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Objectives: To describe U.S. practice regarding administration of sedation and analgesia to patients on noninvasive ventilation (NIV) for acute respiratory failure (ARF) and to determine the association of this practice with odds of intubation or death., Design: A retrospective multicenter cohort study., Setting: A total of 1017 hospitals contributed data between January 2010 and September 2020 to the Premier Healthcare Database, a nationally representative healthcare database in the United States., Patients: Adult (≥ 18 yr) patients admitted to U.S. hospitals requiring NIV for ARF., Interventions: None., Measurements and Main Results: We identified 433,357 patients on NIV of whom (26.7% [95% CI] 26.3%-27.0%) received sedation or analgesia. A total of 50,589 patients (11.7%) received opioids only, 40,646 (9.4%) received benzodiazepines only, 20,146 (4.6%) received opioids and benzodiazepines, 1.573 (0.4%) received dexmedetomidine only, and 2,639 (0.6%) received dexmedetomidine in addition to opioid and/or benzodiazepine. Of 433,357 patients receiving NIV, 50,413 (11.6%; 95% CI, 11.5-11.7%) patients underwent invasive mechanical ventilation on hospital days 2-5 or died on hospital days 2-30. Intubation was used in 32,301 patients (7.4%; 95% CI, 7.3-7.6%). Further, death occurred in 24,140 (5.6%; 95% CI, 5.5-5.7%). In multivariable analysis adjusting for relevant covariates, receipt of any medication studied was associated with increased odds of intubation or death. In inverse probability weighting, receipt of any study medication was also associated with increased odds of intubation or death (average treatment effect odds ratio 1.38; 95% CI, 1.35-1.40)., Conclusions: The use of sedation and analgesia during NIV is common. Medication exposure was associated with increased odds of intubation or death. Further investigation is needed to confirm this finding and determine whether any subpopulations are especially harmed by this practice., Competing Interests: This article was supported by an Institutional National Research Service Award (T32) funded by the National Institute of Health, National Heart, Lung, and Blood Institute (T32 HL007085). Dr. Ho disclosed government work. Dr. Sottile’s institution received funding from the National Heart, Lung, and Blood Institute; he received support for article research from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

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 through the Environmental Influences on Child Health Outcomes Program. Data on prenatal exposure to opioids, nicotine, marijuana, and alcohol were collected from children ages 6 to 11 years ( N  = 256). Problem behavior was assessed using the Child Behavior Checklist (school-age version), and verbal IQ (VIQ) and performance IQ (PIQ) were assessed using the Weschler Intelligence Scale for Children, Fifth Edition. 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., Conclusion: 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., Key Points: · The neurodevelopmental consequences of prenatal polysubstance exposure are poorly understood.. · Children with prenatal polysubstance exposure exhibited reduced IQ and elevated problem behavior.. · We found significant behavior problems in children with average PIQ and below-average VIQ.. · This may represent a unique endophenotype related to prenatal nicotine exposure.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: We aimed to understand the association between maternal stress in the first year of life and childhood body mass index (BMI) from 2 to 4 years of age in a large, prospective United States-based consortium of cohorts., Methods: We used data from the Environmental influences on Child Health Outcomes program. The main exposure was maternal stress in the first year of life measured with the Perceived Stress Scale (PSS). The main outcome was the first childhood BMI percentile after age 2 until age 4 years. We used an adjusted linear mixed effects model to examine associations between BMI and PSS quartile., Results: The mean BMI percentile in children was 59.8 (SD 30) measured at 3.0 years (SD 1) on average. In both crude models and models adjusted for maternal BMI, age, race, ethnicity, infant birthweight, and health insurance status, no linear associations were observed between maternal stress and child BMI., Conclusions: Among 1694 maternal-infant dyads, we found no statistically significant relationships between maternal perceived stress in the first year of life and child BMI after 2 through 4 years., Impact: Although existing literature suggests relationships between parental stress and childhood BMI, we found no linear associations between maternal stress in the first year of life and childhood BMI at 2-4 years of age among participants in ECHO cohorts. Higher maternal stress was significantly associated with Hispanic ethnicity, Black race, and public health insurance. Our analysis of a large, nationally representative sample challenges assumptions that maternal stress in the first year of life, as measured by a widely used scale, is associated with offspring BMI., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: In the United States, disparities in gestational age at birth by maternal race, ethnicity, and geography are theorized to be related, in part, to differences in individual- and neighborhood-level socioeconomic status (SES). Yet, few studies have examined their combined effects or whether associations vary by maternal race and ethnicity and United States Census region., Methods: We assembled data from 34 cohorts in the Environmental influences on Child Health Outcomes (ECHO) program representing 10,304 participants who delivered a liveborn, singleton infant from 2000 through 2019. We investigated the combined associations of maternal education level, neighborhood deprivation index (NDI), and Index of Concentration at the Extremes for racial residential segregation (ICE Race ) on gestational weeks at birth using linear regression and on gestational age at birth categories (preterm, early term, post-late term relative to full term) using multinomial logistic regression., Results: After adjustment for NDI and ICE Race , gestational weeks at birth was significantly lower among those with a high school diploma or less (-0.31 weeks, 95% CI: -0.44, -0.18), and some college (-0.30 weeks, 95% CI: -0.42, -0.18) relative to a master's degree or higher. Those with a high school diploma or less also had an increased odds of preterm (aOR 1.59, 95% CI: 1.20, 2.10) and early term birth (aOR 1.26, 95% CI: 1.05, 1.51). In adjusted models, NDI quartile and ICE Race quartile were not associated with gestational weeks at birth. However, higher NDI quartile (most deprived) associated with an increased odds of early term and late term birth, and lower ICE Race quartile (least racially privileged) associated with a decreased odds of late or post-term birth. When stratifying by region, gestational weeks at birth was lower among those with a high school education or less and some college only among those living in the Northeast or Midwest. When stratifying by race and ethnicity, gestational weeks at birth was lower among those with a high school education or less only for the non-Hispanic White category., Conclusion: In this study, maternal education was consistently associated with shorter duration of pregnancy and increased odds of preterm birth, including in models adjusted for NDI and ICE Race ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dunlop, Burjak, Dean, Alshawabkeh, Avalos, Aschner, Breton, Charifson, Cordero, Dabelea, D’Sa, Duarte, Elliott, Eick, Ferrara, Fichorova, Ganiban, Gern, Hedderson, Herbstman, Hipwell, Huddleston, Karagas, Karr, Kerver, Koinis-Mitchell, Lyall, Madan, Marsit, McEvoy, Meeker, Oken, O’Shea, Padula, Sathyanarayana, Schantz, Schmidt, Snowden, Stanford, Weiss, Wright, Wright, Zhang and McGrath.)

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 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g., air pollution, neighborhood socioeconomic status), family (e.g., parental mental health), and individuals (e.g., diet, genomics)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Importance: Emotional and behavioral dysregulation during early childhood are associated with severe psychiatric, behavioral, and cognitive disorders through adulthood. Identifying the earliest antecedents of persisting emotional and behavioral dysregulation can inform risk detection practices and targeted interventions to promote adaptive developmental trajectories among at-risk children., Objective: To characterize children's emotional and behavioral regulation trajectories and examine risk factors associated with persisting dysregulation across early childhood., Design, Setting, and Participants: This cohort study examined data from 20 United States cohorts participating in Environmental influences on Child Health Outcomes, which included 3934 mother-child pairs (singleton births) from 1990 to 2019. Statistical analysis was performed from January to August 2022., Exposures: Standardized self-reports and medical data ascertained maternal, child, and environmental characteristics, including prenatal substance exposures, preterm birth, and multiple psychosocial adversities., Main Outcomes and Measures: Child Behavior Checklist caregiver reports at 18 to 72 months of age, with Dysregulation Profile (CBCL-DP = sum of anxiety/depression, attention, and aggression)., Results: The sample included 3934 mother-child pairs studied at 18 to 72 months. Among the mothers, 718 (18.7%) were Hispanic, 275 (7.2%) were non-Hispanic Asian, 1220 (31.8%) were non-Hispanic Black, 1412 (36.9%) were non-Hispanic White; 3501 (89.7%) were at least 21 years of age at delivery. Among the children, 2093 (53.2%) were male, 1178 of 2143 with Psychosocial Adversity Index [PAI] data (55.0%) experienced multiple psychosocial adversities, 1148 (29.2%) were exposed prenatally to at least 1 psychoactive substance, and 3066 (80.2%) were term-born (≥37 weeks' gestation). Growth mixture modeling characterized a 3-class CBCL-DP trajectory model: high and increasing (2.3% [n = 89]), borderline and stable (12.3% [n = 479]), and low and decreasing (85.6% [n = 3366]). Children in high and borderline dysregulation trajectories had more prevalent maternal psychological challenges (29.4%-50.0%). Multinomial logistic regression analyses indicated that children born preterm were more likely to be in the high dysregulation trajectory (adjusted odds ratio [aOR], 2.76; 95% CI, 2.08-3.65; P < .001) or borderline dysregulation trajectory (aOR, 1.36; 95% CI, 1.06-1.76; P = .02) vs low dysregulation trajectory. High vs low dysregulation trajectories were less prevalent for girls compared with boys (aOR, 0.60; 95% CI, 0.36-1.01; P = .05) and children with lower PAI (aOR, 1.94; 95% CI, 1.51-2.49; P < .001). Combined increases in PAI and prenatal substance exposures were associated with increased odds of high vs borderline dysregulation (aOR, 1.28; 95% CI, 1.08-1.53; P = .006) and decreased odds of low vs high dysregulation (aOR, 0.77; 95% CI, 0.64-0.92; P = .005)., Conclusions and Relevance: In this cohort study of behavioral dysregulation trajectories, associations were found with early risk factors. These findings may inform screening and diagnostic practices for addressing observed precursors of persisting dysregulation as they emerge among at-risk children.

Background: Opioid use has disproportionally impacted pregnant people and their fetuses. Previous studies describing opioid use among pregnant people are limited by geographic location, type of medical coverage, and small sample size. We described characteristics of a large, diverse group of pregnant people who were enrolled in the Environmental Influences on Child Health Outcomes (ECHO) Program, and determined which characteristics were associated with opioid use during pregnancy. Materials and Methods: Cross-sectional data obtained from 21,905 pregnancies of individuals across the United States enrolled in the ECHO between 1990 and 2021 were analyzed. Medical records, laboratory testing, and self-report were used to determine opioid-exposed pregnancies. Multiple imputation methods using fully conditional specification with a discriminant function accounted for missing characteristics data. Results: Opioid use was present in 2.8% ( n  = 591) of pregnancies. The majority of people who used opioids in pregnancy were non-Hispanic White (67%) and had at least some college education (69%). Those who used opioids reported high rates of alcohol use (32%) and tobacco use (39%) during the pregnancy; although data were incomplete, only 5% reported heroin use and 86% of opioid use originated from a prescription. After adjustment, non-Hispanic White race, pregnancy during the years 2010-2012, higher parity, tobacco use, and use of illegal drugs during pregnancy were each significantly associated with opioid use during pregnancy. In addition, maternal depression was associated with increased odds of opioid use during pregnancy by more than two-fold (adjusted odds ratio 2.42, 95% confidence interval: 1.95-3.01). Conclusions: In this large study of pregnancies from across the United States, we found several factors that were associated with opioid use among pregnant people. Further studies examining screening for depression and polysubstance use may be useful for targeted interventions to prevent detrimental opioid use during pregnancy, while further elucidation of the reasons for use of prescription opioids during pregnancy should be further explored.

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., (© 2022 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Background and Aims: A complex systems perspective has been advocated to explore multi-faceted factors influencing public health issues, including alcohol consumption and associated harms. This scoping review aimed to identify studies that applied a complex systems perspective to alcohol consumption and the prevention of alcohol-related harms in order to summarize their characteristics and identify evidence gaps., Methods: Studies published between January 2000 and September 2020 in English were located by searching for terms synonymous with 'complex systems' and 'alcohol' in the Scopus, MEDLINE, Web of Science and Embase databases, and through handsearching and reference screening of included studies. Data were extracted on each study's aim, country, population, alcohol topic, system levels, funding, theory, methods, data sources, time-frames, system modifications and type of findings produced., Results: Eighty-seven individual studies and three systematic reviews were identified, the majority of which were conducted in the United States or Australia in the general population, university students or adolescents. Studies explored types and patterns of consumption behaviour and the local environments in which alcohol is consumed. Most studies focused on individual and local interactions and influences, with fewer examples exploring the relationships between these and regional, national and international subsystems. The body of literature is methodologically diverse and includes theory-led approaches, dynamic simulation models and social network analyses. The systematic reviews focused on primary network studies., Conclusions: The use of a complex systems perspective has provided a variety of ways of conceptualizing and analyzing alcohol use and harm prevention efforts, but its focus ultimately has remained on predominantly individual- and/or local-level systems. A complex systems perspective represents an opportunity to address this gap by also considering the vertical dimensions that constrain, shape and influence alcohol consumption and related harms, but the literature to date has not fully captured this potential., (© 2020 Society for the Study of Addiction.)

Objective: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used in spinal arthrodesis procedures to enhance bony fusion. Research has suggested that it is the most cost-effective fusion enhancer, but there are significant upfront costs for the healthcare system. The primary objective of this study was to determine whether intraoperative dosing and corresponding costs changed with surgeon cost awareness. The secondary objective was to describe surgical complications before and after surgeon awareness of rhBMP-2 cost., Methods: A retrospective medical record review was conducted to identify patients who underwent spinal arthrodesis procedures performed by a single surgeon, supplemented with rhBMP-2, from June 2016 to June 2018. Collected data included rhBMP-2 dosage, rhBMP-2 list price, and surgical complications. Expected Medicare reimbursement was calculated. Data were analyzed before and after surgeon awareness of rhBMP-2 cost., Results: Forty-eight procedures were performed using rhBMP-2, 16 before and 32 after surgeon cost awareness. Prior to cost awareness, the most frequent rhBMP-2 dosage level was x-small (38.9%, n = 7), followed by large (27.8%, n = 5) and small (22.2%, n = 4). After cost awareness, the most frequent rhBMP-2 dosage was xx-small (56.8%, n = 21), followed by x-small (21.6%, n = 8) and large (13.5%, n = 5). The rhBMP-2 average cost per surgery was $4116.56 prior to surgeon cost awareness versus $2268.38 after. Two complications were observed in the pre-cost awareness surgical group; 2 complications were observed in the post-cost awareness surgical group., Conclusions: Surgeon awareness of rhBMP-2 cost resulted in use of smaller rhBMP-2 doses, decreased rhBMP-2 cost per surgery, and decreased overall hospital admission charges, without a detectable increase in surgical complications.

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., Competing Interests: The authors have declared that no competing interests exist.

Millions of uninsured people use health care services every year. We estimated providers' uncompensated care costs in 2013 to be between $74.9 billion and $84.9 billion. We calculated that in the aggregate, at least 65 percent of providers' uncompensated care costs were offset by government payments designed to cover the costs. Medicaid and Medicare were the largest sources of such government payments, providing $13.5 billion and $8.0 billion, respectively. Anticipating fewer uninsured people and lower levels of uncompensated care, the Affordable Care Act reduces certain Medicare and Medicaid payments. Such cuts in government funding of uncompensated care could pose challenges to some providers, particularly in states that have not adopted the Medicaid expansion or where implementation of health care reform is proceeding slowly.

Objective: Under Food and Drug Administration investigational device exemption, the Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT) has been testing the safety of less aggressive anticoagulation than recommended by the American College of Cardiology/American Heart Association guidelines after implantation of an approved bileaflet mechanical valve., Methods: In this first limb of the PROACT, patients with elevated risk factors for thromboembolism were randomized at 33 US centers to receive lower dose warfarin (test international normalized ratio [INR], 1.5-2.0) or continue standard warfarin (control INR, 2.0-3.0), 3 months after mechanical aortic valve replacement. The INR was adjusted by home monitoring; all patients received 81 mg aspirin daily. Adverse events were independently adjudicated., Results: A total of 375 aortic valve replacement patients were randomized into control (n = 190) and test (n = 185) groups from September 2006 to December 2009. The mean age ± standard deviation was 55.2 ± 12.5 years; 79% were men; and 93% were in sinus rhythm preoperatively. Calcific degeneration was present in 67%; active endocarditis was excluded. Concomitant procedures included coronary artery bypass grafting (27%), aortic aneurysm repair (14%), and other (25%). The follow-up duration averaged 3.82 years (755.7 patient-years [pt-yrs] for control; 675.2 pt-yrs for test). The mean INR was 2.50 ± 0.63 for the control and 1.89 ± 0.49 for the test groups (P < .0001). The test group experienced significantly lower major (1.48% vs 3.26%/pt-yr; P = .047) and minor (1.32% vs 3.41%/pt-yr; P = .021) bleeding rates. The incidence of stroke, transient ischemic attack, total neurologic events, and all-cause mortality were similar between the 2 groups., Conclusions: INR can be safely maintained between 1.5 and 2.0 after aortic valve replacement with this approved bileaflet mechanical prosthesis. With low-dose aspirin, this resulted in a significantly lower risk of bleeding, without a significant increase in thromboembolism., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.

A trend in food labeling is to make claims related to agricultural management, and this is occurring with dairy labels. A survey study was conducted to compare retail milk for quality (antibiotics and bacterial counts), nutritional value (fat, protein, and solids-not-fat), and hormonal composition (somatotropin, insulin-like growth factor-1 [IGF-1], estradiol, and progesterone) as affected by three label claims related to dairy-cow management: conventional, recombinant bovine somatotropin (rbST)-free (processor-certified not from cows supplemented with rbST), or organic (follows US Department of Agriculture organic practices). Retail milk samples (n=334) from 48 states were collected. Based on a statistical analysis that reflected the sampling schema and distributions appropriate to the various response variables, minor differences were observed for conventional, rbST-free, and organic milk labels. Conventionally labeled milk had the lowest (P<0.05) bacterial counts compared to either milk labeled rbST-free or organic; however, these differences were not biologically meaningful. In addition, conventionally labeled milk had significantly less (P<0.05) estradiol and progesterone than organic milk (4.97 vs 6.40 pg/mL and 12.0 vs 13.9 ng/mL, respectively). Milk labeled rbST-free had similar concentrations of progesterone vs conventional milk and similar concentrations of estradiol vs organic milk. Concentrations of IGF-1 in milk were similar between conventional milk and milk labeled rbST-free. Organic milk had less (P<0.05) IGF-1 than either conventional or rbST-free milk (2.73 ng/mL vs 3.12 and 3.04 ng/mL, respectively). The macronutrient profiles of the different milks were similar, except for a slight increase in protein in organic milk (about 0.1% greater for organic compared to other milks). Label claims were not related to any meaningful differences in the milk compositional variables measured. It is important for food and nutrition professionals to know that conventional, rbST-free, and organic milk are compositionally similar so they can serve as a key resource to consumers who are making milk purchase (and consumption) decisions in a marketplace where there are misleading milk label claims.

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.

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.

For various reasons, many people wish to execute an advance directive for healthcare. Like other important life decisions, choices about healthcare should be consistent with the person's religious faith and values. To help people prepare an advance directive that is both accurate and reflective of Christian teaching and values, we have written the following document. Copies of An Advance Directive for Future Health Care Decisions: A Christian Perspective may be obtained in booklet form from Center for Health Care Ethics, 1402 S. Grand Blvd., St. Louis, MO 63104.

Knowledge of the issues involving sterilization for mentally retarded adolescents is limited. Data were obtained from 69 interviewed parents whose mentally retarded daughters were attending the Cincinnati Adolescent Clinic. (A companion paper focuses on the experience of these girls with sexual activity, sexual abuse, and contraceptive use.) Forty-six percent of the parents had considered sterilization for their daughters. Twenty-six percent were still seeking the operation. Interest in sterilization especially correlated with increased severity of retardation (P less than .005) and with difficulty teaching menstrual hygiene (P less than .005). Parents of mildly retarded females sought tubal ligation, and those with severely retarded daughters chose hysterectomy and stressed their concern about menstrual management. Eighty-five percent of the parents favored a state statute that would enable sterilization under certain conditions and limitations. In general, few parents supported either an extremely restrictive or permissive position about sterilization.