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Summary Background Child mortality from sickle cell disease in sub-Saharan Africa is presumed to be high but is not well quantified. This uncertainty contributes to the neglect of sickle cell disease and delays the prioritisation of interventions. In this study, we estimated the mortality of children in Nigeria with sickle cell disease, and the proportion of national under-5 mortality attributable to sickle cell disease. Methods We did a model-estimated, population-level analysis of data from Nigeria's 2018 Demographic and Health Survey (DHS) to estimate the prevalence and geographical distribution of HbSS and HbSC genotypes assuming Hardy-Weinberg equilibrium near birth. Interviews for the survey were done between Aug 14 and Dec 29, 2018, and the embedded sickle cell disease survey was done in a randomly selected third of the overall survey's households. We developed an approach for estimating child mortality from sickle cell disease by combining information on tested children and their untested siblings. Tested children were aged 6–59 months at the time of the survey. Untested siblings born 0–14 years before the survey were also included in analyses. Testing as part of the DHS was done without regard to disease status. We analysed mortality differences using the inheritance-derived genotypic distribution of untested siblings older than the tested cohort, enabling us to estimate excess mortality from sickle cell disease for the older-sibling cohort (ie, those born between 2003 and 2013). Findings We analysed test results for 11 186 children aged 6–59 months from 7411 households in Nigeria. The estimated average birth prevalence of HbSS was 1·21% (95% CI 1·09–1·37) and was 0·24% (0·19–0·31) for HbSC. We obtained data for estimating child mortality from 10 195 tested children (who could be matched to the individual mother survey) and 17 205 of their untested siblings. 15 227 of the siblings were in the older-sibling cohort. The group of children with sickle cell disease born between 2003 and 2013 with at least one younger sibling in the survey had about 370 excess under-5 deaths per 1000 livebirths (95% CI 150–580; p=0·0008) than children with HbAA. The estimated national average under-5 mortality for children with sickle cell disease born between 2003 and 2013 was 490 per 1000 livebirths (95% CI 270–700), 4·0 times higher (95% CI 2·1–6·0) than children with HbAA. About 4·2% (95% CI 1·7–6·9) of national under-5 mortality was attributable to excess mortality from sickle cell disease. Interpretation The burden of child mortality from sickle cell disease in Nigeria continues to be disproportionately higher than the burden of mortality of children without sickle cell disease. Most of these deaths could be prevented if adequate resources were allocated and available focused interventions were implemented. The methods developed in this study could be used to estimate the burden of sickle cell disease elsewhere in Africa and south Asia. Funding Sickle Pan African Research Consortium, and the Bill & Melinda Gates Foundation.

Summary Background Vietnam has emerged as one of the world's leading success stories in responding to COVID-19. After a prolonged period of little to no transmission, there was an outbreak of unknown source in July, 2020, in the Da Nang region, but the outbreak was quickly suppressed. We aimed to use epidemiological, behavioural, demographic, and policy data from the COVID-19 outbreak in Da Nang to calibrate an agent-based model of COVID-19 transmission for Vietnam, and to estimate the risk of future outbreaks associated with reopening of international borders in the country. Methods For this modelling study, we used comprehensive data from June 15 to Oct 15, 2020, on testing, COVID-19 cases, and quarantine breaches within an agent-based model of SARS-CoV-2 transmission to model a COVID-19 outbreak in Da Nang in July, 2020. We applied this model to quantify the risk of future outbreaks in Vietnam in the 3 months after the reopening of international borders, under different behavioural scenarios, policy responses (ie, closure of workplaces and schools), and ongoing testing. Findings We estimated that the outbreak in Da Nang between July and August, 2020, resulted in substantial community transmission, and that higher levels of symptomatic testing could have mitigated this transmission. We estimated that the outbreak peaked on Aug 2, 2020, with an estimated 1060 active infections (95% projection interval 890–1280). If the population of Vietnam remains highly compliant with mask-wearing policies, our projections indicate that the epidemic would remain under control even if a small but steady flow of imported infections escaped quarantine into the community. However, if complacency increases and testing rates are relatively low (10% of symptomatic individuals are tested), the epidemic could rebound again, resulting in an estimated 2100 infections (95% projected interval 1050–3610) in 3 months. These outcomes could be mitigated if the behaviour of the general population responds dynamically to increases in locally acquired cases that exceed specific thresholds, but only if testing of symptomatic individuals is also increased. Interpretation The successful response to COVID-19 in Vietnam could be improved even further with higher levels of symptomatic testing. If the previous approaches are used in response to new COVID-19 outbreaks, epidemic control is possible even in the presence of low levels of imported cases. Funding Ministry of Science and Technology (Vietnam). Translation For the Vietnamese translation of the abstract see Supplementary Materials section.

Objectives To determine the feasibility of having caregivers assist in recognition of clinical deterioration in children hospitalized with febrile illness in a resource-limited setting. Design Single-center, prospective, interventional pilot study. Setting General pediatric wards at Kenyatta National Hospital, Nairobi, Kenya's largest public tertiary-care hospital. Patients Children hospitalized with acute febrile illness, accompanied by caregivers available at the bedside for 24 hours soon after hospital admission. Interventions Caregivers were trained to recognize signs of critical illness using the Family-Assisted Severe Febrile Illness Therapy tool, which quantifies patients' work of breathing, mental status, and perfusion, producing color-coded flags to signal illness severity. Caregivers' Family-Assisted Severe Febrile Illness Therapy assessments were compared with healthcare professional assessments and to established Pediatric Early Warning Scores (PEWS). An initial study stage was followed by refinement of training and a larger second stage with intervention/control arms. Measurements and main results A total of 107 patient/caregiver pairs were enrolled in the interventional arm; 106 caregivers underwent Family-Assisted Severe Febrile Illness Therapy training and were included in the analysis. Patient characteristics included median age 1.1 years (0.2-10 yr), 55 (52%) female, and diagnoses: pneumonia (64 [60%]), meningitis (38 [36%]), gastroenteritis (24 [23%]), and malaria (21 [20%]). Most caregivers had primary (34 [32%]) or secondary (53 [50%]) school education. Fourteen of 106 patients (13%) died during their stay, six within 2 days. Across all severity levels, caregiver Family-Assisted Severe Febrile Illness Therapy assessments matched professionals in 87% and 94% for stages 1 and 2, respectively. Caregiver Family-Assisted Severe Febrile Illness Therapy assessments had a moderate to strong correlation with coinciding Pediatric Early Warning Scores and were sensitive to life-threatening deterioration: for all six patients who died within 2 days of admission, caregiver assessment reached the highest alert level. Conclusions Caregiver involvement in recognition of critical illness in hospitalized children in low-resource settings may be feasible. This may facilitate earlier detection of clinical deterioration where staffing is severely limited by constrained resources. Further validation of the Family-Assisted Severe Febrile Illness Therapy tool is warranted, followed by its application in a larger multisite patient population to assess provider response and associated clinical outcomes.

BACKGROUND: In newborns with gastroschisis, both primary repair and delayed fascial closure with initial silo placement are considered safe with similar outcomes although cost differences have not been explored. METHODS: A retrospective review was performed of newborns admitted with gastroschisis at a single center from 2011–2016. Demographic, clinical, and cost data during the initial hospitalization were collected. Differences between procedure costs and clinical endpoints were analyzed using multivariable linear regression adjusting for prematurity, complicated gastroschisis, and performance of additional operations. RESULTS: 80 patients with gastroschisis met inclusion criteria. Rates of primary fascial, primary umbilical cord closure, and delayed closure were 14%, 65%, and 21%, respectively. Delayed closure was associated with an increase in total hospital costs by 57% compared to primary repair (p

The bidirectional interaction between undernutrition and infection can be devastating to child health. Nutritional deficiencies stunt growth, impair immunity, increase susceptibility to both infection and more severe outcomes from common infections. Simultaneously, infections compound undernutrition by increasing metabolic demand, reducing food intake, and impairing nutrient absorption. Treatment of acute malnutrition (wasting) can reverse at least some of its deleterious effects and reduce susceptibility to, and transmission of, infectious diseases. Nutrition-specific approaches may be packaged with other interventions, including immunization, to support overall child health. To understand how mass nutritional supplementation, treatment of wasting, and vaccination affect the dynamics of a vaccine-preventable infection, we developed a population-level, compartmental model of measles transmission of children aged 6-23 months old, stratified by nutrition status. We simulated a range of scenarios to assess the potential reductions in measles infection and mortality associated with targeted therapeutic feeding for children who are wasted and with a mass supplementation intervention. Nutrition interventions were assumed to reduce susceptibility to measles-related death and to increase engagement with the health sector, leading to increased vaccination rates. We found that if all wasted children receive therapeutic feeding, and if this leads to an increase in measles vaccination uptake, up to 12%, 20%, and 23% reductions in measles infections, measles-attributable mortality, and overall mortality among wasted children, respectively, could be averted. Combination of wasting treatment and mass supplementation coverage followed by an increase in vaccination coverage of non-wasted children from a baseline of 75% to 85%, leads to a 64-66% reduction in measles infection and mortality and 27% reduction in overall mortality among wasted children, compared with the wasting treatment alone. Our work highlights the synergistic benefits that may be achieved by leveraging mass nutritional supplementation as a touch point with the health system, to increase rates of vaccination in order to improve child survival beyond what would be expected from the additive benefits of each intervention.

Background Half of global child deaths occur in sub-Saharan Africa. Understanding child mortality patterns and risk factors will help inform interventions to reduce this heavy toll. The Nanoro Health and Demographic Surveillance System (HDSS), Burkina Faso was described previously, but patterns and potential drivers of heterogeneity in child mortality in the district had not been studied. Similar studies in other districts indicated proximity to health facilities as a risk factor, usually without distinction between facility types. Methods Using Nanoro HDSS data from 2009 to 2013, we estimated the association between under-5 mortality and proximity to inpatient and outpatient health facilities, seasonality of death, age group, and standard demographic risk factors. Results Living in homes 40–60 min and > 60 min travel time from an inpatient facility was associated with 1.52 (95% CI: 1.13–2.06) and 1.74 (95% CI: 1.27–2.40) greater hazard of under-5 mortality, respectively, than living in homes Conclusions Our results emphasize the importance of geographical proximity to health care, distinguish between inpatient and outpatient facilities, and also show a seasonal effect, probably driven by malaria.

Previous studies from low-resource countries have highlighted concerns surrounding non-specific effects of whole-cell pertussis vaccination, particularly in females. We sought to examine the effects of sex and birth weight on health services utilization following first exposure to whole-cell pertussis vaccine. Using a self-controlled case series design and by calculating relative incidence ratios (RIRs), we compared the relative incidence of emergency department visits and/or hospital admissions between sexes and between birth weight quintiles. Females had a higher relative incidence of events following vaccination compared to males (RIR = 1.13, 95% CI: 0.99, 1.30), which persisted after adjustment for birth weight (RIR = 1.12, 95% CI: 0.97, 1.28). We also observed a trend of increasing relative incidence of events over decreasing quintiles of birth weight; infants in the lowest quintile had a 26% higher relative event rate compared to the highest quintile, which was robust to adjustment for sex (Unadjusted RIR = 1.26, 95% CI: 1.01, 1.56; Adjusted RIR = 1.23, 95% CI: 0.99, 1.53). The risk of all-cause health services utilization immediately following vaccination, was elevated in female infants and infants having lower birth weight. Further study is warranted to determine if vaccine dosing should take infant weight into account.

IntroductionAdolescent pregnancy is a known health risk to mother and child. Statements and reports of health outcomes typically group mothers under 20 years old together. Few studies examined this risk at a finer age resolution, none of them comprehensively, and with differing results.MethodsWe analyzed Demographic and Health Surveys (DHS) data from 2004-2018 in Sub-Saharan Africa (SSA) and South Asia, on firstborn children of mothers 25 years old or younger. We examined the association between maternal age and stillbirths, and rates of neonatal (NNMR), infant (IMR), and under-5 mortality (U5MR), using mixed-effects logistic regression adjusting for major demographic variables and exploring the impact of maternal health-seeking.ResultsIn both regions and across all endpoints, mortality rates of children born to mothers aged ConclusionsAdolescent pregnancy is associated with dramatically worse child survival and mitigated by health-seeking behavior, likely reflecting a combination of biological and social factors. Refining maternal age reporting will avoid masking the increased risk to children born to very young adolescent mothers. Collection of additional biological and social data may better reveal mediators of this relationship. Targeted intervention strategies to reduce unintended pregnancy at earlier ages may also improve child survival.What is already known?Most previous studies treat under-20 mothers as a single group when looking at risk of child health outcomes.Few studies have assessed the risk gradient versus age within this group, focusing only on neonatal and infant mortality rather than broader child survival outcomes.These studies found a higher risk of neonatal and infant mortality among younger adolescent mothers, even after adjusting for socio-economic, demographic and health service accessibility variables.The risk gradients for stillbirths and under-5 mortality outcomes of children born to adolescent mothers remain unexplored.What are the new findings?This is the most comprehensive, multi-regional study to-date that investigated the potential impacts of adolescent pregnancy, examining multiple child survival endpoints from stillbirths to under-5 mortality, and quantifying the risk gradient as a function of maternal age from adolescence through young adulthood.Children of mothers younger than 16 faced 2-4 times higher risk of death at all child mortality stages (stillbirths, neonatal, infant, and under-5) in both sub-Saharan Africa and South Asia regions.The association extends across socio-economic status (SES) groups in both urban and rural settings and stays consistent when controlling for maternal education and health seeking risk factors.What do the new findings imply?We recommend revision of maternal-age-group reporting conventions to make the increased child survival risk with adolescent pregnancy more visible.To improve child survival outcomes, improving health-seeking behavior and quality of maternal care, as well as targeted interventions to reduce unintended pregnancy among adolescents and mitigate its harmful consequences are needed.Collecting additional data on the social and biological aspects of adolescent pregnancy could help understand the impact size of these mediators on child health outcomes.

Background: Sickle cell disease (SCD) child mortality in sub-Saharan Africa (SSA) is presumably high but not well-quantified. This contributes to the neglect of SCD and delays the prioritization of interventions. Nigeria has the world’s largest SCD population. Methods: We used Nigeria’s 2018 Demographic and Health Survey (DHS) data to estimate prevalence and geographic distribution of HbSS and HbSC genotypes. We developed a novel approach for estimating SCD child mortality, combining information on tested children (n=10195) and their untested siblings (n=17205). Mortality differences were decomposed using the inheritance-derived genotypic distribution of untested siblings older than the tested cohort, enabling us to estimate excess SCD mortality for the older-sibling cohort (i.e., born between 2003 and 2013, n=15227). Findings: The average birth prevalence of HbSS and HbSC in Nigeria was 1.20% (95% CI: 1.11-1.32%) and 0.23% (95% CI: 0.18-0.28%), respectively. Children born during 2003-2013 with at least one younger sibling in the survey with SCD suffered about 99 (95% CI: 55,144) excess deaths per 1,000 live births, compared with children whose tested siblings were all HbAA. After decomposition, we estimate that children born in 2003-2013 with SCD suffered 480 (95% CI: 270,700) deaths per 1000 live births, 4.0 times (95%CI: 2.1-6.0) higher than comparable children with HbAA. About 4.2% (95%CI: 1.6%-6.8%) of national U5M was attributable to excess SCD mortality. Interpretation: SCD child mortality burden in Nigeria continues to be disproportionately high. The vast majority of these deaths could be prevented if available focused interventions were implemented. The methodology developed here can be used to estimate the burden elsewhere in Africa and South Asia. Funding Statement: APO and DLC are employees of the Bill & Melinda Gates Foundation; OEN is the Nigeria PI of the Sickle Pan African Research Consortium (NHLBI Grant No 1U24HL135881). Declaration of Interests: FBP declares personal fees from Bluebird Bio, outside of the submitted work. All other authors declare no competing interests.

BackgroundHalf of global child deaths occur in sub-Saharan Africa. Understanding child mortality patterns and risk factors will help inform interventions to reduce this heavy toll. The Nanoro Health and Demographic Surveillance System (HDSS), Burkina Faso was described previously, but spatial patterns of child mortality in the district had not been studied. Similar studies in other districts indicated accessibility to health facilities as a risk factor, usually without distinction between facility types.MethodsUsing Nanoro HDSS data from 2009 to 2013, we estimated the association between under-5 mortality and accessibility to inpatient and outpatient health facilities, seasonality of death, and age group.ResultsLiving in homes 40-60 minutes and >60 minutes travel time from an inpatient facility was associated with 1.52 (95% CI: 1.13-2.06) and 1.74 (1.27-2.40) greater hazard of under-5 mortality, respectively, than living in homes ConclusionsOur results emphasize the importance of geographical accessibility to health care, and also distinguish between inpatient and outpatient facilities.

Prader-Willi syndrome (PWS, OMIM # 176270) and Down syndrome (DS, OMIM #190685) are neurodevelopmental genetic disorders with higher rates of autism spectrum disorder (ASD). The Aberrant Behavior Checklist (ABC) is a caregiver rating scale that assesses maladaptive behaviors. Overlapping symptoms exist between PWS, DS, and ASD, including maladaptive behaviors. We aimed to evaluate ABC profiles between PWS, DS, and ASD alone (without known genetic syndrome). In addition, we hypothesized PWS and DS with a comorbid ASD positive screen or diagnosis would have similar ABC profiles to ASD alone. ABC data from the following cohorts were analyzed: PWS (Seattle Children's Hospital, n = 28, mean age = 12.8 ± 4.9 years; University of Florida, n = 35, mean age = 9.3 ± 7.1 years), DS (Johns Hopkins, n = 406, mean age = 8.1 ± 2.4 years), and ASD (University of Florida, n = 102, mean age = 10.8 ± 3.5 years). ASD alone had significantly higher ABC scores. Subgroups of PWS and DS with a comorbid ASD positive screen or diagnosis had similarities in scores with the ASD only group, with subscale patterns unique to each syndrome. The ABC indicated worse maladaptive behaviors in children with ASD, including those with genetic syndromes. Although more studies are needed to evaluate the utility and the accuracy of the ABC as a tool to screen for ASD in special populations, it may be a useful adjunct in screening those children with PWS or DS who need more in depth ASD evaluation.

BACKGROUND: The advent of regional multidisciplinary intestinal rehabilitation programs has been associated with improved survival in pediatric intestinal failure. Yet, the optimal timing of referral for intestinal rehabilitation remains unknown. We hypothesized that the degree of intestinal failure-associated liver disease (IFALD) at initiation of intestinal rehabilitation would be associated with overall outcome. METHODS: The multicenter, retrospective Pediatric Intestinal Failure Consortium (PIFCon) database was used to identify all subjects with baseline bilirubin data. Conjugated bilirubin (CBili) was used as a marker for IFALD, and we stratified baseline bilirubin values as CBili4 mg/dL. The association between baseline CBili and mortality was examined using Cox proportional hazards regression. RESULTS: Of 272 subjects in the database, 191 (70%) children had baseline bilirubin data collected. 38% and 28% of patients had CBili>4 mg/dL and CBili4 mg/dL, prematurity, race, and small bowel atresia. On regression analysis controlling for age, prematurity, and diagnosis, the risk of mortality was increased by 3-fold for baseline CBili 2–4 mg/dL (HR 3.25 [1.07 – 9.92], p=0.04) and 4-fold for baseline CBili>4 mg/dL (HR 4.24 [1.51–11.92], p=0.006). On secondary analysis, CBili>4 mg/dL at baseline was associated with a lower chance of attaining enteral autonomy. CONCLUSION: In children with intestinal failure treated at intestinal rehabilitation programs, more advanced IFALD at referral is associated with increased mortality and decreased prospect of attaining enteral autonomy. Early referral of children with intestinal failure to intestinal rehabilitation programs should be strongly encouraged.

OBJECTIVES Ventricular assist devices have gained popularity in the management of refractory heart failure in children listed for heart transplantation. Our primary aim was to compare the composite endpoint of all-cause pretransplant mortality and loss of transplant eligibility in children who were treated with a ventricular assist device versus a medically managed cohort. DESIGN This was a retrospective cohort analysis. SETTINGS Data were obtained from the Scientific Registry of Transplant Recipients. PATIENTS The at-risk population (n = 1,380) was less than 18 years old, either on a ventricular assist device (605 cases) or an equivalent-severity, intensively medically treated group (referred to as MED, 775 cases). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The impact of ventricular assist devices was estimated via Cox proportional hazards regression (hazard ratio), dichotomizing 1-year outcomes to "poor" (22%: 193 deaths, 114 too sick) versus all others (940 successful transplants, 41 too healthy, 90 censored), while adjusting for conventional risk factors. Among children 0-12 months old, ventricular assist device was associated with a higher risk of poor outcomes (hazard ratio, 2.1; 95% CI, 1.5-3.0; p < 0.001). By contrast, ventricular assist device was associated with improved outcomes for ages 12-18 (hazard ratio, 0.3; 95% CI, 0.1-0.7; p = 0.003). For candidates 1-5 and 6-11 years old, there were no differences in outcomes between the ventricular assist device and MED groups (hazard ratio, 0.8 and 1.0, p = 0.43 and 0.9). The interaction between ventricular assist devices and age group was strongly significant (p < 0.001). CONCLUSIONS This is a comparative study of ventricular assist devices versus medical therapy in children. Age is a significant modulator of waitlist outcomes for children with end-stage heart failure supported by ventricular assist device, with the impact of ventricular assist devices being more beneficial in adolescents.

BACKGROUND: Erythropoietin stimulating agent hyporesponsiveness (ESAH) is associated with increased cardiovascular mortality in patients with end-stage renal disease (ESRD) on hemodialysis. Dynamic treatment Regimes (DTR), a type of clinical decision support (CDS) tool that guide the prescription of specific therapies in response to variations in patient states, have been used to guide treatment for chronic clinical problems that require frequent monitoring and therapy changes. Our objective is to explore the role of utilizing a DTR to reduce ESAH in pediatric hemodialysis patients. METHODS: Retrospective analysis of ESRD patients on hemodialysis who received ESAs. Dosing was adjusted using a locally developed protocol designed to target a hemoglobin between 10–12 g/dl. Analyzing this protocol as a DTR, we assessed adherence to the protocol over time measuring how the hypo-response index (ESA dose/hemoglobin value) changed due to varying levels of adherence. RESULTS: 18 patients met study criteria. Median hemoglobin was 11.4 g/dl (range: 6.1–15.4), and median weekly ESA dose (darbepoetin-equivalent) was 0.4 mcg/kg/dose (range: 0–2.1). Full adherence to the DTR was identified in 266 (71%) of the 4 week periods, with a median average adherence score of 0.80 (range: 0.63–0.91). As adherence to the DTR improved, ESAH decreased. During the last 12 weeks, 13 out of 18 patients had lower average ESA/hemoglobin ratio than the first 12 weeks. CONCLUSION: A DTR appears to be well-suited to the treatment of anemia in ESRD and reduces ESAH. Our work shows the potential of DTRs to drive the development and evaluation of clinical practice guidelines.

Background Image quality of high resolution chest computed tomographies (HRCTs) depends on adequate breath holds at end inspiration and end expiration. We hypothesized that implementation of spirometry-assisted breath holds in children undergoing HRCTs would improve image quality over that obtained with voluntary breath holds by decreasing motion artifact and atelectasis. Methods This is a retrospective case-control study of HRCTs obtained at a tertiary care children’s hospital before and after implementation of a spirometry-assisted CT protocol, in which children ≥8 years of age are first trained in supine slow vital capacity maneuvers and then repeat the maneuvers in the CT scanner, coached by a respiratory therapist. Spirometry-assisted CT scans (cases) were matched by age, gender and diagnosis (cystic fibrosis vs other) to CT scans obtained with voluntary breath holds in the 6 years before implementation of the spirometry assistance protocol (controls), and evaluated by 2 blinded pediatric radiologists. Results Among both cases and controls ( N = 50 each), 10 carried the diagnosis of cystic fibrosis and 40 had other diagnoses. Mean age was 12.9 years (range: 7.5-20.1) among cases and 13.0 (7.1-19.7) among controls. Mean (SD) inspiratory image density among cases was −852 (37) Hounsfield units (HU) and −828 (43) among controls ( p = 0.006). Mean (SD) expiratory image density was −629 (95) HU among cases and −688 (83) HU among controls ( p = 0.002). Mean (SD) change in image density between inspiratory and expiratory images was +222 (85) HU among cases and +140 (76) HU among controls ( p p = 0.39 by Fisher’s exact test), and on expiratory images in 20 cases and 18 controls ( p > 0.80). Atelectasis was present on inspiratory images in 8 cases and 9 controls and on expiratory images in 9 cases and 10 controls ( p > 0.80). Conclusions Spirometry-assisted CTs had a significantly greater difference in lung density between inspiratory and expiratory scans than those performed with voluntary breath holds, likely improving the ability to detect air trapping. No appreciable difference in image quality was detected for the presence of motion artifact or atelectasis.

Limited data exist on drug resistance and antiretroviral treatment (ART) outcomes in HIV-1-infected children in West Africa. We determined the prevalence of baseline resistance and correlates of virologic failure (VF) in a cohort of ART-naive HIV-1-infected children10 years of age initiating ART in Mali.Reverse transcriptase and protease genes were sequenced at baseline (before ART) and at 6 months. Resistance was defined according to the Stanford HIV Genotypic Resistance database. VF was defined as viral load ≥1000 copies/mL after 6 months of ART. Logistic regression was used to evaluate factors associated with VF or death1 month after enrollment. Post hoc, antiretroviral concentrations were assayed on baseline samples of participants with baseline resistance.One-hundred twenty children with a median age 2.6 years (interquartile range: 1.6-5.0) were included. Eighty-eight percent reported no prevention of mother-to-child transmission exposure. At baseline, 27 (23%), 4 (3%) and none had non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor or protease inhibitor resistance, respectively. Thirty-nine (33%) developed VF and 4 died1 month post-ART initiation. In multivariable analyses, poor adherence [odds ratio (OR): 6.1, P = 0.001], baseline NNRTI resistance among children receiving NNRTI-based ART (OR: 22.9, P0.001) and protease inhibitor-based ART initiation among children without baseline NNRTI resistance (OR: 5.8, P = 0.018) were significantly associated with VF/death. Ten (38%) with baseline resistance had detectable levels of nevirapine or efavirenz at baseline; 7 were currently breastfeeding, but only 2 reported maternal antiretroviral use.Baseline NNRTI resistance was common in children without reported NNRTI exposure and was associated with increased risk of treatment failure. Detectable NNRTI concentrations were present despite few reports of maternal/infant antiretroviral use.

The purpose of the project was to compare the temporal artery thermometer (TAT) to the digital probe thermometer readings at axillary or oral sites, to determine the relative precision and sensitivity of the three methods of thermometry, to compare their readings to core temperature when feasible, and to survey patient and family thermometer preferences.A randomized crossover design in a 70-bed surgical unit over eight months. Two sets of temperature measurements were obtained for each patient: TAT, axillary, oral (depending on patient ability) and a bladder temperature representing core body temperature (when available). Each method was used twice on each patient, to examine within-method precision. Following measurement, patients or caregivers provided their thermometer preference. For younger/nonverbal patients, a professional observer recorded a disruption score. N=298 patients were enrolled RESULTS: TAT was more precise than oral and axillary thermometers (p0.001 vs. axillary, p=0.001 vs. oral). TAT measurements were higher on average than axillary and oral, by 0.7°C and 0.6°C respectively (p0.001). TAT's disruption score for younger patients was 0.6 points lower on average than axillary (p0.001). 84% of patients and families who indicated a clear thermometry preference chose TAT. Only 3 patients had bladder-temperature devices, and therefore accuracy could not be analyzed.TAT is more precise, more fever sensitive, less disruptive to younger children, and more preferred by patients and families.TAT is an acceptable temperature measure that could be substituted for oral or axillary temperature in acute care pediatric settings.

Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 106 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease–negative (MRD−) remission rate for this phase 1 study was 89%. The MRD− remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis. This trial was registered at www.clinicaltrials.gov as #NCT02028455.

To evaluate disease-specific and age-related factors contributing to health-related quality of life (HRQOL). in children with intestinal failure.A prospective study of HRQOL was performed in a regional intestinal rehabilitation program. Parent-proxy Pediatric Quality of Life Inventory surveys were administered annually to families of 91 children with intestinal failure over a 6-year period. Survey data was stratified by age and compared with pediatric HRQOL data in healthy and chronically ill populations. Linear mixed-effect models using multivariable regression were constructed to identify associations with HRQOL.A total of 180 surveys were completed by 91 children and their families. HRQOL scores were lowest for children ages 5-7 years (P .001) and 8-12 years (P .01), and these changes were primarily related to school dimension scores. In multivariable regression, age of 5 years and older and developmental delay were independently associated with lower HRQOL scores. The trend toward lower HRQOL scores parallels reference data from healthy and chronically ill children, although patients with intestinal failure scored lower than both populations at school age.Children with intestinal failure experience lower parent-proxy HRQOL scores in the 5-7 and 8-12 year age groups primarily related to school dimension scores. Multicenter data to validate these findings and identify interventions to improve QOL for children with intestinal failure are needed.

Background Just-in-time (JIT) training refers to education occurring immediately prior to clinical encounters. An in situ JIT room in a pediatric emergency department (ED) was created for procedural education. Objective We examined trainee self-reported JIT room use, its impact on trainee self-perception of procedural competence/confidence, and the effect its usage has on the need for intervention by supervising physicians during procedures. Methods Cross-sectional survey study of a convenience sample of residents rotating through the ED and supervising pediatric emergency medicine physicians. Outcomes included JIT room use, trainee procedural confidence, and frequency of supervisor intervention during procedures. Results Thirty-one of 32 supervising physicians (97%) and 122 of 186 residents (66%) completed the survey, with 71% of trainees reporting improved confidence, and 68% reporting improved procedural skills (P Conclusions Use of the JIT room led to improved trainee confidence and supervisor reports of less procedural intervention. Although it carries financial and time costs, an in situ JIT room may be important for convenient JIT training.

OBJECTIVES Recent advances in medical and surgical management have led to improved long-term survival in children with intestinal failure. Yet, limited data exist on their neurodevelopmental and cognitive outcomes. The aim of the present study was to measure neurodevelopmental outcomes in children with intestinal failure. METHODS Children enrolled in a regional intestinal failure program underwent prospective neurodevelopmental and psychometric evaluation using a validated scoring tool. Cognitive impairment was defined as a mental developmental index

Introduction The lack of specific policies on how many children must be present at a vaccinating location before a healthcare worker can open a measles-containing vaccine (MCV) – i.e. the vial-opening threshold – has led to inconsistent practices, which can have wide-ranging systems effects. Methods Using HERMES-generated simulation models of the routine immunization supply chains of Benin, Mozambique and Niger, we evaluated the impact of different vial-opening thresholds (none, 30% of doses must be used, 60%) and MCV presentations (10-dose, 5-dose) on each supply chain. We linked these outputs to a clinical- and economic-outcomes model which translated the change in vaccine availability to associated infections, medical costs, and DALYs. We calculated the economic impact of each policy from the health system perspective. Results The vial-opening threshold that maximizes vaccine availability while minimizing costs varies between individual countries. In Benin (median session size = 5), implementing a 30% vial-opening threshold and tailoring distribution of 10-dose and 5-dose MCVs to clinics based on session size is the most cost-effective policy, preventing 671 DALYs ($471/DALY averted) compared to baseline (no threshold, 10-dose MCVs). In Niger (median MCV session size = 9), setting a 60% vial-opening threshold and tailoring MCV presentations is the most cost-effective policy, preventing 2897 DALYs ($16.05/ DALY averted). In Mozambique (median session size = 3), setting a 30% vial-opening threshold using 10-dose MCVs is the only beneficial policy compared to baseline, preventing 3081 DALYs ($85.98/DALY averted). Across all three countries, however, a 30% vial-opening threshold using 10-dose MCVs everywhere is the only MCV threshold that consistently benefits each system compared to baseline. Conclusion While the ideal vial-opening threshold policy for MCV varies by supply chain, implementing a 30% vial-opening threshold for 10-dose MCVs benefits each system by improving overall vaccine availability and reducing associated medical costs and DALYs compared to no threshold.

Objective To evaluate whether quantitative metrics of white matter fractional anisotropy (FA) and mean diffusivity (MD) were different in patients presenting to our clinic with persistent symptoms after a concussion. Design Matched control retrospective study. Setting Primary not-for-profit Institution. Patients Consecutive patients seen at a primary care institution's Sports Concussion Clinic for sport-related concussion that underwent diffusion tensor imaging. Interventions (Independent variables): Type of sports, days from Injury, number of symptoms, weeks out when Magnetic Resonance Imaging (MRI) ordered, history of psychological issues, length of symptoms, age, sex, MRI imaging data. Main outcome measure Difference in white matter FA and MD. Results Seventeen concussion patients, ages 9 and 17 (average = 12.5 years; median = 13 years, 11 males and 6 females), were matched with age and gender controls who had an MRI following a complaint of headache. Patients reported an average of 11.5 concussion symptoms, out of a total possible 22 and were seen at an average of 30 days post injury. No region met tract based spatial statistics criteria for significant differences between concussed and healthy control groups (all p > 0.05). Similarly, when comparing group averages from the atlas based regional summaries, no region met the 0.2 false discovery rate (FDR) threshold for significant differences (the smallest unadjusted p-values were 0.02 for MD and 0.14 for FA). Conclusions Our results did not show measurable diffusion tensor imaging (DTI) changes with standard clinical data acquisition and quantitative processing for the individual patient. At this time DTI should not be considered a technique that can diagnose concussion within an individual subject.

OBJECTIVE Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease. An inexpensive and rapid imaging tool, infrared thermal imaging, was evaluated for its utility to detect active bone lesions in extremities of children with CNO. METHODS Children with suspected active CNO and healthy controls were enrolled. All subjects underwent infrared thermal imaging of the lower extremities. Patients in the CNO group also received a magnetic resonance imaging (MRI) examination. Hyperintensity within bone marrow on a fluid-sensitive T2-weighted MRI sequence was considered confirmatory for inflammation. Infrared thermal data were analyzed using custom software by dividing the leg below the knee into 3 equal segments longitudinally and adding the distal femur segment as an equal length above the knee. Median and 95th percentile temperatures were recorded for each leg segment. Temperature differences between inflamed and uninflamed segments in all subjects (both intersubject and intrasubject) were evaluated using a linear mixed-effects model. RESULTS Thirty children in the suspected/known CNO group and 31 healthy children were enrolled. In the healthy control group, males had significantly higher temperature in their lower extremities than females (P < 0.05). There was no difference in temperature detected between inflamed leg segments of patients with CNO versus uninflamed leg segments of the healthy control group. However, within the CNO group, significantly higher temperatures were detected for inflamed versus uninflamed distal tibia/fibula segments (P < 0.01). CONCLUSION Children with active CNO lesions in the distal tibia/fibula exhibited higher regional temperatures on average than healthy extremities. Larger studies are warranted to further evaluate the clinical utility of infrared thermal imaging for CNO detection.

OBJECTIVES: To assess providers’ recommendations as to comfort care versus medical and surgical management in clinical scenarios of newborns with severe bowel loss and to assess how a variety of factors influence providers’ decision making. STUDY DESIGN: We conducted a survey of pediatric surgeons and neonatologists via the American Pediatric Surgical Association and American Academy of Pediatrics Section of Neonatal-Perinatal Medicine. We examined how respondents’ recommendations were affected by a variety of patient and provider factors. RESULTS: 288 neonatologists and 316 pediatric surgeons responded. Irrespective of remaining bowel length, comfort care was recommended by 73% of providers for a premature infant with necrotizing enterocolitis and 54% for a full-term infant with midgut volvulus. Presence of comorbidities and earlier gestational age increased the proportion of providers recommending comfort care. Neonatologists were more likely to recommend comfort care than surgeons across all scenarios (odds ratio 1.45–2.00, P < .05), and this difference was more pronounced with infants born closer to term. In making these recommendations, neonatologists placed more importance on neurodevelopmental outcomes (p90% in infants with intestinal failure, a majority of providers still recommend comfort care in infants with massive bowel loss. Significant differences were identified in clinical decision-making between surgeons and neonatologists. These data reinforce the need for targeted education on long-term outcomes in intestinal failure to neonatal and surgical providers.

Deposition of the complement split product C4d is a phenomenon studied extensively as a marker for complement activation in antibody-mediated transplant rejection. C4d also is observed in placental disease processes including spontaneous abortion, infarct, and villitis of unknown origins. Massive chronic intervillositis is a rare placental abnormality associated with increased risk of growth restriction, fetal death, and recurrent fetal loss. In this study, we evaluated C4d immunostaining in placentas with accumulation of intervillous monocytes with and without villitis. Archived placentas from Kosair Children's Hospital (Louisville, KY) and Seattle Children's Hospital (Seattle, WA) were selected and divided into 4 groups, 16 cases of intervillositis with complicated pregnancy, 15 cases of uncomplicated intervillositis, 20 cases of complicated villitis, and 13 cases of uncomplicated villitis, all with varying degrees of monocytic cells in the intervillous space. Representative specimen blocks were immunohistochemically stained for C4d. The percentage of positive staining of the microvillous surface of the syncytiotrophoblast was scored by five pathologists, and the following consensus score was determined: 0 = 0% to 5%; 1 = 5% to 25%; 2 = 25% to 75%; and 3 ≥ 75%. C4d immunostain localized to the microvillous border of syncytiotrophoblast in many of the placentas. C4d staining was more strongly associated with intervillositis than with villitis (odds ratio: 6.3; confidence interval: 2.1–18.7; P = 0.001).

Background: Cohort studies of the relationship between air pollution exposure and chronic health effects require predictions of exposure over long periods of time. Objectives: We developed a unified modeling approach for predicting fine particulate matter, nitrogen dioxide, oxides of nitrogen, and black carbon (as measured by light absorption coefficient) in six U.S. metropolitan regions from 1999 through early 2012 as part of the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air). Methods: We obtained monitoring data from regulatory networks and supplemented those data with study-specific measurements collected from MESA Air community locations and participants’ homes. In each region, we applied a spatiotemporal model that included a long-term spatial mean, time trends with spatially varying coefficients, and a spatiotemporal residual. The mean structure was derived from a large set of geographic covariates that was reduced using partial least-squares regression. We estimated time trends from observed time series and used spatial smoothing methods to borrow strength between observations. Results: Prediction accuracy was high for most models, with cross-validation R2 (R2CV) > 0.80 at regulatory and fixed sites for most regions and pollutants. At home sites, overall R2CV ranged from 0.45 to 0.92, and temporally adjusted R2CV ranged from 0.23 to 0.92. Conclusions: This novel spatiotemporal modeling approach provides accurate fine-scale predictions in multiple regions for four pollutants. We have generated participant-specific predictions for MESA Air to investigate health effects of long-term air pollution exposures. These successes highlight modeling advances that can be adopted more widely in modern cohort studies. Citation: Keller JP, Olives C, Kim SY, Sheppard L, Sampson PD, Szpiro AA, Oron AP, Lindström J, Vedal S, Kaufman JD. 2015. A unified spatiotemporal modeling approach for predicting concentrations of multiple air pollutants in the Multi-Ethnic Study of Atherosclerosis and Air Pollution. Environ Health Perspect 123:301–309; http://dx.doi.org/10.1289/ehp.1408145

Background: Air pollution is linked to low lung function and to respiratory events, yet little is known of associations with lung structure. Objectives: We examined associations of particulate matter (PM2.5, PM10) and nitrogen oxides (NOx) with percent emphysema-like lung on computed tomography (CT). Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) recruited participants (45–84 years of age) in six U.S. states. Percent emphysema was defined as lung regions < –910 Hounsfield Units on cardiac CT scans acquired following a highly standardized protocol. Spirometry was also conducted on a subset. Individual-level 1- and 20-year average air pollution exposures were estimated using spatiotemporal models that included cohort-specific measurements. Multivariable regression was conducted to adjust for traditional risk factors and study location. Results: Among 6,515 participants, we found evidence of an association between percent emphysema and long-term pollution concentrations in an analysis leveraging between-city exposure contrasts. Higher concentrations of PM2.5 (5 μg/m3) and NOx (25 ppb) over the previous year were associated with 0.6 (95% CI: 0.1, 1.2%) and 0.5 (95% CI: 0.1, 0.9%) higher average percent emphysema, respectively. However, after adjustment for study site the associations were –0.6% (95% CI: –1.5, 0.3%) for PM2.5 and –0.5% (95% CI: –1.1, 0.02%) for NOx. Lower lung function measures (FEV1 and FVC) were associated with higher PM2.5 and NOx levels in 3,791 participants before and after adjustment for study site, though most associations were not statistically significant. Conclusions: Associations between ambient air pollution and percentage of emphysema-like lung were inconclusive in this cross-sectional study, thus longitudinal analyses may better clarify these associations with percent emphysema. Citation: Adar SD, Kaufman JD, Diez-Roux AV, Hoffman EA, D’Souza J, Stukovsky KH, Rich SS, Rotter JI, Guo X, Raffel LJ, Sampson PD, Oron AP, Raghunathan T, Barr RG. 2015. Air pollution and percent emphysema identified by computed tomography in the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect 123:144–151; http://dx.doi.org/10.1289/ehp.1307951

Objective.The validity of our current definitions for clinically inactive disease (CID) in juvenile idiopathic arthritis (JIA) based on physical examination is challenged by the development of advanced musculoskeletal imaging tools. We aimed to prospectively determine the prevalence of abnormal ultrasound (US) findings in children with CID in JIA and their clinical significance.Methods.Children aged ≥ 4 years with CID and a history of arthritis from a single tertiary center were approached over 1 year. Standard US of knees, tibiotalar joints, subtalar joints, and wrists were performed at baseline and at a followup visit. US images were scored by 2 pediatric musculoskeletal radiologists.Results.Forty children with CID were enrolled and followed clinically. The median duration of inactive disease was 1 year. The most common International League of Associations for Rheumatology JIA categories were extended oligoarticular JIA (30%) and rheumatoid factor–negative polyarthritis (38%). At baseline, among a total of 289 joints scanned, 24 joints (8%) had at least 1 abnormal finding in 18 (45%) of 40 subjects. When evaluated at the individual joint level against flares identified during followup exams, these baseline US findings had a sensitivity of 15% and a positive predictive value of 12%. The predictive performance of the second US was even less.Conclusion.Our study demonstrates that nearly half of children with CID had abnormal US findings in 1 of 8 commonly affected joints. These findings did not correlate with subsequent clinical flares in up to 2 years of followup.

BACKGROUND Post-traumatic hydrocephalus (PTH) is a potentially treatable cause of poor recovery from traumatic brain injury (TBI) that remains poorly understood, particularly among children. OBJECTIVE To better understand the risk factors for pediatric PTH using a large, multi-institutional database. METHODS We conducted a retrospective cohort study using administrative data from 42 pediatric hospitals participating in the Pediatric Health Information System. All patients ≤21 yr surviving a hospitalization with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for TBI were identified. The primary outcome was PTH, defined by an ICD-9-CM procedure code for surgical management of hydrocephalus within 6 mo. Data were analyzed using multivariable logistic regression. RESULTS We identified 91 583 patients ≤21 yr with TBI, 846 of whom developed PTH. Odds of PTH were significantly higher in children

The objective of this study is to describe the epidemiology of intestinal carriage with extended-spectrum-cephalosporin-resistant Enterobacteriaceae in children with index infections with these organisms. Patients with resistant Escherichia coli or Klebsiella bacteria isolated from the urine or a normally sterile site between January 2006 and December 2010 were included in this study. Available infection and stool isolates underwent phenotypic and molecular characterization. Clinical data relevant to the infections were collected and analyzed. Overall, 105 patients were identified with 106 extended-spectrum-cephalosporin-resistant E. coli ( n = 92) or Klebsiella ( n = 14) strains isolated from urine or a sterile site. Among the 27 patients who also had stool screening for resistant Enterobacteriaceae , 17 (63%) had intestinal carriage lasting a median of 199 days (range, 62 to 1,576). There were no significant differences in demographic, clinical, and microbiological variables between those with and those without intestinal carriage. Eighteen (17%) patients had 37 subsequent resistant Enterobacteriaceae infections identified: 31 urine and 6 blood. In a multivariable analysis, antibiotic intake in the 91 days prior to subsequent urine culture was significantly associated with subsequent urinary tract infection with a resistant organism (hazard ratio, 14.3; 95% confidence interval [CI], 1.6 to 130.6). Intestinal carriage and reinfection were most commonly due to bacterial strains of the same sequence type and with the same resistance determinants as the index extended-spectrum-cephalosporin-resistant Enterobacteriaceae , but carriage and reinfection with different resistant Enterobacteriaceae strains also occurred.

Background Pediatrics and pediatric nephrology lag behind adult medicine in producing randomized controlled trials (RCTs). Physician attitudes have been shown to play a significant role in RCT enrollment. Methods We surveyed members of the American Society of Pediatric Nephrology regarding beliefs about RCTs and factors influencing decisions to recommend RCT enrollment. Regression analyses were used to identify the effects of variables on an aggregate score summarizing attitudes toward RCTs. Results One hundred thirty replies were received. Sixty-six percent had enrolled patients in RCTs. Respondents in practice for more than 15 years were more likely to have recruited a patient to an RCT than those in practice for less than 5 years. Respondents were more willing to recommend RCT enrollment if the study was multicenter, patients were sicker or had a poorer prognosis, or if the parent or participant received a financial incentive versus the provider. In multiple regression analysis, history of enrolling patients in an RCT was the only significant predictor of higher aggregate RCT-friendly attitude. Conclusions Many pediatric nephrologists have never enrolled a patient in an RCT, particularly those in practice for less than 5 years. Respondents who have not enrolled patients in RCTs have a less RCT-friendly attitude. Provision of improved training and resources might increase participation of junior providers in RCTs.

The development of models that provide accurate spatio-temporal predictions of ambient air pollution at small spatial scales is of great importance for the assessment of potential health effects of air pollution. Here we present a spatio-temporal framework that predicts ambient air pollution by combining data from several different monitoring networks and deterministic air pollution model(s) with geographic information system covariates. The model presented in this paper has been implemented in an R package, SpatioTemporal, available on CRAN. The model is used by the EPA funded Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) to produce estimates of ambient air pollution; MESA Air uses the estimates to investigate the relationship between chronic exposure to air pollution and cardiovascular disease. In this paper we use the model to predict long-term average concentrations of $$\text {NO}_{x}$$ in the Los Angeles area during a 10 year period. Predictions are based on measurements from the EPA Air Quality System, MESA Air specific monitoring, and output from a source dispersion model for traffic related air pollution (Caline3QHCR). Accuracy in predicting long-term average concentrations is evaluated using an elaborate cross-validation setup that accounts for a sparse spatio-temporal sampling pattern in the data, and adjusts for temporal effects. The predictive ability of the model is good with cross-validated $$R^2$$ of approximately $$0.7$$ at subject sites. Replacing four geographic covariate indicators of traffic density with the Caline3QHCR dispersion model output resulted in very similar prediction accuracy from a more parsimonious and more interpretable model. Adding traffic-related geographic covariates to the model that included Caline3QHCR did not further improve the prediction accuracy.

BACKGROUND AND OBJECTIVES:Appendicitis guidelines recommend either narrower- or extended-spectrum antibiotics for treatment of complicated appendicitis. The goal of this study was to compare the effectiveness of extended-spectrum versus narrower-spectrum antibiotics for children with appendicitis.METHODS:We performed a retrospective cohort study of children aged 3 to 18 years discharged between 2011 and 2013 from 23 freestanding children’s hospitals with an appendicitis diagnosis and appendectomy performed. Subjects were classified as having complicated appendicitis if they had a postoperative length of stay ≥3 days, a central venous catheter placed, major or severe illness classification, or ICU admission. The exposure of interest was receipt of systemic extended-spectrum antibiotics (piperacillin ± tazobactam, ticarcillin ± clavulanate, ceftazidime, cefepime, or a carbapenem) on the day of appendectomy or the day after. The primary outcome was 30-day readmission for wound infection or repeat abdominal surgery. Multivariable logistic regression, propensity score weighting, and subgroup analyses were used to control for confounding by indication.RESULTS:Of 24 984 patients, 17 654 (70.7%) had uncomplicated appendicitis and 7330 (29.3%) had complicated appendicitis. Overall, 664 (2.7%) patients experienced the primary outcome, 1.1% among uncomplicated cases and 6.4% among complicated cases (P < .001). Extended-spectrum antibiotic exposure was significantly associated with the primary outcome in complicated (adjusted odds ratio, 1.43 [95% confidence interval, 1.06 to 1.93]), but not uncomplicated, (adjusted odds ratio, 1.32 [95% confidence interval, 0.88 to 1.98]) appendicitis. These odds ratios remained consistent across additional analyses.CONCLUSIONS:Extended-spectrum antibiotics seem to offer no advantage over narrower-spectrum agents for children with surgically managed acute uncomplicated or complicated appendicitis.

Importance Airway management in infants with Robin sequence is challenging. Objective upper airway measures associated with severe airway compromise requiring tracheotomy are needed to guide decision making. Objectives To define objective upper airway measures in infants with Robin sequence from craniofacial computed tomography (CT) and to identify those measures in Robin sequence associated with tracheotomy. Design, Setting, and Participants A cohort study (2003 to 2014, over 1-year follow-up) of 37 infants with Robin sequence evaluated for surgical management and 37 selected age- and sex-matched controls without a craniofacial condition conducted in a pediatric institution’s craniofacial center. Main Outcomes and Measures Define and compare CT-generated upper airway measures in these groups: infants with Robin sequence vs controls, and infants with Robin sequence with vs without tracheotomy. A negative difference signifies lower values for the Robin sequence and tracheotomy groups. Clinical data collected included age and height at time of CT scan, sex, tracheotomy presence, associated syndrome, and laboratory indicators of hypoventilation and hypoxemia. To evaluate interrater reliability, 2 raters performed each measurement in the Robin sequence group. Results In 74 infants, 17 of 28 measures were different between infants with Robin sequence and those in the control group. Tracheotomy was performed in 14 of 37 (38%) infants with Robin sequence. Infants with tracheotomy more commonly had associated syndromes (12 of 14 [86%] vs 11 of 23 [48%]) and a history of hypoventilation and hypoxemia (13 of 14 [93%] vs 15 of 23 [65%]). Five of the 11 measures associated with tracheotomy were reliable and simpler to measure with the following mean differences (95% CIs) between groups: tongue length, 0.87 (0.26 to 1.48); tongue position relative to palate, 0.83 (0.22 to 1.45); mandibular total length, −0.8 (−1.42 to −0.19); gonial angle, 0.71 (0.08 to 1.34); and inferior pogonial angle, 0.66 (0.02 to 1.29). Using a receiver operating characteristic analysis, a composite score of these 5 measures for predicting tracheotomy risk yielded an area under the curve of 0.83 and achieved 86% sensitivity and 74% specificity. Conclusions and Relevance Computed tomography measures quantifying tongue position and mandibular configuration can identify infants with Robin sequence, and importantly, differentiate those who have severe upper airway compromise requiring tracheotomy. Following validation, these measures can be used for objective upper airway assessment and for expediting clinical decision-making in these challenging cases for which no such tools currently exist.

OBJECTIVES:Among patients with food-related anaphylaxis, to describe trends in emergency and hospital care and determine the revisit rate.METHODS:This retrospective cohort study included children 6 months to 18 years of age with food-related anaphylaxis from 37 children’s hospitals between 2007 and 2012. Summary statistics and trends for patient characteristics were evaluated. Multivariable regression was used to identify predictors for hospital admission. Revisit rates to either the emergency department (ED) and/or inpatient unit were calculated.RESULTS:7303 patients were evaluated in the ED; 3652 (50%) were admitted to the hospital. Hospital admission rates varied widely (range, 20%–98%). Food-related anaphylaxis increased from 41 per 100 000 ED visits to 72 per 100 000 while hospital admission rates did not change. Males (odds ratio [OR], 1.2 [95% confidence interval (CI), 1.0–1.4]), patients CONCLUSIONS:The incidence of food-related anaphylaxis in pediatric EDs is increasing, but rates of hospital admission are stable. Hospital admission is common but widely variable. Further research is needed to identify optimal management practices for this potentially life-threatening problem.

BACKGROUND: Epidemiological studies that assess the health effects of long-term exposure to ambient air pollution are used to inform public policy. These studies rely on exposure models that use data collected from pollution monitoring sites to predict exposures at subject locations. Land use regression (LUR) and universal kriging (UK) have been suggested as potential prediction methods. We evaluate these approaches on a dataset including measurements from three seasons in Los Angeles, CA. METHODS: The measurements of gaseous oxides of nitrogen (NOx) used in this study are from a "snapshot" sampling campaign that is part of the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air). The measurements in Los Angeles were collected during three two-week periods in the summer, autumn, and winter, each with about 150 sites. The design included clusters of monitors on either side of busy roads to capture near-field gradients of traffic-related pollution. LUR and UK prediction models were created using geographic information system (GIS)-based covariates. Selection of covariates was based on 10-fold cross-validated (CV) R(2) and root mean square error (RMSE). Since UK requires specialized software, a computationally simpler two-step procedure was also employed to approximate fitting the UK model using readily available regression and GIS software. RESULTS: UK models consistently performed as well as or better than the analogous LUR models. The best CV R(2) values for season-specific UK models predicting log(NOx) were 0.75, 0.72, and 0.74 (CV RMSE 0.20, 0.17, and 0.15) for summer, autumn, and winter, respectively. The best CV R(2) values for season-specific LUR models predicting log(NOx) were 0.74, 0.60, and 0.67 (CV RMSE 0.20, 0.20, and 0.17). The two-stage approximation to UK also performed better than LUR and nearly as well as the full UK model with CV R(2) values 0.75, 0.70, and 0.70 (CV RMSE 0.20, 0.17, and 0.17) for summer, autumn, and winter, respectively. CONCLUSION: High quality LUR and UK prediction models for NOx in Los Angeles were developed for the three seasons based on data collected for MESA Air. In our study, UK consistently outperformed LUR. Similarly, the 2-step approach was more effective than the LUR models, with performance equal to or slightly worse than UK.

With emerging evidence that diesel exhaust exposure poses distinct risks to human health, the need for fine-scale models of diesel exhaust pollutants is growing. We modeled the spatial distribution of several nitrated polycyclic aromatic hydrocarbons (NPAHs) to identify fine-scale gradients in diesel exhaust pollution in two Seattle, WA neighborhoods. Our modeling approach fused land-use regression, meteorological dispersion modeling, and pollutant monitoring from both fixed and mobile platforms. We applied these modeling techniques to concentrations of 1-nitropyrene (1-NP), a highly specific diesel exhaust marker, at the neighborhood scale. We developed models of two additional nitroarenes present in secondary organic aerosol: 2-nitropyrene and 2-nitrofluoranthene. Summer predictors of 1-NP, including distance to railroad, truck emissions, and mobile black carbon measurements, showed a greater specificity to diesel sources than predictors of other NPAHs. Winter sampling results did not yield stable models, likely due to regional mixing of pollutants in turbulent weather conditions. The model of summer 1-NP had an R(2) of 0.87 and cross-validated R(2) of 0.73. The synthesis of high-density sampling and hybrid modeling was successful in predicting diesel exhaust pollution at a very fine scale and identifying clear gradients in NPAH concentrations within urban neighborhoods.

Intestinal neuronal dysplasia type B (IND) denotes an increased proportion of hyperplastic submucosal ganglia, as resolved histochemically in 15-μm-thick frozen sections. IND has been reported proximal to the aganglionic segment in patients with Hirschsprung disease (HSCR) and is putatively associated with a higher rate of postsurgical dysmotility. We developed and validated histological criteria to diagnose IND-like submucosal ganglion cell hyperplasia (IND-SH) in paraffin sections and used the approach to study the incidence and clinical and/or genetic associations of IND-SH at the proximal margins of HSCR pull-through resection specimens. Full-circumference paraffin sections from the proximal margins of 64 HSCR colonic pull-through specimens and 24 autopsy controls were immunostained for neuron-specific Hu antigen, and nucleated ganglion cells in each submucosal ganglion were counted. In controls, an age-related decline in the relative abundance of “giant” ganglia (≥7 nucleated Hu-positive [Hu+] ganglion cells) was observed. A conservative diagnostic threshold for IND-SH (control mean ± 3× standard deviation) was derived from 15 controls less than 25 weeks of age. No control exceeded this threshold, whereas in the same age range, IND-SH was observed at the proximal margins in 15% (7 of 46) of HSCR resections, up to 15 cm proximal to the aganglionic segment. No significant correlation was observed between IND-SH and length of or distance from the aganglionic segment, sex, trisomy 21, RET or SEMA3C/D polymorphisms, or clinical outcome, but analysis of more patients, with better long-term follow-up will be required to clarify the significance of this histological phenotype.

Background. More than 80% of surgical inpatients at US children’s hospitals receive antibiotics, accounting for >40% of all inpatient pediatric antibiotic use. We aimed to examine the collective pool of all systemic antibiotics prescribed to children hospitalized for surgical conditions and identify common surgical conditions with highly variable and potentially unnecessary antibiotic use, because these conditions may represent antimicrobial stewardship priorities. Methods. We conducted a retrospective cross-sectional study of surgical inpatients discharged in 2012 at 37 freestanding children’s hospitals. We captured all systemic antibiotic use as days of therapy (DOT), and we reported surgical conditions by frequency and contribution to overall antibiotic use. We used multivariable logistic and Poisson regression with marginal standardization to estimate (1) the standardized proportion and (2) DOT of condition-specific targeted antibiotic use among top surgical condition patients. Results. Among 151 345 surgical inpatients, 82.9% received antimicrobials for a median 2 DOT per subject (interquartile range, 1–5; range, 1–958). The most commonly received antibiotics were cefazolin (16.7% of all DOT), vancomycin (12.5%), and piperacillin/tazobactam (6.9%). The top 10 conditions contributing most to antibiotic use accounted for 51.3% of all antibiotic use. Among these, adjusted use of postoperative and perioperative vancomycin varied across hospitals among craniotomy and cardiothoracic surgery subjects (all P < .001); adjusted use of broad-spectrum antipseudomonal agents varied across hospitals among gastrointestinal surgery subjects (all P< .001). Conclusions. Use of (1) vancomycin for pediatric cardiothoracic and neurosurgical patients and (2) broadspectrum antipseudomonal agents for gastrointestinal surgery patients represent potentially high-yield targets for stewardship efforts to reduce unnecessary antimicrobial use.

Gastroschisis is a newborn anomaly requiring emergent surgical intervention. We review our experience with gastroschisis to examine trends in contemporary surgical management.Infants who underwent initial surgical management of gastroschisis from 1996 to 2014 at a pediatric hospital were reviewed. Closure techniques included primary fascial repair using suture or sutureless umbilical closure, and staged repair using sutured or spring-loaded silo (SLS). Data were separated into 3 clinical eras: pre-SLS (1996 to 2004), SLS (2005 to 2008), and umbilical closure (2009 to 2014).In the pre-SLS era, 60% (34/57) of infants with gastroschisis underwent primary repair. With the advent of SLS, there was a decrease in primary repair (15%, 10/68, P.0001). Following introduction of sutureless umbilical closure, 61% (47/77) of infants have undergone primary repair. On multivariate regression, primary repair was associated with shorter intensive care unit stays (P .001) and time to initiate enteral nutrition (P.01).Following introduction of a less invasive technique for gastroschisis repair, most infants with gastroschisis were able to be repaired primarily. Primary repair should be considered in all babies with gastroschisis and favorable anatomy.

To examine the effects of Reiki as an adjuvant therapy to opioid therapy for postoperative pain control in pediatric patients.This was a double-blind, randomized controlled study of children undergoing dental procedures. Participants were randomly assigned to receive either Reiki therapy or the control therapy (sham Reiki) preoperatively. Postoperative pain scores, opioid requirements, and side effects were assessed. Family members were also asked about perioperative care satisfaction. Multiple linear regressions were used for analysis.Thirty-eight children participated. The blinding procedure was successful. No statistically significant difference was observed between groups on all outcome measures.Our study provides a successful example of a blinding procedure for Reiki therapy among children in the perioperative period. This study does not support the effectiveness of Reiki as an adjuvant therapy to opioid therapy for postoperative pain control in pediatric patients.

Traffic related air pollution (TRAP) has been associated with increased atherosclerosis, left ventricular mass, myocardial infarction; endothelial dysfunction may mediate these effects. In the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air), an interquartile (25th to 75th

Introduction: Multiply recurrent pre-B-cell ALL, and particularly relapse following allo-HSCT, has dismal outcomes due in large part to ineffectual therapies. The primary objectives of the Phase 1 portion of the PLAT-02 study (NCT02028455) were to determine the feasibility of manufacturing products of defined composition and transgene expression, the safety of the cryopreserved T cell product infusion, and to describe the full toxicity profile, including development of clinically significant GVHD in the post-allo-HSCT cohort. Methods: Subjects on the PLAT-02 study undergo apheresis, with their CD4 and CD8 T cell subsets prepared immunomagnetically. Following anti-CD3xCD28 bead stimulation, T cell lines are transduced with a SIN lentiviral vector that directs the co-expression of the FMC63scFv:IgG4hinge:CD28tm:4-1BB:ζ CAR and the selection/tracking/suicide construct EGFRt. Transduced cells are propagated using recombinant human cytokine cocktails to numbers suitable for clinical use over 10-22 days, during which time they are subjected to EGFRt immunomagnetic positive selection. Shortly following lymphodepleting chemotherapy, cryopreserved CD4/EGFRt+ and CD8/EGFRt+ T cell products are thawed and infused at the bedside such that patients receive a 1:1 ratio of EGFRt+ CD4 and CD8 T cells at the protocol-prescribed dose level. Results: 45 subjects have been enrolled and 43 have been treated from dose level 1 (5 x 105 CAR-T cells/kg) through 4 (10 x 106 CAR-T cells/kg). Therapeutic T cell products were released on all 45 enrolled subjects, with 1 subject requiring a second apheresis. Two subjects died of disease prior to their infusion. All 43 infused subjects received lymphodepletion chemotherapy prior to T cell infusion (cyclophosphamide, n=27; fludarabine/cyclophosphamide; n=14 cyclophosphamide/etoposide n=1; fludarabine n=1,). 91% (39/43) of subjects received infusions at the desired 1:1 CD4:CD8 ratio and their infusions were well tolerated with only 1 related AE >grade 2. 93% (40/43) of subjects had a documented MRD-negative CR within 21 days following CAR-T cell therapy. The 12 month event-free survival (EFS) is 50.8% (95% CI 36.6, 69.9) and 12 month OS is 69.5% (95% CI 55.8, 86.5). All responding subjects exhibited in vivo expansion of CAR-T cells. The % of CAR T cell expansion over time is not impacted by dose level or lymphodepletion but is impacted by disease burden (p=0.004) and total CD19 antigen burden (p=0.001) at the time of lymphodepletion. The median duration of functional CAR-T cell persistence as measured by ongoing B-cell aplasia (BCA) is impacted by the total CD19 antigen burden in the bone marrow at time of lymphodepletion (>15% vs Conclusions: Infusions of defined composition CD4:CD8 CD19 CAR/EGFRt+ T cells/kg produce high rates of MRD-negative CR in pediatric and young adult B-cell ALL patients. Based on intent to treat analyses without a proliferation screen, we have found it is feasible to generate CAR products from each of the enrolled subjects. Despite the high rates of MRD-negative CR, the durability of remission is highly influenced by the functional persistence of CAR-T cells. Strategies to enhance persistence are currently being investigated, including episodic antigen stimulation through subject derived tAPC engineered to express truncated CD19. Disclosures Gardner: Amgen: Honoraria. Li:Juno Therapeutics: Employment, Equity Ownership. Jensen:Juno Therapeutics, Inc: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

3048Background: CD19 CAR-T cell has proven efficacy for treatment of aggressive ALL. However, limited CAR-T cell persistence and/orCD19 loss are barriers to therapeutic success. Methods: A Phase I ...

Exposure to traffic-related air pollution is associated with risk of cardiovascular disease and mortality. We examined whether exposure to diesel exhaust increased blood pressure (BP) in human subjects. We analyzed data from 45 nonsmoking subjects, 18 to 49 years of age in double-blinded, crossover exposure studies, randomized to order. Each subject was exposed to diesel exhaust, maintained at 200 μg/m 3 of fine particulate matter, and filtered air for 120 minutes on days separated by ≥2 weeks. We measured BP pre-exposure, at 30-minute intervals during exposure, and 3, 5, 7, and 24 hours from exposure initiation and analyzed changes from pre-exposure values. Compared with filtered air, systolic BP increased at all of the points measured during and after diesel exhaust exposure; the mean effect peaked between 30 and 60 minutes after exposure initiation (3.8 mm Hg [95% CI: −0.4 to 8.0 mm Hg] and 5.1 mm Hg [95% CI: 0.7–9.5 mm Hg], respectively). Sex and metabolic syndrome did not modify this effect. Combining readings between 30 and 90 minutes, diesel exhaust exposure resulted in a 4.4-mm Hg increase in systolic BP, adjusted for participant characteristics and exposure perception (95% CI: 1.1–7.7 mm Hg; P =0.0009). There was no significant effect on heart rate or diastolic pressure. Diesel exhaust inhalation was associated with a rapid, measurable increase in systolic but not diastolic BP in young nonsmokers, independent of perception of exposure. This controlled trial in humans confirms findings from observational studies. The effect may be important on a population basis given the worldwide prevalence of exposure to traffic-related air pollution.