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Objective To report a more accurate prevalence estimate of late pregnancy nicotine exposures. Study design A cross-sectional study during a 2-month period in 2019. Participants were women delivering in any of the six county maternity hospitals who consented to universal drug testing at the time of delivery as part of routine hospital admission. Results Of 2531 tested samples, 18.7% tested positive for high levels of cotinine indicating primary smoking or other primary use of tobacco products. Together, 33.0% of the study population tested positive for nicotine exposure during late pregnancy compared to vital records which reported 8.2% cigarette smoking during the third trimester of pregnancy and 10.5% cigarette smoking at any time during pregnancy through maternal self-report. Conclusion Captured vital birth smoking measures vastly underreport actual primary exposures to nicotine products. Vital birth data also fail to capture secondhand exposures which constitute a significant proportion of the population.

The objective was to use population-based electronic health records for surveillance of intrauterine exposures to substances of abuse, including opioids, and to monitor changes in exposure rates over time. This retrospective, descriptive analysis utilized geocoded neonatal physician billing records representing intrauterine exposures to substances of abuse detected through universal maternal drug testing. Census tract-level exposure rates were identified among the newborn population of Hamilton County, Ohio between 2014 and 2016. Among 27,896 newborns, the authors detected an intrauterine opioid exposure rate of 37.9 per 1000 infants, with 10.5 per 1000 experiencing severe opioid withdrawal (neonatal abstinence syndrome). Individual data were mapped to 222 US census tracts. Tract-level opioid exposure rates ranged from 0.0 to 607.1 (median: 32.9) per 1000 live births. Secondary use of electronic health record data has potential to aid in intrauterine opioid exposure and other public health surveillance efforts without disrupting clinical workflows or placing an additional burden on limited resources. Surveillance of intrauterine opioid exposures may inform stakeholders and enable targeting of interventions and prevention strategies toward the highest risk populations.

To report a more accurate prevalence estimate of late pregnancy nicotine exposures.A cross-sectional study during a 2-month period in 2019. Participants were women delivering in any of the six county maternity hospitals who consented to universal drug testing at the time of delivery as part of routine hospital admission.Of 2531 tested samples, 18.7% tested positive for high levels of cotinine indicating primary smoking or other primary use of tobacco products. Together, 33.0% of the study population tested positive for nicotine exposure during late pregnancy compared to vital records which reported 8.2% cigarette smoking during the third trimester of pregnancy and 10.5% cigarette smoking at any time during pregnancy through maternal self-report.Captured vital birth smoking measures vastly underreport actual primary exposures to nicotine products. Vital birth data also fail to capture secondhand exposures which constitute a significant proportion of the population.

Rationale: Advances in neonatal critical care have greatly improved the survival of preterm infants, but the long-term complications of prematurity, including bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. Although VEGF (vascular endothelial growth factor) improves lung structure and function in rodent BPD models, severe side effects of VEGF therapy prevent its use in patients with BPD.Objectives: To test whether nanoparticle delivery of proangiogenic transcription factor FOXM1 (forkhead box M1) or FOXF1 (forkhead box F1), both downstream targets of VEGF, can improve lung structure and function after neonatal hyperoxic injury.Methods: Newborn mice were exposed to 75% O2 for the first 7 days of life before being returned to a room air environment. On Postnatal Day 2, polyethylenimine-(5) myristic acid/polyethylene glycol-oleic acid/cholesterol nanoparticles containing nonintegrating expression plasmids with Foxm1 or Foxf1 cDNAs were injected intravenously. The effects of the nanoparticles on lung structure and function were evaluated using confocal microscopy, flow cytometry, and the flexiVent small-animal ventilator.Measurements and Main Results: The nanoparticles efficiently targeted endothelial cells and myofibroblasts in the alveolar region. Nanoparticle delivery of either FOXM1 or FOXF1 did not protect endothelial cells from apoptosis caused by hyperoxia but increased endothelial proliferation and lung angiogenesis after the injury. FOXM1 and FOXF1 improved elastin fiber organization, decreased alveolar simplification, and preserved lung function in mice reaching adulthood.Conclusions: Nanoparticle delivery of FOXM1 or FOXF1 stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury. Delivery of proangiogenic transcription factors has promise as a therapy for BPD in preterm infants.

Background The use of medications to treat respiratory conditions of extreme prematurity is often based upon studies of adults or children over 2 years of age. Little is known about the spectrum of medications used or dosing ranges. To inform the design of future studies, we conducted a prospective analysis of respiratory medication exposure among 832 extremely low gestational age neonates. Methods The prematurity and respiratory outcomes program (PROP) enrolled neonates less than 29-week gestation from 6 centers incorporating 13 clinical sites. We collected recorded daily "respiratory" medications given along with dosing information through 40-week postmenstrual age or neonatal intensive care unit discharge if earlier. Results PROP participants were exposed to a wide range of respiratory medications, often at doses beyond published recommendations. Nearly 50% received caffeine and furosemide beyond published recommendations for cumulative dose. Those who developed bronchopulmonary dysplasia were more likely to receive treatment with respiratory medications. However, more than 30% of PROP subjects that did not develop bronchopulmonary dysplasia also were treated with diuretics, systemic steroids, and other respiratory medications. Conclusion Extremely preterm neonates in PROP were exposed to high doses of medications at levels known to generate significant adverse effects. With limited evidence for efficacy, there is an urgent need for controlled trials in this vulnerable patient population.

Objectives To describe the implementation of the first phase of a regional perinatal data repository and to provide a roadmap for others to navigate technical, privacy, and data governance concerns in implementing similar resources. Methods Our implementation integrated regional physician billing records with maternal and infant electronic health records from an academic delivery hospital. These records, representing births during 2013-2015, constituted a data core supporting linkage to additional ancillary data sets. Measures obtained from pediatric follow-up, urgent care, emergency, and inpatient encounters were linked at the individual level as were measures obtained by home visitors during pre- and postnatal encounters. Residential addresses were geocoded supporting linkage to area-level measures. Results Integrated data contained regional billing records for 69,290 newborns representing approximately 81% of all regional live births and nearly 95% of live births in the region's most populous county. Billing records linked to 7293 infant delivery hospital records and 7107 corresponding maternal hospital records. Manual review demonstrated 100% validity of matches among audited records. Additionally, 2430 home visiting records were linked to the data core as were pediatric primary care, urgent care, emergency department, and inpatient visits representing 42,541 children. More than 99% of the newborn billing records were geocoded and assigned a census tract identifier. Conclusions for Practice Our approach to methodological and regulatory challenges affords opportunities for expansion of systems to integrate electronic health records originating from additional medical centers as well as individual- and area-level linkage to additional data sets relevant to perinatal health.

OBJECTIVES: To measure between-center variation in loop diuretic use for infants developing severe bronchopulmonary dysplasia (BPD) in United States children’s hospitals, and to compare mortality and age at discharge among infants from low versus high use centers. STUDY DESIGN: We performed a retrospective cohort study of preterm infants

Objective To better address barriers arising from missing and unreliable identifiers in neonatal medical records, we evaluated agreement and discordance among traditional and non-traditional linkage fields within a linked neonatal data set. Study Design The retrospective, descriptive analysis represents infants born from 2013–2015. We linked children’s hospital neonatal physician billing records to newborn medical records originating from an academic delivery hospital and evaluated rates of agreement, discordance, and missingness for a set of 12 identifier field pairs used in the linkage algorithm. Result We linked 7,293 of 7,404 physician billing records (98.5%), all of which were deemed valid upon manual review. Linked records contained a mean of 9.1 matching and 1.6 non-matching identifier pairs. Only 4.8% had complete agreement among all 12 identifier pairs. Conclusion Our approach to selection of linkage variables and data formatting preparatory to linkage have generalizability which may inform future neonatal and perinatal record linkage efforts.

Objectives To develop generalizable methods for estimating the economic impact of preterm birth at the community level on initial hospital expenditures, educational attainment and lost earnings as well as to estimate potential savings associated with reductions in preterm birth. Study design The retrospective, population-based analysis used vital statistics and population demographics from Hamilton County, Ohio, USA, in 2012. Methods We adjusted previously reported, mean initial hospital cost estimates (stratified by each week of gestation) to 2012 dollars using national cost-to-charge ratios. Next, we calculated excess costs attributable to prematurity and potential hospital cost savings, which could be realized by prolonging each preterm pregnancy by a single week of gestation. Using reported associations among preterm birth, educational attainment and adult earnings, we developed generalizable formulas to calculate lost academic degrees and lost income estimates attributable to preterm birth. The formulas generated estimates based on local population demographics. Results The annual initial hospital cost associated with 1444 preterm infants was estimated at $93 million. In addition, over 9000 fewer college degrees and over $300 million in lost annual earnings were attributed to local adults who were born preterm. Prolonging each preterm birth by 1 week could potentially reduce initial hospital expenditures by over $25 million. Additional potential savings could be realized as healthier infants attain higher levels of education and earnings as adults. Conclusions The generalizable methods developed for estimating the economic impact of preterm birth at the community level can be used by any community in which vital statistics and population demographics are available. Cost estimates can serve to rally support for local stakeholder investment in developing strategies for preterm birth intervention leading to improved pregnancy outcomes.

Only recently has physical space design become more widely recognized as playing a critical role in delivery of care, with an emerging body of literature on the application of human factors approaches to design and evaluation. This chapter describes the use of human factors approaches to develop and conduct an evaluation of a proposed Neonatal Intensive Care Unit redesign in a Midwestern children's hospital. Methods included observations and knowledge elicitation from stakeholders to characterize their goals, challenges, and needs. This characterization is integral to informing the design of user-centered solutions, including physical space design. We also describe an approach to evaluating the proposed design that yielded actionable recommendations specific to hospital-driven design goals.

Infant mortality rate is generally regarded as a fundamental indicator of population health and is often used to validate public health interventions. Hamilton County, Ohio, has one of the highest rates in the nation. Most deaths that do not occur in the hospital fall under the jurisdiction of a coroner/medical examiner. We reviewed all infant deaths evaluated by the Hamilton County Coroner from 2006 to 2013 in order to identify opportunities for public health interventions. We predicted that the majority of these infant deaths were unintentional, but preventable. The eligible population included live born infants, who died less than one year of age. There were 217 cases of infant deaths during this time frame and 14 primary causes of death identified in this cohort. Sleep related deaths made up the majority of deaths (n = 141, 65%), a mean of 17.6 per year. This analysis identifies unsafe sleep patterns, particularly co-bedding and inappropriate sleep surface, as the most frequent contributing factors. Therefore, the coroner/medical examiner, working with public health and healthcare providers can generate information to drive targeted improvements in the outcome for infants.

Objective Determine association of home visiting with subsequent pregnancy outcomes Study Design Retrospective study of Ohio mothers delivering their first infant from 2007–2009. First, we compared mothers enrolled in home visiting to a matched eligible group. Second, we compared outcomes within home visiting based on program participation (low < 25% of recommended home visits, moderate 25–75%, high 75–100% and very high >100%). Time to subsequent pregnancy within 18 months was evaluated using Cox proportional hazards regression; logistic regression tested the likelihood of subsequent preterm birth. Result Of 1,516 participants, 1,460 were matched 1:1 to a comparison mother (n=2,920). After multivariable adjustment, enrollment was associated with no difference in pregnancy spacing or subsequent preterm birth. Among those enrolled, moderate vs. low participants had reduced risk of repeat pregnancy over 18 months (hazard ratio 0.68, p=0.003). Conclusion Increased pregnancy spacing is observed among women with at least moderate home visiting participation.

The objective of this study is to identify maternal characteristics associated with non-smoking during a subsequent pregnancy after first pregnancy smoking. We conducted a retrospective population-based analysis of Ohio vital birth records from 2007 to 2013. We used logistic regression to calculate adjusted odds ratios with 95% confidence intervals for detection of characteristics associated with non-smoking during a subsequent pregnancy after first pregnancy smoking. Among 75 190 mothers, 75.6% were non-smokers and 13.7% were smokers during both pregnancies. During their first pregnancy, 49.7% of 15 075 smokers quit. Of them, 50.1% remained non-smokers during their subsequent pregnancy. Women who reduced, but continued smoking during their first pregnancy, were more than five times as likely to smoke during their subsequent pregnancy than women who quit (odds ratio (95% confidence interval): 2.85 (2.43 to 3.35) vs 0.55 (0.45 to 0.67)). Interventions targeting complete cessation, rather than reduction in smoking among first-time mothers, may be the most effective at optimizing long-term health benefits.

Objective Despite practice recommendations that all newborns be examined within 3–5 days after discharge, many are not seen within this timeframe. Our objective was to determine the association between care coordination and timing of newborn follow-up. Methods This retrospective study evaluated 6251 newborns from eight maternity hospitals who scheduled a primary care appointment at one of two academic pediatric practices over 3.5 years. Two programs were sequentially implemented: (1) newborn discharge coordination, and (2) primary care intake coordination. Primary outcome was days between discharge and follow-up, dichotomized as ≤ or >5 days. Number of rescheduled appointments and loss to follow-up were also assessed. Adjusted relative risks (RR) and odds ratios (OR) were determined by piecewise generalized linear and logistic regression. Results Among 5943 newborns with a completed visit, 52.9 % were seen within 5 days of discharge (mean 6.7 days). After multivariable adjustment, the pre-exposure period (8 months) demonstrated a downward monthly trend in completing early follow-up (RR 0.93, p

Purpose The purpose of the study was to conduct an individual-level analysis of hospital utilization during the first year of life to test the hypothesis that community material deprivation increases health care utilization. Methods We used a population-based perinatal data repository based on linkage of electronic health records from regional delivery hospitals to subsequent hospital utilization at the region's only dedicated children's hospital. Zero-inflated Poisson and Cox proportional hazards regression models were used to quantify the causal role of a census tract–based deprivation index on the total number, length, and time until hospital utilization during the first year of life. Results After adjusting for any neonatal intensive care unit admission, chronic complex conditions, race and ethnicity, insurance status, birth season, and very low birth weight, we found that a 10% increase in the deprivation index caused a 1.032-fold increase (95% confidence interval (CI), [1.025–1.040]) in post initial hospitalization length of stay, a 1.011-fold increase (95% CI, [1.002–1.021]) in number of post initial hospital encounters, and 1.022-fold increase (95% CI, [1.009–1.035]) in hazard for hospitalization utilization during the first year of life. Conclusions Interventions designed to reduce material deprivation and income inequalities could significantly reduce infant hospital utilization.

The importance of triangulating multiple sources of data in the design of tools, technology, and clinical workspaces has not been explicitly addressed in the applied human factors literature. In this paper, we describe an applied human factors case study in which Cognitive Task Analysis was used to triangulate the needs, goals, and design requirements from various stakeholder groups for the design of a Newborn Intensive Care Unit. To facilitate development of common ground on the design goals, in our interviews, we asked questions about (a) stated design goals to elicit the perspectives of meaning across the user groups and (b) schematic renderings of the proposed space. They served as a way to establish a representative definition of each design goal accounting for the perspectives of all user groups. We found that each role brought a perspective and a level of detail based on his/her role goals and lived experience to the design goals. The goals and tradeoffs illuminated by our approach can only be identified when multiple perspectives are collected. Source triangulation should be pursued as part of standard human factors methods to achieve design and evaluation objectives in the context of complex sociotechnical systems.

Despite prior efforts to develop pregnancy risk prediction models, there remains a lack of evidence to guide implementation in clinical practice. The current aim was to develop and validate a risk tool grounded in social determinants theory for use among at-risk Medicaid patients.This was a retrospective cohort study of 409 women across 17 Cincinnati health centers between September 2013 and April 2014. The primary outcomes included preterm birth, low birth weight, intrauterine fetal demise, and neonatal death. After random allocation into derivation and validation samples, a multivariable model was developed, and a risk scoring system was assessed and validated using area under the receiver operating characteristic curve (AUROC) values.The derived multivariable model (n=263) included: prior preterm birth, interpregnancy interval, late prenatal care, comorbid conditions, history of childhood abuse, substance use, tobacco use, body mass index, race, twin gestation, and short cervical length. Using a weighted risk score, each additional point was associated with an odds ratio of 1.57 for adverse outcomes, p0.001, AUROC=0.79. In the validation sample (n=146), each additional point conferred an odds ratio of 1.20, p=0.03, AUROC=0.63. Using a cutoff of 20% probability for the outcome, sensitivity was 29%, with specificity 82%. Positive and negative predictive values were 22% and 85%, respectively.Risk scoring based on social determinants can discriminate pregnancy risk within a Medicaid population; however, performance is modest and consistent with prior prediction models. Future research is needed to evaluate whether implementation of risk scoring in Medicaid prenatal care programs improves clinical outcomes.

Bronchopulmonary dysplasia (BPD) is the most common respiratory consequence of premature birth and contributes to significant short- and long-term morbidity, mortality and resource utilization. Initially defined as a radiographic, clinical and histopathological entity, the chronic lung disease known as BPD has evolved as obstetrical and neonatal care have improved the survival of lower gestational age infants. Now, definitions based on the need for supplementary oxygen at 28 days and/or 36 weeks provide a useful reference point in the neonatal intensive-care unit (NICU), but are no longer based on histopathological findings, and are neither designed to predict longer term respiratory consequences nor to study the evolution of a multifactorial disease. The aims of this review are to critically examine the evolution of the diagnosis of BPD and the challenges inherent to current classifications. We found that the increasing use of respiratory support strategies that administer ambient air without supplementary oxygen confounds oxygen-based definitions of BPD. Furthermore, lack of reproducible, genetic, biochemical and physiological biomarkers limits the ability to identify an impending BPD for early intervention, quantify disease severity for standardized classification and approaches and reliably predict the long-term outcomes. More comprehensive, multidisciplinary approaches to overcome these challenges involve longitudinal observation of extremely preterm infants, not only those with BPD, using genetic, environmental, physiological and clinical data as well as large databases of patient samples. The Prematurity and Respiratory Outcomes Program (PROP) will provide such a framework to address these challenges through high-resolution characterization of both NICU and post-NICU discharge outcomes.

OBJECTIVE: To determine if daily respiratory status improved more in extremely low gestational age premature infants after diuretic exposure compared with those not exposed in modern neonatal intensive care units (NICU). STUDY DESIGN: The Prematurity and Respiratory Outcomes Program (PROP) was a multi-center observational cohort study of 835 extremely premature infants, gestational ages 23 0/7–28 6/7 weeks, enrolled in the first week of life from 13 U.S. tertiary NICUs. We analyzed the PROP study daily medication and respiratory support records of infants up to 34 weeks postmenstrual age. We determined whether there was a temporal association between administration of diuretics and an acute change in respiratory status in premature infants in the NICU, using an ordered categorical ranking of respiratory status. RESULTS: Infants in the diuretic exposed group of PROP were of lower mean gestational age and lower mean birth weight (p 1) for each day after the initial day of diuretic exposure. CONCLUSIONS: Our analysis did not support the ability of diuretics to substantially improve the extremely premature infant’s respiratory status. Further study of both safety and efficacy of diuretics in this setting are warranted. TRIAL REGISTRATION: Clinicaltrials.gov NCT01435187

OBJECTIVE: To determine patterns of respiratory medications used in neonatal intensive care unit (NICU) graduates. STUDY DESIGN: The Prematurity Respiratory Outcomes Program enrolled 835 babies

To use a large current prospective cohort of infants29 weeks to compare bronchopulmonary dysplasia (BPD) rates in black and white infants.The Prematurity and Respiratory Outcome Program (PROP) enrolled 835 infants born in 2011-2013 at29 weeks of gestation; 728 black or white infants survived to 36 weeks postmenstrual age (PMA). Logistic regression was used to compare BPD outcomes (defined as supplemental oxygen requirement at 36 weeks PMA) between the races, adjusted for gestational age (GA), antenatal steroid use, intubation at birth, and surfactant use at birth.Of 707 black or white infants with available BPD outcomes, BPD was lower in black infants (38% vs 45%), even though they were of significantly lower GA. At every GA, BPD was more common in white infants. The aOR for BPD was 0.60 (95% CI, 0.42-0.85; P = .004) for black infants compared with white infants after adjusting for GA. Despite the lower rate of BPD, black infants had a higher rate of first-year post-prematurity respiratory disease (black, 79%; white, 63%).In this large cohort of recently born preterm infants at29 weeks GA, compared with white infants, black infants had a lower risk of BPD but an increased risk of persistent respiratory morbidity.

We report a study of monitor alarm response conducted in the newly designed Transitional Care Center (TCC) at Cincinnati Children’s Hospital Medical Center. A key component of the new TCC design has been the development and implementation of a Monitor Technician (MT) position. We examined the MT role from a human factors perspective, with particular focus on the MT’s coordination and communication with nurses (RNs) and respiratory therapists (RTs). We conducted observations and Cognitive Task Analysis interviews of MTs, RNs, and RTs. In this paper, we describe the value of the MT’s role and define the challenges associated with the MT’s responsibilities. MTs serve an important support function, but they face challenges in locating RNs/RTs to respond to alarms and at times, may be the only “eyes on” the patients, making training and preparation a critical aspect of the MT’s function. In response to findings, CCHMC has taken a number of steps to improve alarm and alert responses and provide further support to the MT’s role. The current study serves as a demonstration of the principles and methods that human factors can offer to healthcare organizations to support patient safety and quality of care.

To assess the utility of clinical predictors of persistent respiratory morbidity in extremely low gestational age newborns (ELGANs).We enrolled ELGANs (29 weeks' gestation) at ≤7 postnatal days and collected antenatal and neonatal clinical data through 36 weeks' postmenstrual age. We surveyed caregivers at 3, 6, 9, and 12 months' corrected age to identify postdischarge respiratory morbidity, defined as hospitalization, home support (oxygen, tracheostomy, ventilation), medications, or symptoms (cough/wheeze). Infants were classified as having postprematurity respiratory disease (PRD, the primary study outcome) if respiratory morbidity persisted over ≥2 questionnaires. Infants were classified with severe respiratory morbidity if there were multiple hospitalizations, exposure to systemic steroids or pulmonary vasodilators, home oxygen after 3 months or mechanical ventilation, or symptoms despite inhaled corticosteroids. Mixed-effects models generated with data available at 1 day (perinatal) and 36 weeks' postmenstrual age were assessed for predictive accuracy.Of 724 infants (918 ± 234 g, 26.7 ± 1.4 weeks' gestational age) classified for the primary outcome, 68.6% had PRD; 245 of 704 (34.8%) were classified as severe. Male sex, intrauterine growth restriction, maternal smoking, race/ethnicity, intubation at birth, and public insurance were retained in perinatal and 36-week models for both PRD and respiratory morbidity severity. The perinatal model accurately predicted PRD (c-statistic 0.858). Neither the 36-week model nor the addition of bronchopulmonary dysplasia to the perinatal model improved accuracy (0.856, 0.860); c-statistic for BPD alone was 0.907.Both bronchopulmonary dysplasia and perinatal clinical data accurately identify ELGANs at risk for persistent and severe respiratory morbidity at 1 year.ClinicalTrials.gov: NCT01435187.

Objective The objective of this study was to evaluate the potential impact to the U.S. health care system by adopting a novel test that identifies women at risk for spontaneous preterm birth. Methods A decision-analytic model was developed to assess clinical and cost outcomes over a 1-year period. The use of a prognostic test to predict spontaneous preterm birth in a hypothetical population of women reflective of the U.S. population (predictive arm) was compared with the current baseline rate of spontaneous preterm birth and associated infant morbidity and mortality (baseline care arm). Results In a population of 3,528,593 births, our model predicts a 23.5% reduction in infant mortality (8,300 vs. 6,343 deaths) with use of the novel test. The rate of acute conditions at birth decreased from 11.2 to 8.1%; similarly, the rate of developmental disabilities decreased from 13.2 to 11.5%. The rate of spontaneous preterm birth decreased from 9.8 to 9.1%, a reduction of 23,430 preterm births. Direct medical costs savings was $511.7M (− 2.1%) in the first year of life. Discussion The use of a prognostic test for reducing spontaneous preterm birth is a dominant strategy that could reduce costs and improve outcomes. More research is needed once such a test is available to determine if these results are borne out upon real-world use.

Objectives Assess the influence of maternal race on the association between interpregnancy interval (IPI) and risk of small for gestational age (SGA) and large for gestational age (LGA) births. Methods Statewide population-based cohort study of 380,520 singleton births. We calculated risk of SGA and LGA births following IPIs of 0 to

Introduction Infant mortality rate is a sensitive metric for population health and well-being. Challenges in achieving accurate reporting of these data can lead to inaccurate targeting of public health interventions. We analyzed a cohort from a pediatric tertiary care referral medical center to evaluate concordance between autopsy cause of death (COD) and death certificate documentation for infants

Structural Aspects of Prenatal and Postnatal Development and Growth of the Lung Respiratory Epithelial Cell Gene Transcription Role of Transcription Factors in the Development of the Pulmonary Epithelium Epithelial-Mesenchymal Interactions in Lung Development Differentiation of the Alveolar Epithelium in the Fetal Lung Airway Gland Growth and Differentiation Clara Cells Growth and Differentiation of Tracheobronchial Epithelial Cells Development of Innervation in the Lung Development of Airway Smooth Muscle Laminin in Lung Development Collagens and Elastic Fiber Proteins in Lung Development Cell-Cell and Cell-Matrix Interactions in Development of the Lung Vasculature Neuropeptides and Lung Development Developmental and Hormonal Regulation of the Surfactant System Lung Injury When Development is Interrupted by Premature Birth In Vitro Models of Lung Development and Cytodifferentiation Hormonal Control of Compensatory Lung Growth

In this systematic review, the authors summarize the current evidence in the literature regarding diagnosis, treatment, and long-term outcomes in neonates with tongue-based airway obstruction (TBAO) and assess the level of evidence of included studies.The terms Pierre Robin syndrome/sequence, micrognathia, retrognathia, and cleft palate were combined with airway obstruction, treatment, tongue-lip plication, and osteogenesis distraction to perform an Ovid literature search, yielding 341 references. The authors excluded references containing patients with isolated choanal/nasal obstruction, patients older than 12 months, and expert opinion papers, yielding 126 articles.The authors searched 3 electronic databases and reference lists of existing reviews from 1980 to October 2010 for articles pertaining to the diagnosis, treatment, and outcomes of TBAO. Reviewers assigned a level of evidence score based on Oxford's Centre for Evidence Based Medicine scoring system and recorded relevant information.Most studies were case studies and single-center findings. The lack of standardization of diagnostic and treatment protocols and the heterogeneity of cohorts both within and between studies precluded a meta-analysis. There was little evidence beyond expert opinion and single-center evaluation regarding diagnosis, treatment, and long-term outcomes of neonates with TBAO.The variability in the phenotype of the cohorts studied and the absence of standardized indications for intervention preclude deriving any definitive conclusions regarding diagnostic tools to evaluate this patient population, treatment choices, or long-term outcomes. A coordinated multicenter study with a standardized diagnostic and treatment algorithm is recommended to develop evidence for the diagnosis and treatment of neonates with TBAO.

To develop a specific, targeted intervention strategy for reducing preterm birth through use of geographic analysis. We utilized Hamilton County, Ohio vital records and Census data from 2003 to 2006. Spatial scanning statistics allowed determination of the prevalence of preterm birth for any geographical point. Attributable risk calculations demonstrated heterogeneity of risk factors within areas of high or low preterm birth prevalence. Three geographically separate areas with high preterm birth proportions (>16%) had differing primary risk factors for preterm birth, including short interpregnancy interval, previous preterm birth, and low prepregnancy weight, despite similarities in demographics and physical location. Primary risk factors also differed when comparing areas with high and low preterm birth proportions, with diabetes and smoking having primary associations in the lower risk areas. Each local region of high preterm birth proportion as well as those with average or low proportion displayed distinct hierarchies of attributable risk. The heterogeneous distribution of preterm birth proportion within an urban county is complex and requires location specific analysis to develop targeted interventions.

The pulmonary lymphatic vasculature plays a vital role in maintaining fluid homeostasis required for efficient gas exchange at capillary alveolar barriers and contributes to lung fluid clearance at birth. To further understanding of pulmonary lymphatic function at birth, lineage-tracing analysis of mouse lung was used. Lineage analysis confirmed that lymphatic endothelial cells (LEC) bud from extrapulmonary lymphatics and demonstrated that LEC migrate into developing lung along precise pathways. LEC cluster first in the primary bronchovascular region then along the secondary broncho-arterial regions and along veins. Small lymphatic vessels in distal lung develop from LEC that have migrated into lung mesenchyme from the extrapulmonary lymphatics. Finally, proximal and distal lymphatics remodel to form vessels with lumens in stereotypical locations. Loss of function analysis with lung-specific expression of a secreted form of the extracellular domain of vascular endothelial growth factor receptor-3 (dnR3) caused significant embryonic pulmonary lymphatic hypoplasia with fourfold reduction in distal LEC. Lung-specific expression of dnR3 did not affect blood vascular development, overall lung organogenesis or lymphatic development in other organs. Neonatal mice with pulmonary lymphatic hypoplasia developed respiratory distress with significantly increased mortality. During the transition to air breathing, lymphatic hypoplasia adversely affected fetal lung fluid clearance as determined by wet/dry weight analysis and morphometric analysis of bronchovascular cuffing and mesenchymal thickening. Surfactant synthesis was unaffected. Together, these data demonstrate that lung lymphatics develop autonomously and that pulmonary lymphatic hypoplasia is detrimental to survival of the neonate due to impaired lung fluid clearance.

NFATc1 transcription factor is critical for lineage selection in T-cell differentiation, cardiac valve morphogenesis and osteoclastogenesis. We identified a role for calcineurin-NFAT signaling in lymphatic development and patterning. NFATc1 was colocalized with lymphatic markers Prox-1, VEGFR-3 and podoplanin on cardinal vein as lymphatic endothelial cells (LEC) are specified and as they segregate into lymph sacs and mature lymphatics. In NFATc1 null mice, Prox-1, VEGFR-3 and podoplanin positive endothelial cells sprouted from the cardinal vein at E11.5, but poorly coalesced into lymph sacs. NFAT activation requires the phosphatase calcineurin. Embryos treated in utero with the calcineurin inhibitor cyclosporine-A showed cytoplasmic NFATc1, diminished podoplanin and FGFR-3 expression by the lymphatics and irregular patterning of the LEC sprouts coming off the jugular lymph sac, which suggests a role for calcineurin-NFAT signaling in lymphatic patterning. In a murine model of injury-induced lymphangiogenesis, NFATc1 was expressed on the neolymphatics induced by lung-specific overexpression of VEGF-A. Mice lacking the calcineurin Abeta regulatory subunit, with diminished nuclear NFAT, failed to respond to VEGF-A with increased lymphangiogenesis. In vitro, endogenous and VEGF-A-induced VEGFR-3 and podoplanin expression by human microvascular endothelial cells was reduced by siRNA to NFATc1, to levels comparable to reductions seen with siRNA to Prox-1. In reporter assays, NFATc1 activated lymphatic specific gene promoters. These results demonstrate the role of calcineurin-NFAT pathway in lymphangiogenesis and suggest that NFATc1 is the principle NFAT involved.

Background With improved survival rates, short- and long-term respiratory complications of premature birth are increasing, adding significantly to financial and health burdens in the United States. In response, in May 2010, the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) funded a 5-year $18.5 million research initiative to ultimately improve strategies for managing the respiratory complications of preterm and low birth weight infants. Using a collaborative, multi-disciplinary structure, the resulting Prematurity and Respiratory Outcomes Program (PROP) seeks to understand factors that correlate with future risk for respiratory morbidity. Methods/Design The PROP is an observational prospective cohort study performed by a consortium of six clinical centers (incorporating tertiary neonatal intensive care units [NICU] at 13 sites) and a data-coordinating center working in collaboration with the NHLBI. Each clinical center contributes subjects to the study, enrolling infants with gestational ages 23 0/7 to 28 6/7 weeks with an anticipated target of 750 survivors at 36 weeks post-menstrual age. In addition, each center brings specific areas of scientific focus to the Program. The primary study hypothesis is that in survivors of extreme prematurity specific biologic, physiologic and clinical data predicts respiratory morbidity between discharge and 1 year corrected age. Analytic statistical methodology includes model-based and non-model-based analyses, descriptive analyses and generalized linear mixed models. Discussion PROP incorporates aspects of NICU care to develop objective biomarkers and outcome measures of respiratory morbidity in the

Understanding the basic processes of late-stage pulmonary vascular development is essential as this period corresponds to the stage when preterm infants have increased chance of survival. During this period, refinement of the gas exchange unit leads to close apposition of the capillary vasculature and airway epithelium through thinning of the mesenchyme, formation of alveolar septae and functional adaptation of endothelial cells into vessels including pulmonary lymphatics. The pulmonary lymphatic network promotes efficient gas exchange through maintaining interstitial fluid balance. Through conditional transgene regulation, we found that a modest, pathologically relevant increase in vascular endothelial growth factor A (VEGF-A) in distal lung during only the perinatal period adversely affected final refinement of the gas exchange unit. VEGF-A induction disrupted the established vascular network, increased endothelial cell number, altered endothelial ultrastructure and reduced mesenchymal thinning. In addition, VEGF-A induction caused a 3-fold increase in small vessels identified as lymphatics in distal lung. mRNA levels of lymphangiogenic factors VEGF-D/-C were unchanged, while levels of the cognate receptor VEGFR-3 increased. The responses to VEGF-A induction in the perinatal period differ from those during early lung development when endothelial migration, but not proliferation altered initial vascular patterning (Akeson, A.L., Greenberg, J.M., Cameron, J.E., Thompson, F.Y., Brooks, S.K., Wiginton, D., Whitsett, J.A., 2003. Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung. Dev. Biol. 264, 443-455). The late-stage response resembles that of adult lung to VEGF-inducing stimuli including injury and disease. These data suggest that VEGF-A influences the balance between development of blood and lymphatic vasculature during lung organogenesis.

Pulmonary vascular development requires precise temporal and spatial expression of vascular endothelial growth factor-A (VEGF-A). Diminished expression of VEGF-A in preterm infants may contribute to the pathophysiology of respiratory distress syndrome. Because exogenous replacement of VEGF-A has been proposed as a therapeutic for respiratory distress syndrome, we used conditional activation of VEGF-A in bronchial epithelial cells to assess the effects of increase of VEGF-A on lung morphogenesis and survival in the developing mouse. Increased expression of VEGF-A in late stages of gestation was lethal at birth. Although born alive, the pups remained cyanotic and failed to establish respiration. Vascular and epithelial morphology of the main bronchus and primary and secondary bronchi were altered with neovascularization of the mucosal folds and partial obstruction of the conducting airways. Erythrocytes were observed in the pulmonary interstitium and in intra-alveolar spaces, indicating vascular leak. Increased diameter of pulmonary arteries and angioectatic structures were observed in VEGF-expressing mice. Bronchial expression of VEGF-A alters late-stage morphogenesis of conducting airways and primary bronchial arteries and causes respiratory failure at birth.

Mammalian lung development is mediated through complex interactions between foregut endoderm and surrounding mesenchyme. As airway branching progresses, the mesenchyme undergoes dramatic remodeling and differentiation. Little is understood about the mechanisms that direct mesenchymal organization during lung development. A screen for candidate genes mediating this process identified Slit, a ligand for the Roundabout (Robo) receptor previously associated with guidance of axonal projections during central nervous system development. Here, we demonstrate by in situ hybridization that two Slit genes (Slit-2 and Slit-3) and two Robo genes (Robo-1 and Robo-2) are expressed in fetal lung mesenchyme. Slit-2 and Robo-1 expression is present throughout mesenchyme at midgestation and is not detectable by newborn day 1. Slit-3 and Robo-2 expression is restricted to specific, complementary subsets of mesenchyme. Robo-2 is expressed in mesenchymal cells immediately adjacent to large airways, whereas Slit-3 expression predominates in mesenchyme remote from airway epithelium. The temporal and spatial distribution of Slit and Robo mRNAs indicate that these genes may direct the functional organization and differentiation of fetal lung mesenchyme.

Vascular endothelial growth factor-A (VEGF-A) is required for vascular development throughout the embryo and has been proposed to play an important role in pulmonary vascular patterning. Expressed by the embryonic respiratory epithelium, VEGF-A signals endothelial cells within the splanchnic mesenchyme. To refine understanding of the spatial and temporal role of VEGF-A in lung morphogenesis, isoform VEGF164 was expressed under conditional control in distal and proximal airway epithelial cells. Unexpectedly, increased expression of VEGF164 in distal lung disrupted peripheral vascular net assembly and arrested branching of airways tubules without altering endothelial cell proliferation or apoptosis. Peripheral airway branching and vascular smooth muscle patterning were also altered. In contrast, expression of VEGF164 by epithelial cells of the conducting airways caused atypical evaginations of small capillary-like vessels into large airways but did not alter peripheral vascular net assembly or branching morphogenesis. These data demonstrate that the differential response of endothelial cells in distal vascular beds and large central blood vessels is established early in lung development. Precise temporal and spatial expression of VEGF-A is required for vascular patterning during lung morphogenesis. Disruption of pulmonary vascular assembly perturbs reciprocal interactions with epithelium leading to altered airway branching morphogenesis.

In this paper we examine new ''phase-field'' models with semi-diffuse interfaces. These models have the property that the -1/+1 planar phase transitions take place over a finite interval. The models also support multiple interface solutions with interfaces centered at arbitrary points L{sub 1} < L{sub 2} < ... < L{sub N}. These solutions correspond to local minima of an entropy functional rather than saddle points and are dynamically stable. The classical models have no such exact solutions but they do support solutions with N equally spaced transition points where the order parameter transitions between valves p{sub min}(N) and p{sub max}(N) satisfying -1 < p{sub min}(N) < 0 < p{sub max} (N) < 1. These solutions of the classical model are saddle points of the entropy functional associated with those models and are not dynamically stable.

We present a new model for traffic on a multilane freeway (with n lanes). Our basic descriptors are the car density $\rho$ (in cars/mile), taken across all lanes in the freeway, and the average car velocity u (in miles/hour). The flux of cars across all lanes is given by $\rho u = {\sum^n_{i=1}}\rho_i u_i$, where $\rho_i$ is the car density in the ith lane, and ui the velocity of cars in the ith lane. We shall track only $\rho$ and u and not what is going on in each individual lane. On such multilane freeways, one often observes distinct stable equilibrium relationships between car velocity and density. Prototypical situations involve two equilibria, $$ v=v_1(\rho) > v = v_2 (\rho), \ \ \ 0 \leq \rho < \rho_{\rm max,} where $v_1(\cdot)$ and $v_2(\cdot)$ are monotone decreasing and satisfy $v_1 (\rho_{\rm max})=v_2(\rho_{\rm max})=0$. The upper curve is typically stable for densities satisfying $0 \leq \rho \leq \rho_1$, whereas the lower curve is stable for densities satisfying $ \rho_2 \leq \rho \leq \rh...

The lung has specific vascular patterning requirements for effective gas exchange at birth, including alignment of airways and blood vessels and lymphatic vessels. Vascular endothelial growth factors (VEGF) are potent effectors of vascular development. We examined the temporal and spatial expression of VEGF-D and specific VEGF-A isoforms at each stage of lung development. VEGF-D, expressed only by cadherin-11-positive cells of the mesenchyme, is first detected at embryonic day (E) 13.5, a period of active vasculogenesis. VEGFR-3, its cognate receptor, is detected earlier on days E11.5 to E14.5, in both blood vessels and lymphatic vessels and later, on day E17.5, in only lymphatic vessels. VEGF-A is expressed in the mesenchyme throughout lung development and also by the epithelium midway through organogenesis. Before E14, the predominant forms of VEGF-A are the soluble isoforms, VEGF-A120 and 164. Not until E14.5 do epithelial cells at the tips of expanding airways express VEGF-A, including VEGF-A188, an isoform with high affinity for extracellular matrix. Our results demonstrate unique temporal and spatial expression of VEGF-D and specific VEGF-A isoforms during lung development and suggest these related factors have distinct functions in vascular and lymphatic patterning of the lung.

In a recent paper Aw and Rascle [SIAM J. Appl. Math., 60 (2000), pp. 916--938] introduced a new model of traffic on a uni-directional highway. Here the author studies an extension of this model, one which accounts for drivers attempting to travel at the maximum allowable speed. The author looks at a Lagrangian reformulation of this problem, a formulation that leads to an effective computational algorithm for solving the resulting system.

Objective: The goal of this study was to evaluate risk factors for readmission among late-preterm (34–36 weeks’ gestation) infants in clinical practice. Methods: This was a retrospective, matched case-control study of late-preterm infants receiving care across 8 regional hospitals in 2009 in the United States. Those readmitted within 28 days of birth were matched to non-readmitted infants at a ratio of 1:3 according to birth hospital, birth month, and gestational age. Step-wise modeling with likelihood ratio tests were used to develop a multivariable logistic regression model. A subgroup analysis of hyperbilirubinemia readmissions was also performed. Results: Of 1861 late-preterm infants delivered during the study period, 67 (3.6%) were readmitted within 28 days of birth. These were matched to 201 control infants, for a final sample of 268 infants. In multivariable regression, each additional day in length of stay was associated with a significantly reduced odds ratio (OR) for readmission (0.57, P = .004); however, for those infants delivered vaginally, there was no significant association between length of stay and readmission (adjusted OR: 1.08, P = .16). A stronger inverse relationship was observed in subgroup analysis for hyperbilirubinemia readmissions, with the adjusted OR associated with increased length of stay 0.40 (P = .002) for infants born by cesarean delivery but 1.14 (P = .27) for those delivered vaginally. Conclusions: Infants born via cesarean delivery with longer length of hospital stay have a decreased risk for readmission. As hospitals implement protocols to standardize length of stay, mode of delivery may be a useful factor to identify late-preterm infants at higher risk for readmission.

Objective To evaluate the efficacy of a universal maternal drug testing protocol for all mothers in a community hospital setting that experienced a 3-fold increase in neonatal abstinence syndrome (NAS) over the previous 5 years. Study design We conducted a retrospective cohort study between May 2012 and November 2013 after the implementation of universal maternal urine drug testing. All subjects with positive urine tests were reviewed to identify a history or suspicion of drug use, insufficient prenatal care, placental abruption, sexually transmitted disease, or admission from a justice center, which would have prompted urine testing using our previous risk-based screening guidelines. We also reviewed the records of infants born to mothers with a positive toxicology for opioids to determine whether admission to the special care nursery was required. Results Out of the 2956 maternal specimens, 159 (5.4%) positive results were recorded. Of these, 96 were positive for opioids, representing 3.2% of all maternity admissions. Nineteen of the 96 (20%) opioid-positive urine tests were recorded in mothers without screening risk factors. Seven of these 19 infants (37%) required admission to the special care nursery for worsening signs of NAS, and 1 of these 7 required pharmacologic treatment. Conclusion Universal maternal drug testing improves the identification of infants at risk for the development of NAS. Traditional screening methods underestimate in utero opioid exposure.

In this paper we focus on melting and solidification processes described by phase-field models and obtain rigorous estimates for such processes. These estimates are derived in Section 2 and guarantee the convergence of solutions to non-constant equilibrium patterns. The most basic results conclude with the inequality (2.31). The estimates in the remainder of Section 2 illustrate what obtains if the initial data is progressively more regular and may be omitted on first reading. We also present some interesting numerical simulations which demonstrate the equilibrium structures and the approach of the system to non-constant equilibrium patterns. The novel feature of these calculations is the linking of the small parameter in the system, {delta}, to the grid spacing, thereby producing solutions with approximate sharp interfaces. Similar ideas have been used by Caginalp and Sokolovsky [1]. A movie of these simulations may be found at http:www.math.cmu.edu/math/people/greenberg.html.

During development, the lung mesenchyme has a dynamic relationship with the branching airway. Embryonic lung mesenchyme is loosely packed and composed of indistinguishable cells, yet it is the source of vascular progenitors that will become endothelial cells, smooth muscle cells and fibroblasts. In the lung, vessel development in the periphery proceeds first through vasculogenesis, the migration and assembly of cells into a primitive network, and subsequently, through angiogenesis, the sprouting of vessels from this network. As a way to assess the cellular and molecular mechanisms of lung vascularization, we have isolated and cloned cell lines from mouse fetal lung mesenchyme (MFLM). Two of these MFLM cell lines, MFLM-4 and MFLM-91U, display characteristics of an endothelial lineage. RNA analysis demonstrates transcripts for the vascular endothelial growth factor receptors R1 and R2, the receptor tyrosine kinases, Tie-1 and Tie-2, as well as the Tie-2 ligands, Ang-1 and -2. The MFLM cell lines form extensive networks of capillary-like structures with lumens when cultured on a reconstituted basement membrane. In vivo, following blastocyst injection, the MFLM cells chimerize endothelium of the lung and areas of the heart vasculature. The results from these studies suggest that MFLM-4 and MFLM-91U, derived from embryonic lung mesenchyme, can function in vitro and in vivo as endothelial precursors and as models of cardiopulmonary vascularization. Dev Dyn 2000;217:11-23.

This paper presents a new model for the ferroelectric behavior of materials. The usual Maxwell’s equations are supplemented with a constitutive relation in which the electric displacement equals a constant times the electric field plus an internal polarization variable. The latter evolves according to an internal set of Maxwell equations. This model is suggested by one presented by one of the authors for elastic behavior with phase change. The model admits hysteretic behavior. The asymptotic behavior with respect to time is studied and it is shown that the system tends to a steady state in which the polarization is governed by a nonlinear elliptic equation. It is shown that this equation has multiple solutions which correspond to microstructure.

Using vital records and census data representing 165,136 singleton births from 2003–2006, geospatial filtering and density estimates enabled the calculation of preterm birth rates at each geographical point within three urban Ohio counties. Adjusted attributable risk calculations were used to identify risk factors associated with regions of high and low rates of preterm birth. Among the three counties, affected populations varied in size as well as in demographic composition. Variation in the risk factors from one region to another suggests that a single one size fits all intervention strategy would be unlikely to efficiently or effectively impact the complex preterm birth problem. Although more useful in areas with a heterogeneous distribution of preterm birth, application of the presented approach supports the development of efficient community-level health intervention strategies by identifying communities with the highest potential impact and allowing for the prioritization of efforts on specific risk factors within those communities.

T-cell acute lymphoblastic leukemia (T-ALL) is a relatively uncommon disease, constituting only approximately 15% of newly diagnosed acute lymphoblastic leukemias (ALL) in the United States, or roughly 300 cases per year. Outside of the United States, in countries such as Egypt and India, T-ALL may represent as much as 50% of all ALL's but still remains an overall rare disease. The clinical importance of T-ALL lies in its poor responsiveness to therapy that has proved highly effective with standard B-cell precursor ALL (BCP-ALL). The scientific importance of human T-ALL has resided in its role as a cancer prototype, permitting the identification of novel genes centrally involved in both neoplastic change and normal cellular differentiation. One of these genes, SCL/tal, has received significant attention due to its intimate involvement in T-ALL, as well as in normal hematopoiesis. Although a tremendous amount has been recently discovered about SCL/tal, its exact roles in leukemogenesis and normal hematopoiesis remain obscure.