A cluster-randomized trial of water, sanitation, handwashing and nutritional interventions on stress and epigenetic programming.

A regulated stress response is essential for healthy child growth and development trajectories. We conducted a cluster-randomized trial in rural Bangladesh (funded by the Bill & Melinda Gates Foundation, ClinicalTrials.gov NCT01590095) to assess the effects of an integrated nutritional, water, sanitation, and handwashing intervention on child health. We previously reported on the primary outcomes of the trial, linear growth and caregiver-reported diarrhea. Here, we assessed additional prespecified outcomes: physiological stress response, oxidative stress, and DNA methylation (N = 759, ages 1-2 years). Eight neighboring pregnant women were grouped into a study cluster. Eight geographically adjacent clusters were block-randomized into the control or the combined nutrition, water, sanitation, and handwashing (N + WSH) intervention group (receiving nutritional counseling and lipid-based nutrient supplements, chlorinated drinking water, upgraded sanitation, and handwashing with soap). Participants and data collectors were not masked, but analyses were masked. There were 358 children (68 clusters) in the control group and 401 children (63 clusters) in the intervention group. We measured four F2-isoprostanes isomers (iPF(2α)-III; 2,3-dinor-iPF(2α)-III; iPF(2α)-VI; 8,12-iso-iPF(2α)-VI), salivary alpha-amylase and cortisol, and methylation of the glucocorticoid receptor (NR3C1) exon 1F promoter including the NGFI-A binding site. Compared with control, the N + WSH group had lower concentrations of F2-isoprostanes isomers (differences ranging from -0.16 to -0.19 log ng/mg of creatinine, P < 0.01), elevated post-stressor cortisol (0.24 log µg/dl; P < 0.01), higher cortisol residualized gain scores (0.06 µg/dl; P = 0.023), and decreased methylation of the NGFI-A binding site (-0.04; P = 0.037). The N + WSH intervention enhanced adaptive responses of the physiological stress system in early childhood.

Stress biomarkers and child development in young children in Bangladesh.

BACKGROUND: Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh. METHODS: We assessed physiologic measures of stress in the first two years of life using measures of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol and glucocorticoid receptor gene methylation), the sympathetic-adrenal-medullary (SAM) system (salivary alpha-amylase, heart rate, and blood pressure), and oxidative status (F2-isoprostanes). We assessed child development in the first two years of life with the MacArthur-Bates Communicative Development Inventories (CDI), the WHO gross motor milestones, and the Extended Ages and Stages Questionnaire (EASQ). We compared development outcomes of children at the 75th and 25th percentiles of stress biomarker distributions while adjusting for potential confounders using generalized additive models, which are statistical models where the outcome is predicted by a potentially non-linear function of predictor variables. RESULTS: We analyzed data from 684 children (49% female) at both 14 and 28 months of age; we included an additional 765 children at 28 months of age. We detected a significant relationship between HPA axis activity and child development, where increased HPA axis activity was associated with poor development outcomes. Specifically, we found that cortisol reactivity (coefficient -0.15, 95% CI (-0.29, -0.01)) and post-stressor levels (coefficient -0.12, 95% CI (-0.24, -0.01)) were associated with CDI comprehension score, post-stressor cortisol was associated with combined EASQ score (coefficient -0.22, 95% CI (-0.41, -0.04), and overall glucocorticoid receptor methylation was associated with CDI expression score (coefficient -0.09, 95% CI (-0.17, -0.01)). We did not detect a significant relationship between SAM activity or oxidative status and child development. CONCLUSIONS: Our observations reveal associations between the physiological evidence of stress in the HPA axis with developmental status in early childhood. These findings add to the existing evidence exploring the developmental consequences of early life stress.

The Minority and Rural Coronavirus Insights Study: Design and Baseline Characteristics of a Minority Cohort.

The Minority and Rural Coronavirus Insights Study (MRCIS) is an ongoing prospective cohort study examining health disparities associated with SARS-CoV-2 infection among medically underserved populations. This report describes procedures implemented to establish the MRCIS cohort and examines the factors associated with the molecular and serological assessment of SARS-CoV-2 infection status at participant enrollment. Participants were recruited from 5 geographically dispersed federally qualified health centers between November 2020 and April 2021. At baseline, participants completed a detailed demographic survey and biological samples were collected for testing. SARS-CoV-2 infection status was determined based on the combined molecular and serological test results. Chi-squared and logistic regression analyses were conducted to examine associations between sociodemographic factors, COVID-19 safety measures, existing comorbidities, and SARS-CoV-2 infection status. The final cohort included 3238 participants. The mean age of participants was 50.2 ± 15.8 years. Most participants identified as female (60.0%), heterosexual or straight (93.0%), White (47.6%), and Hispanic or Latino (49.1%). Approximately 26.1% of participants had at least one positive SARS-CoV-2 test result. The main effect model included age, sex, and race/ethnicity. Compared with adults ≥65 years, participants in all other age groups had ∼2 times increased odds of a positive SARS-CoV-2 test result. In addition, racial/ethnic minorities had ∼2 times increased odds of a positive SARS-CoV-2 infection status compared with non-Hispanic Whites. A unique cohort of a traditionally medically underserved minority population was established. Significant racial and ethnic disparities in SARS-CoV-2 infection status at baseline were discovered.

Capturing emergency dispatch address points as geocoding candidates to quantify delimited confidence in residential geolocation.

BACKGROUND: In response to citizens' concerns about elevated cancer incidence in their locales, US CDC proposed publishing cancer incidence at sub-county scales. At these scales, confidence in patients' residential geolocation becomes a key constraint of geospatial analysis. To support monitoring cancer incidence in sub-county areas, we presented summary metrics to numerically delimit confidence in residential geolocation. RESULTS: We defined a concept of Residential Address Discriminant Power (RADP) as theoretically perfect within all residential addresses and its practical application, i.e., using Emergency Dispatch (ED) Address Point Candidates of Equivalent Likelihood (CEL) to quantify Residential Geolocation Discriminant Power (RGDP) to approximate RADP. Leveraging different productivity of probabilistic, deterministic, and interactive geocoding record linkage, we simultaneously detected CEL for 5,807 cancer cases reported to North Carolina Central Cancer Registry (NC CCR)- in January 2022. Batch-match probabilistic and deterministic algorithms matched 86.0% cases to their unique ED address point candidates or a CEL, 4.4% to parcel site address, and 1.4% to street centerline. Interactively geocoded cases were 8.2%. To demonstrate differences in residential geolocation confidence between enumeration areas, we calculated sRGDP for cancer cases by county and assessed the existing uncertainty within the ED data, i.e., identified duplicate addresses (as CEL) for each ED address point in the 2014 version of the NC ED data and calculated ED_sRGDP by county. Both summary RGDP (sRGDP) (0.62-1.00) and ED_sRGDP (0.36-1.00) varied across counties and were lower in rural counties (p < 0.05); sRGDP correlated with ED_sRGDP (r = 0.42, p < 0.001). The discussion covered multiple conceptual and economic issues attendant to quantifying confidence in residential geolocation and presented a set of organizing principles for future work. CONCLUSIONS: Our methodology produces simple metrics - sRGDP - to capture confidence in residential geolocation via leveraging ED address points as CEL. Two facts demonstrate the usefulness of sRGDP as area-based summary metrics: sRGDP variability between counties and the overall lower quality of residential geolocation in rural vs. urban counties. Low sRGDP for the cancer cases within the area of interest helps manage expectations for the uncertainty in cancer incidence data. By supplementing cancer incidence data with sRGDP and ED_sRGDP, CCRs can demonstrate transparency in geocoding success, which may help win citizen trust.

Stress Biomarkers and Child Development in Young Children in Bangladesh.

Background: Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh. Methods: We assessed physiologic measures of stress in the first two years of life using measures of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol and glucocorticoid receptor gene methylation), the sympathetic-adrenal-medullary (SAM) system (salivary alpha-amylase, heart rate, and blood pressure), and oxidative status (F2-isoprostanes). We assessed child development in the first two years of life with the MacArthur-Bates Communicative Development Inventories (CDI), the WHO gross motor milestones, and the Extended Ages and Stages Questionnaire (EASQ). We compared development outcomes of children at the 75th and 25th percentiles of stress biomarker distributions while adjusting for potential confounders (hereafter referred to as contrasts) using generalized additive models, which are statistical models where the outcome is predicted by a potentially non-linear function of predictor variables. Results: We analyzed data from 684 children (49% female) at both 14 and 28 months of age; we included an additional 765 children at 28 months of age. We observed 135 primary contrasts of the differences in child development outcomes at the 75th and 25th percentiles of stress biomarkers, where we detected significant relationships in 5 out of 30 contrasts (17%) of HPA axis activity, 1 out of 30 contrasts (3%) of SAM activity, and 3 out of 75 contrasts (4%) of oxidative status. These findings revealed that measures of HPA axis activity were associated with poor development outcomes. We did not find consistent evidence that markers of SAM system activity or oxidative status were associated with developmental status. Conclusions: Our observations reveal associations between the physiological evidence of stress in the HPA axis with developmental status in early childhood. These findings add to the existing evidence exploring the developmental consequences of early life stress.

The genomic landscape of familial glioma.

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Demographic Determinants and Geographical Variability of COVID-19 Vaccine Hesitancy in Underserved Communities: Cross-sectional Study.

BACKGROUND: COVID-19 hospitalizations and deaths disproportionately affect underserved and minority populations, emphasizing that vaccine hesitancy can be an especially important public health risk factor in these populations. OBJECTIVE: This study aims to characterize COVID-19 vaccine hesitancy in underserved diverse populations. METHODS: The Minority and Rural Coronavirus Insights Study (MRCIS) recruited a convenience sample of adults (age≥18, N=3735) from federally qualified health centers (FQHCs) in California, the Midwest (Illinois/Ohio), Florida, and Louisiana and collected baseline data in November 2020-April 2021. Vaccine hesitancy status was defined as a response of "no" or "undecided" to the question "Would you get a coronavirus vaccine if it was available?" ("yes" categorized as not hesitant). Cross-sectional descriptive analyses and logistic regression models examined vaccine hesitancy prevalence by age, gender, race/ethnicity, and geography. The expected vaccine hesitancy estimates for the general population were calculated for the study counties using published county-level data. Crude associations with demographic characteristics within each region were assessed using the chi-square test. The main effect model included age, gender, race/ethnicity, and geographical region to estimate adjusted odds ratios (ORs) and 95% CIs. Interactions between geography and each demographic characteristic were evaluated in separate models. RESULTS: The strongest vaccine hesitancy variability was by geographic region: California, 27.8% (range 25.0%-30.6%); the Midwest, 31.4% (range 27.3%-35.4%); Louisiana, 59.1% (range 56.1%-62.1%); and Florida, 67.3% (range 64.3%-70.2%). The expected estimates for the general population were lower: 9.7% (California), 15.3% (Midwest), 18.2% (Florida), and 27.0% (Louisiana). The demographic patterns also varied by geography. An inverted U-shaped age pattern was found, with the highest prevalence among ages 25-34 years in Florida (n=88, 80.0%,) and Louisiana (n=54, 79.4%; P<.05). Females were more hesitant than males in the Midwest (n= 110, 36.4% vs n= 48, 23.5%), Florida (n=458, 71.6% vs n=195, 59.3%), and Louisiana (n= 425, 66.5% vs. n=172, 46.5%; P<.05). Racial/ethnic differences were found in California, with the highest prevalence among non-Hispanic Black participants (n=86, 45.5%), and in Florida, with the highest among Hispanic (n=567, 69.3%) participants (P<.05), but not in the Midwest and Louisiana. The main effect model confirmed the U-shaped association with age: strongest association with age 25-34 years (OR 2.29, 95% CI 1.74-3.01). Statistical interactions of gender and race/ethnicity with the region were significant, following the pattern found by the crude analysis. Compared to males in California, the associations with the female gender were strongest in Florida (OR=7.88, 95% CI 5.96-10.41) and Louisiana (OR=6.09, 95% CI 4.55-8.14). Compared to non-Hispanic White participants in California, the strongest associations were found with being Hispanic in Florida (OR=11.18, 95% CI 7.01-17.85) and Black in Louisiana (OR=8.94, 95% CI 5.53-14.47). However, the strongest race/ethnicity variability was observed within California and Florida: the ORs varied 4.6- and 2-fold between racial/ethnic groups in these regions, respectively. CONCLUSIONS: These findings highlight the role of local contextual factors in driving vaccine hesitancy and its demographic patterns.

Ten Years of the Nepal Ambulance Service: Successful and Sustainable Efforts.

We describe the evolution of the nonprofit Nepal Ambulance Service (NAS) in a narrative of its 10-y history, presenting geographical, social, cultural, and financial considerations that permeated the development of NAS. We gathered narrative information from the NAS leadership and partners to detail key organizational considerations regarding the implementation and maintenance of the prehospital system in Nepal. We describe the response of NAS to the 2015 earthquake and summarize transport data for 6 mo before and 6 mo after the event. The data collected included the date and time of calls received, time to ambulance dispatch, on-scene time, time to arrival at the hospital, time until the ambulance crew was back in service, patient age and sex, chief complaints, and work shift time of the ambulance crew. To characterize the time to response and transport after the 2015 earthquake, we present the means and standard deviations of the time intervals. There was an overall increase in calls and, specifically, trauma-related calls after the 2015 earthquake. The time from a call placed to dispatch was stable, approximately 2 min, throughout the period, whereas the time from dispatch to the scene and arrival at the scene varied widely. We discuss the response to coronavirus disease 2019 (COVID-19). The NAS provided care to 1230 patients with COVID-19. The descriptive data show how well NAS responded to a major national disaster and the recent pandemic.

Acceleration of opioid-related EMS runs in the spring of 2020: The National Emergency Medical Services Information System data for 2018-2020.

BACKGROUND: State- and county-level reports suggest that the COVID-19 pandemic exacerbated the opioid crisis. We examined US national trends of nonfatal opioid overdose in 2020 in comparison to pre-COVID years 2018-2019. METHODS: We used National Emergency Medical Services Information System (NEMSIS) data to conduct a temporal analysis from 2018 to 2020. Opioid-related EMS run was defined using five scenarios of naloxone administration. To determine annual patterns and slope inflection points, we used the Prophet model of the time series analysis. Linear slopes and their 95% confidence intervals (CIs) were calculated for pre-stay-at-home (pre-SaH) and SaH periods in 2020 and compared to the slopes during the same time in 2018-2019. Three cut-points for SaH start were considered: March 19, 24, and 29. RESULTS: We identified 91,065, 144,802, and 242,904 opioid-related EMS runs in 2018-2020, respectively. In 2020, opioid-related runs increased in January-June, with a pronounced acceleration in March, which coincides with the stay-at-home (SaH) orders. In both 2018 and 2019, opioid-related runs increased in January-August without the spring acceleration. In 2020, weekly increases (95% CI) during SaH for all examined cut-points were significantly greater than in pre-SaH: 18.09 (16.03-20.16) vs. 6.44 (3.42-9.47) for March 19, 17.77 (15.57-19.98) vs. 4.85 (2.07-7.64) for March 24, 18.03 (15.68-20.39) vs. 4.97(2.4-7.54) for March 29. No significant difference was found between these periods in 2018-2019. CONCLUSIONS: The acceleration of opioid-related EMS runs during the SaH period of 2020 suggests that EMS data may serve as an early warning system for local health jurisdictions to deploy harm reduction/prevention resources.

A Pilot Study of Associations Between Visceral Fat, IL-6, and Urinary F2-Isoprostanes in Older Adults Exposed to a Diet Intervention.

BACKGROUND: Short-term markers of successful visceral adipose tissue (VAT) loss are needed. Urinary F2-isoprostanes might serve as a marker for intensified lipid metabolism, whereas circulating IL-6 might stimulate fat oxidation and enhance mobilization of VAT. OBJECTIVES: This pilot study was designed to explore the hypotheses that 1) reduction in VAT is associated with increase in IL-6, and 2) that increases in urinary F2-isoprostanes are associated with increases in IL-6 and reduction in VAT. METHODS: Eighteen participants (aged 60-75 y, BMI 30-40 kg/m2) were randomly assigned to either a very-low-carbohydrate diet (VLCD; <10:25:>65% energy from carbohydrate:protein:fat) or a low-fat diet (LFD; 55:25:20%) for 8 wk. Changes in fat distribution were assessed by MRI. Four urinary F2-isoprostane isomers were quantified in 24-h urine collection using LC-MS/MS analyses. Changes in 4 F2-isoprostane isomers were summarized using factor analysis (Δ-F2-isoprostane factor). Statistical significance was set at P < 0.1. RESULTS: Within the VLCD group, change in VAT was inversely associated with change in IL-6 (r = -0.778, P = 0.069) and Δ-F2-isoprostane factor (r = -0.690, P = 0.086), demonstrating that participants who maintained higher concentrations of F2-isoprostane factor across the intervention showed greater decreases in VAT. A positive relation between Δ-F2-isoprostane factor and change in IL-6 was observed (r = 0.642, P = 0.062). In the LFD group, no significant associations between changes in VAT, F2-isoprostane factor, or IL-6 were observed. CONCLUSIONS: Results from this exploratory study in older adults with obesity suggest that, in the context of a VLCD, IL-6 could be involved in VAT mobilization, and urinary F2-isoprostanes could reflect intensified oxidation of mobilized fatty acids.Trial registration: This study is registered at clinicaltrials.gov as NCT02760641.

Attribute Associations as a Practical Approach to Account for Uncertainty in Residential Geolocation of Cancer Surveillance Data.

This methodology article proposes a basic framework for assessing confidence in residential address through attribute sets of the tumor record that enable or modify spatiotemporal relationships in cancer surveillance data. A first step in assessing confidence for a statutory downstream data steward, like the Central Cancer Registry (CCR), is identifying sets of attributes whose domains are independently controlled by data stewards outside of the CCR. These include attribute sets that comprise the digital entities of person, time, and place. In this article, we describe the uncertainty in the geolocation of a cancer patient at the time of diagnosis, focusing on multiple stewardship of the cancer surveillance data. We also propose an approach to account for this uncertainty that is practical within the framework of existing cancer registry data coding, processing conventions, and legislative mandates for cancer surveillance.

Geospatial analysis of multiple cancers in individuals in the US, 2004-2014.

BACKGROUND: There is a projected rapid increase in cancer survivors in the US population, from 15.5 million in 2016 to 26.1 million by 2040. Improvements in treatment and detection have led to increased survival, however, there is now a risk of developing new cancers as a result of environment toxins, behavioral risk factors, genetic predisposition, and late-term effects of radiation and chemotherapeutic treatments. This study takes a geospatial approach to examining the place of occurrence of multiple cancers originating in the population of four screenable cancers-female breast, colorectal, prostate, and cervical cancers-among the US population. METHODS: During 2004-2014, 6,523,532 primary cancer patients with one of these four screenable cancers were examined, and subsequent primary cancers (multiple cancers of any type) were noted. Individual level analyses estimated the odds of diagnosis with multiple cancers controlling for age, sex, and race-ethnicity. Change in effects on odds of multiple cancer diagnoses with age, sex, and race-ethnicity were evaluated controlling separately for late-stage diagnosis of the primary cancer or each primary cancer diagnosis type. County-level spatial cluster analysis was employed to identify and visualize higher than average multiple cancer rates. RESULTS: Over half of the study population were female and almost 30% of the study population were diagnosed at late-stage for their first cancer. Multiple occurrences of all cancers increased during the time period for patients with initial breast or colorectal cancers. Among BC primary cancer cases, subsequent multiple cancers were mostly new breast cancers. By contrast, for CRC primary cancer cases, subsequent multiple cancers were about equally likely to be new CRC cases or other cancer types. Sex, age and race-ethnicity were all significantly associated with multiple cancers. In the model controlling for CRC as the primary type, the age and race-ethnicity effects were somewhat different than for all the other models. Thus, there was something distinctly different about the multiple cancer incidence among patients with CRC as their primary cancer as compared to patients with BC, CVC, or PC primaries. In subsequent analyses by county, there were distinct geospatial patterns in multiple cancer rates with most high-rate clusters occurring in the north- and mid-west US. CONCLUSIONS: There were distinct individual level and geospatial disparities in multiple cancer diagnoses for the study population of all primary breast, colorectal, cervical, or prostate cancer patients during the decade studied. It is importance to emphasize continued screening for cancer survivors and research on personal and environmental drivers of multiple primary cancers.

Increasing Incidence of Liposarcoma: A Population-Based Study of National Surveillance Databases, 2001-2016.

Rare cancers, affecting 1 in 5 cancer patients, disproportionally contribute to cancer mortality. This research focuses on liposarcoma, an understudied rare cancer with unknown risk factors and limited treatment options. Liposarcoma incident cases were identified from the U.S. Surveillance, Epidemiology, and End Result (SEER) program and the combined SEER-National Program of Cancer Registries (CNPCR) between 2001-2016. Incidence rates (age-adjusted and age-specific), 5-year survival, and the time trends were determined using SEER*stat software. Three-dimensional visualization of age-time curves was conducted for males and females. SEER liposarcoma cases represented ~30% (n = 11,162) of the nationwide pool (N = 37,499). Both sources of data showed males accounting for ~60% of the cases; 82%-86% cases were identified among whites. Age-adjusted incidence was greater among males vs. females and whites vs. blacks, whereas survival did not differ by sex and race. The dedifferentiated (57.2%), pleomorphic (64.1%), and retroperitoneal (63.9%) tumors had the worse survival. Nationwide, liposarcoma rates increased by 19%, with the annual percent increase (APC) of 1.43% (95% confidence interval (CI): 1.12-1.74). The APC was greater for males vs. females (1.67% vs. 0.89%) and retroperitoneal vs. extremity tumors (1.94% vs. 0.58%). Thus, incidence increased faster in the high-risk subgroup (males), and for retroperitoneal tumors, the low-survival subtype. The SEER generally over-estimated the rates and time trends compared to nationwide data but under-estimated time trends for retroperitoneal tumors. The time trends suggest an interaction between genetic and non-genetic modifiable risk factors may play a role in the etiology of this malignancy. Differences between SEER and CNCPR findings emphasize the need for nationwide cancer surveillance.

Glioma risk associated with extent of estimated European genetic ancestry in African Americans and Hispanics.

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR≥0.4 ), and ≥15% NAA (AMR≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10-4 ; 11p11.12, p = 7.0 × 10-4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10-6 ) in 7q21.3. Among AMR≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10-4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10-4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies.

Lack of association between modifiable exposures and glioma risk: a Mendelian randomization analysis.

BACKGROUND: The etiological basis of glioma is poorly understood. We have used genetic markers in a Mendelian randomization (MR) framework to examine if lifestyle, cardiometabolic, and inflammatory factors influence the risk of glioma. This methodology reduces bias from confounding and is not affected by reverse causation. METHODS: We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wide association study of 12 488 glioma patients and 18 169 controls. We used the estimated odds ratio of glioma associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures:Lifestyle and dietary factors-height, plasma insulin-like growth factor 1, blood carnitine, blood methionine, blood selenium, blood zinc, circulating adiponectin, circulating carotenoids, iron status, serum calcium, vitamins (A1, B12, B6, E, and 25-hydroxyvitamin D), fatty acid levels (monounsaturated, omega-3, and omega-6) and circulating fetuin-A;Cardiometabolic factors-birth weight, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, total triglycerides, basal metabolic rate, body fat percentage, body mass index, fasting glucose, fasting proinsulin, glycated hemoglobin levels, diastolic and systolic blood pressure, waist circumference, waist-to-hip ratio; andInflammatory factors- C-reactive protein, plasma interleukin-6 receptor subunit alpha and serum immunoglobulin E. RESULTS: After correction for the testing of multiple potential risk factors and excluding associations driven by one single nucleotide polymorphism, no significant association with glioma risk was observed (ie, PCorrected > 0.05). CONCLUSIONS: This study did not provide evidence supporting any of the 37 factors examined as having a significant influence on glioma risk.

Update on triple-negative breast cancer disparities for the United States: A population-based study from the United States Cancer Statistics database, 2010 through 2014.

BACKGROUND: Triple-negative breast cancer (TNBC) has been associated with a more aggressive histology, poorer prognosis, and nonresponsiveness to hormone therapy. It is imperative that cancer research identify factors that drive disparities and focus on prevention. METHODS: Using the United States Cancer Statistics database, the authors examined differences between TNBCs compared with all other breast cancers with regard to age, race/ethnicity, and stage at diagnosis. RESULTS: A total of 1,151,724 cases of breast cancer were identified from 2010 through 2014, with the triple-negative phenotype accounting for approximately 8.4% of all cases. In unadjusted analyses, non-Hispanic black women (odds ratio [OR], 2.27; 95% CI, 2.23-2.31) and Hispanic women (OR, 1.22; 95% CI, 1.19-1.25) had higher odds of diagnosis when compared with non-Hispanic white women. Women aged <40 years had the highest odds of diagnosis compared with women aged 50 to 64 years (OR, 1.95; 95% CI, 1.90-2.01). Diagnosis at American Joint Committee on Cancer stage III and beyond conferred higher odds of the diagnosis of TNBC (OR for stage III, 1.69 [95% CI, 1.68-1.72]; and OR for stage IV, 1.47 [95% CI, 1.43-1.51]). Results varied slightly in adjusted analyses. CONCLUSIONS: The results of the current study demonstrated that there is a significant burden of disease in TNBC diagnosed among women of color, specifically non-Hispanic black women, and younger women. Additional studies are needed to determine drivers of disparities between race, age, and stage of disease at diagnosis.

Publisher Correction: Mendelian randomisation study of the relationship between vitamin D and risk of glioma.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma.

Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 × 10-6, we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 × 10-6). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis. SIGNIFICANCE: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.