr). When we compared workers' kidney function before the AKI episode to their kidney function at last follow-up, 10 participants with AKI developed de novo estimated glomerular filtration rate < 60mL/min/1.73m2 and 11 had a >30% decrease in estimated glomerular filtration rate. LIMITATIONS: Follow-up limited to 1 year and some loss to follow-up in the prospective component of the study. Broad definition of AKI that includes both acute and subacute kidney injury. CONCLUSIONS: In a group of sugarcane workers with normal preharvest kidney function, newly decreased kidney function developing during the harvest season was common. Of those with kidney injury, nearly half had established CKD 12 months later.

Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football.

Importance: Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). Objective: To determine the neuropathological and clinical features of deceased football players with CTE. Design, Setting, and Participants: Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. Exposures: Participation in American football at any level of play. Main Outcomes and Measures: Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. Results: Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre-high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. Conclusions and Relevance: In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.

Biomarkers of Kidney Injury Among Nicaraguan Sugarcane Workers.

BACKGROUND: In Central America, an epidemic of chronic kidney disease of unknown cause disproportionately affects young male agricultural workers. STUDY DESIGN: Longitudinal cohort study. SETTING & PARTICIPANTS: 284 sugarcane workers in 7 jobs were recruited from one company in northwestern Nicaragua. Blood and urine samples were collected before and near the end of the 6-month harvest season. PREDICTORS: Job category (cane cutter, seeder, seed cutter, agrichemical applicator, irrigator, driver, and factory worker); self-reported water and electrolyte solution intake. OUTCOMES & MEASUREMENTS: Changes in levels of urinary kidney injury biomarkers normalized to urine creatinine level, including neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), N-acetyl-ß-d-glucosaminidase (NAG), and albumin; serum creatinine-based estimated glomerular filtration rate (eGFR). RESULTS: Mean eGFR was 113 mL/min/1.73 m(2) and <5% of workers had albuminuria. Field workers had increases in NGAL and IL-18 levels that were 1.49 (95% CI, 1.06 to 2.09) and 1.61 (95% CI, 1.12 to 2.31) times as high, respectively, as in non-field workers. Cane cutters and irrigators had the greatest increases in NGAL levels during the harvest, whereas cane cutters and seeders had the greatest increases in IL-18 levels. Electrolyte solution consumption was associated with lower mean NGAL and NAG levels among cane cutters and lower mean IL-18 and NAG levels among seed cutters; however, there was no overall effect of hydration among all workers. On average, workers with the largest increases in NGAL and NAG levels during the harvest had declines in eGFRs of 4.6 (95% CI, 1.0 to 8.2) and 3.1 (95% CI, -0.6 to 6.7) mL/min/1.73 m(2), respectively. LIMITATIONS: Surrogate exposure measure, loss to follow-up. CONCLUSIONS: Results are consistent with the hypothesis that occupational heat stress and volume depletion may be associated with the development of kidney disease, and future studies should directly measure these occupational factors. The presence of urine tubular injury markers supports a tubulointerstitial disease that could occur with repeated tubular injury.

Characterization of Mesoamerican Nephropathy in a Kidney Failure Hotspot in Nicaragua.

BACKGROUND: Mesoamerican nephropathy (MeN) is a kidney disease of unknown cause that mainly affects working-age men in Central America. Despite being a major cause of morbidity and mortality in this region, its clinical characteristics have not been well defined. STUDY DESIGN: Cross-sectional family-based study. SETTING & PARTICIPANTS: 266 members of 24 families with high chronic kidney disease (CKD) burdens in a MeN hotspot in Northwestern Nicaragua. We compared clinical and biochemical characteristics of affected individuals first with their unaffected relatives and then with NHANES (National Health and Nutrition Examination Survey) participants with CKD in order to reveal identifying features of MeN. PREDICTOR: CKD defined as serum creatinine level ≥ 1.5mg/dL in men and ≥1.4mg/dL in women. OUTCOMES: Clinical and biochemical parameters, including serum sodium, potassium, bicarbonate, calcium, magnesium, phosphorus, and uric acid. RESULTS: Hyperuricemia, in many cases severe, was common among patients with MeN. Uric acid levels in patients with MeN were higher than those in NHANES participants (mean, 9.6 vs 7.4mg/dL for men in each group) despite more frequent use of uric acid-lowering medications in Nicaraguan individuals (71.7% vs 11.2%). In multivariable linear mixed-effects regression analysis, uric acid levels were 2.0mg/dL (95% CI, 1.0-3.0; P<0.001) higher in patients with MeN compared with their NHANES counterparts after adjusting for age, estimated glomerular filtration rate, and uric acid-lowering therapies. In contrast to prior reports, hyponatremia and hypokalemia were not common. LIMITATIONS: CKD defined by single serum creatinine measurement; population likely not representative of full MeN phenotype spectrum across Central America; major differences between MeN and NHANES groups in important characteristics such as age, ancestry, and recruitment method. CONCLUSIONS: Hyperuricemia out of proportion to the degree of decreased kidney function was common among Nicaraguan patients with MeN. Our results suggest that rather than being solely a consequence of CKD, hyperuricemia may play a role in MeN pathogenesis, a hypothesis that deserves further study.

Urine biomarkers of kidney injury among adolescents in Nicaragua, a region affected by an epidemic of chronic kidney disease of unknown aetiology.

BACKGROUND: An epidemic of chronic kidney disease (CKD) of non-traditional aetiology has been recently recognized by health authorities as a public health priority in Central America. Previous studies have identified strenuous manual work, agricultural activities and residence at low altitude as potential risk factors; however, the aetiology remains unknown. Because individuals are frequently diagnosed with CKD in early adulthood, we measured biomarkers of kidney injury among adolescents in different regions of Nicaragua to assess whether kidney damage might be initiated during childhood. METHODS: Participants include 200 adolescents aged 12-18 years with no prior work history from four different schools in Nicaragua. The location of the school served as a proxy for environmental exposures and geographic locations were selected to represent a range of factors that have been associated with CKD in adults (e.g. altitude, primary industry and CKD mortality rates). Questionnaires, urine dipsticks and kidney injury biomarkers [interleukin-18, N-acetyl-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL) and albumin-creatinine ratio] were assessed. Biomarker concentrations were compared by school using linear regression models. RESULTS: Protein (3.5%) and glucose (1%) in urine measured by dipstick were rare and did not differ by school. Urine biomarkers of tubular kidney damage, particularly NGAL and NAG, showed higher concentrations in those schools and regions within Nicaragua that were defined a priori as having increased CKD risk. Painful urination was a frequent self-reported symptom. CONCLUSIONS: Although interpretation of these urine biomarkers is limited because of the lack of population reference values, results suggest the possibility of early kidney damage prior to occupational exposures in these adolescents.

Identification of Biomarkers of Exposure to FTOHs and PAPs in Humans Using a Targeted and Nontargeted Analysis Approach.

Although historic perfluorinated compounds are currently under scrutiny and growing regulatory control in the world, little is known about human exposure to other polyfluorinated compounds presently in use. Fluorotelomer alcohols (FTOHs) and polyfluoroalkyl phosphate esters (PAPs) are known to degrade to terminal perfluorinated acids and toxic reactive intermediates through metabolic pathways. Therefore, it is important to characterize their human exposure by the identification of unique biomarkers. With the use of liquid chromatography-mass spectrometry-time-of-flight analysis (LC-MS-TOF), we developed a workflow for the identification of metabolites for the 8:2 FTOH and 8:2 diPAP. Analysis of serum and urine of dosed rats indicated the 8:2 FTOH-sulfate and the 8:2 diPAP as potential biomarkers. These compounds, as well as 25 other fluorinated compounds and metabolites, were analyzed in human serum and urine samples from the general population (n = 100) and office workers (n = 30). The 8:2 FTOH-sulfate was measured for the first time in human samples in 5 to 10% of the serum samples, ranging from 50 to 80 pg/mL. The 8:2 diPAP was measured in 58% of the samples, ranging from 100 to 800 pg/mL. This study indicates the FTOH-sulfate conjugate as a biomarker of exposure to FTOHs and PAPs in humans.

High-risk HPV types and head and neck cancer.

Although HPV16 has been strongly implicated in oropharyngeal carcinogenesis, the role of other high-risk HPV types in the etiology of head and neck cancer remains unclear. To date, few data exist addressing the nature of the association between antibodies to oncogenic proteins of non-HPV16 HPVs in relation to head and neck cancer. We examined the relationship between multiple HPV types (HPV6, 11, 16, 18, 31, 33, 45, 52, 58) and head and neck squamous cell carcinoma (HNSCC) in a large population-based case-control study (1069 cases and 1107 controls). Serological measures for HPV types included antibodies to L1, E6 and/or E7. In a secondary analysis, we excluded HPV16 seropositive subjects to examine independent associations with other high-risk HPVs. All analyses were adjusted for age, race, sex, education, smoking and alcohol consumption. Statistically significant associations were observed for HPV16, 18, 33 and 52 and risk of HNSCC after mutually adjusting for HPV types. Among HPV16 seronegative subjects, elevated risks of HNSCC were observed for HPV18 E6 (OR = 4.19, 95% CI = 1.26-14.0), HPV33 E6 (OR = 7.96, 95% CI = 1.56-40.5) and HPV52 E7 (OR = 3.40, 95% CI = 1.16-9.99). When examined by tumor type, associations with HPV18 and HPV33 remained statistically significant for oropharyngeal cancer, and HPV52 was associated with oral cancer. In addition, magnitude of associations for HNSCC increased markedly with increasing number of seropositive high-risk HPV infections. High-risk HPV types, other than HPV16, are likely to be involved in the etiology of HNSCC.

Temporal variability of polybrominated diphenyl ether (PBDE) serum concentrations over one year.

Polybrominated diphenyl ethers (PBDEs) are flame retardant chemicals used in consumer products. They are common contaminants in human serum and associated with adverse health effects. Our objectives were to characterize PBDE serum concentrations in a New England cohort and assess temporal variability of this exposure biomarker over a one-year period. We collected three repeated measurements at six-month intervals from 52 office workers from the greater Boston (MA, United States) area from 2010 to 2011. The intraclass correlation coefficient for BDEs 28, 47, 99, 100, and 153 ranged from 0.87 to 0.99, indicating that a single serum measurement can reliably estimate exposure over a one-year period. This was true for both lipid adjusted and nonlipid adjusted concentrations. The kappa statistics, quantifying the level of agreement of categorical exposure classification, based on medians, tertiles, or quartiles ranged from 0.67 to 0.90. Some congeners showed nonsignificant increases from sampling round 1 (winter) to round 2 (summer) and significant decreases from round 2 to round 3 (winter). This study highlights the high reliability of a single serum PBDE measurement for use in human epidemiologic studies.

Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players.

BACKGROUND AND OBJECTIVES: Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health. METHODS: Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid ß1-42, p-tau181, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI. RESULTS: In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau181: B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau181 (158%), and FA (287%) than the unexposed men. DISCUSSION: Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau181 and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.

Clinical Outcomes and Tau Pathology in Retired Football Players: Associations With Diagnosed and Witnessed Sleep Apnea.

Background and Objectives: Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. Methods: The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. Results: Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. Discussion: Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.

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 nonsignificant 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.

Periodontal disease and mouthwash use are risk factors for head and neck squamous cell carcinoma.

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 non-alcoholic 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 non-alcoholic mouthwashes.