Development and Multicenter Case-Control Validation of Urinary Comprehensive Genomic Profiling for Urothelial Carcinoma Diagnosis, Surveillance, and Risk-Prediction.

PURPOSE: Urinary comprehensive genomic profiling (uCGP) uses next-generation sequencing to identify mutations associated with urothelial carcinoma and has the potential to improve patient outcomes by noninvasively diagnosing disease, predicting grade and stage, and estimating recurrence risk. EXPERIMENTAL DESIGN: This is a multicenter case-control study using banked urine specimens collected from patients undergoing initial diagnosis/hematuria workup or urothelial carcinoma surveillance. A total of 581 samples were analyzed by uCGP: 333 for disease classification and grading algorithm development, and 248 for blinded validation. uCGP testing was done using the UroAmp platform, which identifies five classes of mutation: single-nucleotide variants, copy-number variants, small insertion-deletions, copy-neutral loss of heterozygosity, and aneuploidy. UroAmp algorithms predicting urothelial carcinoma tumor presence, grade, and recurrence risk were compared with cytology, cystoscopy, and pathology. RESULTS: uCGP algorithms had a validation sensitivity/specificity of 95%/90% for initial cancer diagnosis in patients with hematuria and demonstrated a negative predictive value (NPV) of 99%. A positive diagnostic likelihood ratio (DLR) of 9.2 and a negative DLR of 0.05 demonstrate the ability to risk-stratify patients presenting with hematuria. In surveillance patients, binary urothelial carcinoma classification demonstrated an NPV of 91%. uCGP recurrence-risk prediction significantly prognosticated future recurrence (hazard ratio, 6.2), whereas clinical risk factors did not. uCGP demonstrated positive predictive value (PPV) comparable with cytology (45% vs. 42%) with much higher sensitivity (79% vs. 25%). Finally, molecular grade predictions had a PPV of 88% and a specificity of 95%. CONCLUSIONS: uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients.

Phase Ia Study of Anti-NaPi2b Antibody-Drug Conjugate Lifastuzumab Vedotin DNIB0600A in Patients with Non-Small Cell Lung Cancer and Platinum-Resistant Ovarian Cancer.

PURPOSE: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody-drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). PATIENTS AND METHODS: LIFA was administered to patients with non-small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). RESULTS: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). CONCLUSIONS: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Community Socioeconomic Deprivation and Nonalcoholic Fatty Liver Disease Severity.

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity. Obesity is associated with lower socioeconomic status (SES). An independent link between pediatric NAFLD and SES has not been elucidated. The objective of this study was to evaluate the distribution of socioeconomic deprivation, measured using an area-level proxy, in pediatric patients with known NAFLD and to determine whether deprivation is associated with liver disease severity. METHODS: Retrospective study of patients <21 years with NAFLD, followed from 2009 to 2018. The patients' addresses were mapped to census tracts, which were then linked to the community deprivation index (CDI; range 0--1, higher values indicating higher deprivation, calculated from six SES-related variables available publicly in US Census databases). RESULTS: Two cohorts were evaluated; 1 with MRI (magnetic resonance imaging) and/or MRE (magnetic resonance elastography) findings indicative of NAFLD (n = 334), and another with biopsy-confirmed NAFLD (n = 245). In the MRI and histology cohorts, the majority were boys (66%), non-Hispanic (77%-78%), severely obese (79%-80%), and publicly insured (55%-56%, respectively). The median CDI for both groups was 0.36 (range 0.15-0.85). In both cohorts, patients living above the median CDI were more likely to be younger at initial presentation, time of MRI, and time of liver biopsy. MRI-measured fat fraction and liver stiffness, as well as histologic characteristics were not different between the high- and low-deprivation groups. CONCLUSIONS: Children with NAFLD were found across the spectrum of deprivation. Although children from more deprived neighborhoods present at a younger age, they exhibit the same degree of NAFLD severity as their peers from less deprived areas.

Perspectives from the Society for Pediatric Research: interventions targeting social needs in pediatric clinical care.

The social determinants of health (SDoH) are defined by the World Health Organization as the "conditions in which people are born, grow, live, work, and age." Within pediatrics, studies have highlighted links between these underlying social, economic, and environmental conditions, and a range of health outcomes related to both acute and chronic disease. Additionally, within the adult literature, multiple studies have shown significant links between social problems experienced during childhood and "adult diseases" such as diabetes mellitus and hypertension. A variety of potential mechanisms for such links have been explored including differential access to care, exposure to carcinogens and pathogens, health-affecting behaviors, and physiologic responses to allostatic load (i.e., toxic stress). This robust literature supports the importance of the SDoH and the development and evaluation of social needs interventions. These interventions are also driven by evolving economic realities, most importantly, the shift from fee-for-service to value-based payment models. This article reviews existing evidence regarding pediatric-focused clinical interventions that address the SDoH, those that target basic needs such as food insecurity, housing insecurity, and diminished access to care. The paper summarizes common challenges encountered in the evaluation of such interventions. Finally, the paper concludes by introducing key opportunities for future inquiry.

Effects of RG7652, a Monoclonal Antibody Against PCSK9, on LDL-C, LDL-C Subfractions, and Inflammatory Biomarkers in Patients at High Risk of or With Established Coronary Heart Disease (from the Phase 2 EQUATOR Study).

RG7652 (MPSK3169A), a fully human immunoglobulin G1 (IgG1) monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9), blocks the interaction between PCSK9 and low-density lipoprotein (LDL) receptor. EQUATOR (ClinicalTrials.govNCT01609140), a randomized, double-blind, and dose-ranging phase 2 study, evaluated RG7652 in patients (1) at high risk for or (2) with coronary heart disease (CHD). The primary end point was change in LDL cholesterol (LDL-C) from baseline to day 169. Patients (n = 248; median age, 64 years; 57% men; 52% with established CHD; 82% on statins) with baseline LDL-C levels of 90 to 250 mg/dl (mean, 126 mg/dl) continuing on standard-of-care therapy were randomized to receive 1 of 5 RG7652 doses or placebo, subcutaneously every 4, 8, or 12 weeks for 24 weeks. Significant dose-dependent reductions in LDL-C levels from baseline to nadir (56 to 74 mg/dl [48% to 60%]) were observed in all RG7652-dosed patients; effects persisted to day 169 with the highest doses (reduction vs placebo up to 62 mg/dl [51%]) with no unexpected safety signals. RG7652 reduced apolipoprotein B and lipoprotein(a) levels. LDL-C subfraction analysis by nuclear magnetic resonance spectroscopy revealed a prominent decrease in large LDL-C and some decrease in small LDL particles. There was significant reduction in mean particle size of LDL-C on day 169 but no significant reductions in systemic markers of inflammation (high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha). RG7652 reduced LDL-C levels and was well tolerated in patients at high risk for or with CHD on standard-of-care therapy. In conclusion, RG7562 treatment affected large LDL-C and, to a lesser extent, small LDL-C particles; RG7562 did not affect systemic circulating pro-inflammatory cytokines or high-sensitivity C-reactive protein.

Radiosurgical Treatment Verification Using Removable Megavoltage Radiation Detectors.

Introduction Accurate dose delivery is critical to the success of stereotactic radiosurgery. Unfortunately, verification of the accuracy of treatment delivery remains a challenging problem. Existing radiosurgery delivery paradigms are limited in their ability to verify the accurate delivery of radiation beams using data sampled from the beam after it has traversed the patient. The Zap-X Radiosurgery System (Zap Surgical Systems, San Carlos, CA) addresses this issue by implementing a fully integrated treatment delivery system that utilizes a factory commissioned megavoltage (MV) imager to measure the transmitted beam. The measured intensity is then compared with an expected value in order to confirm that treatment is proceeding as expected. The purpose of this study was to evaluate a prototype system and investigate the accuracy of an attenuation model used in generating the expected transmitted intensity values. Methods A prototype MV imager was used to measure transmitted beam intensities at various exposure levels and through several thicknesses of solid water. The data were used to evaluate imager linearity and model accuracy. Results Experimental results indicate that a quadratic attenuation model is appropriate for predicting beam attenuation and that the imager exhibits excellent dose linearity. Conclusions The MV imager system is shown to be capable of accurately acquiring the data needed to confirm treatment validity.

Phase I Study of the Anti-CD22 Antibody-Drug Conjugate Pinatuzumab Vedotin with/without Rituximab in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma.

Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients.Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common grade ≥3 adverse event. Peripheral neuropathy-related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses.Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. Clin Cancer Res; 23(5); 1167-76. ©2016 AACR.

Medical and Social Determinants of Health Associated with Intensive Care Admission for Asthma in Children.

RATIONALE: Risk factors for severe asthma exacerbations in children requiring admission to the intensive care unit (ICU) may occur in variety of medical, environmental, economic, and socioeconomic domains. OBJECTIVES: We sought to characterize medical and sociodemographic risk factors among children who required admission to the intensive care unit for asthma. METHODS: Data were obtained from the Greater Cincinnati Asthma Risk Study, a population-based, prospective, observational cohort of children admitted for treatment of acute asthma or bronchodilator-responsive wheezing. Data collected on 774 children included race, socioeconomic status, allergen sensitization, environmental exposures, psychosocial strain, and financial hardship. Analyses compared children admitted to the ICU to those admitted to a medical inpatient unit. MEASUREMENTS AND MAIN RESULTS: One hundred sixty-one (20.9%) children required admission to intensive care. There was no difference in sex, race, insurance status, caregiver educational level, income, financial strain, psychological distress, or marital status between the ICU and non-ICU cohorts. Risk for medication nonadherence assessed by parent report was not different between groups. Although previous hospital admission or emergency department visit history did not differ between the groups, prior ICU admission was more common among those admitted to the ICU at the index admission (27 vs. 16%, P = 0.002). Children requiring intensive care admission were more likely to be sensitized to multiple aeroallergens. Exposure to cigarette smoke (measured as salivary cotinine), although a risk factor for hospital admission, was negatively associated with risk of ICU admission. CONCLUSIONS: Social and economic risk factors typically predictive of increased asthma morbidity, including exposure to tobacco smoke, were not associated with ICU admission among a population of children admitted to the hospital for treatment of acute asthma. Intrinsic disease factors, including allergic sensitization, may be more important predictors of ICU admission.

Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). METHODS: In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. FINDINGS: Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. INTERPRETATION: Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. FUNDING: Genentech.

Family hardships and serum cotinine in children with asthma.

BACKGROUND AND OBJECTIVE: A better understanding of how poverty-related hardships affect child health could highlight remediable intervention targets. Tobacco smoke exposure may be 1 such consequence of family hardship. Our objective was to explore the relationship between family hardships and tobacco exposure, as measured by serum cotinine, a tobacco metabolite, among children hospitalized for asthma. METHODS: We prospectively enrolled a cohort of 774 children, aged 1 to 16 years, admitted for asthma or bronchodilator-responsive wheezing. The primary outcome was detectable serum cotinine. We assessed family hardships, including 11 financial and social variables, through a survey of the child's caregiver. We used logistic regression to evaluate associations between family hardship and detectable cotinine. RESULTS: We had complete study data for 675 children; 57% were African American, and 74% were enrolled in Medicaid. In total, 56% of children had detectable cotinine. More than 80% of families reported ≥ 1 hardship, and 41% reported ≥ 4 hardships. Greater numbers of hardships were associated with greater odds of having detectable cotinine. Compared with children in families with no hardships, those in families with ≥ 4 hardships had 3.7-fold (95% confidence interval, 2.0-7.0) greater odds of having detectable serum cotinine in adjusted analyses. Lower parental income and educational attainment were also independently associated with detectable serum cotinine. CONCLUSIONS: Family hardships are prevalent and associated with detectable serum cotinine level among children with asthma. Family hardships and tobacco smoke exposure may be possible targets for interventions to reduce health disparities.

Traffic-related air pollution and asthma hospital readmission in children: a longitudinal cohort study.

OBJECTIVE: To examine the association between exposure to traffic-related air pollution (TRAP) and hospital readmission for asthma or bronchodilator-responsive wheezing. STUDY DESIGN: A population-based cohort of 758 children aged 1-16 years admitted for asthma or bronchodilator-responsive wheezing was assessed for asthma readmission within 12 months. TRAP exposure was estimated with a land use regression model using the home address at index admission, with TRAP dichotomized at the sample median (0.37 µg/m3). Covariates included allergen-specific IgE, tobacco smoke exposure, and social factors obtained at enrollment. Associations between TRAP exposure and readmission were assessed using logistic regression and Cox proportional hazards models. RESULTS: The study cohort was 58% African American and 32% white; 19% of the patients were readmitted within 12 months of the original admission. Higher TRAP exposure was associated with a higher readmission rate (21% vs. 16%; P = .05); this association was not significant after adjusting for covariates (aOR, 1.4; 95% CI, 0.9-2.2). Race modified the observed association; white children with high TRAP exposure had 3-fold higher odds of asthma readmission (OR, 3.0; 95% CI, 1.1-8.1), compared with white children with low TRAP exposure. In African American children, TRAP exposure was not associated with increased readmission (OR, 1.1; 95% CI, 0.6-1.8). In children with high TRAP exposure, TRAP exposure was associated with decreased time to readmission in white children (hazard ratio, 3.2; 95% CI, 1.5-6.7) compared with African American children (hazard ratio, 1.0; 95% CI, 0.7-1.4). African American children had a higher readmission rate overall. CONCLUSION: TRAP exposure is associated with increased odds of hospital readmission in white children, but not in African American children.

Role of financial and social hardships in asthma racial disparities.

BACKGROUND AND OBJECTIVES: Health care reform offers a new opportunity to address child health disparities. This study sought to characterize racial differences in pediatric asthma readmissions with a focus on the potential explanatory role of hardships that might be addressed in future patient care models. METHODS: We enrolled 774 children, aged 1 to 16 years, admitted for asthma or bronchodilator-responsive wheezing in a population-based prospective observational cohort. The outcome was time to readmission. Child race, socioeconomic status (measured by lower income and caregiver educational attainment), and hardship (caregivers looking for work, having no one to borrow money from, not owning a car or home, and being single/never married) were recorded. Analyses used Cox proportional hazards. RESULTS: The cohort was 57% African American, 33% white, and 10% multiracial/other; 19% were readmitted within 12 months. After adjustment for asthma severity classification, African Americans were twice as likely to be readmitted as whites (hazard ratio: 1.98; 95% confidence interval: 1.42 to 2.77). Compared with whites, African American caregivers were significantly more likely to report lower income and educational attainment, difficulty finding work, having no one to borrow money from, not owning a car or home, and being single/never married (all P ≤ .01). Hardships explained 41% of the observed racial disparity in readmission; jointly, socioeconomic status and hardship explained 49%. CONCLUSIONS: African American children were twice as likely to be readmitted as white children; hardships explained >40% of this disparity. Additional factors (eg, pollution, tobacco exposure, housing quality) may explain residual disparities. Targeted interventions could help achieve greater child health equity.

Cotinine in children admitted for asthma and readmission.

OBJECTIVE: To explore the relationship between tobacco smoke exposure (reported versus biomarker) and rates of readmission for children hospitalized for asthma. METHODS: We enrolled a prospective cohort of 774 children aged 1 to 16 years admitted for asthma or bronchodilator-responsive wheezing. The primary outcome was at least 1 asthma- or wheeze-related readmission within 1 year. Caregivers reported any tobacco exposure at home, in a secondary residence, or in the car. We measured serum and saliva cotinine levels with mass spectrometry. We used logistic regression to evaluate associations between tobacco exposure and readmissions. RESULTS: A total of 619 children had complete tobacco exposure data; 57% were African American and 76% had Medicaid. Seventeen percent of children were readmitted within 1 year. Tobacco exposure rates were 35.1%, 56.1%, and 79.6% by report, serum, and saliva measures, respectively. Caregiver report of any tobacco exposure was not associated with readmission (adjusted odds ratio: 1.18; 95% confidence interval: 0.79-1.89), but having detectable serum or salivary cotinine was associated with increased odds of readmission (adjusted odds ratio [95% confidence interval]: 1.59 [1.02-2.48] and 2.35 [1.22-4.55], respectively). Among children whose caregivers reported no tobacco exposure, 39.1% had detectable serum cotinine and 69.9% had detectable salivary cotinine. Of the children with reported exposure, 87.6% had detectable serum cotinine and 97.7% had detectable salivary cotinine. CONCLUSIONS: Detectable serum and salivary cotinine levels were common among children admitted for asthma and were associated with readmission, whereas caregiver report of tobacco exposure was not.

Social-emotional problems in preschool-aged children: opportunities for prevention and early intervention.

OBJECTIVES: To estimate the prevalence of positive screens for social-emotional problems among preschool-aged children in a low-income clinical population and to explore the family context and receptivity to referrals to help guide development of interventions. DESIGN: Observational, cross-sectional study. SETTING: Two urban primary care clinics. PARTICIPANTS: A total of 254 parents of 3- and 4-year-old children at 2 urban primary care clinics. MAIN OUTCOME MEASURES: Score on a standardized screen for social-emotional problems (Ages and Stages Questionnaire: Social-Emotional) and answers to additional survey questions about child care arrangements, parental depressive symptoms, and attitudes toward preschool and behavioral health referrals. RESULTS: Twenty-four percent (95% CI, 16.5%-31.5%) of children screened positive for social-emotional problems. Among those screening positive, 45% had a parent with depressive symptoms, and 27% had no nonparental child care. Among parents of children who screened positive for social-emotional problems, 79% reported they would welcome or would not mind a referral to a counselor or psychologist; only 16% reported a prior referral. CONCLUSIONS: In a clinical sample, 1 in 4 low-income preschool-aged children screened positive for social-emotional problems, and most parents were amenable to referrals to preschool or early childhood mental health. This represents an opportunity for improvement in primary prevention and early intervention for social-emotional problems.

Enhancing accurate identification of food insecurity using quality-improvement techniques.

BACKGROUND AND OBJECTIVES: Infants who live in households experiencing food insecurity are at risk for negative health and developmental outcomes. Despite large numbers of households within our population experiencing food insecurity, identification of household food insecurity during standard clinical care is rare. The objective of this study was to use quality-improvement methods to increase identification of household food insecurity by the second-year pediatric residents working in the Pediatric Primary Care Center from 1.9% to 15.0% within 6 months. A secondary aim was to increase the proportion of second-year pediatric residents identifying food insecurity. METHODS: A team was formed to identify key drivers thought to be critical to the process of identifying food insecurity during well-child care. This project addressed 5 key drivers and tested interventions based on these drivers over a 6-month period at a hospital-based primary care site that serves ∼15 000 children from underserved neighborhoods. Tests included implementing an evidence-based electronic screen for food insecurity, educational interventions to improve understanding of food insecurity, empowerment exercises targeting clinicians and families, and gaining buy-in and support from ancillary personnel. RESULTS: Implementation of these changes led to an increase in the identification rate of household food insecurity from 1.9% to 11.2% over the 6 months (P < .01). The proportion of residents identifying food insecurity increased from 37.5% to 91.9% (P < .01). CONCLUSIONS: Application of quality-improvement methods in a primary care clinic increased ability to effectively screen and positively identify households with food insecurity in this population.

Comparison of biomarkers and parent report of tobacco exposure to predict wheeze.

OBJECTIVE: To identify the optimal measure of active and passive prenatal tobacco exposure to predict wheeze in early life. STUDY DESIGN: We conducted a birth cohort study of 398 mother-infant dyads enrolled during the second trimester of pregnancy and followed through age 2 years. We measured tobacco exposure with maternal report, serum cotinine level, and meconium cotinine level. We assessed wheeze with parent report every 6 months. We used a repeated measures logistic regression model. RESULTS: Of 367 children with respiratory data, 26% percent had parent reported active or passive prenatal maternal tobacco exposure, but cotinine was detected in 61% of mothers during pregnancy. Compared with children of mothers in the fifth percentile of tobacco exposure, children of mothers in the 95th percentile had increased odds of wheeze when exposure was measured with maternal serum cotinine level (adjusted OR, 2.6; 95% CI, 1.3-5.2; P < .006) versus meconium cotinine level (adjusted OR, 2.0; 95% CI, 1.0-4.0; P = .04) and total parent-reported exposure (adjusted OR, 1.7; 95% CI, 1.1-2.7; P = .01). CONCLUSIONS: Serum cotinine, a biomarker of tobacco exposure, was more strongly associated with wheeze than parent-reported exposure. Studies that rely on parent report of prenatal tobacco exposure may underestimate risk of wheeze.

White blood cell DNA adducts in a cohort of asthmatic children exposed to environmental tobacco smoke.

PURPOSE: Exposure to environmental tobacco smoke (ETS) leads to molecular damage in the form of DNA adducts. While lung cancer risk is higher among African Americans compared to White Americans, a few studies have tested for racial differences in DNA adducts among children exposed to ETS. The purpose of this study was to test whether African American children have higher DNA adducts levels compared to White children adjusted for ETS exposure. METHODS: Data and biologic specimens were drawn from an existing cohort of 212 asthmatic children. These subjects participated in a 12-month ETS-reduction trial that employed HEPA air cleaners with active filter cartridges and sham filter cartridges. White blood cell (WBC) DNA was analyzed for DNA adducts using (32)P-postlabeling. We assessed ETS exposure using a validated air nicotine dosimeter. We determined the independent relationship between African American race and DNA adduct levels adjusted for ETS exposure and air cleaner use. RESULTS: The mean age of the subjects was 8.4 years; 55% were African American. There was no difference in DNA adduct levels between African American and White children (11.8 vs. 11.2 adducts per 10(9) nucleotides, p = 0.86), despite slightly higher levels of air nicotine exposure (3.4 vs. 2.2 µg/m(3), p = 0.14). African American children used their air cleaners less often than White children. We found that the best predictor of DNA adduct levels was the duration of air cleaner use (r = -0.133, p = 0.056). This association was independent of cartridge type. CONCLUSIONS: We did not see differences in adduct levels by race even after accounting for the level of ETS exposure. However, there was a marginal inverse association between air cleaner use and adducts. Additional research is required to understand this phenomenon.

Associations of Fraction of Exhaled Nitric Oxide with Beta Agonist Use in Children with Asthma.

The fraction of exhaled nitric oxide (FeNO), a measure of airway inflammation, is a potential noninvasive tool to guide asthma management in children. It remains unclear, however, if FeNO adds any information beyond clinical assessment of asthma control. We evaluated the associations of FeNO level with short acting beta agonist use and compared it with other clinical asthma assessments. We examined a prospective cohort study of 225 tobacco-smoke-exposed children aged 6-12 years with doctor-diagnosed asthma, including measures of FeNO, reported days of short acting beta agonist use, and unscheduled asthma visits. FeNO was analyzed in relation to current and future (3 months later) short acting beta agonist use. Mean FeNO at baseline, 6, and 12 months was 15.5, 15.7, and 16.8 ppb. In multivariable analyses, higher FeNO level was associated with increased short acting beta agonist use but only among children who were not on inhaled corticosteroids. Among those not on an inhaled steroid, there was a 12% increase in current and 15% increase in future days of short acting beta agonist use for every 10 ppb increase in FeNO level. FeNO levels remained associated with current short acting beta agonist use even after adjusting for unscheduled asthma visits. FeNO levels remained associated with future short acting beta agonist use even after adjusting for current short acting beta agonist use or unscheduled asthma visits. We conclude that FeNO levels are associated with short acting beta agonist use but only among children who are not on an inhaled corticosteroid.

Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder.

OBJECTIVE: The study objective was to determine the independent and joint associations of prenatal tobacco and childhood lead exposures with attention-deficit/hyperactivity disorder (ADHD), as defined by current diagnostic criteria, in a national sample of US children. METHODS: Data are from the 2001-2004 National Health and Nutrition Examination Survey, a cross-sectional, nationally representative sample of the US population. Participants were 8 to 15 years of age (N = 2588). Prenatal tobacco exposure was measured by report of maternal cigarette use during pregnancy. Lead exposure was assessed by using current blood lead levels. The Diagnostic Interview Schedule for Children was used to ascertain the presence of ADHD in the past year, on the basis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. RESULTS: A total of 8.7% (95% confidence interval [CI]: 7.3%-10.1%) of children met criteria for ADHD. Prenatal tobacco exposure (adjusted odds ratio [aOR]: 2.4 [95% CI: 1.5-3.7]) and higher current blood lead concentrations (aOR for third versus first tertile: 2.3 [95% CI: 1.5-3.8]) were independently associated with ADHD. Compared with children with neither exposure, children with both exposures (prenatal tobacco exposure and third-tertile lead levels) had an even greater risk of ADHD (aOR: 8.1 [95% CI: 3.5-18.7]) than would be expected if the independent risks were multiplied (tobacco-lead exposure interaction term, P < .001). CONCLUSIONS: Prenatal tobacco and childhood lead exposures are associated with ADHD in US children, especially among those with both exposures. Reduction of these common toxicant exposures may be an important avenue for ADHD prevention.

Environmental exposures, nitric oxide synthase genes, and exhaled nitric oxide in asthmatic children.

Exhaled nitric oxide (FeNO), a measure of airway inflammation, is being explored as a tool to guide asthma management in children. Investigators have identified associations of genetic polymorphisms in nitric oxide synthase genes (NOS1 and NOS3) with FeNO levels; however, none have explored whether these polymorphisms modify the relationship of environmental exposures with FeNO. The objective of this project was to evaluate the association of NOS polymorphisms and environmental exposures with FeNO levels among children with asthma. We conducted a 12-month prospective cohort study of 225 tobacco-smoke exposed children (6-12 years) with doctor-diagnosed asthma. We assessed environmental exposures (tobacco, indoor allergens, & airborne particulates), polymorphisms in NOS1 (an intronic AAT tandem repeat) and NOS3 (G894T), and FeNO levels. There was no association of NOS1 or NOS3 polymorphisms with FeNO levels. There were no significant interactions of environmental exposures and the NOS1 polymorphism with FeNO levels. In contrast, there was an interaction of the NOS3 polymorphism and airborne nicotine concentration with FeNO levels (P = 0.01). Among GG genotype individuals, nicotine exposure did not affect FeNO levels; however, among individuals with at least one T allele, higher nicotine exposure was associated with lower FeNO levels (approximately 5 ppb decrease from the lowest to the highest quartile). We conclude that genetic differences may explain some of the conflicting results in studies of the effects of tobacco smoke exposure on FeNO levels and may make FeNO interpretation difficult for a subset of children with asthma.