Publications by authors named "Assaf P Oron"

50 Publications

Covasim: An agent-based model of COVID-19 dynamics and interventions.

PLoS Comput Biol 2021 Jul 26;17(7):e1009149. Epub 2021 Jul 26.

Institute for Disease Modeling, Global Health Division, Bill & Melinda Gates Foundation, Seattle, Washington, United States of America.

The COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim (COVID-19 Agent-based Simulator), an open-source model developed to help address these questions. Covasim includes country-specific demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, long-term care facilities, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing and protective equipment; pharmaceutical interventions, including vaccination; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. Implemented in pure Python, Covasim has been designed with equal emphasis on performance, ease of use, and flexibility: realistic and highly customized scenarios can be run on a standard laptop in under a minute. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine epidemic dynamics and inform policy decisions in more than a dozen countries in Africa, Asia-Pacific, Europe, and North America.
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http://dx.doi.org/10.1371/journal.pcbi.1009149DOI Listing
July 2021

Patterns of child mortality in rural area of Burkina Faso: evidence from the Nanoro health and demographic surveillance system (HDSS).

BMC Public Health 2021 Jul 19;21(1):1425. Epub 2021 Jul 19.

Institute for Disease Modeling, Global Health Division, Bill & Melinda Gates Foundation, 500 5th Ave N, Seattle, WA, 98109, USA.

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 < 20 min from an inpatient facility. No such association was found for outpatient facilities. The wet season (July-November) was associated with 1.28 (95% CI: 1.07, 1.53) higher under-5 mortality than the dry season (December-June), likely reflecting the malaria season.

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.
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http://dx.doi.org/10.1186/s12889-021-11483-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287796PMC
July 2021

Estimating and mitigating the risk of COVID-19 epidemic rebound associated with reopening of international borders in Vietnam: a modelling study.

Lancet Glob Health 2021 07 12;9(7):e916-e924. Epub 2021 Apr 12.

Institute for Disease Modeling, Global Health Division, Bill & Melinda Gates Foundation, Seattle, WA, USA; School of Physics, University of Sydney, Sydney, NSW, Australia.

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.
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http://dx.doi.org/10.1016/S2214-109X(21)00103-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041387PMC
July 2021

Feasibility of Family-Assisted Severity of Illness Monitoring for Hospitalized Children in Low-Income Settings.

Pediatr Crit Care Med 2021 02;22(2):e115-e124

Departments of Global Health, Epidemiology, Infectious Disease, University of Washington, Seattle, WA.

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.
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http://dx.doi.org/10.1097/PCC.0000000000002582DOI Listing
February 2021

The Sickle Cell Disease Ontology: Enabling Collaborative Research and Co-Designing of New Planetary Health Applications.

OMICS 2020 10;24(10):559-567

Department of Public Health Sciences, Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, Illinois, USA.

Sickle cell disease (SCD) is one of the most common blood disorders impacting planetary health. Over 300,000 newborns are diagnosed with SCD each year globally, with an increasing trend. The sickle cell disease ontology (SCDO) is the most comprehensive multidisciplinary SCD knowledge portal. The SCDO was collaboratively developed by the SCDO working group, which includes experts in SCD and data standards from across the globe. This expert review presents highlights and lessons learned from the fourth SCDO workshop that marked the beginning of applications toward planetary health impact, and with an eye to empower and cultivate multisite SCD collaborative research. The workshop was organized by the Sickle Africa Data Coordinating Center (SADaCC) and attended by 44 participants from 14 countries, with 2 participants connecting remotely. Notably, from the standpoint of democratizing and innovating scientific meeting design, an SCD patient advocate also presented at the workshop, giving a broader real-life perspective on patients' aspirations, needs, and challenges. A major component of the workshop was new approaches to harness SCDO to harmonize data elements used by different studies. This was facilitated by a web-based platform onto which participants uploaded data elements from previous or ongoing SCD-relevant research studies before the workshop, making multisite collaborative research studies based on existing SCD data possible, including multisite cohort, SCD global clinical trials, and SCD community engagement approaches. Trainees presented proposals for systematic literature reviews in key SCD research areas. This expert review emphasizes potential and prospects of SCDO-enabled data standards and harmonization to facilitate large-scale global SCD collaborative initiatives. As the fields of public and global health continue to broaden toward planetary health, the SCDO is well poised to play a prominent role to decipher SCD pathophysiology further, and co-design diagnostics and therapeutics innovation in the field.
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http://dx.doi.org/10.1089/omi.2020.0153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549008PMC
October 2020

Caring for Africa's sickle cell children: will we rise to the challenge?

BMC Med 2020 04 28;18(1):92. Epub 2020 Apr 28.

Centre of Excellence for Sickle Cell Disease Research & Training, University of Abuja, Abuja, Nigeria.

Background: Most of the world's sickle cell disease (SCD) burden is in Africa, where it is a major contributor to child morbidity and mortality. Despite the low cost of many preventive SCD interventions, insufficient resources have been allocated, and progress in alleviating the SCD burden has lagged behind other public-health efforts in Africa. The recent announcement of massive new funding for research into curative SCD therapies is encouraging in the long term, but over the next few decades, it is unlikely to help Africa's SCD children substantially.

Main Discussion: A major barrier to progress has been the absence of large-scale early-life screening. Most SCD deaths in Africa probably occur before cases are even diagnosed. In the last few years, novel inexpensive SCD point-of-care test kits have become widely available and have been deployed successfully in African field settings. These kits could potentially enable universal early SCD screening. Other recent developments are the expansion of the pneumococcal conjugate vaccine towards near-universal coverage, and the demonstrated safety, efficacy, and increasing availability and affordability of hydroxyurea across the continent. Most elements of standard healthcare for SCD children that are already proven to work in the West, could and should now be implemented at scale in Africa. National and continental SCD research and care networks in Africa have also made substantial progress, assembling care guidelines and enabling the deployment and scale-up of SCD public-health systems. Substantial logistical, cultural, and awareness barriers remain, but with sufficient financial and political will, similar barriers have already been overcome in efforts to control other diseases in Africa.

Conclusion And Recommendations: Despite remaining challenges, several high-SCD-burden African countries have the political will and infrastructure for the rapid implementation and scale-up of comprehensive SCD childcare programs. A globally funded effort starting with these countries and expanding elsewhere in Africa and to other high-burden countries, including India, could transform the lives of SCD children worldwide and help countries to attain their Sustainable Development Goals. This endeavor would also require ongoing research focused on the unique needs and challenges of SCD patients, and children in particular, in regions of high prevalence.
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http://dx.doi.org/10.1186/s12916-020-01557-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187492PMC
April 2020

Variation in hospital costs for gastroschisis closure techniques.

Am J Surg 2020 05 9;219(5):764-768. Epub 2020 Mar 9.

University of Washington School of Medicine, Seattle, WA, 98195, USA; Seattle Children's Hospital, Seattle, WA, 98105, USA. Electronic address:

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 to 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 < 0.001). In addition, delayed closure was associated with increased total and NICU LOS (p < 0.05), parenteral nutrition duration (p = 0.02), ventilator days (p < 0.001), time to goal enteral feeds (p = 0.01), and all cost sub-categories except ward room costs (p < 0.01).

Conclusion: Delayed fascial closure was associated with significantly greater hospital costs during the index admission.
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http://dx.doi.org/10.1016/j.amjsurg.2020.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728576PMC
May 2020

Factors Associated with Health-Related Quality of Life in Children with Intestinal Failure.

J Pediatr 2020 01 4;216:13-18.e1. Epub 2019 Oct 4.

Seattle Children's Hospital, Seattle, WA; University of Washington School of Medicine, Seattle, WA.

Objective: To evaluate disease-specific and age-related factors contributing to health-related quality of life (HRQOL). in children with intestinal failure.

Study Design: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jpeds.2019.08.049DOI Listing
January 2020

Modeling the economic impact of different vial-opening thresholds for measles-containing vaccines.

Vaccine 2019 04 23;37(17):2356-2368. Epub 2019 Mar 23.

HERMES Logistics Modeling Team, Baltimore, MD & Pittsburgh, PA, United States; Global Obesity Prevention Center (GOPC) at Johns Hopkins University, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.vaccine.2019.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467546PMC
April 2019

Effects of sex and birth weight on non-specific health services use following whole-cell pertussis vaccination: a self-controlled case series analysis.

Hum Vaccin Immunother 2019 5;15(10):2399-2404. Epub 2019 Apr 5.

Clinical Epidemiology Program, Ottawa Hospital Research Institute , Ottawa , Ontario , Canada.

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.
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http://dx.doi.org/10.1080/21645515.2019.1586029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816393PMC
February 2020

Effect Modification by Baseline Mortality in the MORDOR Azithromycin Trial.

Am J Trop Med Hyg 2020 09;103(3):1295-1300

Department of Ophthalmology, University of California, San Francisco, San Francisco, California.

We examined whether baseline mortality risk, as a function of child age and site, modified the azithromycin mortality-reduction effect in the (MORDOR) clinical trial. We used the Cox proportional hazards model with an interaction term. Three models were examined representing three sources for the baseline-risk covariate: two using sources external to MORDOR and the third leveraging data within MORDOR. All three models provided moderate evidence for the effect becoming stronger with increasing baseline mortality ( = 0.02, 0.02, and 0.07, respectively) at the rate of approximately 6-12% additional mortality reduction per doubling of baseline mortality. Etiological and programmatic implications of these findings are discussed.
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http://dx.doi.org/10.4269/ajtmh.18-1004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470539PMC
September 2020

Efficacy of Mass Azithromycin Distribution for Reducing Childhood Mortality Across Geographic Regions.

Am J Trop Med Hyg 2020 09;103(3):1291-1294

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.

Mass azithromycin distribution has been shown to reduce all-cause mortality in preschool children in sub-Saharan Africa. However, substantial heterogeneity in the apparent effect has been noted across geographic settings, suggesting a greater relative benefit in higher mortality settings. Here, we evaluated the relationship between the underlying mortality rate and the efficacy of azithromycin for the prevention of child mortality using data from multiple sites in Ethiopia, Malawi, Niger, and Tanzania. Between regions, we find no strong evidence of effect modification of the efficacy of azithromycin distribution for the prevention of child mortality by the underlying mortality rate ( = 0.12), although a modest effect is consistent with our findings. Higher mortality settings could be prioritized, however, because of the larger number of deaths which could be averted with azithromycin distribution.
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http://dx.doi.org/10.4269/ajtmh.18-1003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470520PMC
September 2020

Comparison of Aberrant Behavior Checklist profiles across Prader-Willi syndrome, Down syndrome, and autism spectrum disorder.

Am J Med Genet A 2018 12 21;176(12):2751-2759. Epub 2018 Dec 21.

Seattle Children's Hospital, Division of Psychiatry, University of Washington, Seattle, Washington.

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.
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http://dx.doi.org/10.1002/ajmg.a.40665DOI Listing
December 2018

A Pilot Study of Infrared Thermal Imaging to Detect Active Bone Lesions in Children With Chronic Nonbacterial Osteomyelitis.

Arthritis Care Res (Hoboken) 2019 11;71(11):1430-1435

Seattle Children's Hospital and University of Washington, Seattle.

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.
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http://dx.doi.org/10.1002/acr.23804DOI Listing
November 2019

Attitudes Surrounding the Management of Neonates with Severe Necrotizing Enterocolitis.

J Pediatr 2018 08 10;199:186-193.e3. Epub 2018 May 10.

Division of Pediatric General and Thoracic Surgery, Seattle Children's Hospital, Seattle, WA.

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: There were 288 neonatologists and 316 pediatric surgeons who 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. The 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 (OR, 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 (P < .001), and surgeons emphasized experience with long-term quality of life (P < .001).

Conclusion: Despite a contemporary survival of >90% 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.
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http://dx.doi.org/10.1016/j.jpeds.2018.03.074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063789PMC
August 2018

Using dynamic treatment regimes to understand erythropoietin-stimulating agent hyporesponsiveness.

Pediatr Nephrol 2018 08 4;33(8):1411-1417. Epub 2018 Apr 4.

Division of Nephrology, Seattle Children's Hospital, Seattle, WA, USA.

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 clinical decision support (CDS) tool that guides the prescription of specific therapies in response to variations in patient states, have been used to guide treatment for chronic illnesses 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 and 12 g/dl. Analyzing this protocol as a DTR, we assessed adherence to the protocol over time measuring how the hyporesponse index (ESA dose/hemoglobin value) changed due to varying levels of adherence.

Results: Eighteen 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.

Conclusions: 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.
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http://dx.doi.org/10.1007/s00467-018-3948-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827568PMC
August 2018

Flares of Disease in Children with Clinically Inactive Juvenile Idiopathic Arthritis Were Not Correlated with Ultrasound Findings.

J Rheumatol 2018 06 1;45(6):851-857. Epub 2018 Apr 1.

From Pediatric Rheumatology, Department of Pediatrics, the Center for Clinical and Translational Research (CCTR), and Pediatric Radiology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.

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.
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http://dx.doi.org/10.3899/jrheum.170681DOI Listing
June 2018

Association of ambient pollution with inhaler use among patients with COPD: a panel study.

Occup Environ Med 2018 05 13;75(5):382-388. Epub 2018 Mar 13.

Veterans Administration Puget Sound Health Care System, Seattle, Washington, USA.

Background: Studies have linked ambient air pollution to chronic obstructive pulmonary disease (COPD) healthcare encounters. However, the association between air quality and rescue medication use is unknown.

Objectives: We assessed the role of air pollution exposure for increased short-acting beta-2-agonist (SABA) use in patients with COPD through use of remote monitoring technology.

Methods: Participants received a portable electronic inhaler sensor to record the date, time and location for SABA use over a 3-month period. Ambient air pollution data and meteorological data were collected from a centrally located federal monitoring station. Mixed-effects Poisson regression was used to examine the association of daily inhaler use with pollutant levels. Four criteria pollutants (PM, PM, O and NO), two particulate matter species (elemental carbon (EC) and organic carbon), estimated coarse fraction of PM (PM) and four multipollutant air quality measures were each examined separately, adjusting for covariates that passed a false discovery rate (FDR) screening.

Results: We enrolled 35 patients with COPD (94.3% male and mean age: 66.5±8.5) with a mean forced expiratory volume in 1 s (FEV) % predicted of 44.9+17.2. Participants had a median of 92 observation days (range 52-109). Participants' average SABA inhaler use ranged from 0.4 to 13.1 puffs/day (median 2.8). Controlling for supplemental oxygen use, long-acting anticholinergic use, modified Medical Research Council Dyspnoea Scale and influenza season, an IQR increase in PM concentration (8.0 µg/m) was associated with a 6.6% increase in daily puffs (95% CI 3.5% to 9.9%; FDR <0.001). NO and EC concentration were also significantly associated with inhaler use (3.9% and 2.9% per IQR increase, respectively).

Conclusions: Exposure to increased ambient air pollution were associated with a significant increase in SABA use for patients with COPD residing in a low-pollution area.
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http://dx.doi.org/10.1136/oemed-2017-104808DOI Listing
May 2018

Comparison of Transplant Waitlist Outcomes for Pediatric Candidates Supported by Ventricular Assist Devices Versus Medical Therapy.

Pediatr Crit Care Med 2018 05;19(5):442-450

Department of Pediatrics, Seattle Children's Hospital, Seattle, WA.

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.
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http://dx.doi.org/10.1097/PCC.0000000000001503DOI Listing
May 2018

Post-Traumatic Hydrocephalus in Children: A Retrospective Study in 42 Pediatric Hospitals Using the Pediatric Health Information System.

Neurosurgery 2018 10;83(4):732-739

Harborview Injury Prevention Research Center, Harborview Medical Center, Seattle, Washington.

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 <1 yr compared to older age groups. A total of 48.7% of PTH cases were victims of abuse (adjusted odds ratio [aOR] 2.62, 95% confidence interval [CI] 2.16-3.18). PTH was more common after craniotomy (aOR 1.60, 95% CI 1.30-1.97). Craniectomy without early cranioplasty was associated with markedly increased odds of PTH (aOR 3.67, 95% CI 2.66-5.07), an effect not seen in those undergoing cranioplasty within 30 d (aOR 1.19, 95% CI 0.75-1.89).

Conclusion: PTH was seen in 0.9% of children who sustained a TBI and was more common in those <1 yr. Severe injury, abuse, and craniectomy with delayed cranioplasty were associated with greatly increased likelihood of PTH. Early cranioplasty in children who require craniectomy may reduce the risk for PTH.
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http://dx.doi.org/10.1093/neuros/nyx470DOI Listing
October 2018

The extent of intestinal failure-associated liver disease in patients referred for intestinal rehabilitation is associated with increased mortality: an analysis of the Pediatric Intestinal Failure Consortium database.

J Pediatr Surg 2018 Jul 5;53(7):1399-1402. Epub 2017 Sep 5.

Seattle Children's Hospital and University of Washington School of Medicine, Seattle, WA.

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 CBili<2 mg/dL, CBili 2-4 mg/dL, and CBili>4 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 CBili <2 mg/dL, respectively, at baseline. All-cause mortality was 23%. On univariate analysis, mortality was associated with CBili 2-4 mg/dL, CBili >4 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.

Level Of Evidence: Treatment Study, Level III.
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http://dx.doi.org/10.1016/j.jpedsurg.2017.08.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837922PMC
July 2018

Precision, Sensitivity and Patient Preference of Non-Invasive Thermometers in a Pediatric Surgical Acute Care Setting.

J Pediatr Nurs 2017 Jul - Aug;35:36-41. Epub 2017 Mar 7.

Seattle Children's Hospital, Seattle, WA, USA; Seattle Children's Research Institute, Seattle, WA, USA.

Purpose: 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.

Design & Methods: 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 (p<0.001 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 (p<0.001). TAT's disruption score for younger patients was 0.6 points lower on average than axillary (p<0.001). 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.

Conclusions: TAT is more precise, more fever sensitive, less disruptive to younger children, and more preferred by patients and families.

Practice Implications: TAT is an acceptable temperature measure that could be substituted for oral or axillary temperature in acute care pediatric settings.
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http://dx.doi.org/10.1016/j.pedn.2017.02.003DOI Listing
May 2018

Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults.

Blood 2017 06 13;129(25):3322-3331. Epub 2017 Apr 13.

Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.

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 10 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.
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http://dx.doi.org/10.1182/blood-2017-02-769208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482103PMC
June 2017

High Rates of Baseline Drug Resistance and Virologic Failure Among ART-naive HIV-infected Children in Mali.

Pediatr Infect Dis J 2017 Nov;36(11):e258-e263

From the *Department of Pediatrics, Division of Infectious Diseases, University of Washington, and †Seattle Children's Hospital, Seattle, Washington; ‡Unité d'Epidémiologie Moléculaire de la Résistance du VIH aux ARV, SEREFO, §University of Sciences, Techniques and Technologies of Bamako, and ¶Department of Pediatrics, University Hospital Gabriel Touré, Bamako, Mali; ‖Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois; **Seattle Children's Research Institute, Children's Core for Biomedical Statistics, Seattle, Washington; ††Department of Virology, Sorbonne Université, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'épidémiologie et de Santé Publique, ‡‡Department of Pharmaco-Toxicology, APHP, Bichat-Claude Bernard Hospital, and §§Paris Diderot University, Sorbonne Paris Cité, IAME, INSERM UMR 1137, Paris, France; and ¶¶Department of Pediatrics, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children's Hospital, Chicago, Illinois.

Background: 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 children <10 years of age initiating ART in Mali.

Methods: 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 death >1 month after enrollment. Post hoc, antiretroviral concentrations were assayed on baseline samples of participants with baseline resistance.

Results: 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 died >1 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, P < 0.001) 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.

Conclusions: 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.
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http://dx.doi.org/10.1097/INF.0000000000001575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5554754PMC
November 2017

Characterization of Inpatient Cystic Fibrosis Pulmonary Exacerbations.

Pediatrics 2017 Feb;139(2)

Divisions of Pulmonary Medicine and Sleep Medicine and.

Background And Objectives: Pulmonary exacerbations lead to significant morbidity and mortality in patients with cystic fibrosis (CF). National consensus guidelines exist, but few studies report current practice in the treatment and monitoring of pulmonary exacerbations. The goal of this study was to characterize consistency and variability in the inpatient management of CF-related pulmonary exacerbations. We focused on the use of guideline-recommended maintenance therapies, antibiotic selection and treatment regimens, use of systemic corticosteroids, and frequency of lung function testing. We hypothesized that significant variability in these treatment practices exists nationally.

Methods: This trial was a retrospective cross-sectional study. It included patients with CF aged ≤18 years hospitalized for pulmonary exacerbations between July 1, 2010, and June 30, 2015, at hospitals within the US Pediatric Health Information System database that are also Cystic Fibrosis Foundation-accredited care centers. One exacerbation per patient was randomly selected over the 5-year study period.

Results: From 38 hospitals, 4827 individual pulmonary exacerbations were examined. Median length of stay was 10.0 days (interquartile range, 6-14.0 days). Significant variation was seen among centers in the use of hypertonic saline (11%-100%), azithromycin (5%-83%), and systemic corticosteroids (3%-61%) and in the frequency of lung function testing. Four different admission antibiotic regimens were used >10% of the time, and the most commonly used admission antibiotic regimen comprised 2 intravenous antibiotics with no additional oral or inhaled antibiotics (29%).

Conclusions: Significant variation exists in the treatment and monitoring of pulmonary exacerbations across Pediatric Health Information System-participating, Cystic Fibrosis Foundation-accredited care centers. Results from this study can inform future research working toward standardized inpatient pulmonary exacerbation management to improve CF care for children and adolescents.
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http://dx.doi.org/10.1542/peds.2016-2642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472380PMC
February 2017

Perceptions on the Impact of a Just-in-Time Room on Trainees and Supervising Physicians in a Pediatric Emergency Department.

J Grad Med Educ 2016 Dec;8(5):754-758

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 ( < .05, +1.4-point average skills improvement on a 5-point Likert scale). Trainees perceived no difference among supervising physicians intervening in procedures with or without JIT room use ( = .30, paired difference -0.0 points). Nearly all supervisors reported improved trainee procedural confidence, and 77% reported improved trainee procedural skills after JIT room use ( < .05, paired difference +1.8 points); 58% of supervisors stated they intervene in procedures without trainee JIT room use, compared with 42% with JIT room use ( < .05, paired difference -0.4 points).

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.
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http://dx.doi.org/10.4300/JGME-D-15-00730.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5180532PMC
December 2016

Extended- Versus Narrower-Spectrum Antibiotics for Appendicitis.

Pediatrics 2016 07;138(1)

Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania;

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.
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http://dx.doi.org/10.1542/peds.2015-4547DOI Listing
July 2016

Upper Airway Computed Tomography Measures and Receipt of Tracheotomy in Infants With Robin Sequence.

JAMA Otolaryngol Head Neck Surg 2016 08;142(8):750-7

Division of Pediatric Otolaryngology, Department of Otolaryngology-Head and Neck Surgery, University of Washington and Seattle Children's, Seattle.

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.
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http://dx.doi.org/10.1001/jamaoto.2016.1010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279067PMC
August 2016

Emergency and Hospital Care for Food-Related Anaphylaxis in Children.

Hosp Pediatr 2016 May;6(5):269-74

Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, Washington; and Center for Clinical & Translational Research, Seattle Children's Research Institute, Seattle, Washington.

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 < 1 year old (OR, 1.8 [95% CI, 1.3-2.5]), those with anaphylaxis to either peanut (OR, 1.2 [95% CI, 1.0-1.5]) or tree nut (OR, 1.7 [95% CI, 1.3-2.1]), and patients with asthma (OR, 7.4 [95% CI, 5.8-9.3]) or a chronic complex condition (OR, 5.2 [95% CI, 3.0-9.0]) were more likely to be admitted to the hospital. The 3-day revisit rate was 3% for patients discharged from the ED and 0.6% for those admitted on the index visit.

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.
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http://dx.doi.org/10.1542/hpeds.2015-0153DOI Listing
May 2016

Intestinal Neuronal Dysplasia-Like Submucosal Ganglion Cell Hyperplasia at the Proximal Margins of Hirschsprung Disease Resections.

Pediatr Dev Pathol 2015 Nov-Dec;18(6):466-76. Epub 2015 Dec 23.

1 Department of Laboratories, Seattle Children's Research Institute, Seattle, WA 98101, USA.

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.
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http://dx.doi.org/10.2350/15-07-1675-OA.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809533PMC
April 2016
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