Evaluating participant engagement in a preconception cohort study in relation to the Dobbs decision.

BACKGROUND: On June 24th, 2022, the United States (US) Supreme Court's ruling in Dobbs v. Jackson, et al. (hereafter, the Dobbs decision) removed federal-level protections for induced abortion, sparking concerns about reproductive rights and health privacy. Although other pregnancy outcomes (e.g. spontaneous abortion, ectopic pregnancy) are not explicit targets of post-Dobbs abortion bans, study participants may be worried about how their reproductive health data are used by researchers in the post-Dobbs era. OBJECTIVE: To evaluate the extent to which the Dobbs decision influenced participant's engagement in a preconception cohort study. METHODS: We leveraged data spanning 20 weeks before and after the Dobbs decision (4 February 2022, to 11 November 2022) from US participants in Pregnancy Study Online (PRESTO), an internet-based prospective preconception cohort study of couples attempting conception. We categorised participants' state-level abortion access by residential location: banned or restricted rights; limited access; and protected rights. We evaluated three participant engagement outcomes: follow-up questionnaire completion; report of a pregnancy; and clicking on the invitation link for a fertility-tracking app. We fit separate linear regression models and restricted cubic splines to compare outcome prevalence before and after the Dobbs decision by state-level abortion category. RESULTS: A total of 585 newly enrolled participants and 1247 already-enrolled participants received 2802 invitations to complete a follow-up questionnaire. In states with limited or protected abortion rights, we observed little change in participant engagement. In states with banned or restricted abortion rights, however, we observed a 27.12 percentage point reduction (95% confidence interval -43.68, -10.51) in the prevalence of clicking on the invitation link for the fertility-tracking app comparing the post- versus pre-Dobbs periods. CONCLUSIONS: There was some evidence of reduced participant engagement after the Dobbs decision in states with banned or restricted abortion rights, indicating potentially deleterious effects on the conduct of reproductive health studies.

Roadway construction as a natural experiment to examine air pollution impacts on infant health.

Traffic-related air pollution (TRAP) poses a significant public health risk that is associated with adverse birth outcomes. Large roadway infrastructure projects present a natural experiment to examine how resulting congestion change is associated with adverse birth outcomes for nearby populations. This study is designed to examine the influence of living close to a roadway before, during, and after a construction project using a difference-in-differences design. We integrated data on all large roadway construction projects (defined as widening of existing roads, building new roads, improving bridges, installing intelligent transportation systems, improving intersections, and installing or upgrading traffic signals) in Texas from 2007 to 2016 with Vital Statistic data for all births with residential addresses within 1 km of construction projects. Our outcomes included term low birth weight, term birth weight, preterm birth, and very preterm birth. Using a difference-in-differences design, we included births within 3 years of construction start and 2 years of construction end. In our main model, the exposed group is limited to pregnant individuals residing within 300 m of a construction project, and the control group includes those living within 300-1000 m from a project. We used regression models to estimate the influence of construction on infant health. We included 1,360 large roadway construction projects linked to 408,979 births. During construction, we found that the odds of term low birth weight increased by 19% (95% CI: 1.05, 1.36). However, we saw little evidence of an association for other birth outcomes. Contrary to our hypothesis of decreased TRAP after construction ends, we did not observe consistent improvements post-construction for pregnant individuals living within 300 m. Continued consideration of the influence of traffic congestion programs on birth outcomes is necessary to inform future policy decisions.

A population-based cohort study of electronic tolling, traffic congestion, and adverse birth outcomes.

BACKGROUND: Although traffic-related air pollution is largely regulated at the federal level, congestion reduction projects may reduce local traffic and air pollution to levels that create positive co-benefits for population health. In recent years, many urban areas have implemented electronic tolling systems to improve traffic conditions. OBJECTIVE: Quantify associations between implementing electronic tolling and local changes in traffic and infant health. METHODS: Using a population-based birth cohort (Texas, 1999-2016), we calculated residential proximity to the nearest tolled road segment within 5 km (n = 625,279) and examined changes in local traffic before and after toll implementation. Using a difference-in-differences design, we compared four markers of adverse birth outcomes (term birth weight, term low birth weight, preterm birth, very preterm birth) among infants from pregnant people residing < 0.5 km from a road segment before and after the tolls were implemented and compared them to a contemporaneous population of pregnant people residing at 2-5 km. RESULTS: We observed minimal changes in local traffic after the implementation of tolling. Among births within 500 m of a tolled road, we found little evidence of an association between the implementation of tolling and adverse birth outcomes (term birth weight [ß: -4.5, 95 % CI: -11.7, 2.6], term low birth weight [OR: 1.00, 95 % CI: 0.89, 1.13], preterm birth [OR: 0.99, 95 % CI: 0.92, 1.05], very preterm birth [OR: 1.00, 95 % CI: 0.84, 1.18]), compared to the contemporaneous control group of births at 2-5 km. In sub-analyses, we found some evidence of a reduced association between toll booth removal and preterm birth (OR: 0.84, 95 % CI: 0.70, 1.01) but not for other outcomes or tolling types. DISCUSSION: In this large population-based retrospective cohort study of births in Texas, we found little evidence that the implementation of tolling was consistently associated with improvements in local infant health outcomes.

Association between job control and time to pregnancy in a preconception cohort.

OBJECTIVE: To evaluate associations between low job control (operationalized as job independence and freedom to make decisions) and time to pregnancy. Low job control, a form of workplace stress, is associated with adverse health outcomes ranging from cardiovascular disease to premature mortality; few studies have specifically examined its association with reproductive outcomes. DESIGN: We used data from Pregnancy Study Online, an internet-based preconception cohort study of couples trying to conceive in the United States and Canada. We estimated fecundability ratios (FRs) and 95% confidence intervals (CIs) via proportional probability regression models, adjusting for sociodemographic and behavioral characteristics. SETTING: Not applicable (Web-based study). PATIENTS: Participants self-identified as female, were aged 21-45 years, and reported ≤6 cycles of pregnancy attempt time at enrollment (2018-2022). EXPOSURE: We assessed job control by matching participants' baseline self-reported occupation and industry with standardized occupation codes from the National Institute for Occupational Safety and Health's Industry and Occupation Computerized Coding System, then linking codes to O∗NET job exposure scores for job independence and freedom to make decisions. MAIN OUTCOME MEASURE: Our main outcome measure was fecundability. Participants completed self-administered questionnaires at baseline and every 8 weeks for up to 12 months or until reported pregnancy, whichever occurred first. RESULTS: Among 3,110 participants, lower job independence was associated with reduced fecundability. Compared with the fourth (highest) quartile, corresponding to the most job independence, FRs (95% CI) for first (lowest), second, and third quartiles were 0.92 (0.82-1.04), 0.84 (0.74-0.95), and 0.99 (0.88, 1.11), respectively. Lower freedom to make decisions was associated with slightly reduced fecundability (first vs. fourth quartile: FR = 0.92; 95% CI: 0.80-1.05). CONCLUSION: Lower job control, a work-related stressor, may adversely influence time to pregnancy. Because job control is a condition of work (i.e., not modifiable by individuals), these findings may strengthen arguments for improving working conditions as a means of improving worker health, including fertility.

Ambient air pollution and rate of spontaneous abortion.

Spontaneous abortion (SAB), defined as a pregnancy loss before 20 weeks of gestation, affects up to 30% of conceptions, yet few modifiable risk factors have been identified. We estimated the effect of ambient air pollution exposure on SAB incidence in Pregnancy Study Online (PRESTO), a preconception cohort study of North American couples who were trying to conceive. Participants completed questionnaires at baseline, every 8 weeks during preconception follow-up, and in early and late pregnancy. We analyzed data on 4643 United States (U.S.) participants and 851 Canadian participants who enrolled during 2013-2019 and conceived during 12 months of follow-up. We used country-specific national spatiotemporal models to estimate concentrations of particulate matter <2.5 µm (PM2.5), nitrogen dioxide (NO2), and ozone (O3) during the preconception and prenatal periods at each participant's residential address. On follow-up and pregnancy questionnaires, participants reported information on pregnancy status, including SAB incidence and timing. We fit Cox proportional hazards regression models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of time-varying prenatal concentrations of PM2.5, NO2, and O3 with rate of SAB, adjusting for individual- and neighborhood-level factors. Nineteen percent of pregnancies ended in SAB. Greater PM2.5 concentrations were associated with a higher incidence of SAB in Canada, but not in the U.S. (HRs for a 5 µg/m3 increase = 1.29, 95% CI: 0.99, 1.68 and 0.94, 95% CI: 0.83, 1.08, respectively). NO2 and O3 concentrations were not appreciably associated with SAB incidence. Results did not vary substantially by gestational weeks or season at risk. In summary, we found little evidence for an effect of residential ambient PM2.5, NO2, and O3 concentrations on SAB incidence in the U.S., but a moderate positive association of PM2.5 with SAB incidence in Canada.

Air pollution and fecundability in a North American preconception cohort study.

BACKGROUND: Animal and epidemiologic studies indicate that air pollution may adversely affect fertility. However, the level of evidence is limited and specific pollutants driving the association are inconsistent across studies. METHODS: We used data from a web-based preconception cohort study of pregnancy planners enrolled during 2013-2019 (Pregnancy Study Online; PRESTO). Eligible participants self-identified as female, were aged 21-45 years, resided in the United States (U.S.) or Canada, and were trying to conceive without fertility treatments. Participants completed a baseline questionnaire and bi-monthly follow-up questionnaires until conception or 12 months. We analyzed data from 8,747 participants (U.S.: 7,304; Canada: 1,443) who had been trying to conceive for < 12 cycles at enrollment. We estimated residential ambient concentrations of particulate matter < 2.5 µm (PM2.5), nitrogen dioxide (NO2), and ozone (O3) using validated spatiotemporal models specific to each country. We fit country-specific proportional probabilities regression models to estimate the association between annual average, menstrual cycle-specific, and preconception average pollutant concentrations with fecundability, the per-cycle probability of conception. We calculated fecundability ratios (FRs) and 95% confidence intervals (CIs) and adjusted for individual- and neighborhood-level confounders. RESULTS: In the U.S., the FRs for a 5-µg/m3 increase in annual average, cycle-specific, and preconception average PM2.5 concentrations were 0.94 (95% CI: 0.83, 1.08), 1.00 (95% CI: 0.93, 1.07), and 1.00 (95% CI: 0.93, 1.09), respectively. In Canada, the corresponding FRs were 0.92 (95% CI: 0.74, 1.16), 0.97 (95% CI: 0.87, 1.09), and 0.94 (95% CI: 0.80, 1.09), respectively. Likewise, NO2 and O3 concentrations were not strongly associated with fecundability in either country. CONCLUSIONS: Neither annual average, menstrual cycle-specific, nor preconception average exposure to ambient PM2.5, NO2, and O3 were appreciably associated with reduced fecundability in this cohort of pregnancy planners.

Large saccular intracranial aneurysm in a child with RASA1-associated capillary malformation-arteriovenous malformation syndrome: illustrative case.

BACKGROUND: Large cerebral aneurysms are much less common in children than in adults. Thus, when present, these lesions require careful surgical evaluation and comprehensive genetic testing. RASA1-associated capillary malformation-arteriovenous malformation (RASA1-CM-AVM) syndrome is a rare disorder of angiogenic remodeling known to cause port-wine stains and arteriovenous fistulas but not previously associated with pediatric aneurysms. OBSERVATIONS: The authors report the case of a previously healthy 6-year-old boy who presented with seizure-like activity. Imaging demonstrated a lesion in the right ambient cistern with compression of the temporal lobe. Imaging characteristics were suggestive of a thrombosed aneurysm versus an epidermoid cyst. The patient underwent craniotomy, revealing a large saccular aneurysm, and clip ligation and excision were performed. Postoperative genetic analysis revealed a RASA1-CM-AVM syndrome. LESSONS: This is a rare case of a RASA1-associated pediatric cerebral aneurysm in the neurosurgical literature. This unique case highlights the need for maintaining a broad differential diagnosis as well as the utility of genetic testing for detecting underlying genetic syndromes in young children presenting with cerebral aneurysms.

Neighborhood Characteristics and Elevated Blood Pressure in Older Adults.

Importance: The local environment remains an understudied contributor to elevated blood pressure among older adults. Untargeted approaches can identify neighborhood conditions interrelated with racial segregation that drive hypertension disparities. Objective: To evaluate independent associations of sociodemographic, economic, and housing neighborhood factors with elevated blood pressure. Design, Setting, and Participants: In this cohort study, the sample included Health and Retirement Study participants who had between 1 and 3 sets of biennial sphygmomanometer readings from 2006 to 2014 or 2008 to 2016. Statistical analyses were conducted from February 5 to November 30, 2021. Exposures: Fifty-one standardized American Community Survey census tract variables (2005-2009). Main Outcomes and Measures: Elevated sphygmomanometer readings over the study period (6-year period prevalence): a value of at least 140 mm Hg for systolic blood pressure and/or at least 90 mm Hg for diastolic blood pressure. Participants were divided 50:50 into training and test data sets. Generalized estimating equations were used to summarize multivariable associations between each neighborhood variable and the period prevalence of elevated blood pressure, adjusting for individual-level covariates. Any neighborhood factor associated (Simes-adjusted for multiple comparisons P ≤ .05) with elevated blood pressure in the training data set was rerun in the test data set to gauge model performance. Lastly, in the full cohort, race- and ethnicity-stratified associations were evaluated for each identified neighborhood factor on the likelihood of elevated blood pressure. Results: Of 12 946 participants, 4565 (35%) had elevated sphygmomanometer readings (median [IQR] age, 68 [63-73] years; 2283 [50%] male; 228 [5%] Hispanic or Latino, 502 [11%] non-Hispanic Black, and 3761 [82%] non-Hispanic White). Between 2006 and 2016, a lower likelihood of elevated blood pressure was observed (relative risk for highest vs lowest tertile, 0.91; 95% CI, 0.86-0.96) among participants residing in a neighborhood with recent (post-1999) in-migration of homeowners. This association was precise among participants with non-Hispanic White and other race and ethnicity (relative risk, 0.91; 95% CI, 0.85-0.97) but not non-Hispanic Black participants (relative risk, 0.97; 95% CI, 0.85-1.11; P = .48 for interaction) or Hispanic or Latino participants (relative risk, 0.84; 95% CI, 0.65-1.09; P = .78 for interaction). Conclusions and Relevance: In this cohort study of older adults, recent relocation of homeowners to a neighborhood was robustly associated with reduced likelihood of elevated blood pressure among White participants but not their racially and ethnically marginalized counterparts. Our findings indicate that gentrification may influence later-life blood pressure control.

Changes in Socioeconomic Disparities for Traffic-Related Air Pollution Exposure During Pregnancy Over a 20-Year Period in Texas.

Importance: Air pollution presents clear environmental justice issues. However, few studies have specifically examined traffic-related air pollution (TRAP), a source driven by historically racist infrastructure policies, among pregnant individuals, a population susceptible to air pollution effects. How these disparities have changed over time is also unclear but has important policy implications. Objective: To examine changes in TRAP exposure by sociodemographic characteristics among recorded pregnancies over a 20-year period. Design, Setting, and Participants: This population-based birth cohort study used descriptive analysis among pregnant individuals in Texas from 1996 to 2016. All pregnant individuals with valid residential address, socioeconomic, and demographic data were included. Individual-level race and ethnicity, education, and maternal birthplace data were extracted from birth certificates and neighborhood-level household income and historical neighborhood disinvestment (ie, redlining) data were assessed via residential addresses. Data analysis occurred between June 2022 and June 2023. Main Outcomes and Measures: The main outcome, TRAP exposure at residential addresses, was assessed via traffic levels, represented by total and truck-specific vehicle miles traveled (VMT) within 500 m; nitrogen dioxide (no2) concentrations from a spatial-temporal land use regression model (ie, vehicle tailpipe emissions); and National Air Toxic Agency cancer risk index from on-road vehicle emissions. TRAP exposure differences were assessed by sociodemographic indicators over the 1996 to 2016 period. Results: Among 7 043 598 pregnant people (mean [SD] maternal age, 26.8 [6.1] years) in Texas from 1996 to 2016, 48% identified as Hispanic or Latinx, 4% identified as non-Hispanic Asian or Pacific Islander, 12% identified as non-Hispanic Black, and 36% identified as non-Hispanic White. There were differences in TRAP for pregnant people by all sociodemographic variables examined. The absolute level of these disparities decreased from 1996 to 2016, but the relative level of these disparities increased: for example, in 1996, non-Hispanic Black pregnant individuals were exposed to a mean (SD) 15.3 (4.1) ppb of no2 vs 13.5 (4.4) ppb of no2 for non-Hispanic White pregnant individuals, compared with 2016 levels of 6.7 (2.4) ppb no2 for Black pregnant individuals and 5.2 (2.4) ppb of no2 for White pregnant individuals. Large absolute and relative differences in traffic levels were observed for all sociodemographic characteristics, increasing over time. For example, non-Hispanic Black pregnant individuals were exposed to a mean (SD) of 22 836 (32 844) VMT within 500 m of their homes, compared with 12 478 (22 870) VMT within 500 m of the homes of non-Hispanic White pregnant individuals in 2016, a difference of 83%. Conclusions and Relevance: This birth cohort study found that while levels of air pollution disparities decreased in absolute terms over the 20 years of the study, relative disparities persisted and large differences in traffic levels remained, requiring renewed policy attention.

Changes in traffic congestion and air pollution due to major roadway infrastructure improvements in Texas.

Traffic-related air pollution (TRAP) is an established health hazard, and roadway construction has the potential to affect TRAP by relieving congestion. The relationship between roadway construction and congestion is of policy importance, but few studies examine it using large samples of construction projects and detailed traffic and air pollution data. We create a dataset of construction projects in Texas and link them to data on air pollution and three variables operationalizing congestion: average annual daily traffic (AADT), AADT per lane, and delay in hours. We use difference-in-difference methods to estimate the effect of widening and intersection improvements on congestion and air pollution. On average over the period during construction, we find that widening increases delay by 42% (95% CI: 30, 56%), but intersection projects do not affect delay. On average and over the first three years post-construction, we find that widening reduces delay by 33% (95% CI: -41, -24%) and reduces NO2 levels within 500 m by 13% (95% CI: -22, -2%), and intersection projects reduce delay by 52% (95% CI: -65, -35%) and reduce NO2 levels within 500 m by 12% (95% CI: -18, -5%). These short-term impacts are relevant for understanding the impact of roadway construction on human health.

COVID-19 vaccination and menstrual cycle characteristics: A prospective cohort study.

We prospectively examined the association between COVID-19 vaccination and menstrual cycle characteristics in an internet-based prospective cohort study. We included a sample of 1,137 participants who enrolled in Pregnancy Study Online (PRESTO), a preconception cohort study of couples trying to conceive, during January 2021-August 2022. Eligible participants were aged 21-45 years, United States or Canadian residents, and trying to conceive without fertility treatment. At baseline and every 8 weeks for up to 12 months, participants completed questionnaires on which they provided information on COVID-19 vaccination and menstrual cycle characteristics, including cycle regularity, cycle length, bleed length, heaviness of bleed, and menstrual pain. We fit generalized estimating equation (GEE) models with a log link function and Poisson distribution to estimate the adjusted risk ratio (RR) for irregular cycles associated with COVID-19 vaccination. We used linear regression with GEE to estimate adjusted mean differences in menstrual cycle length associated with COVID-19 vaccination. We adjusted for sociodemographic, lifestyle, medical and reproductive factors. Participants had 1.1 day longer menstrual cycles after receiving the first dose of COVID-19 vaccine (95 % CI: 0.4, 1.9) and 1.3 day longer cycles after receiving the second dose (95 % CI: 0.2, 2.5). Associations were attenuated at the second cycle post-vaccination. We did not observe strong associations between COVID-19 vaccination and cycle regularity, bleed length, heaviness of bleed, or menstrual pain. In conclusion, COVID-19 vaccination was associated with a ∼1 day temporary increase in menstrual cycle length, but was not appreciably associated with other menstrual cycle characteristics.

It's electric! An environmental equity perspective on the lifecycle of our energy sources.

Energy policy decisions are driven primarily by economic and reliability considerations, with limited consideration given to public health, environmental justice, and climate change. Moreover, epidemiologic studies relevant for public policy typically focus on immediate public health implications of activities related to energy procurement and generation, considering less so health equity or the longer-term health consequences of climate change attributable to an energy source. A more integrated, collective consideration of these three domains can provide more robust guidance to policymakers, communities, and individuals. Here, we illustrate how these domains can be evaluated with respect to natural gas as an energy source. Our process began with a detailed overview of all relevant steps in the process of extracting, producing, and consuming natural gas. We synthesized existing epidemiologic and complementary evidence of how these processes impact public health, environmental justice, and climate change. We conclude that, in certain domains, natural gas looks beneficial (e.g., economically for some), but when considered more expansively, through the life cycle of natural gas and joint lenses of public health, environmental justice, and climate change, natural gas is rendered an undesirable energy source in the United States. A holistic climate health equity framework can inform how we value and deploy different energy sources in the service of public health.

Associations between Residential Greenspace and Fecundability in a North American Preconception Cohort Study.

BACKGROUND: Residential green space can have positive physiological effects on human health through various mechanisms, including reducing stress and/or depression or facilitating physical activity. Although green space has been consistently associated with improved birth outcomes in several studies, there has been limited study of its effect on other reproductive outcomes, including fertility. OBJECTIVE: We examined associations between residential green space and fecundability, the per-cycle probability of conception. METHODS: We analyzed data from 8,563 female participants enrolled between 2013 and 2019 in Pregnancy Study Online (PRESTO), a prospective preconception cohort study of North American couples attempting conception. Participants completed a baseline questionnaire on sociodemographic, behavioral, and reproductive factors, and bimonthly follow-up questionnaires for up to 12 months to ascertain pregnancies. Using geocoded addresses, we calculated residential green space exposure using the Normalized Difference Vegetation Index (NDVI) within 50-, 100-, 250-, and 500-m buffers across multiple temporal scales: annual maximum, seasonal maximum, and seasonal mean. We used proportional probabilities regression models to estimate fecundability ratios (FRs), adjusting for sociodemographic, behavioral, and neighborhood characteristics. We also evaluated the extent to which associations were mediated by reductions in perceived stress or depressive symptoms and increased physical activity. RESULTS: When comparing the highest (≥0.8) with the lowest (<0.2) NDVI exposures within 50m, we observed positive associations in the annual maximum NDVI [FR: 1.33; 95% confidence interval (CI): 1.06, 1.67] and seasonal maximum NDVI (FR: 1.19; 95% CI: 1.00, 1.41) models, but little association in the seasonal mean NDVI models (FR: 0.98; 95% CI: 0.73, 1.30). Restricted cubic splines showed evidence of nonlinearity in this association. Results were similar across buffer distances. Perceived stress, depressive symptoms, and physical activity explained ≤5:0% of mediation across all NDVI metrics. DISCUSSION: In this cohort, greater residential green space was associated with a modest increase in fecundability. https://doi.org/10.1289/EHP10648.

Disparities in spatial access to neurological care in Appalachia: a cross-sectional health services analysis.

Background: Appalachia is rural and socioeconomically deprived with a heavy burden of neurological disorders and poor access to healthcare providers. Rates of neurological disorders are increasing over time without equal increases in providers, indicating that Appalachian disparities are likely to worsen. Spatial access to neurological care has not been robustly explored for U.S. areas, so we aimed to examine disparities in the vulnerable Appalachian region. Methods: Using 2022 CMS Care Compare physician data, we conducted a cross-sectional health services analysis, where we computed spatial accessibility of neurologists for all census tracts in the 13 states with Appalachian counties. We stratified access ratios by state, area deprivation, and rural-urban commuting area (RUCA) codes then utilized Welch two-sample t-tests to compare Appalachian tracts with non-Appalachian tracts. Using stratified results, we identified Appalachian areas where interventions would have the largest impact. Findings: Appalachian tracts (n = 6169) had neurologist spatial access ratios between 25% and 35% lower than non-Appalachian tracts (n = 18,441; p < 0.001). When stratified by rurality and deprivation, three-step floating catchment area spatial access ratios for Appalachian tracts remained significantly lower in the most urban (RUCA = 1 [p < 0.0001) and most rural tracts (RUCA = 9 [p = 0.0093]; RUCA = 10 [p = 0.0227]). We identified 937 Appalachian census tracts where interventions can be targeted. Interpretation: After stratifying by rural status and deprivation, significant disparities in spatial access to neurologists remained for Appalachian areas, indicating both poorer access in Appalachia and that neurologist accessibility cannot be determined solely by remoteness and socioeconomic status. These findings and our identified disparity areas have broad implications for policymaking and intervention targeting in Appalachia. Funding: R.B.B. was supported by NIH Award Number T32CA094186. M.P.M. was supported by NIH-NCATS Award Number KL2TR002547.