Vitamin C Supplementation Among Pregnant Smokers and Airway Function Trajectory in Offspring: A Secondary Analysis of a Randomized Clinical Trial.

This secondary analysis of a randomized clinical trial analyzes the association of vitamin C supplementation in women who smoked during pregnancy with airway function trajectory in their offspring at 4 to 6 years of age.

Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age.

BACKGROUND: We previously reported in the "Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function" randomized clinical trial (RCT) that vitamin C (500 mg/day) supplementation to pregnant smokers is associated with improved respiratory outcomes that persist through 5 years of age. The objective of this study was to assess whether buccal cell DNA methylation (DNAm), as a surrogate for airway epithelium, is associated with vitamin C supplementation, improved lung function, and decreased occurrence of wheeze. METHODS: We conducted epigenome-wide association studies (EWAS) using Infinium MethylationEPIC arrays and buccal DNAm from 158 subjects (80 placebo; 78 vitamin C) with pulmonary function testing (PFT) performed at the 5-year visit. EWAS were performed on (1) vitamin C treatment, (2) forced expiratory flow between 25 and 75% of expired volume (FEF25-75), and (3) offspring wheeze. Models were adjusted for sex, race, study site, gestational age at randomization (≤ OR > 18 weeks), proportion of epithelial cells, and latent covariates in addition to child length at PFT in EWAS for FEF25-75. We considered FDR p < 0.05 as genome-wide significant and nominal p < 0.001 as candidates for downstream analyses. Buccal DNAm measured in a subset of subjects at birth and near 1 year of age was used to determine whether DNAm signatures originated in utero, or emerged with age. RESULTS: Vitamin C treatment was associated with 457 FDR significant (q < 0.05) differentially methylated CpGs (DMCs; 236 hypermethylated; 221 hypomethylated) and 53 differentially methylated regions (DMRs; 26 hyper; 27 hypo) at 5 years of age. FEF25-75 was associated with one FDR significant DMC (cg05814800), 1,468 candidate DMCs (p < 0.001), and 44 DMRs. Current wheeze was associated with 0 FDR-DMCs, 782 candidate DMCs, and 19 DMRs (p < 0.001). In 365/457 vitamin C FDR significant DMCs at 5 years of age, there was no significant interaction between time and treatment. CONCLUSIONS: Vitamin C supplementation to pregnant smokers is associated with buccal DNA methylation in offspring at 5 years of age, and most methylation signatures appear to be persistent from the prenatal period. Buccal methylation at 5 years was also associated with current lung function and occurrence of wheeze, and these functionally associated loci are enriched for vitamin C associated loci. Clinical trial registration ClinicalTrials.gov, NCT01723696 and NCT03203603.

Effect of Vitamin C Supplementation for Pregnant Smokers on Offspring Airway Function and Wheeze at Age 5 Years: Follow-up of a Randomized Clinical Trial.

Importance: Vitamin C supplementation (500 mg/d) for pregnant smokers has been reported to increase offspring airway function as measured by forced expiratory flow (FEF) through age 12 months; however, its effects on airway function at age 5 years remain to be assessed. Objective: To assess whether vitamin C supplementation in pregnant smokers is associated with increased and/or improved airway function in their offspring at age 5 years and whether vitamin C decreases the occurrence of wheeze. Design, Setting, and Participants: This study followed up the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP) double-blind, placebo-controlled randomized clinical trial conducted at 3 centers in the US (in Oregon, Washington, and Indiana) between 2012 and 2016. Investigators and participants remain unaware of the treatment assignments. Forced expiratory flow measurements at age 5 years were completed from 2018 to 2021. Interventions: Pregnant smokers were randomized to vitamin C (500 mg/d) or placebo treatment. Main Outcomes and Measures: The primary outcome was the prespecified measurement of FEF between 25% and 75% expired volume (FEF25-75) by spirometry at age 5 years. Secondary outcomes included FEF measurements at 50% and 75% of expiration (FEF50 and FEF75), forced expiratory volume in 1 second (FEV1), and occurrence of wheeze. Results: Of the 251 pregnant smokers included in this study, 125 (49.8%) were randomized to vitamin C and 126 (50.2%) were randomized to placebo. Of 213 children from the VCSIP trial who were reconsented into this follow-up study, 192 (90.1%) had successful FEF measurements at age 5 years; 212 (99.5%) were included in the analysis of wheeze. Analysis of covariance demonstrated that offspring of pregnant smokers allocated to vitamin C compared with placebo had 17.2% significantly higher mean (SE) measurements of FEF25-75 at age 5 years (1.45 [0.04] vs 1.24 [0.04] L/s; adjusted mean difference, 0.21 [95% CI, 0.13-0.30]; P < .001). Mean (SE) measurements were also significantly increased by 14.1% for FEF50 (1.59 [0.04] vs 1.39 [0.04] L/s; adjusted mean difference, 0.20 [95% CI, 0.11-0.30]; P < .001), 25.9% for FEF75 (0.79 [0.02] vs 0.63 [0.02] L/s; 0.16 [95% CI, 0.11-0.22]; P < .001), and 4.4% for FEV1 (1.13 [0.02] vs 1.09 [0.02] L; 0.05 [95% CI, 0.01-0.09]; P = .02). In addition, offspring of pregnant smokers randomized to vitamin C had significantly decreased wheeze (28.3% vs 47.2%; estimated odds ratio, 0.41 [95% CI, 0.23-0.74]; P = .003). Conclusions and Relevance: In this follow-up study of offspring of pregnant smokers randomized to vitamin C vs placebo, vitamin C supplementation during pregnancy resulted in significantly increased airway function of offspring at age 5 years and significantly decreased the occurrence of wheeze. These findings suggest that vitamin C supplementation for pregnant smokers may decrease the effects of smoking in pregnancy on childhood airway function and respiratory health. Trial Registration: ClinicalTrials.gov Identifier: NCT03203603.

Outcomes of the National Heart, Lung, and Blood Institute K12 program in emergency care research: 7-year follow-up.

BACKGROUND: Long-term follow-up for clinician-scientist training programs is sparse. We describe the outcomes of clinician-scientist scholars in the National Heart Lung and Blood Institute (NHLBI) K12 program in emergency care research up to 8.7 years after matriculation in the program. METHODS: This was a cohort study of faculty clinician-scientist scholars enrolled in a NHLBI K12 research training program at 6 sites across the US, with median follow-up 7.7 years (range 5.7-8.7 years) from the date of matriculation. Scholars completed electronic surveys in 2017 and 2019, with the 2019 survey collecting information for their current work setting, percent time for research, and grant funding from all sources. We used NIH RePorter and online resources to verify federal grants through March 2021. The primary outcome was a funded career development award (CDA) or research project grant (RPG) where the scholar was principal investigator. We included funding from all federal sources and national foundations. RESULTS: There were 43 scholars, including 16 (37%) women. Over the follow-up period, 32 (74%) received an individual CDA or RPG, with a median of 36 months (range 9-83 months) after entering the program. Of the 43 scholars, 23 (54%) received a CDA and 22 (51%) received an RPG, 7 (16%) of which were R01s. Of the 23 scholars who received a CDA, 13 (56%) subsequently had an RPG funded. Time to CDA or RPG did not differ by sex (women vs. men log-rank test p = 0.27) or specialty training (emergency medicine versus other specialties, p = 0.59). CONCLUSIONS: After 7 years of follow-up for this NHLBI K12 emergency care research training program, three quarters of clinician-scientist scholars had obtained CDA or RPG funding, with no notable differences by sex or clinical training.

Expanding Inpatient Addiction Consult Services Through Accountable Care Organizations for Medicaid Enrollees: A Modeling Study.

INTRODUCTION: Addiction consult services (ACS) care for hospitalized patients with substance use disorder, including opioid use disorder (OUD). Medicaid Accountable Care Organizations (ACOs) could enhance access to ACS. This study extends data from Oregon's only ACS to Oregon's 15 regional Medicaid Coordinated Care Organizations (CCOs) to illustrate the potential value of enhanced in- and out-patient care for hospitalized patients with OUD. The study objectives were to estimate the effects of (1) expanding ACS care through CCOs in Oregon, and (2) increasing community treatment access within CCOs, on post-discharge OUD treatment engagement. METHODS: We used a validated Markov model, populated with Oregon Medicaid data from April 2015 to December 2017, to estimate study objectives. RESULTS: Oregon Medicaid patients hospitalized with OUD with care billed to a CCO (n = 5878) included 1298 (22.1%) patients engaged in post-discharge OUD treatment. Simulation of referral to an ACS increased post-discharge OUD treatment engagement to 47.0% (95% confidence interval [CI] 45.7%, 48.3%), or 2684 patients (95% CI 2610, 2758). Ten of fifteen (66.7%) CCOs had fewer than 20% of patients engage in post-discharge OUD care. Without ACS, increasing outpatient treatment such that 20% of patients engage increased the patients engaging in post-discharge OUD care from 12.9% or 296 patients in care at baseline to 20% (95% CI 18.1%, 21.4%) or 453 (95% CI 416, 491). DISCUSSION: ACOs can improve care for patients hospitalized with OUD. Implementing ACS in ACO networks can potentially improve post-discharge OUD treatment engagement, but community treatment systems must be prepared to accept more patients as inpatient addiction care improves.

Causes of Death in the 12 Months After Hospital Discharge Among Patients With Opioid Use Disorder.

BACKGROUND: Patients with substance use disorders are seven times more likely hospitalized than the general population. However, causes of death for recently hospitalized patients with Opioid Use Disorder (OUD) are not well described. This study describes causes of death in the year post-discharge among hospitalized patients with OUD. METHODS: We analyzed data from participants who were at least 18 years old, with Medicaid insurance, and had a diagnosis of OUD during a general hospital admission in Oregon between April 2015 and December 2017. RESULTS: During the study window, 6,654 Oregon Medicaid patients with an OUD diagnosis were hospitalized. Patients were predominately female (56.7%) and White (72.2%), an average age of 44.2 years (SD = 15.4 years) and average hospital length of stay of 6.5 days (SD = 10.9 days). In the 12 months post-discharge, 522 patients died (7.8%); 301 patients from a drug or substance related cause (4.5%), including 71 from drug overdose (1.1%). Stated another way, of those who died within 12 months, 58% of deaths were attributed to drug-related causes, including 13.6% of deaths attributed to overdose; 42% died of non-drug related causes. Drug-related death was the most frequent cause of mortality. CONCLUSIONS: Hospitalized patients with OUD are at high risk of death, from drug and non-drug related causes, in the year after discharge. Future research should consider not only overdose, but a more comprehensive definition of drug-related death in understanding post-discharge mortality among hospitalized patients with OUD, and care systems should work to mitigate the risk of death in this population.

Simulating the impact of Addiction Consult Services in the context of drug supply contamination, hospitalizations, and drug-related mortality.

BACKGROUND: Illicitly manufactured fentanyl (IMF) is increasing in international drug supply chains, and IMF-related opioid overdose deaths are rising in North America. Hospitalizations among patients with opioid use disorder (OUD) are also rising; and, hospitalized patients are at increased risk of overdose and death following hospital discharge. Hospitalization is a key opportunity to engage patients with OUD. Addiction consult services (ACS) can provide effective treatment for patients hospitalized with OUD. This study aims to estimate the effect of increasing IMF contamination on drug-related death among patients hospitalized with OUD, and simulate the role of ACS expansion to mitigate these effects. METHODS: We used a Markov model to mirror care systems for adult patients hospitalized with OUD in Oregon, from the time of hospital admission through 12-months post-discharge, and simulated patients through modeled care systems to evaluate the expansion of Addiction Consult Services in the context of increasing IMF in the drug supply. RESULTS: In a simulated cohort of 10,000 patients, we estimate that 537 patients would die from drug-related causes within 12-months of hospital discharge. In the context of increased IMF in the drug supply, this estimate increased to 913. ACS referral at baseline was 4%; increasing ACS referral to accommodate 10%, 50%, or 100% of hospitalized OUD patients in the state reduces drug-related deaths to 904, 849, and 780, respectively. The number needed to treat for ACS to avoid one drug-related death in the context of increased IMF was 73. CONCLUSIONS: Hospitals should expand interventions to help reduce IMF-related opioid overdoses, including through implementation of ACS. In the context of rising IMF-related deaths, ACS expansion could help connect patients to treatment, offer harm reduction interventions, or both, which can help reduce the risk of opioid-related death.

Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.

Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.

Designing and validating a Markov model for hospital-based addiction consult service impact on 12-month drug and non-drug related mortality.

INTRODUCTION: Addiction consult services (ACS) engage hospitalized patients with opioid use disorder (OUD) in care and help meet their goals for substance use treatment. Little is known about how ACS affect mortality for patients with OUD. The objective of this study was to design and validate a model that estimates the impact of ACS care on 12-month mortality among hospitalized patients with OUD. METHODS: We developed a Markov model of referral to an ACS, post-discharge engagement in SUD care, and 12-month drug-related and non-drug related mortality among hospitalized patients with OUD. We populated our model using Oregon Medicaid data and validated it using international modeling standards. RESULTS: There were 6,654 patients with OUD hospitalized from April 2015 through December 2017. There were 114 (1.7%) drug-related deaths and 408 (6.1%) non-drug related deaths at 12 months. Bayesian logistic regression models estimated four percent (4%, 95% CI = 2%, 6%) of patients were referred to an ACS. Of those, 47% (95% CI = 37%, 57%) engaged in post-discharge OUD care, versus 20% not referred to an ACS (95% CI = 16%, 24%). The risk of drug-related death at 12 months among patients in post-discharge OUD care was 3% (95% CI = 0%, 7%) versus 6% not in care (95% CI = 2%, 10%). The risk of non-drug related death was 7% (95% CI = 1%, 13%) among patients in post-discharge OUD treatment, versus 9% not in care (95% CI = 5%, 13%). We validated our model by evaluating its predictive, external, internal, face and cross validity. DISCUSSION: Our novel Markov model reflects trajectories of care and survival for patients hospitalized with OUD. This model can be used to evaluate the impact of other clinical and policy changes to improve patient survival.

Impact of vitamin C supplementation on placental DNA methylation changes related to maternal smoking: association with gene expression and respiratory outcomes.

BACKGROUND: Maternal smoking during pregnancy (MSDP) affects development of multiple organ systems including the placenta, lung, brain, and vasculature. In particular, children exposed to MSDP show lifelong deficits in pulmonary function and increased risk of asthma and wheeze. Our laboratory has previously shown that vitamin C supplementation during pregnancy prevents some of the adverse effects of MSDP on offspring respiratory outcomes. Epigenetic modifications, including DNA methylation (DNAm), are a likely link between in utero exposures and adverse health outcomes, and MSDP has previously been associated with DNAm changes in blood, placenta, and buccal epithelium. Analysis of placental DNAm may reveal critical targets of MSDP and vitamin C relevant to respiratory health outcomes. RESULTS: DNAm was measured in placentas obtained from 72 smokers enrolled in the VCSIP RCT: NCT03203603 (37 supplemented with vitamin C, 35 with placebo) and 24 never-smokers for reference. Methylation at one CpG, cg20790161, reached Bonferroni significance and was hypomethylated in vitamin C supplemented smokers versus placebo. Analysis of spatially related CpGs identified 93 candidate differentially methylated regions (DMRs) between treatment groups, including loci known to be associated with lung function, oxidative stress, fetal development and growth, and angiogenesis. Overlap of nominally significant differentially methylated CpGs (DMCs) in never-smokers versus placebo with nominally significant DMCs in vitamin C versus placebo identified 9059 candidate "restored CpGs" for association with placental transcript expression and respiratory outcomes. Methylation at 274 restored candidate CpG sites was associated with expression of 259 genes (FDR < 0.05). We further identified candidate CpGs associated with infant lung function (34 CpGs) and composite wheeze (1 CpG) at 12 months of age (FDR < 0.05). Increased methylation in the DIP2C, APOH/PRKCA, and additional candidate gene regions was associated with improved lung function and decreased wheeze in offspring of vitamin C-treated smokers. CONCLUSIONS: Vitamin C supplementation to pregnant smokers ameliorates changes associated with maternal smoking in placental DNA methylation and gene expression in pathways potentially linked to improved placental function and offspring respiratory health. Further work is necessary to validate candidate loci and elucidate the causal pathway between placental methylation changes and outcomes of offspring exposed to MSDP. Clinical trial registration ClinicalTrials.gov, NCT01723696. Registered November 6, 2012. https://clinicaltrials.gov/ct2/show/record/NCT01723696 .

Vitamin C to Pregnant Smokers Persistently Improves Infant Airway Function to 12†Months of Age: A Randomised Trial.

BACKGROUND: Vitamin C (500 mg·day-1) supplementation for pregnant smokers has been reported to increase newborn pulmonary function and infant forced expiratory flows (FEFs) at 3 months of age. Its effect on airway function through 12 months of age has not been reported. OBJECTIVE: To assess whether vitamin C supplementation to pregnant smokers is associated with a sustained increased airway function in their infants through 12 months of age. METHODS: This is a prespecified secondary outcome of a randomised, double-blind, placebo-controlled trial that randomised 251 pregnant smokers between 13 and 23 weeks of gestation: 125 to 500 mg·day-1 vitamin C and 126 to placebo. Smoking cessation counselling was provided. FEFs performed at 3 and 12 months of age were analysed by repeated measures analysis of covariance. RESULTS: FEFs were performed in 222 infants at 3 months and 202 infants at 12 months of age. The infants allocated to vitamin C had significantly increased FEFs over the first year of life compared to those allocated to placebo. The overall increased flows were: 40.2 mL·sec-1 for FEF75 (adjusted 95% CI for difference 6.6 to 73.8; p=0.025); 58.3 mL·sec-1 for FEF50 (95% CI 10.9 to 105.8; p=0.0081); and 55.1 mL·sec-1 for FEF25-75 (95% CI, 9.7 to 100.5; p=0.013). CONCLUSIONS: In offspring of pregnant smokers randomised to vitamin C versus placebo, vitamin C during pregnancy was associated with a small but significantly increased airway function at 3 and 12 months of age, suggesting a potential shift to a higher airway function trajectory curve. Continued follow-up is underway.

A Community-based Assessment of Skin Care, Allergies, and Eczema (CASCADE): an atopic dermatitis primary prevention study using emollients-protocol for a randomized controlled trial.

BACKGROUND: Atopic dermatitis (AD) is a common, chronic skin disorder often beginning in infancy. Skin barrier dysfunction early in life serves as a central event in the pathogenesis of AD. In infants at high risk of developing AD, preventative application of lipid-rich emollients may reduce the risk of developing AD. This study aims to measure the effectiveness of this intervention in a population not selected for risk via a pragmatic, randomized, physician-blinded trial in the primary care setting. METHODS: Infant-parent dyads are recruited from a primary care practice participating through one of four practice-based research networks in Oregon, Colorado, Wisconsin, and North Carolina. Eligible dyads are randomized to the intervention (daily use of lipid-rich emollient) or the control (no emollient) group (n = 625 infants in each) and are followed for 24 months. The primary outcome is the cumulative incidence of physician-diagnosed AD and secondary outcomes include caregiver-reported measures of AD and development of other atopic diseases. Data collection occurs via chart review and surveys, with no study visits required. Data will be analyzed utilizing intention-to-treat principles. DISCUSSION: AD is a common skin condition in infants that affects quality of life and is associated with the development of other atopic diseases. If a safe intervention, such as application of lipid-rich emollients, in the general population effectively decreases AD prevalence, this could alter the guidance given by providers regarding routine skin care of infants. Because of the pragmatic design, we anticipate that this trial will yield generalizable results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03409367. Registered on 11 February 2018.

Immediate impact of the COVID-19 pandemic on CTSA TL1 and KL2 training and career development.

Clinical and Translational Science Award (CTSA) TL1 trainees and KL2 scholars were surveyed to determine the immediate impact of the COVID-19 pandemic on training and career development. The most negative impact was lack of access to research facilities, clinics, and human subjects, plus for KL2 scholars lack of access to team members and need for homeschooling. TL1 trainees reported having more time to think and write. Common strategies to maintain research productivity involved time management, virtual connections with colleagues, and shifting to research activities not requiring laboratory/clinic settings. Strategies for mitigating the impact of the COVID-19 pandemic on training and career development are described.

Oral Vitamin C (500 mg/d) to Pregnant Smokers Improves Infant Airway Function at 3 Months (VCSIP). A Randomized Trial.

Rationale: We reported a randomized trial demonstrating daily supplemental vitamin C to pregnant smokers significantly improved newborn pulmonary function tests. The current study tests these results in a new cohort using infant pulmonary function tests. Objectives: To determine if infants of pregnant smokers randomized to daily supplemental vitamin C would have improved forced expiratory flows (FEFs) at 3 months of age compared with those randomized to placebo, and to investigate the association of the α5 nicotinic acetylcholine receptor. Methods: A randomized, double-blind, placebo-controlled trial was conducted at three centers. Two hundred fifty-one pregnant smokers were randomized at 13-23 weeks of gestation: 125 randomized to vitamin C (500 mg/d) and 126 to placebo. Measurements and Main Results: The primary outcome was FEF75 at 3 months of age performed with the raised volume rapid thoracic compression technique (Jaeger/Viasys). FEF50 and FEF25-75 obtained from the same expiratory curves were prespecified secondary outcomes. The infants of pregnant smokers randomized to vitamin C (n = 113) had the following FEFs at 3 months of age compared with those randomized to placebo (n = 109) as measured by FEF75 (200.7 vs. 188.7 ml/s; adjusted 95% confidence interval [CI] for difference, -3.33 to 35.64; P = 0.10), FEF50 (436.7 vs. 408.5 ml/s; adjusted 95% CI for difference, 6.10-61.30; P = 0.02), and FEF25-75 (387.4 vs. 365.8 ml/s; adjusted 95% CI for difference, 0.92-55.34; P = 0.04). Infant FEFs seemed to be negatively associated with the maternal risk alleles for the α5 nicotinic acetylcholine receptor (rs16969968). Conclusions: Although the primary outcome of FEF75 was not improved after vitamin C supplementation to pregnant smokers, the predetermined secondary outcomes FEF50 and FEF25-75 were significantly improved. These results extend our previous findings and demonstrate improved airway function (FEF50 and FEF25-75) at 3 months of age in infants after vitamin C supplementation to pregnant smokers. Clinical trial registered with www.clinicaltrials.gov (NCT01723696).

The First National Institutes of Health Institutional Training Program in Emergency Care Research: Productivity and Outcomes.

STUDY OBJECTIVE: We assess the productivity, outcomes, and experiences of participants in the National Institutes of Health/National Heart, Lung, and Blood Institute-funded K12 institutional research training programs in emergency care research. METHODS: We used a mixed-methods study design to evaluate the 6 K12 programs, including 2 surveys, participant interviews, scholar publications, grant submissions, and funded grants. The training program lasted from July 1, 2011, through June 30, 2017. We tracked scholars for a minimum of 3 years and up to 5 years, beginning with date of entry into the program. We interviewed program participants by telephone using open-ended prompts. RESULTS: There were 94 participants, including 43 faculty scholars, 13 principal investigators, 30 non-principal investigator primary mentors, and 8 program administrators. The survey had a 74% overall response rate, including 95% of scholars. On entry to the program, scholars were aged a median of 37 years (interquartile range [IQR] 34 to 40 years), with 16 women (37%), and represented 11 disciplines. Of the 43 scholars, 40 (93%) submitted a career development award or research project grant during or after the program; 26 (60%) have secured independent funding as of August 1, 2017. Starting with date of entry into the program, the median time to grant submission was 19 months (IQR 11 to 27 months) and time to funding was 33 months (IQR 27 to 39 months). Cumulative median publications per scholar increased from 7 (IQR 4 to 15.5) at program entry to 21 (IQR 11 to 33.5) in the first post-K12 year. We conducted 57 semistructured interviews and identified 7 primary themes. CONCLUSION: This training program produced 43 interdisciplinary investigators in emergency care research, with demonstrated productivity in grant funding and publications.

Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP): Rationale, design, and methods of a randomized, controlled trial of vitamin C supplementation in pregnancy for the primary prevention of effects of in utero tobacco smoke exposure on infant lung function and respiratory health.

Despite strong anti-smoking efforts, at least 12% of American women cannot quit smoking when pregnant resulting in >450,000 smoke-exposed infants born yearly. Smoking during pregnancy is the largest preventable cause of childhood respiratory illness including wheezing and asthma. Recent studies have shown a protective effect of vitamin C supplementation on the lung function of offspring exposed to in utero smoke in a non-human primate model and an initial human trial. Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function (VCSIP) is a randomized, double-blind, placebo-controlled trial to evaluate pulmonary function at 3months of age in infants delivered to pregnant smokers randomized to 500mg/day of vitamin C versus placebo during pregnancy. Secondary aims evaluate the incidence of wheezing through 12months and pulmonary function testing at 12months of age. Women are randomized between 13 and 23weeks gestation from clinical sites in Portland, Oregon at Oregon Health & Science University and PeaceHealth Southwest Medical Center and in Indianapolis, Indiana at Indiana University and Wishard Hospital. Vitamin C supplementation occurs from randomization to delivery. Monthly contact with participants and monitoring of medical records is performed to document medication adherence, changes in smoking and medical history, and adverse events. Pulmonary function testing of offspring occurs at 3 and 12months of age and incidence of wheezing and respiratory illness through 12months is captured via at least quarterly questionnaires. Ancillary studies are investigating the impact of vitamin C on placental blood flow and DNA methylation.

Vitamin C Prevents Offspring DNA Methylation Changes Associated with Maternal Smoking in Pregnancy.

RATIONALE: Infants whose mothers smoked during pregnancy demonstrate lifelong decreases in pulmonary function. DNA methylation changes associated with maternal smoking during pregnancy have been described in placenta and cord blood at delivery, in fetal lung, and in buccal epithelium and blood during childhood. We demonstrated in a randomized clinical trial ( ClinicalTrials.gov identifier, NCT00632476) that vitamin C supplementation to pregnant smokers can lessen the impact of maternal smoking on offspring pulmonary function and decrease the incidence of wheeze at 1 year of age. OBJECTIVES: To determine whether vitamin C supplementation reduces changes in offspring methylation in response to maternal smoking and whether methylation at specific CpGs is also associated with respiratory outcomes. METHODS: Targeted bisulfite sequencing was performed with a subset of placentas, cord blood samples, and buccal samples collected during the NCT00632476 trial followed by independent validation of selected cord blood differentially methylated regions, using bisulfite amplicon sequencing. MEASUREMENTS AND MAIN RESULTS: The majority (69.03%) of CpGs with at least 10% methylation difference between placebo and nonsmoker groups were restored (by at least 50%) toward nonsmoker levels with vitamin C treatment. A significant proportion of restored CpGs were associated with phenotypic outcome with greater enrichment among hypomethylated CpGs. CONCLUSIONS: We identified a pattern of normalization in DNA methylation by vitamin C supplementation across multiple loci. The consistency of this pattern across tissues and time suggests a systemic and persistent effect on offspring DNA methylation. Further work is necessary to determine how genome-wide changes in DNA methylation may mediate or reflect persistent effects of maternal smoking on lung function.