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Abstract Background Studies have reported mixed findings regarding the impact of the coronavirus disease 2019 (COVID-19) pandemic on pregnant women and birth outcomes. This study used a quasi-experimental design to account for potential confounding by sociodemographic characteristics. Methods Data were drawn from 16 prenatal cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) program. Women exposed to the pandemic (delivered between 12 March 2020 and 30 May 2021) (n = 501) were propensity-score matched on maternal age, race and ethnicity, and child assigned sex at birth with 501 women who delivered before 11 March 2020. Participants reported on perceived stress, depressive symptoms, sedentary behavior, and emotional support during pregnancy. Infant gestational age (GA) at birth and birthweight were gathered from medical record abstraction or maternal report. Results After adjusting for propensity matching and covariates (maternal education, public assistance, employment status, prepregnancy body mass index), results showed a small effect of pandemic exposure on shorter GA at birth, but no effect on birthweight adjusted for GA. Women who were pregnant during the pandemic reported higher levels of prenatal stress and depressive symptoms, but neither mediated the association between pandemic exposure and GA. Sedentary behavior and emotional support were each associated with prenatal stress and depressive symptoms in opposite directions, but no moderation effects were revealed. Conclusions There was no strong evidence for an association between pandemic exposure and adverse birth outcomes. Furthermore, results highlight the importance of reducing maternal sedentary behavior and encouraging emotional support for optimizing maternal health regardless of pandemic conditions.

Pediatric positive health refers to children's assessments of their well-being. The purpose of this study was to contrast positive health for children aged 8 to 17 years with and without chronic physical and mental health conditions.Data were drawn from the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) research program. Participants included 1764 children ages 8 to 17 years from 13 ECHO cohorts. We measured positive health using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Global Health and Life Satisfaction patient-reported outcome (PRO) measures. We used multiple regression to examine cross-sectional associations between the PROs and parent-reported health conditions and sociodemographic variables. We defined a meaningful difference in average scores as a PROMIS T-score difference of3.The sample included 45% 13 to 17-year-olds, 50% females, 8% Latinx, and 23% Black/African-American. Fifty-four percent had a chronic health condition. Of the 16 chronic conditions included in the study, only chronic pain (β = -3.5; 95% CI: -5.2 to -1.9) and depression (β = -6.6; 95% CI: -8.5 to -4.6) were associated with scoring3 points lower on global health. Only depression was associated with3 points lower on life satisfaction (β = -6.2; 95% CI: -8.1 to -4.3). Among those with depression, 95% also had another chronic condition.Many children with chronic conditions have similar levels of positive health as counterparts without chronic conditions. The study results suggest that negative associations between chronic conditions and positive health may be primarily attributable to presence or co-occurrence of depression.

Additional risk-stratification measures are needed in breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC). We aimed to describe oncologic outcomes in a modern cohort treated with NAC, and evaluate the prognostic value of histologic pattern of residual tumor.We included patients with stage I-III breast cancer treated with NAC and surgery from 2004 to 2014. Histologic pattern of residual tumor was evaluated by central pathology review when slides were available. Multivariable Cox regression was performed to evaluate factors associated with locoregional recurrence (LRR), recurrence-free survival (RFS), and overall survival (OS).Among 975 patients, median follow-up was 74.0 months and 10-year rates of LRR, RFS, and OS were 9.8%, 67.6% and 74.4%, respectively. Biologic subtype, pathologic node-positive disease, and pathologic complete response (pCR) were associated with outcomes. Among 666 (68.3%) patients with central pathology review, pattern of residual disease was not significantly associated with LRR. However, both scattered residual tumor and no/minimal response relative to a concentric pattern of response were significantly associated with inferior RFS (scattered: hazard ratio 2.0, p = 0.015; no/minimal response: hazard ratio 2.2, p = 0.021) and OS (scattered: hazard ratio 2.2, p = 0.026; no/minimal response: hazard ratio 2.5, p = 0.023). This finding was most prominent in patients with triple-negative breast cancer.Patients with a scattered relative to concentric pattern of residual tumor after NAC had inferior RFS and OS, nearly as poor as those with no/minimal response. Histologic pattern of residual tumor may represent a novel prognostic measure, particularly in the triple-negative breast cancer population.

Objective: Single-substance exposure effects on neurodevelopmental outcomes, such as problem behavior and intelligence quotient (IQ), have been studied in children for decades. However, the long-term consequences of polysubstance exposure are poorly understood. Study Design: Longitudinal neurodevelopmental data were gathered from cohorts across the United States (U.S.) through the Environmental influences on Child Health Outcomes (ECHO) Program. Data on prenatal exposure to opioids, nicotine, marijuana, and alcohol were collected from children ages 6-11 years (N=256). Problem behavior was assessed using the Child Behavior Checklist (school-age version, CBCL-Sch), and verbal IQ (VIQ) and performance IQ (PIQ) were assessed using the Weschler Intelligence Scale for Children, Fifth Edition (WISC-5). We first identified latent profiles in the overall sample, then evaluated differences in profile membership for children with and without prenatal substance exposure. Results: Latent profile analysis identified two mutually exclusive categories: average VIQ and PIQ, with typical problem behavior; and below-average VIQ with average PIQ and clinically significant problem behavior. Children with prenatal nicotine and polysubstance exposures were more likely to be classified in the below-average VIQ, elevated problem behavior profile compared with children without prenatal nicotine exposure. Conclusions: The presence of clinically significant behavior problems in children with average PIQ, but below-average VIQ, could represent a unique endophenotype related to prenatal nicotine exposure in the context of other prenatal substance exposures.

The Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children’s health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-wide Cohort data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7-11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in five main outcome areas: pre-, peri-, and post-natal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include place- (e.g., air pollution, neighborhood socioeconomic status), family- (e.g., parental mental health), and individual-level (e.g., diet, genomics) factors.

Given inconsistent evidence on preconception or prenatal tobacco use and offspring autism spectrum disorder (ASD), this study assessed associations of maternal smoking with ASD and ASD-related traits. Among 72 cohorts in the Environmental Influences on Child Health Outcomes consortium, 11 had ASD diagnosis and prenatal tobaccosmoking (n = 8648). and 7 had Social Responsiveness Scale (SRS) scores of ASD traits (n = 2399). Cohorts had diagnoses alone (6), traits alone (2), or both (5). Diagnoses drew from parent/caregiver report, review of records, or standardized instruments. Regression models estimated smoking-related odds ratios (ORs) for diagnoses and standardized mean differences for SRS scores. Cohort-specific ORs were meta-analyzed. Overall, maternal smoking was unassociated with child ASD (adjusted OR, 1.08; 95% confidence interval [CI], 0.72-1.61). However, heterogeneity across studies was strong: preterm cohorts showed reduced ASD risk for exposed children. After excluding preterm cohorts (biased by restrictions on causal intermediate and exposure opportunity) and small cohorts (very few ASD cases in either smoking category), the adjusted OR for ASD from maternal smoking was 1.44 (95% CI, 1.02-2.03). Children of smoking (versus non-smoking) mothers had more ASD traits (SRS T-score + 2.37 points, 95% CI, 0.73-4.01 points), with results homogeneous across cohorts. Maternal preconception/prenatal smoking was consistently associated with quantitative ASD traits and modestly associated with ASD diagnosis among sufficiently powered United States cohorts of non-preterm children. Limitations resulting from self-reported smoking and unmeasured confounders preclude definitive conclusions. Nevertheless, counseling on potential and known risks to the child from maternal smoking is warranted for pregnant women and pregnancy planners. LAY SUMMARY: Evidence on the association between maternal prenatal smoking and the child's risk for autism spectrum disorder has been conflicting, with some studies reporting harmful effects, and others finding reduced risks. Our analysis of children in the ECHO consortium found that maternal prenatal tobacco smoking is consistently associated with an increase in autism-related symptoms in the general population and modestly associated with elevated risk for a diagnosis of autism spectrum disorder when looking at a combined analysis from multiple studies that each included both pre- and full-term births. However, this study is not proof of a causal connection. Future studies to clarify the role of smoking in autism-like behaviors or autism diagnoses should collect more reliable data on smoking and measure other exposures or lifestyle factors that might have confounded our results.

BackgroundResearch and clinical practice rely heavily on caregiver-report measures, such as the Child Behavior Checklist 1.5-5 (CBCL/1.5-5), to gather information about early childhood behavior problems and to screen for clinically significant behavior problems. While studies have shown that demographic variables influence ratings of behavior problems, the extent to which the CBCL/1.5-5 functions equivalently at the item level across diverse samples is unknown.MethodsItem-level data of CBCL/1.5-5 on a large sample of young children (N=7827) were drawn from 26 cohorts in the Environmental influences on Child Health Outcomes (ECHO) program. Factor analyses and the alignment method were applied to examine measurement invariance and differential item functioning (DIF) across child- (child age, sex, bilingual status, and neurodevelopmental disorders), and caregiver-level characteristics (caregiver sex, education level, household income level, and depression). Child race was examined in sensitivity analyses.ResultsItem sets with the most impactful DIF across child and caregiver groupings were identified for Internalizing, Externalizing, and Total Problems. The robust item sets, which excluded the high DIF items, showed good reliabilities and high correlations with the original scales for all three constructs. Language version of CBCL administration, caregiver education, and respondent sex showed the most significant impact on the measurement invariance, followed by child age. Sensitivity analyses revealed that child race has a unique impact on DIF over and above socioeconomic status.ConclusionsThe CBCL/1.5-5, a parent-report measure of early childhood behavior problems, showed bias across demographic groups. Robust item sets with less DIF can measure Internalizing, Externalizing, and Total Problems equally as well as the full item sets.

Among breast cancer patients treated with neoadjuvant chemotherapy (NAC) who do not experience a pathologic complete response (pCR), the pattern of residual disease in the breast varies. Pre-treatment clinico-pathologic features that predict the pattern of residual tumor are not well established. To investigate this issue, we performed a detailed review of histologic sections of the post-treatment surgical specimens for 665 patients with stage I-III breast cancer treated with NAC followed by surgery from 2004 to 2014 and for whom slides of the post-NAC surgical specimen were available for review. This included 242 (36.4%) patients with hormone receptor (HR)+/HER2- cancers, 216 (32.5%) with HER2+ tumors, and 207 (31.1%) with triple negative breast cancer (TNBC). Slide review was blinded to pre-treatment clinico-pathologic features. pCR was achieved in 7.9%, 37.0%, and 37.7%, of HR+/HER2- cancers, HER2+ cancers, and TNBC respectively (p < 0.001). Among 389 patients with residual invasive cancer in whom the pattern of residual disease could be assessed, 287 (73.8%) had a scattered pattern and 102 (26.2%) had a circumscribed pattern. In both univariate and multivariate analyses, there was a significant association between tumor subtype and pattern of response. Among patients with HR+/HER2- tumors, 89.4% had a scattered pattern and only 10.6% had a circumscribed pattern. In contrast, among those with TNBC 52.8% had a circumscribed pattern and 47.2% had a scattered pattern (p < 0.001). In addition to subtype, histologic grade and tumor size at presentation were also significantly related to the pattern of residual disease in multivariate analysis, with lower grade and larger size each associated with a scattered response pattern (p = 0.002 and p = 0.01, respectively). A better understanding of the relationship between pre-treatment clinico-pathologic features of the tumor and pattern of residual disease may be of value for helping to guide post-chemotherapy surgical management.

The National Institutes of Health's Environmental influences on Child Health Outcomes (ECHO) Program was designed to address solution-oriented research questions about the links between children's early life environment and their risks of pre-, peri-, and post-natal complications, asthma, obesity, neurodevelopmental disorders, and positive health. Children born very preterm are at increased risk for many of the outcomes on which ECHO focuses, but the contributions of environmental factors to this risk are not well characterized. Three ECHO cohorts consist almost exclusively of individuals born very preterm. Data provided to ECHO from cohorts can be used to address hypotheses about (1) differential risks of chronic health and developmental conditions between individuals born very preterm and those born at term; (2) health disparities across social determinants of health; and (3) mechanisms linking early-life exposures and later-life outcomes among individuals born very preterm. IMPACT: The National Institutes of Health's Environmental Influences on Child Health Outcomes Program is conducting solution-oriented research on the links between children's environment and health. Three ECHO cohorts comprise study participants born very preterm; these cohorts have enrolled, to date, 1751 individuals born in 14 states in the U.S. in between April 2002 and March 2020. Extensive data are available on early-life environmental exposures and child outcomes related to neurodevelopment, asthma, obesity, and positive health. Data from ECHO preterm cohorts can be used to address questions about the combined effects of preterm birth and environmental exposures on child health outcomes.

Background Environmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation. Objective We tested whether EED is associated with micronutrient deficiency risk independent of diet and systemic inflammation, and whether it mediates the relation between intake and micronutrient status. Methods Using data from 1283 children in the MAL-ED (Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health) birth cohort we evaluated the risk of anemia, low retinol, zinc, and ferritin, and high transferrin receptor (TfR) at 15 mo. We characterized gut inflammation and permeability by myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT) concentrations from asymptomatic fecal samples averaged from 9 to 15 mo, and averaged the lactulose:mannitol ratio z-score (LMZ) at 9 and 15 mo. Nutrient intakes from complementary foods were quantified monthly from 9 to 15 mo and densities were averaged for analyses. α-1-Acid glycoprotein at 15 mo characterized systemic inflammation. Relations between variables were modeled using a Bayesian network. Results A greater risk of anemia was associated with LMZ [1.15 (95% CI: 1.01, 1.31)] and MPO [1.16 (1.01, 1.34)]. A greater risk of low ferritin was associated with AAT [1.19 (1.03, 1.37)] and NEO [1.22 (1.04, 1.44)]. A greater risk of low retinol was associated with LMZ [1.24 (1.08, 1.45)]. However, MPO was associated with a lower risk of high transferrin receptor [0.86 (0.74, 0.98)], NEO with a lower risk of low retinol [0.75 (0.62, 0.89)], and AAT with a lower risk of low plasma zinc [0.83 (0.70, 0.99)]. Greater nutrient intake densities (vitamins A and B6, calcium, protein, and zinc) were negatively associated with EED. Inverse associations between nutrient densities and micronutrient deficiency largely disappeared after adjustment for EED, suggesting that EED mediates these associations. Conclusions EED is independently associated with an increased risk of low ferritin, low retinol, and anemia. Greater nutrient density from complementary foods may reduce EED, and the control of micronutrient deficiencies may require control of EED.

Purpose of review To examine the recent literature on extracorporeal septoplasty. Recent findings The literature suggests that extracorporeal septoplasty is an effective approach for both functional and cosmetic treatment of moderate to severe deformities of the caudal and dorsal septum. The procedure can be performed via an endonasal or external approach based on the nature of the deformity and the experience of the surgeon, although recent literature highlights various advantages of an external approach. The use of polydioxanone foil as a scaffold for septal reconstruction is widely accepted, and can enhance the technical performance of this technique. Although reported complication rates are low, tip deprojection and rotation have been observed in cases where extracorporeal septoplasty is performed without simultaneous rhinoplasty. Summary Extracorporeal septoplasty is a useful technique in the armamentarium of surgeons addressing deviations of the dorsal and caudal septum.

Symptoms of addictive disorders often manifest as periodic episodes of sudden relapse followed by a relatively long period of recovery. For most types of addictive disorders, a relapse is precipita...

Purpose: The objective of this study was to characterize the study designs, recruitment strategies, and other study characteristics among cohorts that initiated during pregnancy as part of the Environmental influences on Child Health Outcomes (ECHO) program.Methods: ECHO research programs (cohorts) were reviewed. Only those who had or were currently recruiting during pregnancy were surveyed in 2018 about research recruitment strategies (participant incentives, study burden, community collaboration, and cultural adaptations). Data are presented with cohort characteristics (location, inclusion and exclusion criteria, sociodemographics, medical information, behavioral factors, and biospecimens).Results: Forty-seven of the 84 ECHO pediatric cohorts recruited during pregnancy. Findings demonstrate various recruitment strategies, domains of data collection, and biospecimen collection are all characteristics of successful cohorts.Clinical Implications: These data that include over 50,000 children from families across the country, many in underserved areas, will be used for research with the potential to lead to profound policy changes. Prenatal conditions prenatal conditions such as maternal age, obesity, depression, and drug use can be examined using study data, including biological markers, from pregnancy through childbirth and into childhood and will inform national policies on the role of early life exposures and underlying mechanisms of disease progression.

Among breast cancer patients treated with neoadjuvant chemotherapy (NAC) who do not experience a pathologic complete response (pCR), the pattern of residual disease in the breast varies. Pre-treatment clinico-pathologic features that predict the pattern of residual tumor are not well established. To investigate this issue, we performed a detailed review of histologic sections of the post-treatment surgical specimens for 665 patients with stage I-III breast cancer treated with NAC followed by surgery from 2004 to 2014 and for whom slides of the post-NAC surgical specimen were available for review. This included 242 (36.4%) patients with hormone receptor (HR)+/HER2- cancers, 216 (32.5%) with HER2+ tumors, and 207 (31.1%) with triple negative breast cancer (TNBC). Slide review was blinded to pre-treatment clinico-pathologic features. pCR was achieved in 7.9%, 37.0%, and 37.7%, of HR+/HER2- cancers, HER2+ cancers, and TNBC respectively (p 0.001). Among 389 patients with residual invasive cancer in whom the pattern of residual disease could be assessed, 287 (73.8%) had a scattered pattern and 102 (26.2%) had a circumscribed pattern. In both univariate and multivariate analyses, there was a significant association between tumor subtype and pattern of response. Among patients with HR+/HER2- tumors, 89.4% had a scattered pattern and only 10.6% had a circumscribed pattern. In contrast, among those with TNBC 52.8% had a circumscribed pattern and 47.2% had a scattered pattern (p 0.001). In addition to subtype, histologic grade and tumor size at presentation were also significantly related to the pattern of residual disease in multivariate analysis, with lower grade and larger size each associated with a scattered response pattern (p = 0.002 and p = 0.01, respectively). A better understanding of the relationship between pre-treatment clinico-pathologic features of the tumor and pattern of residual disease may be of value for helping to guide post-chemotherapy surgical management.

Background In a multicountry birth cohort study, we describe rotavirus infection in the first 2 years of life in sites with and without rotavirus vaccination programs. Methods Children were recruited by 17 days of age and followed to 24 months with collection of monthly surveillance and diarrheal stools. Data on sociodemographics, feeding, and illness were collected at defined intervals. Stools were tested for rotavirus and sera for antirotavirus immunoglobulins by enzyme immunoassays. Results A total of 1737 children contributed 22646 surveillance and 7440 diarrheal specimens. Overall, rotavirus was detected in 5.5% (408/7440) of diarrheal stools, and 344 (19.8%) children ever had rotavirus gastroenteritis. Household overcrowding and a high pathogen load were consistent risk factors for infection and disease. Three prior infections conferred 74% (P < .001) protection against subsequent infection in sites not using vaccine. In Peru, incidence of rotavirus disease was relatively higher during the second year of life despite high vaccination coverage. Conclusions Rotavirus infection and disease were common, but with significant heterogeneity by site. Protection by vaccination may not be sustained in the second year of life in settings with high burdens of transmission and poor response to oral vaccines.

Background With three out of four new bladder cancer (BCa) cases occurring in men, an apparent gender disparity exists. We aimed to investigate the role of hormonal and reproductive factors in BCa risk using two large female US prospective cohorts. Methods Our study population comprised 118 256 and 115 383 female registered nurses who were recruited in the Nurses' Health Study (NHS) and NHS II, respectively. Reproductive and hormonal factors and other relevant data were recorded in biennial self-administered questionnaires. Cox-regression analyses were performed to estimate age- and multivariable-adjusted incidence risk ratios (IRRs) and 95% confidence intervals (CIs). Inverse-variance-weighted meta-analysis was used to pool estimates across cohorts. Results During up to 36 years of follow-up, 629 incident BCa cases were confirmed. In the NHS, 22 566 women (21.3%) were postmenopausal at baseline, compared with 2723 women (2.4%) in the NHS II. Among women in the NHS, younger age at menopause (≤45 years) was associated with an increased risk of BCa (IRR: 1.41, 95% CI: 1.11–1.81, Ptrend = 0.01) compared with those with menopause onset at age 50+ years, particularly among ever-smokers (IRR for age at menopause ≤45 years: 1.53, 95% CI: 1.15–2.04; PIntx = 0.16). Age at menarche and first birth, parity, oral-contraceptive use and postmenopausal hormone use were not associated with BCa risk. Conclusions Overall, we found little support for an association between female reproductive factors and BCa risk in these prospective cohort studies. Earlier age at menopause was associated with a higher risk of BCa, particularly among smokers, indicating the potential for residual confounding.

Neonatal opioid withdrawal syndrome (NOWS) has risen in prevalence from 1.2 per 1000 births in 2000 to 5.8 per 1000 births in 2012. Symptoms in neonates may include high-pitched cry, tremors, feeding difficulty, hypertonia, watery stools, and breathing problems. However, little is known about the neurodevelopmental consequences of prenatal opioid exposure in infancy, early childhood, and middle childhood. Even less is known about the cognitive, behavioral, and academic outcomes of children who develop NOWS. We review the state of the literature on the neurodevelopmental consequences of prenatal opioid exposure with a particular focus on studies in which NOWS outcomes were examined. Aiming to reduce the incidence of prenatal opioid exposure in the near future, we highlight the need for large studies with prospectively recruited participants and longitudinal designs, taking into account confounding factors such as socioeconomic status, institutional variations in care, and maternal use of other substances, to independently assess the full impact of NOWS. As a more immediate solution, we provide an agenda for future research that leverages the National Institutes of Health Environmental Influences on Child Health Outcomes program to address many of the serious methodologic gaps in the literature, and we answer key questions regarding the short- and long-term neurodevelopmental health of children with prenatal opioid exposure.

Preterm birth occurs at excessively high and disparate rates in the United States. In 2016, the National Institutes of Health (NIH) launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate the influence of early life exposures on child health. Extant data from the ECHO cohorts provides the opportunity to examine racial and geographic variation in effects of individual- and neighborhood-level markers of socioeconomic status (SES) on gestational age at birth. The objective of this study was to examine the association between individual-level (maternal education) and neighborhood-level markers of SES and gestational age at birth, stratifying by maternal race/ethnicity, and whether any such associations are modified by US geographic region. Twenty-six ECHO cohorts representing 25,526 mother-infant pairs contributed to this disseminated meta-analysis that investigated the effect of maternal prenatal level of education (high school diploma, GED, or less; some college, associate’s degree, vocational or technical training [reference category]; bachelor’s degree, graduate school, or professional degree) and neighborhood-level markers of SES (census tract [CT] urbanicity, percentage of black population in CT, percentage of population below the federal poverty level in CT) on gestational age at birth (categorized as preterm, early term, full term [the reference category], late, and post term) according to maternal race/ethnicity and US region. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Cohort-specific results were meta-analyzed using a random effects model. For women overall, a bachelor’s degree or above, compared with some college, was associated with a significantly decreased odds of preterm birth (aOR 0.72; 95% CI: 0.61–0.86), whereas a high school education or less was associated with an increased odds of early term birth (aOR 1.10, 95% CI: 1.00–1.21). When stratifying by maternal race/ethnicity, there were no significant associations between maternal education and gestational age at birth among women of racial/ethnic groups other than non-Hispanic white. Among non-Hispanic white women, a bachelor’s degree or above was likewise associated with a significantly decreased odds of preterm birth (aOR 0.74 (95% CI: 0.58, 0.94) as well as a decreased odds of early term birth (aOR 0.84 (95% CI: 0.74, 0.95). The association between maternal education and gestational age at birth varied according to US region, with higher levels of maternal education associated with a significantly decreased odds of preterm birth in the Midwest and South but not in the Northeast and West. Non-Hispanic white women residing in rural compared to urban CTs had an increased odds of preterm birth; the ability to detect associations between neighborhood-level measures of SES and gestational age for other race/ethnic groups was limited due to small sample sizes within select strata. Interventions that promote higher educational attainment among women of reproductive age could contribute to a reduction in preterm birth, particularly in the US South and Midwest. Further individual-level analyses engaging a diverse set of cohorts are needed to disentangle the complex interrelationships among maternal education, neighborhood-level factors, exposures across the life course, and gestational age at birth outcomes by maternal race/ethnicity and US geography.

Land-based salmon farming in closed containment recirculation aquaculture systems (RAS) is an emerging industry with the potential for reducing disease prevalence, improving production efficiency, and reducing environmental impacts compared with open net-pen aquaculture. Salinity and oxygen levels are environmental factors that have significant impacts on the physiology of fishes and possibly influence the production efficiency of fishes in aquaculture. These parameters are particularly relevant for fish production in RAS, where most water parameters can be manipulated and tightly controlled. While much is known about the specific mechanisms associated with the acute transfer between FW and SW and the reverse, little is known about the effects of long-term acclimation on ion- and acid/base-regulation, especially at intermediate salinities. We measured gas-exchange, ion-regulation, acid/base balance, and renal function in coho salmon (Oncorhynchus kisutch Walbaum, 1792) acclimated to four salinities (2.5, 5.0, 10, and 30 ppt) for over a year in RAS and investigated how animals prioritize these functions when faced with 24 h exposure to hypoxia (PO2 = 63 mmHg = 8.4 kPa = 3.76–4.48 mg l−1). We show that fish that were long-term acclimated to 30 ppt had substantially higher plasma osmolality and [Na+] than fish acclimated to lower salinities. These changes were associated with a marked reduction in blood pH at 30 ppt relative to 2.5 ppt, and we discuss a possible thermodynamic link between salinity acclimation and acid/base regulation. Further, we show that hypoxia exposure results in changes in plasma osmolality by over 80 mOsm kg−1, but only in 30 ppt water, demonstrating a salinity-dependent trade-off between gas exchange and osmoregulation. This study provides insight into the physiological state and hypoxia sensitivity of market sized salmon reared under industry-relevant conditions in RAS.

Summary Background Enteropathogen infections in early childhood not only cause diarrhoea but contribute to poor growth. We used molecular diagnostics to assess whether particular enteropathogens were associated with linear growth across seven low-resource settings. Methods We used quantitative PCR to detect 29 enteropathogens in diarrhoeal and non-diarrhoeal stools collected from children in the first 2 years of life obtained during the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite cohort study. Length was measured monthly. We estimated associations between aetiology-specific diarrhoea and subclinical enteropathogen infection and quantity and attained length in 3 month intervals, at age 2 and 5 years, and used a longitudinal model to account for temporality and time-dependent confounding. Findings Among 1469 children who completed 2 year follow-up, 35 622 stool samples were tested and yielded valid results. Diarrhoeal episodes attributed to bacteria and parasites, but not viruses, were associated with small decreases in length after 3 months and at age 2 years. Substantial decrements in length at 2 years were associated with subclinical, non-diarrhoeal, infection with Shigella (length-for-age Z score [LAZ] reduction −0·14, 95% CI −0·27 to −0·01), enteroaggregative Escherichia coli (−0·21, −0·37 to −0·05), Campylobacter (−0·17, −0·32 to −0·01), and Giardia (−0·17, −0·30 to −0·05). Norovirus, Cryptosporidium, typical enteropathogenic E coli, and Enterocytozoon bieneusi were also associated with small decrements in LAZ. Shigella and E bieneusi were associated with the largest decreases in LAZ per log increase in quantity per g of stool (−0·13 LAZ, 95% CI −0·22 to −0·03 for Shigella; −0·14, −0·26 to −0·02 for E bieneusi). Based on these models, interventions that successfully decrease exposure to Shigella, enteroaggregative E coli, Campylobacter, and Giardia could increase mean length of children by 0·12–0·37 LAZ (0·4–1·2 cm) at the MAL-ED sites. Interpretation Subclinical infection and quantity of pathogens, particularly Shigella, enteroaggregative E coli, Campylobacter, and Giardia, had a substantial negative association with linear growth, which was sustained during the first 2 years of life, and in some cases, to 5 years. Successfully reducing exposure to certain pathogens might reduce global stunting. Funding Bill & Melinda Gates Foundation.

Optimum management of childhood diarrhoea in low-resource settings has been hampered by insufficient data on aetiology, burden, and associated clinical characteristics. We used quantitative diagnostic methods to reassess and refine estimates of diarrhoea aetiology from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study.We re-analysed stool specimens from the multisite MAL-ED cohort study of children aged 0-2 years done at eight locations (Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Venda, South Africa; Haydom, Tanzania; Fortaleza, Brazil; and Loreto, Peru), which included active surveillance for diarrhoea and routine non-diarrhoeal stool collection. We used quantitative PCR to test for 29 enteropathogens, calculated population-level pathogen-specific attributable burdens, derived stringent quantitative cutoffs to identify aetiology for individual episodes, and created aetiology prediction scores using clinical characteristics.We analysed 6625 diarrhoeal and 30 968 non-diarrhoeal surveillance stools from 1715 children. Overall, 64·9% of diarrhoea episodes (95% CI 62·6-71·2) could be attributed to an aetiology by quantitative PCR compared with 32·8% (30·8-38·7) using the original study microbiology. Viral diarrhoea (36·4% of overall incidence, 95% CI 33·6-39·5) was more common than bacterial (25·0%, 23·4-28·4) and parasitic diarrhoea (3·5%, 3·0-5·2). Ten pathogens accounted for 95·7% of attributable diarrhoea: Shigella (26·1 attributable episodes per 100 child-years, 95% CI 23·8-29·9), sapovirus (22·8, 18·9-27·5), rotavirus (20·7, 18·8-23·0), adenovirus 40/41 (19·0, 16·8-23·0), enterotoxigenic Escherichia coli (18·8, 16·5-23·8), norovirus (15·4, 13·5-20·1), astrovirus (15·0, 12·0-19·5), Campylobacter jejuni or C coli (12·1, 8·5-17·2), Cryptosporidium (5·8, 4·3-8·3), and typical enteropathogenic E coli (5·4, 2·8-9·3). 86·2% of the attributable incidence for Shigella was non-dysenteric. A prediction score for shigellosis was more accurate (sensitivity 50·4% [95% CI 46·7-54·1], specificity 84·0% [83·0-84·9]) than current guidelines, which recommend treatment only of bloody diarrhoea to cover Shigella (sensitivity 14·5% [95% CI 12·1-17·3], specificity 96·5% [96·0-97·0]).Quantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings.BillMelinda Gates Foundation.

Noroviruses are a leading cause of diarrhea in children aged

We evaluated the impact of subclinical enteroaggregative Escherichia coli (EAEC) infection alone and in combination with other pathogens in the first 6 months of life on child growth.Nondiarrheal samples from 1684 children across 8 Multisite Birth Cohort Study, Malnutrition and Enteric Diseases (MAL-ED) sites in Asia, Africa, and Latin America were tested monthly; more than 90% of children were followed-up twice weekly for the first 6 months of life.Children with subclinical EAEC infection did not show altered growth between enrollment and 6 months. Conversely, EAEC coinfection with any other pathogen was negatively associated with delta weight-for-length (P 0.05) and weight-for-age (P 0.05) z scores between 0 and 6 months. The presence of 2 or more pathogens without EAEC was not significantly associated with delta weight-for-length and weight-for-age. The most frequent EAEC coinfections included Campylobacter spp, heat-labile toxin-producing enterotoxigenic E coli, Cryptosporidium spp, and atypical enteropathogenic E coli. Myeloperoxidase levels were increased with EAEC coinfection (P 0.05). EAEC pathogen codetection was associated with lower neopterin levels compared to those of no-pathogen control children (P 0.05). Mothers of children with EAEC coinfections had lower levels of education, poorer hygiene and sanitation, lower socioeconomic status, and lower breast-feeding rates compared to mothers of children in whom no pathogen was detected (P 0.05).These data emphasize the public health importance of subclinical EAEC infection in early infancy in association with other pathogens and the need for improved maternal and child care, hygiene, sanitation, and socioeconomic factors.

Hydroxysteroid-dehydrogenase-17b (HSD17b) genes control the last step in estrogen biosynthesis. The isoenzymes HSD17b2 and HSD17b4 in the uterus preferentially catalyze the conversion of estradiol, the most potent and active form of estrogen, to estrone, the inactive form of estrogen. Endometrial adenocarcinoma is linked to excessive exposure to estrogens. We hypothesized that single nucleotide polymorphisms (SNPs) in genes HSD17b2 and HSD17b4 may alter the enzyme activity, estradiol levels and risk of disease.Pairwise tag SNPs were selected from the HapMap Caucasian database to capture all known common (minor allele frequency0.05) genetic variation with a correlation of at least 0.80. Forty-eight SNPs were genotyped in the case-control studies nested within the Nurses' Health Study (NHS) (cases=544, controls=1296) and the Women's Health Study (WHS) (cases=130, controls=389). The associations with endometrial cancer were examined using conditional logistic regression to estimate odds ratio and 95% confidence intervals adjusted for known risk factors. Results from the two studies were using fixed effects models. We additionally investigated whether SNPs are predictive of plasma estradiol and estrone levels in the NHS using linear regression.Four intronic SNPs were significantly associated with endometrial cancer risk (p-value0.05). After adjustment for multiple testing, we did not observe any significant associations between SNPs and endometrial cancer risk or plasma hormone levels.This is the first study to comprehensively evaluate variation in HSD17b2 and HSD17b4 in relation to endometrial cancer risk. Our findings suggest that variation in HSD17b2 and HSD17b4 does not substantially influence the risk of endometrial cancer in Caucasians.

Objective Together, steroidogenic acute regulator (StAR) and the cholesterol side chain cleavage enzyme (P450scc), which is encoded by CYP11A1 , mediate the initial and rate-limiting step in steroidogenesis. Given the role of estrogens in endometrial carcinogenesis, we hypothesized that genetic variation in StAR and CYP11A1 genes may influence endometrial cancer risk. Methods We genotyped four CYP11A1 tagging single nucleotide polymorphisms (SNPs) and two StAR SNPs in endometrial cancer case–control studies nested within the Nurses' Health Study (553 cases and 1339 controls) and the Women's Health Study (137 cases and 411 controls). We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for endometrial cancer risk factors to examine the association between SNPs/haplotypes and endometrial cancer. Results We observed an increased risk for women carrying the variant allele for rs4555110 (odds ratio (OR)=1.3, 95% confidence interval (CI)=1.1–1.7), rs3825944 (OR=1.4, 95% CI=1.1–1.8), and rs7173655 (OR=1.3, 95% CI=1.0–1.7) CYP11A1 SNPs but no significant associations with CYP11A1 haplotypes. CYP11A1 SNPs were not predictive of plasma estradiol levels. We observed no associations between StAR SNPs and endometrial cancer risk. Conclusions Genetic variants in CYP11A1 may influence endometrial cancer risk or may be markers for causal variants elsewhere. Polymorphisms in StAR are not associated with endometrial cancer risk, but further research is needed.

Common variants in CYP19A1 (the A alleles of rs749292 and rs727479) have been associated with a 10% to 20% increase in circulating estrogen levels in postmenopausal women. We hypothesized that the presence of one or both A alleles in these single nucleotide polymorphisms (SNP) is associated with increased endometrial cancer risk. We tested this hypothesis in a large pooled analysis of 4,998 endometrial cancer cases and 8,285 controls from 10 studies in the Epidemiology of Endometrial Cancer Consortium. The majority of women (>66%) were whites, with smaller proportions of other races and ethnic groups (blacks, Asians, and Latinas) also included in this pooled analysis. Unconditional logistic regression was used to model the association between SNPs/haplotypes and endometrial cancer risk. Carrying the A allele of either of these SNPs was associated with an increased risk of endometrial cancer, with pooled odds ratios per allele of 1.14, 95% confidence interval of 1.09-1.21, and P = 7.1 × 10-7 for rs749292, and odds ratio per allele of 1.08, 95% confidence interval of 1.02-1.14, and P = 0.009 for rs727479. For rs749292, these associations were generally stronger among women age ≥55 years. For both SNPs, risk increased with increasing body mass index, and for rs727479, this pattern seemed stronger among women age ≥55 years (P interaction = 0.007). The combination of A alleles in the two SNPs, either by direct count or by haplotype analysis, did not increase risk above that observed for the individual SNPs. Our study provides evidence that CYP19A1 genetic variation influences susceptibility to endometrial cancer, particularly among older and obese women. (Cancer Epidemiol Biomarkers Prev 2009;18(1):242–7)

Mouse double-minute 2 homologue (MDM2) is a key negative regulator of p53, a tumor suppressor gene that initiates cell cycle arrest and apoptosis in response to DNA damage and other cellular stresses. A T > G polymorphism found in the promoter region of MDM2 (SNP309) increases MDM2 expression and thereby attenuates p53 activity. We genotyped the MDM2 polymorphism SNP309 in endometrial cancer case-control studies nested within the Nurses' Health Study (454 cases and 1,132 controls) and the Women's Health Study (137 cases and 411 controls). Due to a significant difference in genotype distribution by ethnicity, we restricted our analyses to Caucasians. We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for age at menarche, parity and age at first birth, postmenopausal hormone use at diagnosis, age at menopause and menopausal status at diagnosis, first-degree family history of colon cancer, body mass index at diagnosis, and cigarette smoking status at diagnosis. Women with a heterozygous genotype had no greater risk whereas those with a homozygous variant genotype had a greater risk than women with a wild-type genotype for the MDM2 SNP309 (covariate-adjusted odds ratio, 1.87; 95% confidence interval, 1.29-2.73) for endometrial cancer. We observed no association between age at diagnosis and genotype. Women carrying two copies of the MDM2 SNP309 variant may be at greater risk of endometrial cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(4):983–6)

We investigated whether telomere length was associated with the risk of Parkinson’s disease (PD) in a case-control study (96 cases and 172 age-matched controls) nested within the Health Professionals Follow-up Study. Relative ratio of telomere repeat copy number to single-gene copy number in peripheral blood leukocytes was determined by quantitative real time PCR. Men with shorter telomeres had a lower PD risk (multivariate adjusted relative risk for the lowest vs. the highest quartile 0.33; 95% confidence interval: 0.12–0.90). Our results suggest that, contrary to telomere attrition observed in several aging-related diseases, shorter telomeres are not associated with an increased risk of PD.

Cytochrome P450 1A1 (CYP1A1) is involved in the metabolism of estradiol and the activation of polycyclic aromatic hydrocarbons found in tobacco products. Polymorphic variation in CYP1A1 activity may modify susceptibility to endometrial cancer through the oxidative metabolism of estradiol and the activation of tobacco-smoke constituents. We prospectively evaluated the associations between three common CYP1A1 polymorphisms and endometrial cancer risk, as well as the potential modification of these associations by cigarette smoking, in a case-control study nested within the Nurses' Health Study. We investigated the MspI restriction-site polymorphism, a C --A transversion at nucleotide 4887 (Thr461Asn) and a A --G transition at nucleotide 4889 (Ile462Val) among 456 women with endometrial cancer and 1,134 matched controls. We used conditional logistic regression to calculate the adjusted odds ratios (OR) and 95% confidence intervals (CI) to quantify the risk of endometrial cancer among subjects who had at least one variant allele compared with that of subjects homozygous for the wild-type allele. We did not observe any statistically significant associations between the MspI, Thr461Asn or Ile462Val polymorphisms and endometrial cancer risk or any significant effect modification by cigarette-smoking status. These data suggest that these three polymorphisms are not important in determining genetic susceptibility to endometrial cancer, although larger sample sizes are needed to confirm these findings.

Summary Background Most studies of the causes of diarrhoea in low-income and middle-income countries have looked at severe disease in people presenting for care, and there are few estimates of pathogen-specific diarrhoea burdens in the community. Methods We undertook a birth cohort study with not only intensive community surveillance for diarrhoea but also routine collection of non-diarrhoeal stools from eight sites in South America, Africa, and Asia. We enrolled children within 17 days of birth, and diarrhoeal episodes (defined as maternal report of three or more loose stools in 24 h, or one loose stool with visible blood) were identified through twice-weekly home visits by fieldworkers over a follow-up period of 24 months. Non-diarrhoeal stool specimens were also collected for surveillance for months 1–12, 15, 18, 21, and 24. Stools were analysed for a broad range of enteropathogens using culture, enzyme immunoassay, and PCR. We used the adjusted attributable fraction (AF) to estimate pathogen-specific burdens of diarrhoea. Findings Between November 26, 2009, and February 25, 2014, we tested 7318 diarrhoeal and 24 310 non-diarrhoeal stools collected from 2145 children aged 0–24 months. Pathogen detection was common in non-diarrhoeal stools but was higher with diarrhoea. Norovirus GII (AF 5·2%, 95% CI 3·0–7·1), rotavirus (4·8%, 4·5–5·0), Campylobacter spp (3·5%, 0·4–6·3), astrovirus (2·7%, 2·2–3·1), and Cryptosporidium spp (2·0%, 1·3–2·6) exhibited the highest attributable burdens of diarrhoea in the first year of life. The major pathogens associated with diarrhoea in the second year of life were Campylobacter spp (7·9%, 3·1–12·1), norovirus GII (5·4%, 2·1–7·8), rotavirus (4·9%, 4·4–5·2), astrovirus (4·2%, 3·5–4·7), and Shigella spp (4·0%, 3·6–4·3). Rotavirus had the highest AF for sites without rotavirus vaccination and the fifth highest AF for sites with the vaccination. There was substantial variation in pathogens according to geography, diarrhoea severity, and season. Bloody diarrhoea was primarily associated with Campylobacter spp and Shigella spp, fever and vomiting with rotavirus, and vomiting with norovirus GII. Interpretation There was substantial heterogeneity in pathogen-specific burdens of diarrhoea, with important determinants including age, geography, season, rotavirus vaccine usage, and symptoms. These findings suggest that although single-pathogen strategies have an important role in the reduction of the burden of severe diarrhoeal disease, the effect of such interventions on total diarrhoeal incidence at the community level might be limited. Funding Bill & Melinda Gates Foundation.

OBJECTIVE: The authors assessed the association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and scores on the phobic anxiety scale of the Crown-Crisp Experimental Index. METHOD: A total of 1,234 women completed the Crown-Crisp Experimental Index phobic anxiety scale and were genotyped for the COMT polymorphism. The authors used unconditional logistic regression to compute odds ratios and 95% confidence intervals (CIs) to evaluate the association between the COMT genotype and phobic anxiety. RESULTS: The mean scores for the three genotypes were statistically significantly different. Compared to the COMT Met/Met genotype, the age-adjusted odds ratio for scoring ≥6 compared to scoring 0 or 1 were 1.15 (95% CI=0.71–1.85) and 1.99 (95% CI=1.17–3.40) for the COMT Val/Met and COMT Val/Val genotypes, respectively; a significant gene dosage effect was observed. CONCLUSIONS: Our results suggest that the functional COMT polymorphism is associated with the development of phobic anxiety.

Background Stunting results from decreased food intake, poor diet quality, and a high burden of early childhood infections, and contributes to significant morbidity and mortality worldwide. Although food insecurity is an important determinant of child nutrition, including stunting, development of universal measures has been challenging due to cumbersome nutritional questionnaires and concerns about lack of comparability across populations. We investigate the relationship between household food access, one component of food security, and indicators of nutritional status in early childhood across eight country sites. Methods We administered a socioeconomic survey to 800 households in research sites in eight countries, including a recently validated nine-item food access insecurity questionnaire, and obtained anthropometric measurements from children aged 24 to 60 months. We used multivariable regression models to assess the relationship between household food access insecurity and anthropometry in children, and we assessed the invariance of that relationship across country sites. Results Average age of study children was 41 months. Mean food access insecurity score (range: 0–27) was 5.8, and varied from 2.4 in Nepal to 8.3 in Pakistan. Across sites, the prevalence of stunting (42%) was much higher than the prevalence of wasting (6%). In pooled regression analyses, a 10-point increase in food access insecurity score was associated with a 0.20 SD decrease in height-for-age Z score (95% CI 0.05 to 0.34 SD; p = 0.008). A likelihood ratio test for heterogeneity revealed that this relationship was consistent across countries (p = 0.17). Conclusions Our study provides evidence of the validity of using a simple household food access insecurity score to investigate the etiology of childhood growth faltering across diverse geographic settings. Such a measure could be used to direct interventions by identifying children at risk of illness and death related to malnutrition.

Uridine diphosphate-glucuronosyltransferases (UGTs) are a family of phase II-metabolizing enzymes involved in glucuronic acid conjugation of sex steroid hormones. UGT1A1 and UGT2B7 are expressed in the uterus and involved in the conjugation and elimination of estrogens. Chronic exposure to estrogens is associated with endometrial cancer. Functional polymorphisms have been identified in UGT1A1 and UGT2B7. We hypothesized that these variants may be associated with endometrial cancer risk. We conducted a case-control study nested within the Nurses' Health Study and the Women's Health Study to investigate the associations between five polymorphisms and endometrial cancer risk using 593 invasive endometrial cancer cases and 1545 controls. We did observe the suggestion of an inverse association with homozygote variant carriers of UGT1A1*28 and endometrial cancer risk. We did not observe significant associations between individual single nucleotide polymorphisms and UGT1A1 haplotypes and endometrial cancer risk. Our data suggest that these UGT polymorphisms do not contribute significantly to endometrial cancer risk.

Gender and cigarette smoking are among the most consistent predictors of bladder cancer risk. After adjustment for known risk factors, an excess risk remains for males, suggesting that other factors may be responsible for the gender differences. Given limited data on hormonal or reproductive factors and bladder cancer risk, the authors examined these factors among women in the US Nurses' Health Study cohort. During 26 years of follow-up (1976-2002), 336 incident cases of bladder cancer were diagnosed. Cox proportional hazards models were used to estimate incidence rate ratios and 95% confidence intervals between hormonal and reproductive factors and bladder cancer risk. Postmenopausal women, compared with premenopausal women, were at increased risk (incidence rate ratio = 1.93, 95% confidence interval: 0.99, 3.78). For postmenopausal women, early age at menopause (/=45 years) compared with late age at menopause (/=50 years) was associated with a statistically significant increased risk of bladder cancer (incidence rate ratio = 1.63, 95% confidence interval: 1.20, 2.23). The association between age at menopause and bladder cancer risk was modified by cigarette smoking status (p for interaction = 0.01). The authors observed no significant associations of age at menarche, parity, age at first birth, and exogenous hormone use with bladder cancer risk. Findings suggest that menopausal status and age at menopause may play a role in modifying bladder cancer risk among women.

The androgen receptor (AR) gene is a transcription factor responsible for mediating the physiological effects of androgens. Evidence suggests that androgens and the androgen receptor are involved in uterine cell proliferation. A polymorphic CAG repeat in exon 1 of the AR gene encodes a polyglutamine tract that is inversely correlated with the transcriptional activity of this gene. We assessed the association between the functional CAG repeat polymorphism and AR haplotypes and the risk of endometrial cancer in two nested case-control studies within the Nurses' Health Study (n = 222 cases, 666 controls) and the Women's Health Study (n = 137 cases, 411 controls) using conditional and unconditional logistic regression. Associations between AR CAG repeat polymorphism and endometrial cancer risk were similar in the 2 case-control studies. In the pooled analysis, women with an average repeat alleleor =22 repeats compared to22 repeats were at a statistically significant decreased risk of endometrial cancer (odds ratio (OR) = 0.76; 95% confidence interval (CI), 0.59-0.98). Women with one or two long alleles (or =27 repeats) compared to both alleles22 repeats were also at a statistically significant decreased risk (OR = 0.60; 95% CI, 0.36-0.99). We observed a modest yet statistically significant association for each one unit increase in the average repeat length and endometrial cancer risk (OR = 0.94; 95% CI, 0.88-1.00). Associations for the AR CAG average repeat length and endometrial cancer risk differed by menopausal status (p = 0.02). No significant associations between the AR haplotypes and endometrial cancer risk were observed. Our findings suggest that an increasing number of functional CAG repeats may be associated with endometrial carcinogenesis because of AR's reduced ability to recruit coregulators and other transcriptional components. (supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html).

UDP-glucuronosyltransferase (UGT) 1A1 is involved in the inactivation of estradiol (E2) and its oxidized metabolites. These metabolites have been shown to contribute to the development of endometrial cancer in animal studies. Thus UGT1A1 represents a candidate gene in endometrial carcinogenesis. In this study, we established the substrate specificity of UGT1A1 for E2 and its 2- and 4-hydroxylated metabolites. Intrinsic clearances indicated that UGT1A1 had a preference for the glucuronidation of 2-hydroxyestradiol, a metabolite associated with antiproliferative activity. Expression analysis demonstrated that UGT1A1 is present in the nonmalignant endometrium. Subsequently, we sought to determine whether the common UGT1A1 promoter allele, UGT1A1*28 [A(TA)7TAA], which decreases gene transcription, was associated with endometrial cancer risk in a case-control study nested within the Nurses’ Health Study (222 cases, 666 matched controls). Conditional logistic regression demonstrated a significant inverse association with the UGT1A1*28 allele and endometrial cancer risk. Compared with women homozygous for the UGT1A1*1 [A(TA)6TAA] allele, the adjusted odds ratio (OR) was 0.81 [95% confidence interval (CI), 0.56–1.16] for the UGT1A1*1/*28 genotype and 0.40 (95% CI, 0.21–0.75) for the homozygous UGT1A1*28 genotype (Ptrend = 0.007). There was a suggestion of an interaction by menopausal status [OR = 0.39 (95% CI, 0.18–0.85) for premenopausal women and OR = 0.79 (95% CI, 0.55–1.13) for postmenopausal women who carry the UGT1A1*28 allele (Pinteraction = 0.05)]. These observations suggest that lower expression of UGT1A1 decreases the risk of endometrial cancer by reducing the excretion of 2-hydroxyestradiol, the antiproliferative metabolite of E2, in the endometrium.

Estrogen production and metabolism play critical roles inthe development and pathogenesis of endometrial carci-noma. Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are two key enzymes in theestrogen metabolism pathway that result in the hydroxyla-tion and conjugation of estradiol, respectively. We evalu-ated the association between the CYP1B1 Leu432Valand CYP1B1 Asn453Ser polymorphisms and the COMTVal158Met polymorphism and invasive endometrial cancerriskinacase-controlstudynestedwithintheNurses’HealthStudy (n ‹222 cases, 666 controls). We also evaluatedwhether body mass index (BMI), postmenopausal hormone(PMH) use and cigarette smoking modified the associationsof the CYP1B1 and COMT genotypes and endometrialcancer risk. Conditional logistic regression was used tocalculate the adjusted odds ratios (OR) and 95% confi-dence intervals (CI) to quantify the risk of endometrialcancer among subjects who had at least one variant allelecompared with subjects who were homozygous for thewild-type allele. Carriers of the CYP1B1 Ser allele had astatistically significant decreased risk of endometrialcancer (OR ‹0.62; 95% CI, 0.42-- 0.91); there was nosignificant association between the CYP1B1 Val allele andendometrial cancer risk (OR ‹1.10; 95% CI, 0.75-- 1.59).Compared with the COMT Val/Val wildtype genotype, theadjusted OR of endometrial cancer for women with theCOMT Val/Met or COMT Met/Met genotype was 0.96 (95%CI, 0.65-- 1.43). We did not observe any effect modificationby BMI, PMH use and cigarette smoking for the CYP1B1and COMT genotypes. Our data suggest, that the CYP1B1Ser allele may decrease endometrial cancer risk by alteringthe production of catechol estrogens. However, furtherstudies are warranted to elucidate the role of CYP1B1 inendometrial cancer.IntroductionThe production and metabolism of estrogen play critical rolesin the pathogenesis and development of hormone-related can-cers, including endometrial carcinoma. Inherited variability inthe synthesis and metabolism of steroid hormones may affectcancer risk by contributing to individual differences in serumand cellular levels of steroidal parent hormones and hormonemetabolites (1,2). Polymorphisms in estrogen-metabolizinggenes may cause alterations in their biological function andthus potentially contribute to individual disease susceptibil-ities. We hypothesized that functionally relevant polymorph-isms in COMT and CYP1B1 may display individual, as well asadditive, effects on endometrial cancer susceptibility.Cytochrome P450 1B1 (CYP1B1) is a phase I enzyme thatcatalyzes the conversion of 17b-estradiol (E2) to the catecholestrogens,4-hydroxyestradiol(4-OH-E2)and2-hydroxyestradiol(2-OH-E2) and is involved in the activation of polycyclicaromatic hydrocarbons (3). Several single nucleotide poly-morphisms have been identified in CYP1B1. The CYP1B1Leu432Val and Asn453Ser polymorphisms located in exon 3,which encodes the catalytically important heme-bindingdomain of the enzyme, were selected as candidate susceptibil-ity alleles (4,5). These polymorphisms are biologically rele-vant and functional (6-- 9), and have been studied in relation toother hormonally relevant cancers, such as breast cancer(5,10-- 12). Two additional polymorphisms, Arg48Gly andAla119Ser, also result in amino acid substitutions and aretightly linked (4). However, McLellan et al. (13) observed nokinetic differences in E2 hydroxylation activities, and con-cluded that these amino acid substitutions led to similar cata-lytic properties to those of the wildtype genotype. All CYP1B1variants form 4-OH-E2 as their main product (6,8). Hannaet al. (8) determined that inherited CYP1B1 variants dis-played higher estradiol 2- and 4-hydroxylation activitiescompared with their wildtype enzyme. Furthermore, the ratioof product formation of 4-OH-E2 to 2-OH-E2 was higherfor CYP1B1 variants compared with their wildtype counter-part (6,8), potentially contributing to higher tissue levels of4-OH-E2 (8).Catechol-O-methyltransferase (COMT) is a phase II enzymethat is involved in the conjugation and inactivation of catecholestrogens (14). COMT catalyzes the methylation of catecholestrogens to less polar monomethyl ethers. O-Methylationincreases the concentrations of 4-methoxyestradiol (4-MeO-E2) and 2-methoxyestradiol (2-MeO-E2): 2-MeO-E2 pos-sesses anti-proliferative, cytotoxic and apoptotic activitytherefore decreasing the potential for DNA damage (15-- 19).Lachman et al. (20) identified a functional polymorphism inthe COMT gene, a G!A transition at codon 158 in exon 4,leading to a substitution of methionine for valine that results ina thermolabile enzyme with reduced activity. Individuals whoare homozygous for this low activity Met allele have a 3-- 4-fold decrease in activity, resulting in possible increased levels