Ambient long-term exposure to organophosphorus pesticides and the human gut microbiome: an observational study.

BACKGROUND: Organophosphorus pesticides (OP) have been associated with various human health conditions. Animal experiments and in-vitro models suggested that OP may also affect the gut microbiota. We examined associations between ambient chronic exposure to OP and gut microbial changes in humans. METHODS: We recruited 190 participants from a community-based epidemiologic study of Parkinson's disease living in a region known for heavy agricultural pesticide use in California. Of these, 61% of participants had Parkinson's disease and their mean age was 72 years. Microbiome and predicted metagenome data were generated by 16S rRNA gene sequencing of fecal samples. Ambient long-term OP exposures were assessed using pesticide application records combined with residential addresses in a geographic information system. We examined gut microbiome differences due to OP exposures, specifically differences in microbial diversity based on the Shannon index and Bray-Curtis dissimilarities, and differential taxa abundance and predicted Metacyc pathway expression relying on regression models and adjusting for potential confounders. RESULTS: OP exposure was not associated with alpha or beta diversity of the gut microbiome. However, the predicted metagenome was sparser and less evenly expressed among those highly exposed to OP (p = 0.04). Additionally, we found that the abundance of two bacterial families, 22 genera, and the predicted expression of 34 Metacyc pathways were associated with long-term OP exposure. These pathways included perturbed processes related to cellular respiration, increased biosynthesis and degradation of compounds related to bacterial wall structure, increased biosynthesis of RNA/DNA precursors, and decreased synthesis of Vitamin B1 and B6. CONCLUSION: In support of previous animal studies and in-vitro findings, our results suggest that ambient chronic OP pesticide exposure alters gut microbiome composition and its predicted metabolism in humans.

Solar ultraviolet radiation exposure, and incidence of childhood acute lymphocytic leukaemia and non-Hodgkin lymphoma in a US population-based dataset.

BACKGROUND: Acute lymphocytic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) are among the commonest types of childhood cancer. Some previous studies suggested that elevated ultraviolet radiation (UVR) exposures increase ALL risk; many more indicate NHL risk is reduced. METHODS: We assessed age<20 ALL/NHL incidence in Surveillance, Epidemiology and End Results data using AVGLO-derived UVR irradiance/cumulative radiant exposure measures, using quasi-likelihood models accounting for underdispersion, adjusted for age, sex, racial/ethnic group and other county-level socioeconomic variables. RESULTS: There were 30,349 cases of ALL and 8062 of NHL, with significant increasing trends of ALL with UVR irradiance (relative risk (RR) = 1.200/mW/cm2 (95% CI 1.060, 1.359, p = 0.0040)), but significant decreasing trends for NHL (RR = 0.646/mW/cm2 (95% CI 0.512, 0.816, p = 0.0002)). There was a borderline-significant increasing trend of ALL with UVR cumulative radiant exposure (RR = 1.444/MJ/cm2 (95% CI 0.949, 2.197, p = 0.0865)), and significant decreasing trends for NHL (RR = 0.284/MJ/cm2 (95% CI 0.166, 0.485, p < 0.0001)). ALL and NHL trend RR is substantially increased among those aged 0-3. All-age trend RRs are most extreme (increasing for ALL, decreasing for NHL) for Hispanics for both UVR measures. CONCLUSIONS: Our more novel finding, of excess UVR-related ALL risk, is consistent with some previous studies, but is not clear-cut, and in need of replication.

Neighborhood-level Social Determinants of Health and Waitlist Mortality for Liver Transplantation: The Liver Outcomes and Equity Index.

BACKGROUND AND AIMS: To examine neighborhood-level disparities in waitlist mortality for adult liver transplantation (LT), we developed novel area-based social determinants of health (SDOH) index using a national transplant database. METHODS: ZIP Codes of individuals listed for or received LT in the Scientific Registry of Transplant Recipients database between June 18, 2013, and May 18, 2019, were linked to 36 American Community Survey (ACS) variables across 5 SDOH domains for index development. A step-wise principal component analysis was used to construct the Liver Outcomes and Equity (LOEq) index. We then examined the association between LOEq quintiles (Q1 = worst and Q5 = best neighborhood SDOH) and waitlist mortality with competing risk regression among listed adults in the study period and acuity circle (AC) era. RESULTS: The final LOEq index consisted of 13 ACS variables. Of 59 298 adults waitlisted for LT, 30% resided in LOEq Q5 compared with only 14% in Q1. Q1 neighborhoods with worse SDOH were disproportionately concentrated in transplant regions with low median Model for End-Stage Liver Disease at transplant (MMAT) and shorter wait times. Five years cumulative incidence of waitlist mortality was 33% in Q1 in high MMAT regions versus 16% in Q5 in low MMAT regions. Despite this allocation advantage, LOEq Q1-Q4 were independently associated with elevated risk of waitlist mortality compared with Q5, with highest increased hazard of waitlist deaths of 19% (95% CI, 11%-26%) in Q1. This disparity persisted in the AC era, with 24% (95% CI, 10%-40%) increased hazard of waitlist deaths for Q1 versus Q5. CONCLUSIONS: Neighborhood SDOH independently predicts waitlist mortality in adult LT.

Residential Proximity to a Commercial Pesticide Application Site and Risk of Chronic Rhinosinusitis.

Importance: Environmental and occupational toxicants have been shown to be associated with an increased prevalence of chronic rhinosinusitis (CRS). However, few to no studies have evaluated patients for CRS using objective testing and workup protocols that fulfill guidelines for CRS diagnostic criteria. Furthermore, no study, to our knowledge, has investigated the risks of CRS in the context of residential exposure through proximity to a commercial pesticide application site. Objectives: To evaluate associations of residential proximity to a commercial pesticide application site and the prevalence of CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSwoNP). Design, Setting, and Participants: This was a retrospective cohort study of patients who presented to a tertiary care institution for rhinology evaluation between March 1, 2018, and December 31, 2022. Main Outcomes and Measures: The outcome variable was the clinical diagnosis of CRS (CRSwNP, CRSwoNP, or non-CRS control). Patients' residential addresses were utilized to determine pesticide exposure status based on a validated computational geographic information algorithm based on data from the California Pesticide Use Report System. The dichotomous independent variable of exposure status (exposed or non-exposed) was determined by assessing reports of any pesticide applications within 2000 m of each participant's residence in 2017. Multivariable logistic regressions assessing CRS status and CRS subtypes were conducted with pesticide exposure as the primary covariate of interest. The primary study outcome and measurements as well as study hypothesis were all formulated before data collection. Results: Among a total of 310 patients (90 CRSwNP, 90 CRSwoNP, and 130 control), the mean (SD) age was 50 (17) years; 164 (53%) were female. Race and ethnicity information was not considered. Controlling for patient demographic information, smoking history, county of residence, and medical comorbidities, pesticide exposure was associated with an approximately 2.5-fold increase in odds of CRS (adjusted odds ratio, 2.41; 95% CI, 1.49-3.90). Pesticide exposure was associated with similar risks for CRSwNP (adjusted relative risk ratio [aRRR], 2.34; 95% CI, 1.31-4.18) and CRSwoNP (aRRR, 2.42; 95% CI, 1.37-4.30). Conclusions and Relevance: The findings of this retrospective cohort study and analysis revealed that residential exposure to commercial pesticide application within a 2000-m buffer was independently associated with an approximately 2.5-fold increase in odds of being diagnosed with CRS. If validated by additional research, this association would have substantial implications for public health.

Association of nativity with survival among adults with hepatocellular carcinoma.

INTRODUCTION: Immigrants comprise a considerable proportion of those diagnosed with hepatocellular carcinoma (HCC) in the United States. Nativity or birthplace affects incidence and risk factors for HCC, but little is known about its influence on survival after diagnosis. METHODS: We identified 51 533 adults with HCC with available birthplace in the California Cancer Registry between 1988 and 2017. HCC cases were categorized as foreign born or US born and stratified by mutually exclusive race and ethnicity groups. Primary outcome was all-cause mortality. Race and ethnicity-specific Cox regression propensity score-weighted models evaluated the relationship between nativity and death as well as region of birth among foreign-born patients. RESULTS: A total of 40% of all HCC cases were foreign born, and 92.2%, 45.2%, 9.1%, and 5.8% of Asian/Pacific Islander (API), Hispanic, White, and Black patients were foreign born, respectively. Five-year survival rates were higher in foreign-born patients compared with US-born patients: 12.9% vs 9.6% for White patients, 11.7% vs 9.8% for Hispanic patients, 12.8% vs 8.1% for Black patients, and 16.4% vs 12.4% for API patients. Nativity was associated with survival, with better survival in foreign-born patients: White patients: hazard ratio (HR) = 0.86 (95% confidence interval [CI] = 0.81 to 0.90), Hispanic patients: HR = 0.90 (95% CI = 0.86 to 0.93), Black patients: HR = 0.89 (95% CI = 0.76 to 1.05), and API patients: HR = 0.94 (95% CI = 0.88 to 1.00). Among foreign-born patients, lower mortality was observed in those from Central and South America compared with Mexico for Hispanic patients, East Asia compared with Southeast Asia for API patients, and East Europe and Greater Middle East compared with West/South/North Europe for White patients. CONCLUSION: Foreign-born patients with HCC have better survival than US-born patients. Further investigation into the mechanisms of this survival disparity by nativity is needed.

Melanoma survival by age group: Population-based disparities for adolescent and young adult patients by stage, tumor thickness, and insurance type.

BACKGROUND: Melanoma survival literature predominantly represents patients >65 years of age. Study of younger patients may reveal potential age-group-specific differences in survival outcome. OBJECTIVE: Identify factors associated with differences in melanoma survival in 2 age groups, adolescents and young adults (AYAs; ages 15-39) and older adults (ages 40-64). METHODS: This population-based registry study included all cases (n = 81,597) of cutaneous melanoma diagnosed at ages 15 to 64 from 2004 to 2015 in California. Age-group-specific multivariable Cox hazard regressions were used. RESULTS: In the adjusted, age-group-specific models, AYA patients with stage IV melanoma had worse survival (hazard ratio: 20.39, 95% CI: 13.30-31.20) than was observed among older adults (hazard ratio: 10.79, 95% CI: 9.33-12.48). Thicker tumors and public insurance were also associated with worse survival for AYAs than observed in models for older adults. AYAs experienced better survival when detected at earlier stages. LIMITATIONS: Registry data do not routinely collect behavioral information or family history of melanoma. CONCLUSIONS: Survival was much worse for AYAs with stage IV melanoma than observed among older adults. To improve AYA survival, early melanoma detection is critical. Greater awareness, suspicion, and screening for AYA melanoma may disrupt delays in diagnosis and reduce the excess burden of mortality from stage IV melanoma in young patients.

Pediatric Small Renal Masses: Can Tumor Size Predict Histology and the Potential for Nephron-sparing Surgery?

PURPOSE: The majority of children with unilateral renal masses suspicious for malignancy undergo radical nephrectomy, while nephron-sparing surgery is reserved for select cases. We investigated the impact of tumor size on the probability of histology. We hypothesized that pediatric small renal masses are more likely benign or non-Wilms tumor, thus potentially appropriate for nephron-sparing surgery. MATERIALS AND METHODS: The SEER (Surveillance, Epidemiology, and End Results) database was analyzed for patients aged 0-18 years diagnosed with a unilateral renal mass from 2000-2016. Statistical analysis was performed to help determine a tumor size cut point to predict Wilms tumor and assess the predictive value of tumor size on Wilms tumor histology. Additionally, a retrospective review was performed of patients 0-18 years old who underwent surgery for a unilateral renal mass at a single institution from 2005-2019. Statistical analysis was performed to assess the predictive value of tumor size on final histology. RESULTS: From the SEER analysis, 2,016 patients were included. A total of 1,672 tumors (82.9%) were Wilms tumor. Analysis revealed 4 cm to be a suitable cut point to distinguish non-Wilms tumor. Tumors ≥4 cm were more likely Wilms tumor (OR 2.67, P ≤ .001), but this was driven by the statistical significance in children 5-9 years old. From the institutional analysis, 134 patients were included. Ninety-seven tumors (72.3%) were Wilms tumor. Tumors ≥4 cm had higher odds of being Wilms tumor (OR 30.85, P = .001), malignant (OR 6.75, P = .005), and having radical nephrectomy-appropriate histology (OR 46.79, P < .001). CONCLUSIONS: The probability that a pediatric unilateral renal mass is Wilms tumor increases with tumor size. Four centimeters is a logical cut point to start the conversation around defining pediatric small renal masses and may help predict nephron-sparing surgery-appropriate histology.

Prevalence and correlates of skin examination among ethnically diverse young adult survivors of childhood cancer.

BACKGROUND: Skin cancer is the most common secondary malignancy among young adult childhood cancer survivors (YA-CCS). Skin examination to detect skin cancer early (including melanoma as well as basal or squamous cell skin cancers), both physician-based (PSE) and self-skin exam (SSE), is recommended, particularly for radiotherapy-exposed YA-CCS who are at high risk of developing skin cancer. METHODS: Awareness and prevalence of skin examination and demographic, clinical, and healthcare correlates were examined in a population-based sample of YA-CCS with diverse cancer types excluding melanoma. Descriptive frequencies and logistic regression models were conducted using sample weights to correct for non-response bias with PSE, SSE and adherence to both as outcomes. RESULTS: The sample comprised 1064 participants with 53% Latino. Eight percent of participants were aware of the need for skin examination; 9% reported receipt of PSE within past 2 years; 35% reported regular SSE; and 6% were adherent to both. Among the radiotherapy-treated, 10% were aware of the need for skin examination, 10% reported recent PSE; 38% reported regular SSE; and 8% were adherent to both. Healthcare and clinical factors including healthcare self-efficacy, engagement in cancer-related follow-up care, greater treatment intensity and greater number of treatment-related late effects were positively associated with PSE and SSE. Latino YA-CCS were less likely to engage in PSE and SSE. CONCLUSION(S): Adherence to recommended screening for skin cancer was low in this at-risk population, notably for YA-CCS exposed to radiotherapy. The development of effective strategies to expand skin cancer screening is needed in this at-risk population.

Adolescent Use of Flavored Non-Tobacco Oral Nicotine Products.

BACKGROUND AND OBJECTIVES: Flavored non-tobacco oral nicotine products (eg, nicotine pouches and nontherapeutic nicotine gum, lozenges, tablets, gummies), are increasingly marketed in the United States. Prevalence of non-tobacco oral nicotine product use among adolescents is unknown. METHODS: We calculated prevalence of ever and past 6-month use of nicotine pouches, other non-tobacco oral nicotine products (ie, gum, lozenges, tablets, and/or gummies), e-cigarettes, cigarettes, hookah or waterpipe, cigars, cigarillos, and snus among high school students in Southern California between September and December 2021. Generalized linear mixed models tested associations of sociodemographic factors and tobacco-product use with use of any non-tobacco oral nicotine product. RESULTS: Among the sample (n = 3516), prevalence was highest for e-cigarettes (ever: 9.6%, past 6-month: 5.5%), followed by non-tobacco oral nicotine products (ever: 3.4%, past 6-month: 1.7%), and <1% for other products. Ever users of combustible tobacco (adjusted odds ratio [aOR] = 77.6; 95% confidence interval [CI] = 39.7-152) and ever users of noncombustible tobacco (aOR = 40.4; 95% CI= 24.3-67.0) had higher odds of ever using non-tobacco oral nicotine products, compared to never users of combustible and noncombustible tobacco. Use of any non-tobacco oral nicotine product was greater for Hispanic (versus all other races/ethnicities except Asian, aOR = 2.58; 95% CI = 1.36-4.87), sexual minority (versus heterosexual, aOR=1.63; 95% CI = 1.03-2.57), gender minority (versus male, aOR = 2.83; 95% CI = 1.29-6.19), and female (versus male, aOR=1.92, 95% CI = 1.20-3.06) participants. CONCLUSIONS: Non-tobacco oral nicotine products were the second most prevalent nicotine product used by adolescents. They were disproportionately used by certain racial or ethnic, sexual, or gender minority groups, and those with a history of nicotine use. Adolescent non-tobacco oral nicotine product use surveillance should be a public health priority.

Pre-implementation evaluation for an HPV vaccine provider communication intervention among primary care clinics.

OBJECTIVES: Interventions to improve health care provider communication about HPV vaccination can increase vaccine acceptance. Our objectives were to (1) identify clinics in locations with high HPV-associated cancer and low HPV-vaccination rates that would potentially benefit from dissemination of a proposed HPV Provider Communication intervention and (2) use qualitative interviews and a dissemination and implementation framework to assess readiness for change and fit of the HPV Provider Communication intervention to the context of these clinics. METHODS: Local HPV-associated cancer and HPV vaccination rates were assigned to Practice-Based Research Network clinics using data from the Colorado Central Cancer Registry, the Colorado Immunization Information System, and the American Community Survey. Staff from 38 clinics located in areas with high numbers of adolescents not up-to-date for HPV vaccine and high rates of HPV-associated cancers were recruited for qualitative interviews. Interview questions used the Promoting Action on Research Implementation in Health Services (PARIHS) conceptual framework and addressed the proposed intervention, current vaccination practices and prior quality improvement (QI) experience. RESULTS: Twenty-seven interviews were completed with clinicians, clinic managers, and other staff across 17 clinics (9 pediatric, 5 family medicine, 3 public/school-based health). Most clinics had some prior QI experience and there were few thematic differences between sites with more or less foundation for QI/immunization work. Participants were motivated to improve the health of their patients and valued both guidelines and local experience as important evidence to consider adopting an intervention. Interviewees were more interested in implementing the proposed intervention if it aligned with existing priorities and fit within clinic workflows. Facilitation needs included adequate time and external facilitation support for data tracking and analysis. CONCLUSIONS: Qualitative interviews to understand clinic context and fit of an HPV Provider Communication intervention can inform implementation in settings with the highest potential for clinical impact.

Geographic hotspot detection for late-stage hepatocellular carcinoma: novel approach to cancer control.

IMPORTANCE: As hepatocellular carcinoma (HCC)-associated mortality continues to rise in the United States, there is a crucial need for strategies to shift diagnoses from late to early stage in order to improve survival. OBJECTIVE: To describe a population-based geospatial approach to identifying areas with high late-stage HCC burden for intervention. DESIGN: Cross-sectional study between 2008 and 2017. SETTING: Los Angeles County. PARTICIPANTS: All incident cases of HCC with residential address at diagnosis in Los Angeles County were identified from a population-based cancer registry. Late stage included AJCC 7th Edition stages III-IV and unstaged cases. EXPOSURE: Sociodemographic factors. MAIN OUTCOME(S): Geographic "hotspots" or areas with a high density of late-stage HCC, identified using kernel density estimation in ArcMap 10.3.1. RESULTS: 51.8% of 7,519 incident cases of HCC were late stage. We identified a total of 23 late-stage hotspots, including 30.0% of all late-stage cases. Cases within hotspots were more often racial/ethnic minorities, foreign-born, under or uninsured, and of lower socioeconomic status. The age-adjusted incidence rate of late-stage HCC was twofold higher within hotspots (6.85 per 100,000 in hotspots vs 3.38 per 100,000 outside of hotspots). The calculated population-attributable risk was 43%, suggesting that a substantial proportion of late-stage HCC burden could be averted by introducing interventions in hotspot areas. We mapped the relationship between hotspots and federally qualified health centers primary care clinics and subspecialty clinics in Los Angeles County to demonstrate how clinic partnerships can be selected to maximize impact of interventions and resource use. Hotspots can also be utilized to identify "high-risk" neighborhoods that are easily recognizable by patients and the public and to facilitate community partnerships. CONCLUSION AND RELEVANCE: Reducing late-stage HCC through geographic late-stage hotspots may be an efficient approach to improving cancer control and equity.

Diverging Incidence Trends for Hepatocellular Carcinoma in Rural and Urban Settings in the United States.

In the United States, hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths and was the 5th most common cause in 2020.1 One in 5 Americans lives in a rural area,2 yet little is known about temporal changes in HCC incidence by rural-urban residence. Area-specific data are critical to guide public health strategies and clinical interventions. Our study compared the overall and subgroup incidence trends for HCC across rural and urban communities in the United States over the past 20 years using the North American Association of Central Cancer Registries database, which covers 93% of the United States and well-represents the rural United States (North American Association of Central Cancer Registries 14.6% rural vs United States 14.8% rural).3.

Sun protection changes among diverse elementary schoolchildren participating in a sun safety intervention: A latent transition analysis of a randomized controlled trial.

Children are a priority population for skin cancer prevention as excessive sun exposure in childhood increases the risk of melanoma in adulthood. The complexity of sun protective behaviors has posed measurement challenges for trials testing intervention efficacy. The current study evaluated a sun safety intervention for schoolchildren using latent transition analysis (LTA) to examine patterns of sun protection behaviors over time. A three-armed randomized controlled trial was conducted between 2012 and 2016 with two intervention groups (N = 3368) and an observation-only control group (N = 342) among 4th and 5th graders from 24 public schools in Los Angeles County. Both interventions conditions were grouped and compared to controls. Five self-reported sun protective behaviors were measured at baseline and three-month follow-up: use of sunscreen, long sleeves, long pants, hats, and shade seeking. Participants comprised 3710 schoolchildren, mean age 9 years, 47% female and 69% Latino. At baseline, four patterns of sun protection behaviors were found: children who engaged in 1) all sun protective behaviors; 2) few protective behaviors; 3) protective clothing and shade only; and 4) hats only. Children in the control group were likely to remain in their baseline status or transition to a less protective status at three-month follow-up. By contrast, 30% of children in the intervention group transitioned to a more protective status at follow-up. In this RCT of a sun safety intervention, children in the intervention transitioned to more protective behaviors compared to controls. Using LTA enriches understanding of intervention efficacy by modeling the complexity of sun protection behaviors over time. TRIAL REGISTRATION: School-based Randomized Trial of SunSmart Interventions, ClinicalTrials.gov Identifier: NCT04176237 https://clinicaltrials.gov/ct2/show/NCT04176237?cond=School-based+Randomized+Trial+of+SunSmart+Interventions&draw=2&rank=1.

High-Resolution Metabolomic Assessment of Pesticide Exposure in Central Valley, California.

Pesticides are widely used in the agricultural Central Valley region of California. Historically, this has included organophosphates (OPs), organochlorines (OCs), and pyrethroids (PYRs). This study aimed to identify perturbations of the serum metabolome in response to each class of pesticide and mutual associations between groups of metabolites and multiple pesticides. We conducted high-resolution metabolomic profiling of serum samples from 176 older adults living in the California Central Valley using liquid chromatography with high-resolution mass spectrometry. We estimated chronic pesticide exposure (from 1974 to year of blood draw) to OPs, OCs, and PYRs from ambient sources at homes and workplaces with a geographic information system (GIS)-based model. Based on partial least-squares regression and pathway enrichment analysis, we identified metabolites and metabolic pathways associated with one or multiple pesticide classes, including mitochondrial energy metabolism, fatty acid and lipid metabolism, and amino acid metabolism. Utilizing an integrative network approach, we found that the fatty acid ß-oxidation pathway is a common pathway shared across all three pesticide classes. The disruptions of the serum metabolome suggested that chronic pesticide exposure might result in oxidative stress, inflammatory reactions, and mitochondrial dysfunction, all of which have been previously implicated in a wide variety of diseases. Overall, our findings provided a comprehensive view of the molecular mechanisms of chronic pesticide toxicity, and, for the first time, our approach informs exposome research by moving from macrolevel population exposures to microlevel biologic responses.

Adult Population Coverage With Influenza Vaccine and Influenza Hospitalization Rates-Is There a Role for Active Outreach to Immunize At-Risk Neighborhoods?

We evaluated whether Denver neighborhoods with elevated rates of adult hospitalizations for laboratory-confirmed influenza had lower adult coverage with influenza vaccine. Overall vaccine coverage was low. Hospitalization rates were associated with demographic and socioeconomic characteristics. Active immunization of at-risk neighborhoods may be necessary to address disparities in influenza hospitalization rates.

An epigenome-wide association study of ambient pyrethroid pesticide exposures in California's central valley.

BACKGROUND: Pyrethroid pesticide use is increasing worldwide, although the full extent of associated health effects is unknown. An epigenome-wide association study (EWAS) with exploratory pathway analysis may help identify potential pyrethroid-related health effects. METHODS: We performed an exploratory EWAS of chronic ambient pyrethroid exposure using control participants' blood in the Parkinson's Environment and Genes Study in the Central Valley of California (N = 237). We estimated associations of living and working near agricultural pyrethroid pesticide applications in the past 5 years (binary) with site-specific differential methylation, and used a false discovery rate (FDR) cut off of 0.05 for significance. We controlled for age, sex, education, cell count, and an ancestral marker for Hispanic ethnicity. We normalized methylation values for Type I/II probe bias using Beta-Mixture Quantile (BMIQ) normalization, filtered out cross-reactive probes, and evaluated for remaining bias with Surrogate Variable Analysis (SVA). We also evaluated the effects of controlling for cell count and normalizing for Type I/II probe bias by comparing changes in effect estimates and p-values for the top hits across BMIQ and GenomeStudio normalization methods, and controlling for cell count. To facilitate broader interpretation, we annotated genes to the CpG sites and performed gene set overrepresentation analysis, using genes annotated to CpG sites that were associated with pyrethroids at a raw p < 0.05, and controlling for background representation of CpG sites on the chip. We did this for both a biological process context (Gene Ontology terms) using missMethyl, and a disease set context using WebGestalt. For these gene set overrepresentation analyses we also used an FDR cut off of 0.05 for significance of gene sets. RESULTS: After controlling for cell count and applying BMIQ normalization, 4 CpG sites were differentially methylated in relation to pyrethroid exposures. When using GenomeStudio's Illumina normalization, 415 CpG sites were differentially methylated, including all four identified with the BMIQ method. In the gene set overrepresentation analyses, we identified 6 GO terms using BMIQ normalization, and 76 using Illumina normalization, including the 6 identified by BMIQ. For disease sets, we identified signals for Alzheimer's disease, leukemia and several other cancers, diabetes, birth defects, and other diseases, for both normalization methods. We identified minimal changes in effect estimates after controlling for cell count, and controlling for cell count generally weakened p-values. BMIQ normalization, however, resulted in different beta coefficients and weakened p-values. CONCLUSIONS: Chronic ambient pyrethroid exposure is associated with differential methylation at CpG sites that annotate to a wide variety of disease states and biological mechanisms that align with prior research. However, this EWAS also implicates several novel diseases for future investigation, and highlights the relative importance of different background normalization methods in identifying associations.

Evaluation of rates of laboratory-confirmed influenza hospitalization in rural and urban census tracts over eight influenza seasons.

The burden of influenza in rural areas is largely unstudied. Rural populations may be vulnerable yet isolated from circulating virus. Laboratory-confirmed influenza hospitalizations in rural Colorado census tracts over eight influenza seasons were inconsistently distributed across seasons. Rural rates were, on average, lower than urban rates. Race, ethnicity, poverty, health insurance coverage, and distance from a hospital accounted for rate differences. Our interpretation is: 1) influenza regularly circulates in urban areas and inconsistently spreads to rural areas, 2) demographic and socioeconomic factors drive morbidity in exposed populations, and 3) public health interventions targeting high-risk urban census tracts may be beneficial.

Prevalence and correlates of adherence to skin examination among adolescent and young adult survivors of melanoma from the Project Forward Study.

BACKGROUND: Melanoma is a common cancer among adolescents and young adults (AYAs), yet adherence to recommended surveillance and factors related to adherence are not well understood in this population. This study assessed the prevalence and correlates of physician-conducted skin examination (PSE) and skin self-examination (SSE) among AYA-aged long-term survivors of melanoma. PROCEDURES: Melanoma cases were identified from the Los Angeles County cancer registry and surveys were then completed by 128 respondents diagnosed between the ages 0 and 24, with stage 1 melanoma or higher, at least 5 years from diagnosis, and who were between the ages 18 and 39 at the time of survey. RESULTS: Eighty-two percent of AYA melanoma survivors reported SSE within the past 6 months, while 65% reported annual PSE. Greater health care self-efficacy was positively associated with adherence to PSE, SSE, and both types of skin examinations (P < .01). Higher socioeconomic status and having a regular source of primary health care were positively associated with annual PSE and adherence to both surveillance practices (P < .05 and P < .01, respectively). Hispanic ethnicity was negatively associated with annual PSE compared to non-Hispanics (P < .01), and greater depressive symptoms were negatively associated with adherence to both skin examinations (P < .05). CONCLUSIONS: High rates of SSE were observed, but PSE adherence was lower than optimal in this sample. Interventions to improve PSE are needed for at-risk AYA survivors of melanoma, and strategies that help melanoma survivors navigate the health care system and access primary care may facilitate greater adherence.