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Maternal smoking during pregnancy (MSDP), driven by nicotine crossing the placenta, causes lifelong decreases in offspring pulmonary function and vitamin C supplementation during pregnancy prevents some of those changes. We have also shown in animal models of prenatal nicotine exposure that vitamin C supplementation during pregnancy improves placental function. In this study we examined whether vitamin C supplementation mitigates the effects of MSDP on placental structure, function, and gene expression in pregnant human smokers. Doppler ultrasound was performed in a subset of 55 pregnant smokers participating in the "Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function" (VCSIP) randomized clinical trial (NCT01723696) and in 33 pregnant nonsmokers. Doppler ultrasound measurements showed decreased umbilical vein Doppler velocity (Vmax) in placebo-treated smokers that was significantly improved in smokers randomized to vitamin C, restoring to levels comparable to nonsmokers. RNA-sequencing demonstrated that vitamin C supplementation to pregnant smokers was associated with changes in mRNA expression in genes highly relevant to vascular and cardiac development, suggesting a potential mechanism for vitamin C supplementation in pregnant smokers to improve some aspects of offspring health., (© 2024. The Author(s).)

Importance: Although psychological distress is common among survivors of critical illness, there are few tailored therapies., Objective: To determine the optimal method for delivering a mindfulness intervention via a mobile app for critical illness survivors., Design, Setting, and Participants: This randomized clinical trial used a 2 × 2 × 2 factorial design and was conducted at 3 sites among survivors of critical illness with elevated postdischarge symptoms of depression. The study was conducted between August 2019 and July 2023., Interventions: Participants were randomized to 1 of 8 different groups as determined by 3 two-level intervention component combinations: intervention introduction method (mobile app vs therapist call), mindfulness meditation dose (once daily vs twice daily), and management of increasing symptoms (mobile app vs therapist call)., Main Outcomes and Measures: The primary outcome was the 9-item Patient Health Questionnaire (PHQ-9) depression scale score (range, 0-27) at 1 month. Secondary outcomes included anxiety (7-item Generalized Anxiety Disorder) and posttraumatic stress disorder (Posttraumatic Stress Scale) symptoms at 1 and 3 months, adherence, and feasibility. General linear models were used to compare main effects and interactions of the components among intervention groups. A formal decisional framework was used to determine an optimized intervention version., Results: A total of 247 participants (mean [SD] age, 50.2 [15.4] years; 104 [42.1%] women) were randomized. Twice-daily meditation compared with once-daily meditation was associated with a 1.2 (95% CI, 0.04-2.4)-unit lower mean estimated PHQ-9 score at 1 month and a 1.5 (95% CI, 0.1-2.8)-unit lower estimated mean score at 3 months. The other 2 intervention components had no main effects on the PHQ-9. Across-group adherence was high (217 participants [87.9%] using the intervention at trial conclusion) and retention was strong (191 [77.3%] and 182 [73.7%] at 1 and 3 months, respectively)., Conclusions and Relevance: A mindfulness intervention for survivors of critical illness that included an app-based introduction, twice-daily guided meditation, and app-based management of increasing depression symptoms was optimal considering effects on psychological distress symptoms, adherence, and feasibility., Trial Registration: ClinicalTrials.gov Identifier: NCT04038567.

Background: Maternal cigarette smoking during pregnancy (MSDP) is associated with numerous adverse health outcomes in infants and children with potential lifelong consequences. Negative effects of MSDP on placental DNA methylation (DNAm), placental structure, and function are well established., Objective: Our aim was to develop biomarkers of MSDP using DNAm measured in placentas ( N = 96 ), collected as part of the Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function double-blind, placebo-controlled randomized clinical trial conducted between 2012 and 2016. We also aimed to develop a digital polymerase chain reaction (PCR) assay for the top ranking cytosine-guanine dinucleotide (CpG) so that large numbers of samples can be screened for exposure at low cost., Methods: We compared the ability of four machine learning methods [logistic least absolute shrinkage and selection operator (LASSO) regression, logistic elastic net regression, random forest, and gradient boosting machine] to classify MSDP based on placental DNAm signatures. We developed separate models using the complete EPIC array dataset and on the subset of probes also found on the 450K array so that models exist for both platforms. For comparison, we developed a model using CpGs previously associated with MSDP in placenta. For each final model, we used model coefficients and normalized beta values to calculate placental smoking index (PSI) scores for each sample. Final models were validated in two external datasets: the Extremely Low Gestational Age Newborn observational study, N = 426 ; and the Rhode Island Children's Health Study, N = 237 ., Results: Logistic LASSO regression demonstrated the highest performance in cross-validation testing with the lowest number of input CpGs. Accuracy was greatest in external datasets when using models developed for the same platform. PSI scores in smokers only ( n = 72 ) were moderately correlated with maternal plasma cotinine levels. One CpG (cg27402634), with the largest coefficient in two models, was measured accurately by digital PCR compared with measurement by EPIC array ( R 2 = 0.98 )., Discussion: To our knowledge, we have developed the first placental DNAm-based biomarkers of MSDP with broad utility to studies of prenatal disease origins. https://doi.org/10.1289/EHP13838.

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 (FEF 25-75 ), 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 FEF 25-75 . 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. FEF 25-75 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., (© 2024. The Author(s).)

Purpose: Environmental factors such as bathing may play a role in atopic dermatitis (AD) development. This analysis utilized data from the Community Assessment of Skin Care, Allergies, and Eczema (CASCADE) Trial (NCT03409367), a randomized controlled trial of emollient therapy for AD prevention in the general population, to estimate bathing frequency and associated factors within the first 9 weeks of life., Methods: Data were collected from 909 parent/newborn dyads recruited from 25 pediatric and family medicine clinics from the Meta-network Learning and Research Center (Meta-LARC) practice-based research network (PBRN) consortium in Oregon, North Carolina, Colorado, and Wisconsin for the CASCADE trial. Ordinal logistic regression was used to conduct a cross-sectional analysis of the association between bathing frequency (measured in baths per week) and demographic, medical, and lifestyle information about the infant, their family, and their household. Variables were selected using a backwards-stepwise method and estimates from the reduced model are reported in the text., Results: Moisturizer use (OR = 2.03, 95% CI: 1.54-2.68), Hispanic or Latino ethnicity (OR = 1.97, 95% CI: 1.42-2.72), a parental education level lower than a 4-year college degree (OR = 2.48, 95% CI: 1.70-3.62), living in North Carolina or Wisconsin (compared to Oregon; OR = 2.12 and 1.47, 95% CI: 1.53-2.93 and 1.04-2.08, respectively), and increasing child age (in days; OR = 1.02, 95% CI: 1.01-1.02) were significantly associated with more frequent bathing, while pet ownership (OR = 0.67, 95% CI: 0.52-0.87) was significantly associated with less frequent bathing., Conclusions: We found significant ethnic, geographic, and socioeconomic variation in bathing frequency before 9 weeks of age that may be of relevance to AD prevention studies., (© 2023 Wiley Periodicals LLC.)

Background: Pulmonary embolism (PE) is a frequent diagnostic consideration in emergency department (ED) patients, yet diagnosis is challenging because symptoms of PE are nonspecific. Guidelines recommend the use of clinical decision tools to increase efficiency and avoid harms from overtesting, including D-dimer screening in patients not at high risk for PE. Women undergo testing for PE more often than men yet have a lower yield from testing. Our study objective was to determine whether patient sex influenced the odds of received guideline-consistent care., Methods: We performed a retrospective cohort study at two large U.S. academic EDs from January 1, 2016, to December 31, 2018. Nonpregnant patients aged 18-49 years were included if they presented with chest pain, shortness of breath, hemoptysis, or syncope and underwent testing for PE with D-dimer or imaging. Demographic and clinical data were exported from the electronic medical record (EMR). Pretest risk scores were calculated using manually abstracted EMR data. Diagnostic testing was then compared with recommended testing based on pretest risk. The primary outcome was receipt of guideline-consistent care, which required an elevated screening D-dimer prior to imaging in all non-high-risk patients., Results: We studied 1991 discrete patient encounters; 37% (735) of patients were male and 63% (1256) were female. Baseline characteristics, including revised Geneva scores, were similar between sexes. Female patients were more likely to receive guideline-consistent care (70% [874/1256] female vs. 63% [463/735] male, p < 0.01) and less likely to be diagnosed with PE (3.1% [39/1256] female vs. 5.3% [39/735] male, p < 0.05). The most common guideline deviation in both sexes was obtaining imaging without a screening D-dimer in a non-high-risk patient (75% [287/382] female vs. 75% [205/272] male)., Conclusions: In this cohort, females were more likely than males to receive care consistent with current guidelines and less likely to be diagnosed with PE., (© 2023 Society for Academic Emergency Medicine.)

Introduction: The COVID-19 pandemic had an abrupt impact on patient-oriented research early in the pandemic. CTSA Clinical Research Centers (CRCs) rapidly adapted to this challenge, but the continued impact of later phases of the pandemic on CRC operations is not clear., Methods: An online REDCap survey of CTSA CRCs was developed that covered the first 2 years of the pandemic. The survey focused on impact on CRC functions, mitigation strategies, recovery of CRC activities, CRC contributions to COVID-related research, and potential lessons for future public health emergencies. The survey was sent to CRC directors at 61 CTSA Hubs in May 2022., Results: Twenty-seven Hubs (44%) responded to the survey. Most CRCs reported greater than 50% declines in inpatient census in the first year of the pandemic, with less severe impacts on outpatient census. CRCs pivoted to support COVID-related research and adopted innovative technology-driven approaches to support clinical research. Census improved in the second year of the pandemic in most CRCs but often remained below pre-pandemic levels, and greater than half of CRCs reported decreased revenue., Conclusions: CTSA-supported CRCs faced unprecedented challenges at the onset of the COVID-19 pandemic and responded rapidly to support COVID-related research and implement innovative approaches that allowed patient-oriented research activities to resume. However, many CRCs continued to report decreased research activities in the second year of the pandemic, and the long-term effects on CRC operations on finances are not clear. CRCs will likely need to evolve to provide support in nontraditional ways., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2023.)

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.

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., (© 2022 Society for Academic Emergency Medicine.)

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., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)

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., Competing Interests: The authors do not have financial conflicts of interest. Dr. Korthuis serves as principal investigator for NIH-funded trials that accept donated study medications from Alkermes (extended-release naltrexone) and Indivior (buprenorphine-naloxone)., (Copyright © 2021 American Society of Addiction Medicine.)

Background: Headaches with marked, specific response to indomethacin occur in children, but the phenotypic spectrum of this phenomenon has not been well-studied., Methods: We reviewed pediatric patients with headache showing ≥80% improvement with indomethacin, from seven academic medical centers., Results: We included 32 pediatric patients (16 females). Mean headache onset age was 10.9 y (range 2-16 y). Headache syndromes included hemicrania continua (n = 13), paroxysmal hemicrania (n = 10), primary stabbing headache (n = 2), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (n = 1), primary exercise headache (n = 1) and primary cough headache (n = 1). Adverse events were reported in 13, most commonly gastrointestinal symptoms, which often improved with co-administration of gastro-protective agents., Conclusion: Indomethacin-responsive headaches occur in children and adolescents, and include headache syndromes, such as primary cough headache, previously thought to present only in adulthood. The incidence of adverse events is high, and patients must be co-treated with a gastroprotective agent.

Background and Objectives: Children and adolescents with chronic migraine who have continuous headache may have high levels of headache-related disability but have largely been excluded from clinical trials. Understanding patient-valued treatment outcomes may facilitate future study design. The aim of this work was to identify patient-valued outcome measures for headache preventive treatments among adolescents with continuous headache due to chronic migraine and their parents., Methods: Adolescents with an International Classification of Headache Disorders, 3rd edition diagnosis of chronic migraine, who had continuous headache and who were being cared for at a tertiary pediatric headache clinic, and their parents were surveyed to query the value of treatment outcomes in the domains of headache frequency, intensity, functional impact, and associated symptoms. Individual outcomes and categories of outcomes were ranked in order of preference using weighted average rank. Results were rounded to the degree of precision with which they were measured., Results: The survey was completed by 55 adolescents and 60 parents of adolescents with continuous headache due to chronic migraine. Mean age of adolescents was 16 (SD 1, range 12-17) years. Median adolescent-reported duration of continuous headache was 24 (interquartile range [IQR] 12-39) months, and adolescents had tried a median of 2 (IQR 0-5) preventive medications, only 13% of which were perceived as helpful. Overall, the most valued individual outcome measure among both adolescents and parents was a decrease in frequency of more severe headaches; however, outcomes reflecting headache intensity were most valued by adolescents, while outcomes reflecting functional impact were most valued by parents. More than 60% of adolescents felt that it was more important to measure decrease in frequency and intensity of headaches in terms of severe headaches/spikes rather than total headache days. Among associated symptoms, improvement in brain fog was most highly valued by both adolescents and parents., Discussion: The results of this study provide important information about which preventive treatment outcomes are valued by adolescents with continuous headache due to chronic migraine and their parents. Results suggest that adolescents value a decrease in frequency of severe headaches over a decrease in frequency of headache days overall. Generalizability may be limited because the surveyed population was being cared for at a tertiary pediatric headache clinic and generally had headache disorders that were refractory to treatment. These results may help guide future trial design in this population with continuous headache due to chronic migraine., (© 2022 American Academy of Neurology.)

Problem: American Indians and Alaska Natives (AIANs) face significant health disparities that are exacerbated by limited access to high-quality, culturally congruent health care providers. There are no premedical postbaccalaureate programs focused on AIAN students., Approach: The Northwest Native American Center of Excellence designed the Wy'east Pathway in 2018 to increase the number of AIANs matriculating to U.S. medical schools by supporting those on the cusp of matriculation. Wy'east scholars undertake 10 months of structured programming to augment their academic preparation, improve their Medical College Admission Test (MCAT) scores, and enhance their confidence and cultural identity. Cultural events and mentorship opportunities with AIAN faculty, staff, and cultural liaisons are threaded throughout the pathway curriculum to foster cultural resilience, mentorship, and community. Scholars earn conditional acceptance to Oregon Health and Science University (OHSU) School of Medicine if they complete Wy'east and meet the following criteria: pass all examinations in the primary curricular threads, obtain a qualifying MCAT score, and meet professionalism standards., Outcomes: All 14 scholars who successfully completed Wy'east and met criteria in the first 2 cohorts (academic years 2018-2019 and 2019-2020) earned conditional acceptance to OHSU School of Medicine. Ten of the 14 scholars (71.4%) matriculated to OHSU School of Medicine, 2 (14.3%) matriculated to other medical schools, and 2 (14.3%) chose to pursue other health care fields. Wy'east scholars rated the foundational science of medicine and population health and epidemiology threads higher in terms of making them feel better prepared for medical school (mean = 4.71 and 4.83, respectively) than the academic skills and wellness thread (mean = 3.43)., Next Steps: Over the next 5 years, Wy'east will grow incrementally to offer a total of 18 conditional acceptance spots per cohort across 3 medical schools. Longitudinal tracking of Wy'east scholars' medical training and career outcomes will be conducted., (Copyright © 2022 by the Association of American Medical Colleges.)

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., Competing Interests: Declarations of Interest Dr. Korthuis serves as principal investigator for NIH-funded studies that accept donated study medication from Alkermes (extended-release naltrexone) and Indivior (buprenorphine). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Published by Elsevier Inc.)

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 ., (© 2021. The Author(s).)

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., Competing Interests: Dr. Korthuis serves as principal investigator for NIH-funded studies that accept donated study medication from Alkermes (extended-release naltrexone) and Indivior (buprenorphine). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: Preterm birth (PTB), a pressing issue for US maternal-child health, disproportionately impacts women in Appalachia. Transvaginal ultrasound (TVU) cervical length (CL) screening is the most accurate PTB risk predictor but remains underutilized. This study characterizes the knowledge, attitudes and beliefs of patients with prior PTB concerning PTB prevention efforts and TVU CL screening., Methods: Participants were recruited from community-based health centers in Appalachian Kentucky. Semi-structured interviews and likert-scale surveys were conducted with 22 pregnant women with a history of spontaneous PTB. Methods for data collection were guided by the Consolidated Framework for Implementation Research (CFIR)., Results: Most participants reported that TVU was uncomfortable, but none refused it. Most women were able to articulate the benefits of TVU, but several had concerns about its safety in pregnancy. Participants suggested that pregnant women receive more PTB education and self-advocate. They urged providers to take patient concerns seriously, and better educate patients on PTB risks and TVU safety., Discussion: Our study contributes crucial insights about the experience of a vulnerable population as it pertains to PTB prevention and the uptake of TVU CL screening. Our findings emphasize the need for increased efforts to better educate patients on the impact of prematurity and the safety and benefits of TVU CL screening as an evidence-based strategy for PTB prevention., (Copyright © 2021. Published by Elsevier Inc.)

Research experience provides critical training for new biomedical research scientists. Students from underrepresented populations studying science, technology, engineering, and mathematics (STEM) are increasingly recruited into research pathways to diversify STEM fields. However, support structures outside of research settings designed to help these students navigate biomedical research pathways are not always available; nor are program support components outside the context of laboratory technical skills training and formal mentorship well understood. This study leveraged a multi-institutional research training program, Enhancing Cross-Disciplinary Infrastructure and Training at Oregon (EXITO), to explore how nine institutions designed a new curricular structure (Enrichment) to meet a common goal of enhancing undergraduate research training and student success. EXITO undergraduates participated in a comprehensive, 3-year research training program with the Enrichment component offered across nine sites: three universities and six community colleges, highly diverse in size, demographics, and location. Sites' approaches to supporting students in the training program were studied over a 30-month period. All sites independently created their own nonformal curricular structures, implemented interprofessionally via facilitated peer groups. Site data describing design and implementation were thematically coded to identify essential programmatic components across sites, with student feedback used to triangulate findings. Enrichment offered students time to critically reflect on their interests, experiences, and identities in research; network with peers and professionals; and support negotiation of hidden and implicit curricula. Students reported the low-pressure setting and student-centered curriculum balanced the high demands associated with academics and research. Core curricular themes described Enrichment as fostering a sense of community among students, exposing students to career paths and skills, and supporting development of students' professional identities. The non-formal, interprofessional curricula enabled students to model diverse biomedical identities and pathways for each other while informing institutional structures to improve diverse undergraduate students' success in academia and research.

The association of co-occurring prenatal stress and tobacco exposures on childhood wheezing and asthma are not well established. In this study, we compared maternal prenatal hair cortisol concentration (HCC) to the maternal report of infant wheezing (y/n) in the first year of life among mother-infant dyads exposed to tobacco smoke and socioeconomic adversity. Data were obtained from the Vitamin C to Decrease Effects of Smoking in Pregnancy on Infant Lung Function study. Maternal adversity was defined by the level of education, household income, and health insurance provider. Hair was collected at delivery, representing average circulating third-trimester cortisol levels. HCC was log transformed and dichotomized into high/low cortisol groups that were placed into a multivariate model predicting wheeze. Subjects ( n = 132) were primarily White with ≤high school education and receiving government-provided health insurance. Forty-five percent of infants wheezed. Average HCC was 3.39 pg/mg hair. Women with HCC > 3.55 pg/mg were more than twice as likely to report having a child who wheezed (odds ratio 2.56, 95% confidence interval 1.22-5.40; p = 0.01), adjusting for insurance provider and maternal asthma. Among this sample of dyads with prenatal smoke exposure, elevated maternal HCC was associated with child wheeze that was not diminished after consideration of covariates.

Background: Appalachian Kentucky has higher-than-average rates of preterm birth (PTB)-a health disparity associated with increased maternal and fetal/neonatal morbidity and neonatal mortality. Transvaginal ultrasound (TVU) cervical length measurement is the best predictor of PTB risk, but is underutilized in Appalachia. This study explores prenatal care providers' TVU-related knowledge and practices, and identifies barriers and facilitators, which impact the adoption of this evidence-based technology. Materials and Methods: This study recruited providers from three Appalachian Kentucky health care sites. Prenatal care providers took part in semistructured interviews and completed brief survey scales. Questions focused on PTB knowledge, TVU-related barriers, and suggestions for clinician and/or patient-focused interventions. Transcripts were coded using a multistage process based in grounded theory. Descriptive statistics were calculated. Results: Eleven physicians, one nurse practitioner, one physician assistant, and one midwife completed interviews. Average participant age was 44 years with 17 years in practice; 43% of providers were female. Practitioners described the sociodemographic characteristics, health behaviors ( e.g. , smoking, opioid abuse), and comorbid conditions ( e.g. , obesity, hypertension, and diabetes) endemic in Appalachia that heightened their patients' PTB risk. TVU use was reported as important by all respondents, but not all were satisfied with their level of training. The most commonly identified barriers to TVU were patient access to transportation and social support. Participants stressed a need for changing community perceptions regarding consequences of PTB. Conclusions: Providers identified multiple TVU-related barriers and facilitators. These data will inform the design of a multifaceted dissemination and implementation strategy targeting PTB prevention in Appalachia., Competing Interests: No competing financial interests exist., (© Anna Hansen et al. 2020; Published by Mary Ann Liebert, Inc.)

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 FEF 75 (adjusted 95% CI for difference 6.6 to 73.8; p=0.025); 58.3 mL·sec -1 for FEF 50 (95% CI 10.9 to 105.8; p=0.0081); and 55.1 mL·sec -1 for FEF 25-75 (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., (Copyright ©ERS 2020.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (© The Association for Clinical and Translational Science 2020.)

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.

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 FEF 75 at 3 months of age performed with the raised volume rapid thoracic compression technique (Jaeger/Viasys). FEF 50 and FEF 25-75 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 FEF 75 (200.7 vs. 188.7 ml/s; adjusted 95% confidence interval [CI] for difference, -3.33 to 35.64; P  = 0.10), FEF 50 (436.7 vs. 408.5 ml/s; adjusted 95% CI for difference, 6.10-61.30; P  = 0.02), and FEF 25-75 (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 FEF 75 was not improved after vitamin C supplementation to pregnant smokers, the predetermined secondary outcomes FEF 50 and FEF 25-75 were significantly improved. These results extend our previous findings and demonstrate improved airway function (FEF 50 and FEF 25-75 ) at 3 months of age in infants after vitamin C supplementation to pregnant smokers. Clinical trial registered with www.clinicaltrials.gov (NCT01723696).

Background: Little is known about the burden of atopic dermatitis (AD) encountered in US primary care practices and the frequency and type of skin care practices routinely used in children., Objective: To estimate the prevalence of AD in children 0 to 5 years attending primary care practices in the United States and to describe routine skin care practices used in this population., Design: A cross-sectional survey study of a convenience sample of children under the age of 5 attending primary care practices for any reason., Setting: Ten primary care practices in 5 US states., Results: Among 652 children attending primary care practices, the estimated prevalence of ever having AD was 24% (95% CI, 21-28) ranging from 15% among those under the age of 1 to 38% among those aged 4 to 5 years. The prevalence of comorbid asthma was higher among AD participants compared to those with no AD, namely, 12% and 4%, respectively ( P < .001). Moisturizers with high water:oil ratios were most commonly used (ie, lotions) in the non-AD population, whereas moisturizers with low water:oil content (ie, ointments) were most common when AD was present., Conclusions: Our study found a large burden of AD in the primary care practice setting in the US. The majority of households reported skin care practices that may be detrimental to the skin barrier, such as frequent bathing and the routine use of moisturizers with high water: oil ratios. Clinical trials are needed to identify which skin care practices are optimal for reducing the significant burden of AD in the community., Competing Interests: Conflict of interest: none declared., (© Copyright 2019 by the American Board of Family Medicine.)

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., (Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: Colon cancer screening is effective. To complete screening in 80% of individuals over age 50 years by 2018 will require adequate colonoscopy capacity throughout the country, including rural areas, where colonoscopy providers may have less specialized training. Our aim was to study the quality of colonoscopy in rural settings., Methods: The Clinical Outcomes Research Initiative (CORI) and the Oregon Rural Practice-based Research Network (ORPRN) collaborated to recruit Oregon rural practices to submit colonoscopy reports to CORI's National Endoscopic Database (NED). Ten ORPRN sites were compared to non-ORPRN rural (n = 11) and nonrural (n = 43) sites between January 2009 and October 2011. Established colonoscopy quality measures were calculated for all sites., Results: No ORPRN physicians were gastroenterologists compared with 82% of nonrural physicians. ORPRN practices reached the cecum in 87.4% of exams compared with 89.3% of rural sites (P = .0002) and 90.9% of nonrural sites (P < .0001). Resected polyps were less likely to be retrieved (84.7% vs 91.6%; P < .0001) and sent to pathology (77.1% vs 91.3%; P < .0001) at ORPRN practices compared to nonrural sites. The overall polyp detection (39.0% vs 40.3%) was similar (P = .217) between ORPRN and nonrural practices. Of exams with polyps, the rate for largest polyp on exam 6-9 mm was 20.8% at ORPRN sites, compared to 26.8% at nonrural sites (P < .0001), and for polyps >9mm 16.6% vs 18.7% (P = .106)., Conclusion: ORPRN sites performed well on most colonoscopy quality measures, suggesting that high-quality colonoscopy can be performed in rural settings., (© 2016 National Rural Health Association.)

Background: Fever is strongly associated with poor outcome after traumatic brain injury (TBI). We hypothesized that early fever is a direct result of brain injury and thus would be more common in TBI than in patients without brain injury and associated with inflammation., Methods: We prospectively enrolled patients with major trauma with and without TBI from a busy Level I trauma center intensive care unit (ICU). Patients were assigned to one of four groups based on their presenting Head Abbreviated Injury Severity Scale scores: multiple injuries: head Abbreviated Injury Scale (AIS) score greater than 2, one other region greater than 2; isolated head: head AIS score greater than 2, all other regions less than 3; isolated body: one region greater than 2, excluding head/face; minor injury: no region with AIS greater than 2. Early fever was defined as at least one recorded temperature greater than 38.3°C in the first 48 hours after admission. Outcome measures included neurologic deterioration, length of stay in the ICU, hospital mortality, discharge Glasgow Outcome Scale-Extended, and plasma levels of seven key cytokines at admission and 24 hours (exploratory)., Results: Two hundred sixty-eight patients were enrolled, including subjects with multiple injuries (n = 59), isolated head (n = 97), isolated body (n = 100), and minor trauma (n = 12). The incidence of fever was similar in all groups irrespective of injury (11-24%). In all groups, there was a significant association between the presence of early fever and death in the hospital (6-18% vs. 0-3%), as well as longer median ICU stays (3-7 days vs. 2-3 days). Fever was significantly associated with elevated IL-6 at admission (50.7 pg/dL vs. 16.9 pg/dL, p = 0.0067) and at 24 hours (83.1 pg/dL vs. 17.1 pg/dL, p = 0.0025) in the isolated head injury group., Conclusion: Contrary to our hypothesis, early fever was not more common in patients with brain injury, though fever was associated with longer ICU stays and death in all groups. Additionally, fever was associated with elevated IL-6 levels in isolated head injury., Level of Evidence: Prognostic and Epidemiological study, level III.

Background and Purpose: As part of the NIH BUILD initiative to diversify the scientific workforce, the EXITO project is a large multi-institutional effort to provide comprehensive support and training for undergraduates from traditionally underrepresented student populations who aspire to health-related research careers. Portland State University, a major public urban university that prioritizes student access and opportunity, and Oregon Health & Science University, a research-intensive academic health center, lead the EXITO network comprised of eleven 2-year and 4-year institutions of higher education spanning Oregon, Washington, Alaska, Hawaii, Guam, American Samoa, and the Northern Mariana Islands. The EXITO project aims for impact in biomedical research by training diverse scholars from indigenous and underserved communities affected by adverse health disparities., Project Approach: Guided by socio-ecological theory, the EXITO project is a multi-level intervention offering a three-year research training pathway for scholars in the biomedical, behavioral, health, and social sciences. Fundamental components of the model include student outreach and engagement, integrated curricular enhancements, intensive research experiences, multi-faceted developmental mentoring, supportive community and services, and rigorous evaluation and quality improvement. EXITO also advances faculty and institutional development in these domains by holding curriculum development conferences, creating research learning communities, awarding pilot project research funding, providing mentor training and ongoing support, collaborating with other research equity programs, and developing campus infrastructure and services to support scholars with diverse backgrounds and needs., Highlights: The large and geographically broad network of EXITO institutions engages a range of diverse students, including indigenous populations and students beginning post-secondary education at community colleges. The EXITO model specifically accommodates many students transferring from 2-year partner institutions and facilitates seamless transfer to the 4-year institution. EXITO features several approaches to research training, including supported summer entry into research placements, the incorporation of responsible conduct of research content into general education curriculum, and the intentional matching of scholars with three types of mentors (e.g., peer, career, research)., Implications: EXITO provides an example of a comprehensive research training initiative for traditionally underrepresented students that can be implemented across a diverse range of 2-year and 4-year institutions., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a rare World Health Organization (WHO) grade I neoplasm. Gross total resection (GTR) is the treatment of choice, and there is no firm evidence supporting other treatment options when GTR is not feasible., Case Description: We report a 6-year-old boy who, following an initial subtotal resection of a fourth ventricular RGNT, received an individualized chemotherapy protocol with vincristine, etoposide, and carboplatin for 3 cycles. The tumor was stable for 2 years after the completion of chemotherapy but then began to progress, at which point GTR was successfully performed. In addition, we completed a comprehensive literature review of RGNT cases. To date, a total of 104 cases have been reported, 33 of which are pediatric cases. Recurrence has been reported in only 7 cases of all ages (4 in the pediatric population). Radiotherapy has been used in several cases, but adjuvant chemotherapy has been reported only once following a recurrence., Conclusions: We report a case of chemotherapy administration as a first-line treatment for a subtotally resected RGNT. Chemotherapy may be considered as an adjuvant therapy option for RGNT when GTR cannot be achieved. Furthermore, increased incidence of recurrence in the pediatric population may suggest that the tumor biology of RGNT in children differs from that in adults., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To assess reliability, validity, and responsiveness of a 29-item short-form version of the Patient Reported Outcomes Measurement Information System (PROMIS) and a novel “impact score” calculated from those measures., Design: Prospective cohort study., Setting: Rural primary care practices., Subjects: Adults aged ≥ 55 years with chronic musculoskeletal pain, not currently receiving prescription opioids., Methods: Subjects completed the PROMIS short form at baseline and after 3 months. Patient subsets were compared to assess reliability and responsiveness. Construct validity was tested by comparing baseline scores among patients who were or were not applying for Worker's Compensation; those with higher or lower catastrophizing scores; and those with or without recent falls. Responsiveness was assessed with mean score changes, effect sizes, and standardized response means., Results: Internal consistency was good to excellent, with Cronbach's alpha between 0.81 and 0.95 for all scales. Among patients who rated their pain as stable, test-retest scores at 3 months were around 0.70 for most scales. PROMIS scores were worse among patients seeking or receiving worker's compensation, those with high catastrophizing scores, and those with recent falls. Among patients rating pain as “much less” at 3 months, absolute effect sizes for the various scales ranged from 0.24 (Depression) to 1.93 (Pain Intensity)., Conclusions: Results indicate that the PROMIS short 29-item form may be useful for the study of patients with chronic musculoskeletal pain. Our findings also support use of the novel “impact score” recommended by the National Institutes of Health (NIH) Task Force on Research Standards for Chronic Low Back Pain.

Background and Objectives: Optimal BP targets for older adults with CKD are unclear. This study sought to determine whether a nonlinear relationship between BP and mortality-as described for the broader CKD population and for older adults in the general population-is present for older adults with CKD., Design, Setting, Participants, & Measurements: A cohort of 21,015 adults age 65-105 years with a moderate or severe reduction in eGFR (<60 ml/min per 1.73 m(2)) were identified within the Kaiser Permanente Northwest Health Maintenance Organization population. The relationship between baseline systolic BP (SBP; ≤120, 121-130, 131-140, 141-150, >150 mmHg; referent, 131-140 mmHg) and all-cause mortality across age groups (65-70, 71-80, and >80 years) was examined; patients were followed for up to 11 years after cohort entry., Results: The median times at risk were 3.15 years, 3.53 years, and 2.76 years for adults age 65-70, 71-80, and >80 years, respectively. Mortality during follow-up was 19.6% for those age 65-70 years, 33.4% for those age 71-80 years, and 55.7% for those age >80 years. The relationship between SBP and mortality varied as a function of age. The risk of death was highest for patients with the lowest SBP in all age groups. Only among adults age 65-70 years was an SBP>140 mmHg associated with a higher risk of death compared with the referent category. Patterns of age modification of the relationship between SBP and mortality were consistent in all sensitivity analyses., Conclusions: In a cohort of older adults, the relationship between SBP and mortality varied systematically with age. A relationship between higher SBP and mortality was present only for younger members of this cohort and not for those older than 70. These results raise the question of whether the relative benefits and harms of lowering BP to recommended targets for older adults with CKD may vary as a function of age., (Copyright © 2015 by the American Society of Nephrology.)

The diagnostic utility of obtaining chest and abdomen computed tomography (CT) to evaluate for invasive fungal infection (IFI) before and after hematopoietic stem cell transplant (HSCT) remains unclear. The study was conducted as a quality improvement project. Chest and abdomen CT of patients who underwent an allogeneic HSCT over a 13-month period were reviewed. Scans included those performed pretransplant in all patients and days 0 to 100 post-transplant in selected patients. Sixty-six patients had chest and abdomen CT scans pretransplant. Chest CT was suggestive of IFI in 9 patients (13.6%), including 3 patients with prior history of IFI. After transplant, 37 patients had an initial chest CT and 14 patients an initial abdominal CT. The first chest CT post-transplant was suggestive of IFI in 3 patients; all had an abnormal CT pretransplant. After the initial post-transplant evaluation, 15 patients had 28 additional CT scans of the chest and 12 patients 19 additional CT scans of the abdomen. An abnormal chest CT with proven evidence of IFI was seen in only 1 patient. None of the 99 abdominal CT scans performed pre- or post-transplant had evidence of IFI. There is little benefit in obtaining abdominal CT scans in HSCT patients for detecting IFI either pre- or post-transplant., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: To develop mortality risk prediction models for older adults with chronic kidney disease (CKD) that include comorbidities and measures of health status and use not associated with particular comorbid conditions (nondisease-specific measures)., Design: Retrospective cohort study., Setting: Kaiser Permanente Northwest (KPNW) Health Maintenance Organization., Participants: Individuals with severe CKD (estimated glomerular filtration rate<30 mL/min per 1.73 m2; N=4,054; n=1,915 aged 65-79, n=2,139 aged ≥80) who received care at KPNW between 2000 and 2008., Measurements: Cox proportional hazards analysis was used to examine the association between selected participant characteristics and all-cause mortality and to generate age group-specific risk prediction models. Predicted and observed risks were evaluated according to quintile. Predictors from the Cox models were translated into a points-based system. Internal validation was used to provide best estimates of how these models might perform in an external population., Results: The risk prediction models used 16 characteristics to identify participants with the highest risk of mortality at 2 years for adults aged 65 to 79 and 80 and older. Predicted and observed risks agreed within 5% for each quintile; a 4 to 5 times difference in 2-year predicted mortality risk was observed between the highest and lowest quintiles. The c-statistics for each model (0.68-0.69) indicated effective discrimination without evidence of significant overfit (slope shrinkage 0.06-0.09). Models for each age group performed similarly for mortality prediction at 6 months and 2 years in terms of discrimination and calibration., Conclusion: When validated, these risk prediction models may be helpful in supporting discussions about prognosis and treatment decisions sensitive to prognosis in older adults with CKD in real-world clinical settings., (© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.)

Purpose: The purpose of this study was to examine associations between the number and types of patients' chronic diseases and being up to date for breast, cervical, and colorectal cancer screening., Methods: Data were abstracted from medical charts at 4 primary care clinics located in 2 rural Oregon communities. Eligibility criteria included being at least 55 years old and having at least 1 clinic visit in the past 2 years., Results: Of 3433 patients included, 503 (15%) had no chronic illness, 646 (19%) had 1, 786 (23%) had 2, and 1498 (44%) had ≥3 chronic conditions. Women with asthma/chronic lung disease and with cardiovascular disease were less likely to be up o date for mammography screening (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.43-0.80), and those with chronic digestive disorders were more likely to be up to date for mammography (OR, 1.31; 95% CI, 1.03-1.66) compared with those without chronic conditions. Women with arthritis, diabetes mellitus, and hypertension were less likely to be up to date for cervical cancer screening (OR, 0.38; 95% CI, 0.21-0.68) compared with those without chronic conditions. Men with cardiovascular disease were less likely to be up to date for colorectal cancer screening (adjusted OR, 0.59; 95% CI, 0.44-0.80), and women with depression were less likely to be up to date (OR, 0.71; 95% CI, 0.56-0.91) compared with men and women without chronic conditions., Conclusion: Specific chronic conditions were found to be associated with up-to-date status for cancer screening. This finding may help practices to identify patients who need to receive cancer screening., (© Copyright 2014 by the American Board of Family Medicine.)

Background & Aims: Colorectal cancer risk differs based on patient demographics. We aimed to measure the prevalence of significant colorectal polyps in average-risk individuals and to determine differences based on age, sex, race, or ethnicity., Methods: In a prospective study, colonoscopy data were collected, using an endoscopic report generator, from 327,785 average-risk adults who underwent colorectal cancer screening at 84 gastrointestinal practice sites from 2000 to 2011. Demographic characteristics included age, sex, race, and ethnicity. The primary outcome was the presence of suspected malignancy or large polyp(s) >9 mm. The benchmark risk for age to initiate screening was based on white men, 50-54 years old., Results: Risk of large polyps and tumors increased progressively in men and women with age. Women had lower risks than men in every age group, regardless of race. Blacks had higher risk than whites from ages 50 through 65 years and Hispanics had lower risk than whites from ages 50 through 80 years. The prevalence of large polyps was 6.2% in white men 50-54 years old. The risk was similar among the groups of white women 65-69 years old, black women 55-59 years old, black men 50-54 years old, Hispanic women 70-74 years old, and Hispanic men 55-59 years old. The risk of proximal large polyps increased with age, female sex, and black race., Conclusions: There are differences in the prevalence and location of large polyps and tumors in average-risk individuals based on age, sex, race, and ethnicity. These findings could be used to select ages at which specific groups should begin colorectal cancer screening., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Guidelines recommend a 10-year interval between screening colonoscopies with negative results for average-risk individuals. However, many patients are examined at shorter intervals. We investigated outcomes of individuals with no polyps who had repeat colonoscopy in <10 years., Methods: Data were collected using the National Endoscopic Database, from 69 gastroenterology centers, on 264,184 asymptomatic subjects who underwent screening colonoscopies from 2000 through 2006, were found to have no polyps, and received another colonoscopy examination within <10 years., Results: No polyps were found in 147,375 patients during a baseline colonoscopy; 17,525 patients (11.9%) had a follow-up colonoscopy within <10 years, including 1806 (10.3%) who received the follow-up colonoscopy within <1 year. The most common reason for repeating the examination within 1 year was that the first was compromised by inadequate bowel preparation or incomplete examination. Of these patients, 6.5% (95% confidence interval: 5.3-7.6) had large polyp(s) >9 mm-a proportion similar to the prevalence in the average-risk screening population. Reasons that examinations were repeated within 1-5 years included average-risk screening (15.7%), family history of colon polyps or cancer (30.1%), bleeding (31.2%), gastrointestinal symptoms (11.8%), or a positive result from a fecal blood test (5.5%). If the baseline examination was adequate, the incidence of large polyps within 1-5 years after baseline colonoscopy was 3.1% (95% confidence interval: 2.7-3.5) and within years 5-10 years was 3.7% (95% confidence interval: 3.3-4.1)., Conclusions: Repeat colonoscopies within 10 years are of little benefit to patients who had adequate examinations and were found to have no polyps. Repeat colonoscopies are beneficial to patients when the baseline examination was compromised., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Understanding colonoscopy utilization and outcomes can help determine when the procedure is most effective., Objective: To study trends in utilization and outcomes of colonoscopy in the United States from 2000 to 2011., Design: Prospective collection of colonoscopy data., Setting: A total of 84 adult diverse GI practices., Patients: All adult patients receiving colonoscopy for any reason., Intervention: Colonoscopy., Main Outcome Measurements: Polyps >9 mm or suspected malignant tumor., Results: We analyzed 1,372,838 reports. The most common reason for colonoscopy in patients aged <50 years is evaluation of symptoms such as irritable bowel syndrome (IBS) (28.7%) and bleeding or anemia (35.3%). In patients aged 50 to 74 years, colorectal cancer screening accounts for 42.9% of examinations. In patients aged >74 years, surveillance for cancer or polyps is the most common indication. The use of colonoscopy for average-risk screening increased nearly 3-fold during the study period. The prevalence of large polyps increases with age and is higher in men for every procedure indication. The prevalence of large polyps in patients with symptoms of IBS was lower than in those undergoing average-risk screening (odds ratio [OR] 0.85; 95% confidence interval [CI], 0.83-0.87). With increasing age, there was a shift from distal to proximal large polyps. The rate of proximal large polyps is higher in the black population compared with the white population (OR 1.19; 95% CI, 1.13-1.25)., Limitations: In the absence of pathology data, use of surrogate as the main outcome., Conclusion: Colonoscopy utilization changed from 2000 to 2011, with an increase in primary screening. The proximal location of large polyps in the black population and with advancing age has implications for screening and surveillance., (Copyright © 2014 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

We have created an education and career development program within the CTSA structure at OHSU that serves the entire institution. We believe that this is unusual in scope among CTSA programs and has contributed to an increase in career development funding and research skills among fellows and faculty. While the key element is the institutional scope, important elements include: Tailoring programs of emphasis to points of inflection on the career pathway. Minimizing barriers to education by creating a flexible, tuition-free program. An integrated one-stop education and career development approach. An institutional program for career development award applicants as well as recipients. This career development program was developed within the context of a midsize health science university but the overall strategy may be applied to other CTSAs to simplify and reduce costs of education program development.

Importance: Maternal smoking during pregnancy adversely affects offspring lung development, with lifelong decreases in pulmonary function and increased asthma risk. In a primate model, vitamin C blocked some of the in-utero effects of nicotine on lung development and offspring pulmonary function., Objective: To determine if newborns of pregnant smokers randomized to receive daily vitamin C would have improved results of pulmonary function tests (PFTs) and decreased wheezing compared with those randomized to placebo., Design, Setting, and Participants: Randomized, double-blind trial conducted in 3 sites in the Pacific Northwest between March 2007 and January 2011. One hundred fifty-nine newborns of randomized pregnant smokers (76 vitamin C treated and 83 placebo treated) and 76 newborns of pregnant nonsmokers were studied with newborn PFTs. Follow-up assessment including wheezing was assessed through age 1 year, and PFTs were performed at age 1 year., Interventions: Pregnant women were randomized to receive vitamin C (500 mg/d) (n = 89) or placebo (n = 90)., Main Outcomes and Measures: The primary outcome was measurement of newborn pulmonary function (ratio of the time to peak tidal expiratory flow to expiratory time [TPTEF:TE] and passive respiratory compliance per kilogram [Crs/kg]) within 72 hours of age. Secondary outcomes included incidence of wheezing through age 1 year and PFT results at age 1 year. A subgroup of pregnant smokers and nonsmokers had genotyping performed., Results: Newborns of women randomized to vitamin C (n = 76), compared with those randomized to placebo (n = 83), had improved pulmonary function as measured by TPTEF:TE (0.383 vs 0.345 [adjusted 95% CI for difference, 0.011-0.062]; P = .006) and Crs/kg (1.32 vs 1.20 mL/cm H2O/kg [95% CI, 0.02-0.20]; P = .01). Offspring of women randomized to vitamin C had significantly decreased wheezing through age 1 year (15/70 [21%] vs 31/77 [40%]; relative risk, 0.56 [95% CI, 0.33-0.95]; P = .03). There were no significant differences in the 1-year PFT results between the vitamin C and placebo groups. The effect of maternal smoking on newborn lung function was associated with maternal genotype for the α5 nicotinic receptor (rs16969968) (P < .001 for interaction)., Conclusions and Relevance: Supplemental vitamin C taken by pregnant smokers improved newborn PFT results and decreased wheezing through 1 year in the offspring. Vitamin C in pregnant smokers may be an inexpensive and simple approach to decrease the effects of smoking in pregnancy on newborn pulmonary function and respiratory morbidities., Trial Registration: clinicaltrials.gov Identifier: NCT00632476.

Background: The education and training of early career biomedical translational researchers often involves formal mentoring by more experienced colleagues., Purposes: This study investigated the nature of these mentoring relationships from the perspective of mentees. The objective was to understand the challenges and issues encountered by mentees in forming and maintaining productive mentoring relationships., Methods: Three focus groups (n=14) were conducted with early career researchers who had mentored career development awards. Thematic analysis identified, categorized, and illustrated the challenges and issues reported by mentees., Results: The range of mentee challenges was reflected in five major categories: (a) network--finding appropriate mentors to meet various needs; (b) access--structuring schedules and opportunities to receive mentoring; (c) expectations--negotiating the mechanics of the mentoring relationship and its purpose; (d) alignment--managing mentor-mentee mismatches regarding interests, priorities, and goals; and (e) skills and supports--developing the institutional supports to be successful., Conclusions: Mentoring relationships created for academic training and career development contend with tasks common to many other relationships, namely, recognizing compatibility, finding time, establishing patterns, agreeing to goals, and achieving aims. Identifying challenges faced by mentees can facilitate the development of appropriate trainings and supports to foster mentoring relationships in academic and career settings.