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Anxiety disorders emerge during childhood and adolescence and are frequently preceded by subsyndromal anxiety symptoms. Environmental toxicants, including gestational polybrominated diphenyl ether (PBDE) exposure, are associated with neuropsychiatric sequelae; however, the role of PBDEs as risk factors for anxiety in adolescence is unclear.Using data from the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort enrolled from 2003 to 2006, we investigated the relationship between gestational serum PBDE concentrations and anxiety symptoms in adolescents (N = 236). We measured five PBDE congeners (PBDE-28, -47, -99, -100, and -153) at 16 ± 3 weeks of gestation and calculated their sum (∑PBDE). We assessed self-reported anxiety symptoms using the Screen for Child Anxiety Related Emotional Disorders (SCARED) and depressive symptoms using the Children's Depression Inventory (CDI-2) at age 12 years. We estimated the associations of maternal PBDE concentrations with child anxiety and depressive symptoms using multivariable linear regression and modified Poisson regression. Covariates included child sex, maternal race, maternal age at delivery, maternal marital status, maternal education, and household income at the 12-year study visit as well as maternal depressive and anxiety symptoms. Sensitivity analyses were performed to control for maternal lead and mercury at delivery.After adjusting for predetermined covariates, each doubling in maternal PBDE concentrations was associated with increased SCARED scores (e.g., for ∑PBDE, SCARED total score, β = 1.6 95% confidence interval [CI]: 0.3-2.9, p = .019) and a nonsignificant increase in depressive symptoms (e.g., for CDI total score, β = .8, 95% CI: -0.2-1.8, p = .11).Gestational serum PBDE concentrations just before mid-pregnancy and during a period of active cortical and limbic neurogenesis, synaptogenesis and myelogenesis may be a risk factor for developing anxiety symptoms in early adolescence.

Introduction: Turner syndrome (TS) results from a complete or partial loss of the X chromosome and affects 25–50 per 100,000 females. These individuals have characteristic neurocognitive and psychological profiles with an increased lifetime prevalence of mood disorders, such as depression and anxiety. Consensus guidelines recommend the use of psychometrically robust tools to screen for these conditions [Eur J Endocrinol. 2017;177(3):G1–G70 and Gynecol Endocrinol. 2004;19(6):313–9]. We propose a sustainable and informative approach to routine anxiety screening in individuals with TS and describe the prevalence of anxiety, genotype-phenotype associations, and impact of comorbidities on anxiety. Methods: We pilot the use of a self-administered version of the validated Pediatric, Parent Proxy, and Adult Patient-Reported Outcomes Measurement Information System (PROMIS®) Anxiety tool during routine visits to the Cincinnati Children’s Hospital Medical Center (CCHMC) TS clinic from October 2019 to March 2020. Results: Ninety-two eligible TS females, ages 8–62 years, received the PROMIS® Anxiety measure. Elevated anxiety scores, ≥1 standard deviation above the T-score mean, were present in 65% of patients (38% mild, 19% moderate, and 8% severe). Results were discussed during the clinic visit, and referral for further evaluation and treatment was offered. There was no apparent genotype-phenotype association among females with anxiety; however, there appeared to be elevated anxiety symptoms (T-score >60) in those with hearing deficits and also in individuals with three or more medical comorbidities. Of the 55% of patients who filled out the acceptability survey, 88% found the process helpful and ∼50% felt that screening should be performed at least every 6 months. Conclusion: Our study demonstrated a high prevalence of anxiety symptoms within a cohort of 92 females with TS. In alignment with current guidelines, these findings indicate the importance of routine neuropsychological assessments for timely recognition and subsequent management of anxiety, especially as milder presentations may otherwise go unnoticed. We have shown that screening tools, such as the PROMIS® Anxiety measure, can be easily utilized by nonmental health care providers (i.e., endocrinologists) who may see TS patients more frequently and be able to initiate impactful discussions surrounding mental health and further referral to subspecialists for expert management.

Introduction: Adult women with Turner syndrome (TS) have a high prevalence of diabetes and β-cell dysfunction that increases morbidity and mortality, but it is unknown if there is β-cell dysfunction present in youth with TS. This study aimed to determine the prevalence of β-cell dysfunction in youth with TS and the impact of traditional therapies on insulin sensitivity (SI) and insulin secretion. Methods: Cross-sectional, observational study recruited 60 girls with TS and 60 healthy controls (HC) matched on pubertal status. Each subject had a history, physical exam, and oral glucose tolerance test (OGTT). Oral glucose and c-peptide minimal modeling was used to determine β-cell function. Results: Twenty-one TS girls (35%) met criteria for prediabetes. Impaired fasting glucose was present in 18% of girls with TS and 3% HC (p value = 0.02). Impaired glucose tolerance was present in 23% of TS girls and 0% HC (p value p = 0.42). Youth with TS had significant reductions in SI, β-cell responsivity (Φ), and disposition index (DI) compared to HC. These differences remained significant when controlling for body mass index z-score (p values: 0.0006, 0.002, Conclusions: β-Cell dysfunction is present in youth with TS compared to controls. The presence of both reduced insulin secretion and SI suggest a unique TS-related glycemic phenotype. Based on the data from this study, we strongly suggest that providers employ serial OGTT to screen for glucose abnormalities in TS youth.

Linear regression is often used to estimate associations between chemical exposures and neurodevelopment at the mean of the outcome. However, the potential effect of chemicals may be greater among individuals at the ‘tails’ of outcome distributions. Here, we investigated distributional effects on the associations between gestational phthalate exposure and child Autism Spectrum Disorder (ASD)-related behaviors using quantile regression. We harmonized data from the Early Autism Risk Longitudinal Investigation (EARLI) (n = 140) Study, an enriched-risk cohort of mothers who had a child with ASD, and the Health Outcomes and Measures of the Environment (HOME) Study (n = 276), a general population cohort. We measured concentrations of 9 phthalate metabolites in urine samples collected twice during pregnancy. Caregivers reported children’s ASD-related behaviors using the Social Responsiveness Scale (SRS) at age 3–8 years, higher scores indicate more ASD-related behaviors. In EARLI, associations between phthalate concentrations and SRS scores were predominately inverse or null across SRS score quantiles. In HOME, positive associations of mono-n-butyl phthalate, monobenzyl phthalate, mono-isobutyl phthalate, and di-2-ethylhexyl phthalate concentrations with SRS scores increased in strength from the median to 95th percentile of SRS scores. These results suggest associations between phthalate concentrations and SRS scores may be stronger in individuals with higher SRS scores.

We examined the efficacy of a pediatric emergency visit-based screening, brief intervention, and referral to treatment (SBIRT) condition compared to a control condition (Healthy Habits Control, HHC) to help parental smokers quit smoking. We enrolled 750 parental smokers who presented to the pediatric emergency setting with their child into a two-group randomized controlled clinical trial. SBIRT participants received brief cessation coaching, quitting resources, and up to 12-weeks of nicotine replacement therapy (NRT). HHC participants received healthy lifestyle coaching and resources. The primary outcome was point-prevalence tobacco abstinence at six weeks (T1) and six months (T2). The mean (SD) age of parents was 31.8 (7.7) years, and 86.8% were female, 52.7% were Black, and 64.6% had an income of &le, $15,000. Overall abstinence rates were not statistically significant with 4.2% in both groups at T1 and 12.9% and 8.3% in the SBIRT and HHC groups, respectively, at T2. There were statistically significant differences in SBIRT versus HHC participants on the median (IQR) reduction of daily cigarettes smoked at T1 from baseline (&minus, 2 [&minus, 5, 0] versus 0 [&minus, 4, 0], p = 0.0008),at T2 from baseline (&minus, 4 [&minus, 9, &minus, 1] vs. &minus, 5, 0], p = 0.0006), and on the mean (SD) number of quit attempts at T2 from baseline (1.25 (6.5) vs. 0.02 (4.71), p = 0.02). Self-reported quitting rates were higher in SBIRT parents who received NRT (83.3% vs. 50.9%, p = 0.04). The novel use of the pediatric emergency visit to conduct cessation interventions helped parents quit smoking. The near equivalent abstinence rates in both the SBIRT and HHC groups may be due to underlying parental concern about their child&rsquo, s health. Cessation interventions in this setting may result in adult and pediatric public health benefits.

Background and Purpose— The Graeb score is a visual rating scale of intraventricular hemorrhage (IVH) on noncontrast head CT. Little data exist in the hyperacute ( Methods— A retrospective analysis of multicenter prospective intracranial hemorrhage study was performed. oGS and mGS inter-observer agreement and IVH volume correlation on the baseline noncontrast head CT were calculated by intraclass correlation coefficient and Pearson coefficient respectively. Predictors of poor outcome (modified Rankin Scale scores ≥4) at 3 months were identified using a backward stepwise selection multivariable analysis. oGS and mGS performance for modified Rankin Scale scores ≥4 was determined by receiver operating characteristic analysis. Results— One hundred forty-one patients (65±12 years) with median (interquartile range) time to CT of 82.5 (70.3–157.5) minutes were included. IVH was observed in 43 (30%) patients. Inter-observer agreement was excellent for both oGS (intraclass correlation coefficient, 0.90 [95% CI, 0.80–0.95]) and mGS (intraclass correlation coefficient, 0.97 [95% CI, 0.84–0.99]). mGS (R=0.79; P P P =0.02). Models of thresholded oGS and mGS were not different from a model of planimetric baseline intracranial hemorrhage and IVH volume for poor outcome prediction. Area under the curves were 0.70, 0.73, and 0.72, respectively. Conclusions— Excellent correlation for oGS and mGS with IVH volume was seen. Thresholded oGS and mGS are reasonable surrogates for planimetric IVH volume for hyperacute intracranial hemorrhage studies.

Background Breast milk represents the optimal substrate for all infants, including those with a cleft palate for whom growth may be compromised. Objectives Frequency of breast milk feeding at the breast and per feeder (bottle, cup, enteral tube) in infants with cleft palate was determined and compared with rates reported by the Centers for Disease Control and Prevention. A secondary aim was to review growth status of the infants. Design This study represents a 5-year retrospective review using the electronic medical record. Participants and setting Patients were ≤12 months old at the time of the initial, presurgical encounter after a diagnosis of cleft palate had been made and were treated at one of two pediatric cleft palate and craniofacial centers in Ohio between September 30, 2010, and September 30, 2015. Main outcome measures Outcomes measured were breast milk use, reported by mothers and documented in patients' electronic medical records, chronological body weight, as well as weight for length and weight-for-age z scores and percentiles. Statistical analyses performed Descriptive statistics included median with interquartile range and frequency with percentages. World Health Organization z scores were estimated using the Centers for Disease Control and Prevention programs for weight, weight for length, and weight for age at first visit. Comparisons of infants treated at the two hospitals were done using the Wilcoxon rank-sum test or the χ2 test. Results Breast milk consumption (26 infants were breastfed and 84 received human breast milk administered with a device) was 29.5%, markedly below the 2016 Centers for Disease Control and Prevention national statistics for ever receiving breast milk (81%). Anthropometric findings included z scores of −0.95 and −0.42 for weight for age and weight for length, respectively. Conclusions Infants with cleft palate were seldom breastfed, nor was breast milk frequently used. In addition, median weight-for-age and weight-for-length z scores suggest that growth of infants with cleft palate was below normative standards.

Background and Purpose— Computed tomographic angiography and conventional angiography provide timely vascular anatomic information in patients with stroke. However, iodinated contrast dye may cause acute kidney injury (AKI). Within a large, biracial population, we examined in-hospital incidence of new or worsening kidney disease in patients with stroke and its association with administration of intravenous dye. Methods— All adult residents of the Greater Cincinnati/Northern Kentucky region with acute ischemic stroke or intracerebral hemorrhage who presented to an emergency department in 2010 were included. Prevalence of unsuspected kidney disease at the time of emergency department presentation and the incidence of AKI after admission in 2 groups of patients—those who did and those who did not receive intravenous dye—were determined. Results— In 2010, 2299 patients met inclusion criteria (89% ischemic stroke and 11% intracerebral hemorrhage); mean age 69 years (SD 15), 22% black, and 54% women. Among these patients, 37% had kidney disease at baseline, including 22% (516/2299) in whom this was unsuspected. Two percent (2%; 15/853) of patients with baseline kidney disease developed AKI during the hospital stay. Of those with no baseline kidney disease, 1% (14/14 467) developed AKI. There was no association between dye administration and new or worsening kidney disease. Conclusions— Although 22% of patients in the Greater Cincinnati/Northern Kentucky stroke population had unsuspected kidney disease, the incidence of new or worsening kidney disease was low, and AKI was not associated with dye administration. These findings confirm single-center reports that the risk of severe renal complications after contrast dye is small.

Best practice recommendations indicate that aerobic exercise (AEX) should be incorporated into stroke rehabilitation. However, this may be challenging in clinical settings. The purpose of this study was to assess physical therapist (PT) AEX prescription for patients with stroke, including AEX utilization, barriers to AEX prescription, dosing parameters, and safety considerations.A cross-sectional Web-based survey study was conducted. Physical therapists with valid e-mail addresses on file with the state boards of Florida, New Jersey, Ohio, Texas, and Wyoming were eligible to participate. Survey invitations were e-mailed to all licensed PT in these states. Analysis focused on respondents who were currently involved with clinical stroke rehabilitation in common practice settings.Results from 568 respondents were analyzed. Most respondents (88%) agreed that AEX should be incorporated into stroke rehabilitation, but 84% perceived at least one barrier. Median prescribed AEX volume varied between practice settings from 20- to 30-minute AEX sessions, 3 to 5 days per week for 2 to 8 weeks. Prescribed intensity was most commonly light or moderate; intensity was determined by the general response to AEX and patient feedback. Only 2% of respondents reported that the majority of their patients with stroke had stress tests.Most US PTs appear to recognize the importance of AEX for persons poststroke, but clinical implementation can be challenging. Future studies and consensus are needed to clarify best practices and to develop implementation interventions to optimize AEX utilization in stroke rehabilitation.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A167).

The purpose of this study was to assess safety via electrocardiographic (ECG), blood pressure (BP), heart rate (HR), and orthopedic responses to 3 different high-intensity interval training (HIIT) protocols in persons with stroke. Eighteen participants (10 male; 61.9 + 8.3 years of age; 5.8 + 4.2 years poststroke) completed a symptom-limited graded exercise test (GXT) with ECG monitoring to screen for eligibility and determine HR peak. The 3 HIIT protocols involved repeated 30 s bursts of treadmill walking at maximum speed alternated with rest periods of 30 s (P30), 1 min (P60), or 2 min (P120). Sessions were performed in random order and included 5 min warm up, 20 min HIIT, and 5 min cool down. Variables measured included ECG activity, BP, HR, signs and symptoms of cardiovascular intolerance, and orthopedic concerns. Generalized linear mixed models and Tukey–Kramer adjustment were used to compare protocols using p < 0.05. No signs or symptoms of cardiovascular intolerance, significant arrhythmias, ST segment changes, or orthopedic responses resulted in early termination of any HIIT session. HIIT elicited HRs in excess of 88% of measured HRpeak including 6 (P30), 8 (P60), and 2 (P120) participants eliciting a HR response above their GXT HRpeak. Both maximum BP and HR were significantly higher in P30 and P60 relative to P120. Preliminary data indicate that persons with chronic stroke who have been prescreened with an ECG stress test, a symptom-limited GXT, and a harness for fall protection may safely participate in HIIT, generating substantially higher HRs than what is seen in traditional moderate intensity training.

Maternal nutrition during gestation has been investigated for its role in child neurodevelopment. However, little is known about the potential impact of gestational caffeine exposure on child autistic behaviors. Here, we assess the relation between maternal caffeine intake during pregnancy and children’s behavioral traits related to Autism Spectrum Disorder (ASD). We harmonized data from two pregnancy cohorts, Early Autism Risk Longitudinal Investigation (EARLI) (n = 120), an enriched-risk cohort of mothers who previously had a child with ASD, from Pennsylvania, Maryland, and Northern California (2009–2012), and the Health Outcomes and Measures of the Environment (HOME) Study (n = 269), a general population cohort from Cincinnati, Ohio (2003–2006). Mothers self-reported caffeine intake twice during pregnancy. Caregivers reported child behavioral traits related to ASD using the Social Responsiveness Scale (SRS) when children were aged 3–8 years. Higher scores indicate more ASD-related behaviors. We estimated covariate-adjusted differences in continuous SRS T-scores per interquartile range increase in caffeine intake. Self-reported caffeine intake during pregnancy was positively associated with SRS T-scores among children in EARLI (β: 2.0; 95% CI -0.1, 4.0), but to a lesser extent in HOME (β: 0.6; 95% CI -0.5, 1.6). In HOME, pre-pregnancy body mass index (BMI) modified the association between caffeine intake and SRS T-scores, where more positive associations were observed among women with higher BMIs. Our findings suggest gestational caffeine intake may represent a marker of vulnerability to childhood ASD-related behaviors. Additional studies are warranted to extend these findings.

Prenatal exposure to organophosphate pesticides, which is ubiquitous, may be detrimental to neurological development. We examined 327 mother/infant pairs in Cincinnati, Ohio, between 2003 and 2006 to determine associations between prenatal exposure to organophosphate pesticides and neurodevelopment. Twice during pregnancy urinary concentrations of 6 common dialkylphosphates, nonspecific metabolites of organophosphate pesticides, were measured. Aggregate concentrations of diethylphosphates, dimethylphosphates, and total dialkylphosphates were calculated. Bayley Scales of Infant Development, Second Edition-Mental and Psychomotor Developmental indices were administered at ages 1, 2, and 3 years, the Clinical Evaluation of Language Fundamentals-Preschool, Second Edition, at age 4, and the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, at age 5. Mothers with higher urinary total dialkylphosphate concentrations reported higher levels of socioeconomic status and increased fresh fruit and vegetable intake. We found no associations between prenatal exposure to organophosphate pesticides and cognition at 1–5 years of age. In our cohort, exposure to organophosphate pesticides during pregnancy was not associated with cognition during early childhood. It is possible that a higher socioeconomic status and healthier diet may protect the fetus from potential adverse associations with gestational organophosphate pesticide exposure, or that dietary exposure to the metabolites is innocuous and not an ideal measure of exposure to the parent compound.

Background: After stroke, aerobic deconditioning can have a profound impact on daily activities. This is usually measured by the peak oxygen consumption rate achieved during exercise testing (VO2-peak). However, VO2-peak may be distorted by motor function. The oxygen uptake efficiency slope (OUES) and VO2 at the ventilatory threshold (VO2-VT) could more specifically assess aerobic capacity after stroke, but this has not been tested. Objectives: To assess the differential influence of motor function on three measures of aerobic capacity (VO2-peak, OUES, and VO2-VT) and to evaluate the inter-rater reliability of VO2-VT determination post-stroke. Methods: Among 59 persons with chronic stroke, cross-sectional correlations with motor function (comfortable gait speed [CGS] and lower extremity Fugl-Meyer [LEFM]) were compared between the different aerobic capacity measures, after adjustment for covariates, in order to isolate any distorting effect of motor function. Reliability of VO2-VT determination between three raters was assessed with intra-class correlation (ICC). Results: CGS was moderately correlated with VO2-peak (r = 0.52, p r = 0.41, p = 0.002) and VO2-VT (r = 0.37, p = 0.01). LEFM was weakly correlated with VO2-peak (r = 0.26, p = 0.055) and very weakly correlated with OUES (r = 0.19, p = 0.17) and VO2-VT (r = 0.14, p = 0.31). Compared to VO2-peak, VO2-VT was significantly less correlated with CGS (r difference = −0.16, p = 0.02). Inter-rater reliability of VO2-VT determination was high (ICC: 0.93, 95% CI: 0.89–0.96). Conclusions: Motor dysfunction appears to artificially lower measured aerobic capacity. VO2-VT seemed to be less distorted than VO2-peak and had good inter-rater reliability, so it may provide more specific assessment of aerobic capacity post-stroke.

BACKGROUND: Hospital discharge is stressful for children and families. Poor transitional care is linked to unplanned health care reuse. We evaluated the effects of a pediatric transition intervention, specifically a single nurse home visit, on postdischarge outcomes in a randomized controlled trial. METHODS: We randomly assigned 1500 children hospitalized on hospital medicine, neurology services, or neurosurgery services to receive either a single postdischarge nurse-led home visit or no visit. We excluded children discharged with skilled home nursing services. Primary outcomes included 30-day unplanned, urgent health care reuse (composite measure of unplanned readmission, emergency department, or urgent care visit). Secondary outcomes, measured at 14 days, included postdischarge parental coping, number of days until parent-reported return to normal routine, and number of “red flags” or clinical warning signs a parent or caregiver could recall. RESULTS: The 30-day reuse rate was 17.8% in the intervention group and 14.0% in the control group. In the intention-to-treat analysis, children randomly assigned to the intervention group had higher odds of 30-day health care use (odds ratio: 1.33; 95% confidence interval: 1.003–1.76). In the per protocol analysis, there were no differences in 30-day health care use (odds ratio: 1.14; confidence interval: 0.84–1.55). Postdischarge coping scores and number of days until returning to a normal routine were similar between groups. Parents in the intervention group recalled more red flags at 14 days (mean: 1.9 vs 1.6; P < .01). CONCLUSIONS: Children randomly assigned to the intervention had higher rates of 30-day postdischarge unplanned health care reuse. Parents in the intervention group recalled more clinical warning signs 2 weeks after discharge.

BACKGROUND AND OBJECTIVES: Iodine is an essential trace element for maintenance of normal thyroid function. Normal thyroid function is a prerequisite for neurocognitive development and growth in children. In the United States, iodine is not routinely added as a trace element in parenteral nutrition (PN). Our objective was to determine the prevalence of iodine deficiency and hypothyroidism in children on chronic PN. METHODS: This was a cross-sectional study of children 6 months at a tertiary children’s hospital. Primary outcomes were spot urine iodine concentration (UIC), serum thyrotropin, and free thyroxine levels. RESULTS: Twenty-seven patients were identified (74% male). The median age at screening was 48 months (range: 7–213 months). The median duration on PN was 27 months (range: 11–77 months). Seventeen out of 20 patients (85%) were iodine deficient (spot UIC CONCLUSIONS: Children on chronic PN are at risk for developing iodine deficiency and resultant hypothyroidism; hence, these children should be screened for these outcomes. Further studies are needed to define the temporal onset of iodine deficiency and timing to thyroid dysfunction related to PN.

BACKGROUND: Loss-of-control (LOC) eating is common in adults undergoing bariatric surgery and is associated with poorer weight outcomes. Its long-term course in adolescent bariatric surgery patients and associations with weight outcomes are unclear. METHODS: Adolescents (n = 234; age range = 13–19 years) undergoing bariatric surgery across 5 US sites were assessed for postsurgery follow-up at 6 months and 1, 2, 3, and 4 years. Descriptive statistics and generalized linear mixed models were used to describe the prevalence of LOC eating episodes involving objectively large amounts of food and continuous eating, respectively. Generalized linear mixed models investigated the association of any LOC eating with short- and long-term BMI changes. RESULTS: At baseline, objectively large LOC eating was reported by 15.4% of adolescents, and continuous LOC eating by 27.8% of adolescents. Both forms of LOC eating were significantly lower at all postsurgical time points relative to presurgery (range = 0.5%–14.5%; Ps < .05). However, both behaviors gradually increased from 6-month to 4-year follow-up (Ps < .05). Presurgical LOC eating was not related to percent BMI change over follow-up (P = .79). However, LOC eating at 1-, 2-, and 3-year follow-up was associated with lower percent BMI change from baseline at the next consecutive assessment (Ps < .05). CONCLUSIONS: Although presurgical LOC eating was not related to relative weight loss after surgery, postoperative LOC eating may adversely affect long-term weight outcomes. Rates of LOC eating decreased from presurgery to 6-months postsurgery but increased thereafter. Therefore, this behavior may warrant additional empirical and clinical attention.

Background: Early-life exposure to bisphenol A (BPA) may increase childhood obesity risk, but few prospective epidemiological studies have investigated this relationship. Objective: We sought to determine whether early-life exposure to BPA was associated with increased body mass index (BMI) at 2–5 years of age in 297 mother–child pairs from Cincinnati, Ohio (HOME Study). Methods: Urinary BPA concentrations were measured in samples collected from pregnant women during the second and third trimesters and their children at 1 and 2 years of age. BMI z-scores were calculated from weight/height measures conducted annually from 2 through 5 years of age. We used linear mixed models to estimate BMI differences or trajectories with increasing creatinine-normalized BPA concentrations. Results: After confounder adjustment, each 10-fold increase in prenatal (β = –0.1; 95% CI: –0.5, 0.3) or early-childhood (β = –0.2; 95% CI: –0.6, 0.1) BPA concentrations was associated with a modest and nonsignificant reduction in child BMI. These inverse associations were suggestively stronger in girls than in boys [prenatal effect measure modification (EMM) p-value = 0.30, early-childhood EMM p-value = 0.05], but sex-specific associations were imprecise. Children in the highest early-childhood BPA tercile had lower BMI at 2 years (difference = –0.3; 95% CI: –0.6, 0.0) and larger increases in their BMI slope from 2 through 5 years (BMI increase per year = 0.12; 95% CI: 0.07, 0.18) than children in the lowest tercile (BMI increase per year = 0.07; 95% CI: 0.01, 0.13). All associations were attenuated without creatinine normalization. Conclusions: Prenatal and early-childhood BPA exposures were not associated with increased BMI at 2–5 years of age, but higher early-childhood BPA exposures were associated with accelerated growth during this period. Citation: Braun JM, Lanphear BP, Calafat AM, Deria S, Khoury J, Howe CJ, Venners SA. 2014. Early-life bisphenol A exposure and child body mass index: a prospective cohort study. Environ Health Perspect 122:1239–1245; http://dx.doi.org/10.1289/ehp.1408258

Background and Purpose— Approximately 5% of strokes occur in adults aged 18 to 44 years. Substance abuse is a prevalent risk factor for stroke in young adults. We sought to identify trends in substance abuse detection among stroke patients. Methods— Using a population-based design, we sought to identify all patients aged 18 to 54 years experiencing a stroke (ischemic or hemorrhagic) in the Greater Cincinnati and Northern Kentucky Study region during 1993 to 1994, 1999, and 2005. Demographic and clinical characteristics and substance use data were obtained retrospectively from chart review and adjudicated by physicians. Results— The number of young patients identified with a stroke increased from 1993 to 1994 (297) to 2005 (501). Blacks (61% vs 51%; P P P =0.003). The trend was significant for illegal drug use (3.8% in 1993 vs 19.8% in 2005) and ever smoking (49% in 1993 vs 66% in 2005). Documentation of both cocaine and marijuana use increased over time. In 2005, half of young adults with a stroke were current smokers, and 1 in 5 abused illegal drugs. Conclusions— Substance abuse is common in young adults experiencing a stroke. The observed increase in substance abuse is contributing to the increased incidence of stroke in young adults. Patients aged younger than 55 years who experience a stroke should be routinely screened and counseled regarding substance abuse.

Background and Purpose— Acute ischemic stroke (AIS) patients may have raised serum cardiac troponin levels on admission, although it is unclear what prognostic implications this has, and whether elevated levels are associated with cardiac causes of stroke or structural cardiac disease as seen on echocardiogram. We investigated the positivity of cardiac troponin and echocardiogram testing within a large biracial AIS population and any association with poststroke mortality. Methods— Within a catchment area of 1.3 million, we screened emergency department admissions from 2010 using International Classification of Diseases, Ninth Edition , discharge codes 430 to 436 and ascertained all physician-confirmed AIS cases by retrospective chart review. Hypertroponinemia was defined as elevation in cardiac troponin above the standard 99th percentile. Multiple logistic regression was performed, controlling for stroke severity, history of cardiac disease, and all other stroke risk factors. Results— Of 1999 AIS cases, 1706 (85.3%) had a cardiac troponin drawn and 1590 (79.5%) had echocardiograms. Hypertroponinemia occurred in 353 of 1706 (20.7%) and 160 of 1590 (10.1%) had echocardiogram findings of interest. Among 1377 who had both tests performed, hypertroponinemia was independently associated with echocardiogram findings (odds ratio, 2.9; 95% confidence interval, 2–4.2). When concurrent myocardial infarctions (3.5%) were excluded, hypertroponinemia was also associated with increased mortality at 1 year (35%; odds ratio, 3.45; 95% confidence interval, 2.1–5.6) and 3 years (60%; odds ratio, 2.91; 95% confidence interval, 2.06–4.11). Conclusions— Hypertroponinemia in the context of AIS without concurrent myocardial infarction was associated with structural cardiac disease and long-term mortality. Prospective studies are needed to determine whether further cardiac evaluation might improve the long-term mortality rates seen in this group.

Background: Prenatal exposure to organophosphate (OP) insecticides, a widely used class of pesticides, may be associated with decreased gestational age and lower birth weight. Single nucleotide polymorphisms in paroxanase (PON1) enzyme genotypes may modify the relationships between OP exposure and perinatal outcomes. Objective: We examined the relationship of prenatal OP insecticide exposure, measured using urinary dialkyl phosphate (DAP) metabolite concentrations, with gestational age and birth weight. Methods: We measured the concentrations of six nonspecific DAP metabolites of OP insecticides in two maternal spot urine samples collected in a prospective birth cohort. We performed multivariable regression to examine associations between the sum of six DAP concentrations (ΣDAP) with gestational age and birth weight. We also examined whether these associations differed according to infant PON1192 and PON1–108 genotypes. Results: Among 306 mother–infant dyads, a 10-fold increase in ΣDAP concentrations was associated with a decrease in covariate-adjusted gestational age [–0.5 weeks; 95% confidence interval (CI): –0.8, –0.1] and birth weight (–151 g; CI: –287, –16); the decrements in birth weight were attenuated after adjusting for gestational age. The relationship between ΣDAP concentrations and gestational age was stronger for white (–0.7 weeks; CI: –1.1, –0.3) than for black (–0.1 weeks; 95% CI: –0.9, 0.6) newborns. In contrast, there was a greater decrease in birth weight with increasing urinary ΣDAP concentrations for black (–188 g; CI: –395, 19) than for white (–118 g; CI: –296, 60) newborns. Decrements in birth weight and gestational age associated with ΣDAP concentrations were greatest among infants with PON1192QR and PON–108CT genotypes. Conclusions: Prenatal urinary ΣDAP concentrations were associated with shortened gestation and reduced birth weight in this cohort, but the effects differed by race/ethnicity and PON1192/108 genotypes.

This study examined the effects of gender on RNA expression after ischemic stroke (IS). RNA obtained from blood of IS patients ( n = 51; 153 samples at ≤ 3, 5, and 24 hours) and from matched controls ( n = 52) were processed on Affymetrix microarrays. Analyses of covariance for stroke versus control samples were performed separately for both genders and the regulated genes for females compared with males. In all, 242, 227, and 338 male-specific genes were regulated at ≤ 3, 5, and 24 hours after IS, respectively, of which 59 were regulated at all time points. Overall, 774, 3,437, and 571 female-specific stroke genes were regulated at ≤ 3, 5, and 24 hours, respectively, of which 152 were regulated at all time points. Male-specific stroke genes were associated with integrin, integrin-liked kinase, actin, tight junction, Wnt/β-catenin, RhoA, fibroblast growth factors (FGF), granzyme, and tumor necrosis factor receptor (TNFR)2 signaling. Female-specific stroke genes were associated with p53, high-mobility group box-1, hypoxia inducible factor (HIF)1α, interleukin (IL)1, IL6, IL12, IL18, acute-phase response, T-helper, macrophage, and estrogen signaling. Cell death signaling was overrepresented in both genders, although the molecules and pathways differed. Gender affects gene expression in the blood of IS patients, which likely implies gender differences in immune, inflammatory, and cell death responses to stroke.

Objectives— The American Heart Association recently redefined TIA to exclude patients with infarction on neuroimaging. Given its advantages, MRI/diffusion-weighted imaging (DWI) was recommended as the preferred imaging modality. We determined how frequently MRI/DWI was performed for TIA and ascertained the proportion of clinically defined TIA patients who had ischemic lesions on DWI in our community in 2005. Methods— All clinically defined TIA cases among residents of a 5-county region around Cincinnati who presented to emergency departments were identified during 2005. Demographics and medical history, whether MRI/DWI was performed, and DWI findings were recorded. Generalized estimating equations were used to compare groups to account for the design of the study and multiple events per patient. Results— Of 834 TIA events in 799 patients, 323 events (40%) had MRI/DWI performed. Patients who had MRI/DWI were younger (mean, 66 vs 70 years; P =0.03), had less severe prestroke disability (baseline modified Rankin Scale score, 0; 44% vs 34%; P =0.02), were less likely to have previous stroke or TIA (42% vs 56%; P =0.002), and were less likely to have atrial fibrillation (10% vs 16%; P =0.01). Of the 323 events with DWI, 51 (15%) had evidence of acute infarction. Patients with positive DWI were older (75 vs 64 years; P =0.0001) and more likely to have atrial fibrillation (21% vs 7%; P =0.002). Conclusion— Performing MRI/DWI on all clinically defined TIA patients in our community would reveal more cases of actual infarction but would more than double current use. Future studies should assess whether MRI/DWI is warranted for all TIA patients.

Pediatric burn patients are predisposed to excessive weight gain in the reconstructive period, but the cause is unclear. An overweight (OW) or obese (OB) condition is associated with numerous health risks, decreased physical function, and increased morbidity. The purpose of this study was to compare the frequency of OW status in reconstructive, pediatric burn patients with the prevalence in the US population. The authors reviewed the records of 1533 pediatric patients, >1 year from acute burn, admitted for an elective reconstructive procedure. Body mass index between 85th and 95th percentile, according to the National Center for Health Statistics for 2000 growth charts, was classified as OW, and body mass index >95th percentile was classified as OB. Frequency of OW and OB and racial disparity was calculated as a percentage of total patients and compared with pediatric data from National Health and Nutrition Examination Survey for 1999 to 2006, a nationally representative sample. The rate of OW and OB was 16.3 and 24.1%, respectively, in the authors' pediatric burn population. White patients had OW and OB rates of 15.9 and 23.6%, respectively, compared with 18.2 and 30.2%, respectively, in black patients. All OW and OB rates were outside the 95% confidence interval of the nationally representative National Health and Nutrition Examination Survey population. The rates of OW and OB in pediatric reconstructive burn patients exceed the US population standard across age and race stratifications. The prevention and treatment of excessive weight gain should be a component of rehabilitation in pediatric burns.

Combined analysis of the Interventional Management of Stroke I and II trials demonstrated a significant association between microcatheter contrast injections and both intracranial hemorrhage (ICH) and contrast extravasation following combined intravenous (IV) and intra-arterial (IA) thrombolysis. The reliability of these observations was tested in our local registry of IA cases.Treatment angiograms and post-procedure CTs of patients treated with combined IV/IA or IA only recombinant tissue plasminogen activator for ICA-T, M1 or M2 occlusions (n=77) were reviewed. The number of microcatheter injections (MCIs) within/distal to the target occlusion was assigned for every case. The association of MCIs to total ICH, total parenchymal hematoma (PH1+PH2) and PH2 after adjusting for significant covariates was tested.MCIs were used in 21 (27%) cases (range MCI 0-6). Any ICH occurred in 38 (49%) cases, including eight (10%) PH1s and eight (10%) PH2s. The use of MCIs was associated with increased PH (p=0.04), PH2 (p=0.07) and total ICH (p=0.03). MCIs were associated with increased contrast extravasation (CEx) (p=0.02). ICH was observed in all CEx cases (n=5, 100% vs 46% non-CEx; p=0.03), and four (80%) CEx cases developed PH2s (p0.01). MCIs remained associated with total ICH after adjustment for significant covariates of Thromolysis in Cerebral Infarction score, glucose level and presence of atrial fibrillation (OR 3.60; 95% CI 1.12 to 11.49, p=0.03). MCI use was the only significantly associated covariate for total PHs.MCI use was associated with ICH and with clinically significant PHs in this cohort, providing further evidence that MCIs be reduced during IA thrombolysis.

Dr. Kuller makes an excellent point in response to our article.1 Though it is plausible to hypothesize that our finding of sex differences in stroke incidence over time is driven by stroke in older women, after looking at data in age-stratified groups, we found that the sex differences in stroke incidence over time were driven by the middle age groups (ages 45–74), not the oldest age groups. These findings do not change the overall message in the article1—that the rate of stroke is going down more in men than women. We plan to publish data on sex differences in stroke incidence through 2015 and will include age-stratified analyses.

We sought to examine neonatal morbidity in four groups of offspring (asymmetric large for gestational age [LGA], symmetric LGA, asymmetric non-LGA, symmetric non-LGA) exposed in utero to maternal type 1 diabetes, and the association between rate of fetal abdominal circumference growth and asymmetric LGA. We performed a secondary analysis of 302 singleton pregnancies. Neonatal morbidity (respiratory distress syndrome, polycythemia, hypoglycemia, hyperbilirubinemia, acidosis, and composite morbidity [any of the five]) was assessed. Serial ultrasound examinations after 20 weeks' gestation were available for 35 fetuses. Logistic regression and general linear mixed modeling were used for analysis. Asymmetric LGA infants had 3.5-, 2.2-, and 3.2-fold greater odds of hypoglycemia, hyperbilirubinemia, and composite morbidity, respectively, compared with symmetric non-LGA infants. The rate of growth of the abdominal circumference in asymmetric LGA infants (1.11 cm/wk) was greater than for both the symmetric LGA infants (0.87 cm/wk, P = 0.09) and the symmetric non-LGA infants (0.87 cm/wk, P = 0.03). Asymmetric LGA infants are at higher risk for morbidity than symmetric LGA and non-LGA infants. Intrauterine growth rate of the abdominal circumference may potentially be used as a marker to identify the asymmetric LGA and thereby aid in the identification of newborns at greatest risk for perinatal complications.

OBJECTIVES:The objective of this study was to investigate the relationship between exposure to secondhand smoke (SHS) and child sleep patterns among a group of children with asthma who were exposed regularly to tobacco smoke at home.METHODS:We studied 219 children who were enrolled in an asthma intervention trial and were exposed regularly to SHS. Serum cotinine levels were used to measure exposure to tobacco smoke, and sleep patterns were assessed through parent reports using the Children's Sleep Habits Questionnaire. Covariates in adjusted analyses included gender, age, race, maternal marital status, education, and income, prenatal tobacco exposure, maternal depression, Home Observation for Measurement of the Environment total score, household density, asthma severity, and use of asthma medications.RESULTS:Exposure to SHS was associated with sleep problems, including longer sleep-onset delay (P = .004), sleep-disordered breathing (P = .02), parasomnias (P = .002), daytime sleepiness (P = .022), and overall sleep disturbance (P = .0002).CONCLUSIONS:We conclude that exposure to SHS is associated with increased sleep problems among children with asthma.

Previous work demonstrated reduced stage 3+4 and rapid eye movement (REM) sleep following burn injury. This study evaluated the hormonal effects of drug intervention on measures of endocrine status. A secondary objective examined the relationship between hormones and sleep stage distribution.Forty patients 3-18 years of age with a mean percent total body surface area burn of 50.1 +/- 2.9 were randomly assigned to zolpidem or haloperidol utilizing a blinded crossover design. Polysomnography was performed 6 nights, 3/week over 2 weeks. Each week's first night of monitoring was conducted without medication, serving as a baseline. Hormonal levels (epinephrine, norepinephrine, growth hormone, melatonin, dehydroepiandrosterone [DHEA], serotonin, cortisol) were obtained at 0600 h each study day.Both drugs were associated with increased DHEA levels (P.03); no other hormones were affected by medication. Significant inverse correlation was observed between REM sleep and epinephrine (r = -.34, P = .004) and norepinephrine levels (r = -.45, P = .02). A positive relationship existed between serotonin and sleep stage 3+4 (r = 0.24, P = .01) and REM (r = 0.48, P = .01). No other significant associations were identified between hormones and sleep.This work characterizes the relationship between sleep deprivation and select endocrine parameters postburn. Drug interventions utilized in this study were either ineffective or insufficient in modulating improved hormonal response. Significance of zolpidem's and haloperidol's effect on serum levels of DHEA is unclear. The inverse correlation of epinephrine with REM may suggest that hypermetabolism associated with burns is partly due to lack of REM sleep. Questions remain regarding the effects of sleep deprivation on metabolism and clinical outcome.

RATIONALE: Emerging evidence suggests that exposure to environmental tobacco smoke (ETS) may be linked with behavior problems in childhood, but previous research has relied primarily on parent report of exposure, and results are inconclusive. OBJECTIVES: To investigate the relationship between exposure to ETS and child behavior problems among children with asthma. METHODS: The sample included 220 children who were enrolled in an asthma intervention trial and regularly exposed to ETS at home. Serum cotinine was used to measure exposure to tobacco smoke, and behavior problems were assessed by parent report on the Behavior Assessment System for Children. Covariates in adjusted analyses included: sex, age, race, asthma severity, asthma medication, maternal education, prenatal tobacco exposure, maternal depression, and Home Observation for Measurement of the Environment score. RESULTS: Child behavior problems increased with increasing exposure to ETS. A stratified analysis of boys and girls separately indicated higher exposure among girls, but behavior problems were statistically significantly associated with exposure only in boys. Increasing behavior problems included externalizing behavior problems (β = 2.23, p = .02) such as hyperactivity and aggression, internalizing behavior problems (β = 2.19, p = .01) such as depression, and behavior symptoms (β = 2.55, p = .01). CONCLUSIONS: Among children with asthma, exposure to ETS is related to increased child behavior problems among boys.

Patients with stroke may have cognitive deficits that impact their capacity to provide informed consent for research. Some institutional review boards restrict surrogate consent to persons who have specific legal authority to provide it. We examined the importance of surrogate consent in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial, the study that led to the only US Food and Drug Administration-approved treatment for acute ischemic stroke.The NINDS rt-PA Stroke Trial randomized subjects with ischemic stroke to treatment with recombinant tissue plasminogen activator (rt-PA) or placebo. We compared the baseline characteristics and clinical outcomes of subjects enrolled by self-consent with those of subjects enrolled by surrogate consent.Surrogate consent was used to enroll 439 of 624 (70%) subjects. Subjects enrolled by surrogate consent were older (68.5 vs 63.4 years, p0.001), had more severe strokes (median NIH Stroke Scale score 17 vs 9, p0.001), and were less likely to make a good recovery (p0.001 for all measures) than patients who provided their own consent. There was no interaction between method of consent and response to rt-PA. If the trial had used the same sample size and recruited at the same rate but excluded patients who could not provide their own consent, it would have taken 12.5 years to complete.The National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (rt-PA) Stroke Trial would not have been completed in a timely fashion without subjects enrolled by surrogate consent. Furthermore, exclusion of subjects who could not provide their own consent would have severely limited the generalizability and value of trial results.

Background and purpose Treadmill aerobic exercise improves gait, aerobic capacity, and cardiovascular health after stroke, but a lack of specificity in current guidelines could lead to underdosing or overdosing of aerobic intensity. The ventilatory threshold (VT) has been recommended as an optimal, specific starting point for continuous aerobic exercise. However, VT measurement is not available in clinical stroke settings. Therefore, the purpose of this study was to identify an accurate method to predict heart rate at the VT (HRVT) for use as a surrogate for VT. Methods A cross-sectional design was employed. Using symptom-limited graded exercise test (GXT) data from 17 subjects more than 6 months poststroke, prediction methods for HRVT were derived by traditional target HR calculations (percentage of HRpeak achieved during GXT, percentage of peak HR reserve [HRRpeak], percentage of age-predicted maximal HR, and percentage of age-predicted maximal HR reserve) and by regression analysis. The validity of the prediction methods was then tested among 8 additional subjects. Results All prediction methods were validated by the second sample, so data were pooled to calculate refined prediction equations. HRVT was accurately predicted by 80% HRpeak (R, 0.62; standard deviation of error [SDerror], 7 bpm), 62% HRRpeak (R, 0.66; SDerror, 7 bpm), and regression models that included HRpeak (R, 0.62-0.75; SDerror, 5-6 bpm). Discussion and conclusions Derived regression equations, 80% HRpeak and 62% HRRpeak, provide a specific target intensity for initial aerobic exercise prescription that should minimize underdosing and overdosing for persons with chronic stroke. The specificity of these methods may lead to more efficient and effective treatment for poststroke deconditioning.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A114).

Hypovitaminosis D exists postburn. However, evidence-based guidelines for vitamin D repletion are unknown. This investigation examined differences between DFifty patients with total body surface area burn of 55.7% ± 2.6% and full-thickness injury of 40.8% ± 3.8% were enrolled, ranging in age from 0.7-18.4 years. All participants received multivitamin supplementation per standardized clinical protocol. In addition, 100 IU/kg DThere were no significant differences in serum vitamin D levels between groups, but10% of patients had low D25 at discharge, and percent deficiency worsened by the 1-year follow up for the placebo (75%), DThe high incidence of low serum D25 levels 1 year following serious thermal injury indicates prolonged compromise. Continued treatment with vitamin D

Background and Purpose— Sex differences in recombinant tissue-type plasminogen activator (r-tPA) administration are present in some populations. It is unknown whether this is because of eligibility differences or the modifiable exclusion criterion of severe hypertension. Our aim was to investigate sex differences in r-tPA eligibility, in individual exclusion criteria, and in the modifiable exclusion criterion, hypertension. Methods— We included all ischemic stroke patients ≥18 years among residents of the Greater Cincinnati/Northern Kentucky region who presented to 16-area emergency departments in 2005. Eligibility for r-tPA and individual exclusion criteria were determined using 2013 American Heart Association (AHA) and European Cooperative Acute Stroke Study (ECASS) III guidelines. Results— Of 1837 ischemic strokes, 58% were women, 24% were black. Mean age in years was 72.2 for women and 66.1 for men. Eligibility for r-tPA was similar by sex (6.8% men and 6.1% women; P =0.55), even after adjusting for age (7.0% and 5.9%; P =0.32). Similar proportions of women and men arrived beyond 3- and 4.5-hour time windows, but more women had severe hypertension. There were no sex differences in blood pressure treatment rates among those with severe hypertension (14.6% women and 20.8% men; P =0.21). More women were >80 years and had National Institutes of Health Stroke Scale (NIHSS) >25. Conclusions— Within a large, biracial population, eligibility for r-tPA was similar by sex. Women were more likely to have the modifiable exclusion criterion of severe hypertension but were not more likely to be treated. Women were more likely to have 2 of the 5 ECASS III exclusion criteria. Undertreatment of hypertension in women is a potentially modifiable contributor to reported differences in r-tPA administration.

Background and Purpose— Conflicting reports in the literature exist with regard to the association of apolipoprotein E (apo E) alleles and lobar intracerebral hemorrhage (ICH). We genotyped 12 single-nucleotide polymorphisms in the 5′ upstream regulatory, exonic, and intronic regions of the apo E gene and performed genotype and haplotype association analyses. Methods— We prospectively enrolled subjects with hemorrhagic stroke and matched them with 2 controls based on age, race, and sex. Each case was reviewed by a physician to determine case status and location of the ICH. Multivariate logistic-regression modeling with backward elimination was used to determine significant risk factors for lobar ICH. Associations at the genotype and haplotype levels and linkage disequilibrium were conducted according to standard statistical methods. Results— Between May 1997 and December 2002, 315 cases of ICH were recruited, of whom 107 were lobar ICH cases matched to 205 controls. No association was found for apo E2, E3, or E4 with nonlobar ICH. Independent, significant risk factors for lobar ICH included apo E4, untreated hypertension, anticoagulant use, a first-degree relative with ICH, and ≤high school education (compared with >high school education). Treated hypercholesterolemia compared with “no history of hypercholesterolemia” was associated with a decreased risk of lobar ICH. Haplotype association analysis demonstrated a significant association of the apo E gene with lobar ICH among whites ( P P =0.0024). Conclusions— Apo E4 is independently associated with lobar ICH but not nonlobar ICH. Haplotypes of the apo E gene are associated with lobar ICH. Untreated hypertension is a risk factor for lobar ICH.

Lead is a confirmed neurotoxin, but questions remain about lead-associated intellectual deficits at blood lead levels10 microg/dL and whether lower exposures are, for a given change in exposure, associated with greater deficits. The objective of this study was to examine the association of intelligence test scores and blood lead concentration, especially for children who had maximal measured blood lead levels10 microg/dL. We examined data collected from 1,333 children who participated in seven international population-based longitudinal cohort studies, followed from birth or infancy until 5-10 years of age. The full-scale IQ score was the primary outcome measure. The geometric mean blood lead concentration of the children peaked at 17.8 microg/dL and declined to 9.4 microg/dL by 5-7 years of age; 244 (18%) children had a maximal blood lead concentration10 microg/dL, and 103 (8%) had a maximal blood lead concentration7.5 microg/dL. After adjustment for covariates, we found an inverse relationship between blood lead concentration and IQ score. Using a log-linear model, we found a 6.9 IQ point decrement [95% confidence interval (CI), 4.2-9.4] associated with an increase in concurrent blood lead levels from 2.4 to 30 microg/dL. The estimated IQ point decrements associated with an increase in blood lead from 2.4 to 10 microg/dL, 10 to 20 microg/dL, and 20 to 30 microg/dL were 3.9 (95% CI, 2.4-5.3), 1.9 (95% CI, 1.2-2.6), and 1.1 (95% CI, 0.7-1.5), respectively. For a given increase in blood lead, the lead-associated intellectual decrement for children with a maximal blood lead level7.5 microg/dL was significantly greater than that observed for those with a maximal blood lead levelor = 7.5 microg/dL (p = 0.015). We conclude that environmental lead exposure in children who have maximal blood lead levels7.5 microg/dL is associated with intellectual deficits.

Background and Purpose— Risk factors for intracerebral hemorrhage (ICH) vary by location. Incidence rates of ICH are known to be higher in American blacks than whites, but how rates may differ by hemorrhage location is unknown. We sought to define incidence rates for different ICH locations in a biracial population. Methods— All hospitalized patients age ≥20 years with spontaneous ICH were identified in the Greater Cincinnati/Northern Kentucky metropolitan area from May 1998 to July 2001 and August 2002 to April 2003. Incidence rates per 100 000 persons were age, sex, and race adjusted as appropriate to the 2000 US population. Risk ratios (RRs) with 95% CIs were calculated from unadjusted incidence rates. Results— There were 1038 qualifying ICHs. Annual incidence rates per 100 000 persons ≥20 years of age were 48.9 for blacks and 26.6 for whites. Annual incidence rates per 100 000 blacks in lobar, deep cerebral, brain stem, and cerebellar locations were 15.2, 25.7, 5.1, and 2.9, respectively. Annual incidence rates per 100 000 whites in the same locations were 9.4, 13.0, 1.3, and 2.9. The greatest excess risk of ICH in blacks compared with whites was found among young to middle-aged (35 to 54 years) persons with brain stem (RR, 9.8; 95% CI, 4.2 to 23.0) and deep cerebral (RR, 4.5; 3.0 to 6.8) hemorrhage. Conclusions— The excess risk of ICH in American blacks is largely attributable to higher hemorrhage rates in young and middle-aged persons, particularly for deep cerebral and brain stem locations. Hypertension is the predominant risk factor for hemorrhages in these locations.

Background and Purpose— Transient ischemic attacks (TIAs) have been shown to be a strong predictor of subsequent stroke and death. We present the incidence and short-term prognosis of TIA within a large population with a significant proportion of minorities with out-of-hospital TIA. Methods— TIA cases were identified between July 1, 1993 and June 30, 1994 from the Greater Cincinnati/Northern Kentucky population of 1.3 million inhabitants by previously published surveillance methods, including inpatient and out-of-hospital events. Incidence rates were adjusted to the 1990 population, and life-table analyses were used for prognosis. Results— The overall race, age, and gender-adjusted incidence rate for TIA within our population was 83 per 100 000, with age, race, and gender adjusted to the 1990 US population. Blacks and men had significantly higher rates of TIA than whites and women. Risk of stroke after TIA was 14.6% at 3 months, and risk of TIA/stroke/death was 25.2%. Age, race, and sex were not associated with recurrent TIA or subsequent stroke in our population, but age was associated with mortality. Conclusions— Using our incidence rates for TIA in blacks and whites, we conservatively estimate that ≈240 000 TIAs occurred in 2002 in the United States. Our incidence rate of TIA is slightly higher than previously reported, which may be related to the inclusion of blacks and out-of-hospital events. There are racial and gender-related differences in the incidence of TIA. We found a striking risk of adverse events after TIA; however, there were no racial or gender differences predicting these events. Further study is warranted in interventions to prevent these adverse events after TIA.

OBJECTIVE: To explore determinants of sexually transmitted infection screening of asymptomatic women and sexually transmitted infection testing of women with genitourinary symptoms, to investigate the effect of specific genitourinary symptoms on sexually transmitted infection testing, and to examine trends in screening. METHODS: We performed secondary data analysis of nationally representative data from the National Hospital Ambulatory Medical Care Surveys, using 17,458 visits by nonpregnant 15- to 44-year-old women seen in primary care clinics between 1997 and 2000. Point estimates, adjusted odds ratios (ORs) and 95% confidence intervals (CIs) are presented. RESULTS: Sexually transmitted infection screening was performed in 2.4% of visits by women without genitourinary symptoms and was more likely among visits for preventive care (OR 6.9, CI 3.8-12.5), by nonwhite women (OR 4.3, CI 2.3-7.9), and in gynecology clinic (OR 3.9, CI 2.5-6.1). Sexually transmitted infection testing occurred in 13.2% of visits by women with genitourinary symptoms and was associated with Medicaid (OR 2.3, CI 1.4-3.6), preventive care (OR 2.0, CI 1.2-3.2), patient age less than 25 years (OR 1.7, CI 1.0-2.6), and nonwhite race (OR 1.7, CI 1.0-2.6). Among symptomatic women, vaginal symptoms (OR 4.8, CI 2.6-8.9) and abdominal/pelvic pain (OR 2.5, CI 1.4-4.5) were associated with sexually transmitted infection testing. Between 1997 and 2000, sexually transmitted infection screening rates remained stable. CONCLUSION: Despite national guidelines, sexually transmitted infection testing outpaces screening. Few visits by asymptomatic women under age 25 result in screening. Strategies to improve screening in primary care should target nongynecology settings and non-preventive care visits. LEVEL OF EVIDENCE: III.

Objective To determine the incidence and obstetric implications and to identify prospectively women with a poor response to hMG with a normal clomiphene citrate challenge test (CCCT) result. Design Retrospective chart review. Setting Tertiary fertility center. Patient(s) One hundred sixty-three women who underwent ovulation induction with hMG for IUI, and 266 women who underwent ovulation induction with GnRH analogue and hMG for IVF. All had a CCCT before stimulation. Seventy-five percent of IUI patients (123 of 163) and 89% of IVF patients (238 of 266) had normal CCCT results. A poor response to hMG was defined as a response less than the 90th percentile of women with an abnormal CCCT result (peak E 2 [pg/mL] level per ampule hMG used: 90th percentile ≤30). Intervention(s) Clomiphene citrate challenge test and ovulation induction for IUI or IVF. Main outcome measure(s) Response to gonadotropins and pregnancy outcome after treatment. Result(s) Thirty-five percent of IUI patients (43 of 123) and 52% of IVF patients (123 of 238) with a normal CCCT result had a poor response to hMG. Intrauterine insemination patients with a poor response to hMG had significantly lower delivery rates than IUI patients with a normal response (19% vs. 39%). In vitro fertilization patients with a poor response to hMG had similar delivery rates compared with IVF patients with a normal response (32% vs. 35%). For both groups of patients, an FSH >12 mIU/mL (IMx assay) on either day 3 or day 10 (normal ≤14.5 IMx) was highly predictive of a poor response to hMG, the elevated FSH level being a much better predictor than the woman's age. Conclusion(s) A poor response to hMG with a normal CCCT result (false negative) is a common event. A day-3 or day-10 FSH >12 mIU/mL (IMx assay) or 20 mIU/mL (converted to the original RIA) will identify approximately 80% (IUI) and approximately 94% (IVF) of the women who will experience a poor response to hMG. When identified, the data suggest that these patients will benefit significantly from the more aggressive IVF.

To test the hypothesis that, in women with type 1 diabetes, prenatal smoking and caffeine consumption during pregnancy are associated with an increased risk of adverse maternal and perinatal outcomes.A secondary analysis of data on pregnant women with type 1 diabetes from an interdisciplinary program of Diabetes in Pregnancy. Women were interviewed monthly, by a trained non-medical member of the research team, using a standardized questionnaire, to ascertain daily smoking habits and caffeine consumption.Smoking and caffeine information were available on 191 pregnancies, 168 progressing beyond 20 weeks of gestation. Early pregnancy smoking (OR 3.3, 95% CI 1.2, 8.7) and caffeine consumption (OR 4.5, 95% CI 1.2, 16.8) were associated with increased risk of spontaneous abortion when controlling for age, years since diagnosis of diabetes, previous spontaneous abortion, nephropathy and retinopathy. Smoking throughout pregnancy was significantly associated with decreased birth weight and prolonged neonatal hospital stay. Smoking throughout pregnancy (OR 0.2, 95% 0.1, 1.0) and caffeine consumption after 20 weeks (OR 0.3, 95% CI 0.1, 1.0) were associated with reduced risk of pre-eclampsia.Caffeine consumption during early pregnancy, regardless of glycemic control, increases the risk of spontaneous abortion. Smoking throughout pregnancy and caffeine consumption are associated with reduced risk of pre-eclampsia.

The purpose of this study was to evaluate placental lesions found in women with preeclampsia compared with normotensive control subjects and to determine whether the presence of these lesions are related to gestational age at delivery.Placental disease of women with preeclampsia at 24 to 42 weeks of gestation was compared with the placental disease of normotensive gestational age-matched control subjects. The placental lesions that were studied specifically included decidual arteriolopathy, thrombi in the fetal circulation, central infarction, intervillous thrombi, and hypermaturity of villi. Data analysis involved the chi(2) test, the Student t test, and logistic regression; odds ratios and CIs were estimated.Placentas from women with preeclampsia (n=158) and normotensive control subjects (n=156) were evaluated. Among women with preeclampsia, 67% had severe disease. Placental lesions were studied according to gestational age at delivery:28, 28 to 32, 33 to 36, andor=37 weeks of gestation. Of the placental lesions that were studied, decidual arteriolopathy (odds ratio, 23.8, 95% CI 10.0-57.0), hypermaturity of villi (odds ratio, 12.4; 95% CI 5.3-29.2), intervillous thrombi (odds ratio, 1.95;95% CI 1.0-3.7), central infarction (odds ratio, 5.9; 95% CI 3.1-11.1), and thrombi in the fetal circulation (odds ratio, 2.8; 95% CI 1.2-6.6) were found to have significantly higher rates in the preeclamptic group. In contrast, the rate of chorioamnionitis was significantly lower in the preeclamptic group (odds ratio, 0.2; 95% CI 0.1-0.4). The rates of abruptio placentae and meconium staining were not different between the two groups. Within the preeclamptic group, the rates of decidual arteriolopathy (P.0001), central infarction (P=.0001), and hypermaturity of villi (P.0001) were higher the earlier the gestational age at delivery.Placentas in women with preeclampsia have increased amounts of disease. The rate is increased with lower gestational ages at the time of delivery for women with preeclampsia.

Background and Purpose — Subarachnoid hemorrhage (SAH) caused by ruptured intracranial aneurysm affects approximately 16 000 Americans annually, and almost 40% of affected patients die within 30 days despite the best current therapy. Prevention of SAH is therefore of paramount importance. We present a preliminary analysis of risk factors for SAH from our population-based, case-control study. Methods — Cases were prospectively collected and matched 2:1 by age, race, and gender to controls using random digit dialing. Personal risk factor history, family history, neuroimaging data, and genetic samples were obtained. Univariate and bivariate analyses were performed and population-attributable risks estimated. Multivariable analysis was performed using conditional logistic regression. Results — Between June 1997 and February 2000, 107 cases and 197 controls were enrolled. In bivariate analyses, a large proportion of population-attributable risk for SAH could be explained by modifiable risk factors: smoking, hypertension, and heavy alcohol use. In multivariable analysis, current cigarette smoking, history of hypertension, frequent alcohol use, lower body mass index, and a family history of a relative with SAH or intracranial aneurysm were found to be significant, independent risk factors for SAH. Conclusion — Our data confirm previous reports that SAH clusters within some families independent of environmental risk factors, suggesting that SAH has a significant genetic component. Yet, even among families at increased risk of SAH, smoking cessation, treatment of hypertension, and reduced alcohol intake may substantially decrease SAH risk. The independent associations with heavy alcohol use and low body mass index with SAH may be confounded by smoking and require further study.

Objective: Endothelin-1 is reportedly elevated in preeclampsia, and studies in our laboratory have shown that infusion of endothelin-1 produces increased mean arterial pressure, hemoconcentration, and proteinuria, while decreasing uterine blood flow. If a role in preeclampsia is confirmed for endothelin-1, therapeutic intervention may involve selective endothelin-A receptor blockers. Thus, this study was designed to determine the effects of Ro 61-1790, a selective endothelin-A receptor inhibitor, on mean arterial pressure, heart rate, and uteroplacental blood flow in pregnant and nonpregnant sheep. Study Design: Seven pregnant and seven nonpregnant sheep were instrumented with indwelling femoral artery and vein catheters and bilateral uterine artery flow probes, allowing determination of mean arterial pressure, heart rate, and uteroplacental blood flow. After baseline administration, animals received intravenous Ro 61-1790 either 1 mg/kg or 3 mg/kg, and hemodynamic responses were monitored for 120 minutes. Results: Intravenous administration of Ro 61-1790 at 1 mg/kg had no effect on the parameters measured in either group studied. However, at 3 mg/kg, Ro 61-1790 caused an increase in total uterine blood flow in nonpregnant sheep from 22 ± 6 mL/min to 51 ± 15 mL/min. This occurred in the absence of significant changes in mean arterial pressure. In pregnant animals, administration of 3 mg/kg Ro 61-1790 decreased mean (± SEM) uteroplacental blood flow by 20% (from 771 ± 130 mL/min to 621 ± 110 mL/min) and increased uterine vascular resistance transiently. Administration of Ro 61-1790 had no significant effect on fetal mean arterial pressure, heart rate, or oxygenation. Conclusions: These data suggest that endogenous endothelin-1 may play an important role in regulating uterine vascular tone in pregnant and nonpregnant sheep and that inhibition of endogenous endothelin-1 may lead to reductions in uteroplacental perfusion in pregnant animals. (Am J Obstet Gynecol 2002;186:55-60.)

To determine the role of glycemic control in spontaneous preterm delivery in type 1 diabetic women.A secondary analysis of data from women enrolled in the Diabetes in Pregnancy Program prior to 20 weeks was performed. Multiple logistic regression was used to analyze the association between glycohemoglobin A1 in women with spontaneous preterm delivery (n = 53) and women who delivered at term (n = 200). Maternal demographics and obstetric outcomes were also compared between the groups.Glycohemoglobin A1 levels were higher in the spontaneous preterm delivery group than the term group throughout pregnancy, reaching statistical significance after the first trimester. The last glycohemoglobin A1 prior to delivery was 8.1% in the spontaneous preterm delivery group and 7.4% in the term group (p = 0.002). Using multiple logistic regression, each 1% increase in glycohemoglobin A1 increased the risk of spontaneous preterm delivery by 37%.Poor glycemic control is associated with an increased risk of spontaneous preterm delivery, suggesting that strict glycemic control may reduce the rate of preterm delivery in these women.

Zolpidem is a short-acting non-benzodiazepine hypnotic that is used to improve sleep architecture in patients with burn injuries. This study evaluated the relationship between zolpidem administration and sleep parameters in a cohort of children with severe burn injuries. Standard age-based zolpidem dosing practices were employed. Polysomnography data were recorded at 30-second intervals throughout the night. Serum concentrations of zolpidem were measured at 0, 1, 2, 4, 5, 6, and 8 hours after administration of the first dose. The relationship between zolpidem concentrations and sleep parameters was evaluated using Markov mixed-effects pharmacodynamic models. Ten children received two doses of zolpidem at 22:00 and 02:00 hours. The median total amount of sleep was 361.0 (interquartile range [IQR]: 299.0–418.5) minutes; approximately 65% of the normal reference value for an 8-hour period. Slow-wave and rapid eye movement (REM) sleep were also dramatically reduced (18–37% of normal). With two doses of zolpidem, stage 2 sleep was 99% of normal levels. Higher peak zolpidem concentrations were associated with increased stage 2 sleep (r2 = .54; P = .04). Despite this, a median of 120.0 (IQR: 99.5–143.5) transitions between nocturnal sleep stages were recorded, with a median of 55.5 (IQR: 36–75) night-time awakenings per patient. In pediatric burn patients, higher zolpidem serum concentrations were associated with restoration of stage 2 sleep to normal levels. Nonetheless, slow-wave and REM sleep were profoundly depressed with frequent transitions between sleep stages, suggesting that alternative hypnotic agents may be required to restore normal sleep architecture in severely burned children.

AB Poststroke hemiparesis often leads to a vicious cycle of limited activity, deconditioning, and poor cardiovascular health. Accumulating evidence suggests that exercise intensity is a critical factor determining gains in aerobic capacity, cardiovascular protection, and functional recovery after stroke. High-intensity interval training (HIT) is a strategy that augments exercise intensity using bursts of concentrated effort alternated with recovery periods. However, there was previously no stroke-specific evidence to guide HIT protocol selection. Purpose: This study aimed to compare within-session exercise responses among three different HIT protocols for persons with chronic (>6 months after) stroke. Methods: Nineteen ambulatory persons with chronic stroke performed three different 1-d HIT sessions in a randomized order, approximately 1 wk apart. HIT involved repeated 30-s bursts of treadmill walking at maximum tolerated speed, alternated with rest periods. The three HIT protocols were different on the basis of the length of the rest periods, as follows: 30 s (P30), 60 s (P60), or 120 s (P120). Exercise tolerance, oxygen uptake (V[spacing dot above]O2), HR, peak treadmill speed, and step count were measured. Results: P30 achieved the highest mean V[spacing dot above]O2, HR, and step count but with reduced exercise tolerance and lower treadmill speed than P60 or P120 (P30: 70.9% V[spacing dot above]O2peak, 76.1% HR reserve (HRR), 1619 steps, 1.03 m[middle dot]s-1; P60: 63.3% V[spacing dot above]O2peak, 63.1% HRR, 1370 steps, 1.13 m[middle dot]s-1; P120: 47.5% V[spacing dot above]O2peak, 46.3% HRR, 1091 steps, 1.10 m[middle dot]s-1). P60 achieved treadmill speed and exercise tolerance similar to those in P120, with higher mean V[spacing dot above]O2, HR, and step count. Conclusions: For treadmill HIT in chronic stroke, a combination of P30 and P60 may optimize aerobic intensity, treadmill speed, and stepping repetition, potentially leading to greater improvements in aerobic capacity and gait outcomes in future studies.

Diamond-Blackfan anemia (DBA), an inherited marrow failure syndrome, has severe hypoplastic anemia in infancy and association with aplastic anemia, MDS/leukemia, and other malignancies. Short stature is present in most patients. Isolated cases have demonstrated improved growth on growth hormone (GH) therapy.GH treatment data were obtained from 19 children with DBA (6 at our site and 13 from Genentech). Control data from 44 non-GH treated children were provided by Diamond Blackfan Anemia Registry. Annual growth velocity (GV) and height-for-age Z-scores (HAZ) were compared between groups and for up to 4y of GH treatment.Constructed DBA-specific male and female height-for-age charts for non-GH treated patients revealed short stature compared to CDC norms. GH-treated patients had significantly lower HAZ prior to treatment initiation compared to non-GH-treated controls. Among GH-treated patients, GV significantly improved in the first two years relative to pre-treatment. HAZ significantly improved in each of 4y of GH therapy compared to baseline. After 2y of therapy, HAZ for GH-treated patients were not significantly different from controls, demonstrating successful catch-up growth.GH treatment in children with DBA improves both GV and HAZ during treatment sustained for up to 4y. Very short children with DBA can be treated successfully with GH to restore stature to levels comparable to less affected patients. DBA height charts are useful tools for assessing age-specific growth in this typically short population. Careful consideration of individualized benefit of GH therapy versus risk is important in view of long-term underlying ∼5% malignancy risk in DBA.

Objective: The purpose of this study was to determine whether the combined use of maternal antenatal corticosteroids and antibiotic therapy is associated with an increased risk of late-onset neonatal sepsis among very low birth weight infants. Study Design: The outcomes of infants admitted to the 3 Cincinnati neonatal intensive care units between May 1991 and May 2000 were retrospectively evaluated. Late-onset neonatal sepsis was defined either as the occurrence of a positive blood culture obtained after 72 hours of life with clinical signs of sepsis or as the need for >5 consecutive days of antibiotic therapy for presumed sepsis that initiated after 72 hours of life. Wilcoxon rank sum, chi-square test, and multiple logistic regression were used for analysis. Results: Among the parturients delivering the study infants, 434 women (24%) received corticosteroids only, 175 women (9%) received antibiotics only, 819 women (46%) received both corticosteroids and antibiotics, and 370 women (20%) received neither corticosteroids nor antibiotics. Among 1978 study infants, there were 732 infants (41%) with late-onset neonatal sepsis. By univariate analysis, the odds ratio for late-onset neonatal sepsis caused by combined corticosteroid and antibiotic use was 0.96 (95% CI, 0.89%, 1.04%). Multiple logistic regression analysis was used to evaluate the risk of combined corticosteroids and antibiotic use after controlling for potential covariates and confounders. After controlling for outborn birth (odds ratio, 1.3; 95% CI, 1.0%-1.8%), increasing gestational age at delivery (odds ratio, 0.63; 95% CI, 0.60%-0.66%), interaction between white race and male gender ( P =.01) and interaction between antibiotics and prolonged rupture of membranes ( P =.02), the use of corticosteroids and antibiotics was not associated with an increased risk of late-onset neonatal sepsis ( P =.9). Conclusion: The combined use of maternal corticosteroids and antibiotic therapy is not associated with an increased risk for late-onset neonatal sepsis. (Am J Obstet Gynecol 2001;185:1081-5.)

The purpose of this study was to compare the efficacy of different routes of misoprostol administration for cervical ripening and the induction of labor.Three hundred thirty women ator = 32 weeks gestation with a Bishop scoreor = 6 and an indication for induction were randomized to 1 of 3 double-blinded groups: (1) 25 microg orally administered misoprostol plus 25 microg vaginally administered misoprostol, (2) orally administered placebo plus 25 microg vaginally administered misoprostol, or (3) 25 microg orally administered misoprostol plus vaginally administered placebo. Doses were repeated every 4 hours until onset of labor or a maximum of 12 doses were given. The primary outcome of the trial was vaginal delivery within 24 hours of the initiation of induction. Secondary outcomes were the time from induction to delivery, need for oxytocin augmentation, mode of delivery, frequency of side effects, and neonatal and maternal outcome. Analysis of variance, chi-square test, and logistic regression were used for analysis.There were no significant differences in maternal characteristics or indications for induction. The percentage of women who achieved vaginal delivery within 24 hours was highest in the vaginally administered misoprostol group: 67% compared with 53% in the oral-plus-vaginal group (P.05) and 36% in the oral group (P.05). The median time to vaginal delivery was shorter in the vaginal and oral-plus-vaginal misoprostol groups, 13.5 hours and 14.3 hours, respectively, when compared with 23.9 hours in the oral group (P.05). The rate of cesarean delivery was lowest in the vaginal misoprostol group (17% compared with 30% in the oral-plus-vaginal group and 32% in the oral group; P.05). Uterine tachysystole occurred least frequently in the oral misoprostol group (10% compared with 32% in the vaginal group and 34% in the oral-plus-vaginal group; P.05). Uterine hyperstimulation also occurred least frequently in the oral misopro-stol group (4% compared with 15% in the vaginal group and 22% in the oral-plus-vaginal group; P.05).At the doses studied, induction of labor with vaginally administered misoprostol is more efficacious than either oral-plus-vaginal or oral-only route of administration.

Objective: To test the hypothesis that progression of diabetic retinopathy in pregnancy is associated with reduced fetal growth and related neonatal morbidity. Methods: Women with type 1 diabetes ( n = 205) were enrolled before 14 weeks’ gestation in a prospective study of diabetes in pregnancy and treated with intensive insulin therapy. They had serial ophthalmologic evaluations before 20 weeks’ gestation and in late gestation or postpartum. Subjects were divided into two groups based on whether retinopathy progressed (progression group) or remained unchanged (no progression group). Results: Retinopathy progressed in 59 of 205 women (29%) and was associated with advanced White classification ( P = .001): three (5%) were class B, 14 (23%) class C, 24 (41%) class D, and 18 (30%) class F-RF. Reduced fetal growth was associated with progression of retinopathy. Mean birth weight was lower ( P = .02), and more infants were small for gestational age ( P = .02) and had low birth weights ( P = .02) in the progression group. More large-for-gestational-age infants were noted in the no-progression group ( P = .04). Birth weight percentile distributions showed a shift of the curve to the left in the progression group ( P = .03). There were no differences in gestational age at delivery, macrosomia, preterm delivery, respiratory distress syndrome, neonatal hypoglycemia, or neonatal death. Small for gestational age was associated with chronic hypertension (odds ratio [OR] 6.4; 95% confidence interval [CI] 1.5, 27.9) and retinopathy progression (OR 4.7; 95% CI 1.2, 23.8). Conclusion: Development and progression of diabetic retinopathy during pregnancy were associated with reduced fetal growth manifested as increased rate of small-for-gestational-age and low-birth-weight infants.