Faculty Bibliography

Research on early life adversity has begun a shift from cumulative risk approaches to more dimensional approaches. One such dimensional approach to understanding early life adversity uses dimensions of deprivation and threat to differentially predict developmental outcomes, however this framework has not been applied to the context of poverty-related adversity, which encompasses more than deprivation and threat and is characterized by high levels of both these dimensions. Previous studies have found that experiences of deprivation, but not threat, predict executive functions (EF). We propose a model of deprivation and threat as dimensions of poverty-related adversity, and we hypothesized that deprivation, but not threat, would mediate links between early life socioeconomic status (SES) and EF. Data come from the 15-, 24-, and 48-month visits of the Family Life Project (n=1,292). We used latent variables of deprivation and threat in a multiple mediation model with SES as the main predictor, deprivation and threat as mediators predicting 48 month EF. Lower SES was related to higher levels of both deprivation (beta=-0.597, p < 0.01) and threat (beta=-0.628, p < 0.01). Additionally, deprivation (beta=-0.916, p < 0.01), but not threat (beta= 0.307, p=0.112) was significantly negatively related to EF outcomes. The indirect effect of SES on EF through deprivation was significant (beta= 0.548, p =0.013). Finally, deprivation and threat together fully mediated the relationship between SES and EF. Implications for mental and physical health for children growing up in high-poverty contexts will be discussed

A growing body of research demonstrates that early-life stress exposure is linked to later-life health outcomes, with disparities in outcomes emerging as early as childhood. However, the mechanisms by which early stress might contribute to adverse health effects remain poorly understood. One likely mechanism is via altered glucocorticoid activity. Glucocorticoids (e.g., cortisol in humans) are essential for myriad physiological functions, including the maintenance of cardiovascular tone, provision of anti-inflammatory effects, and regulation of growth, behavior, and cognition. Here we assessed if glucocorticoid levels across infancy and toddlerhood were associated with impaired tissue sensitivity to glucocorticoids (glucocorticoid resistance) in early adolescence. Data come from the Family Life Project, a longitudinal study of 1,292 children and their caregivers living in predominantly low-income non-urban communities. Children's resting levels of cortisol were assayed via saliva samples collected in their home at 6, 15, 24, and 48 months of age. Glucocorticoid resistance at 11-12 years of age was assessed using a well-established protocol whereby whole blood was diluted in phosphate buffered saline and cultured with and without endotoxin lipopolysaccharide (LPS) at a range of concentrations of hydrocortisone. Glucocorticoid resistance was quantified by the difference in inflammatory cytokine (IL-6) levels in response to LPS alone versus LPS with the highest concentration of hydrocortisone. Structural equation modeling was used to assess direct effects of a latent variable of early childhood cortisol on glucocorticoid resistance in early adolescence. All models adjusted for demographic covariates, including infant's race, gender, age, and mother's age, as well as child's body mass index, health status, time of blood draw, and body temperature. Analyses revealed a significant positive association between cortisol levels and glucocorticoid resistance, such that higher cortisol in early childhood predicted increased glucocorticoid resistance in early adolescence (b=0.893, p=0.023). Our findings support the idea that prolonged elevation of glucocorticoids in early life may result in a dysregulated response such that the expression and/or function of glucocorticoid receptors become downregulated, leading to glucocorticoid resistance

Use of substances other than nicotine in e-cigarettes, especially marijuana, is becoming increasingly popular in the US. However, population-representative data on such poly-use (nicotine and marijuana) remains limited. We therefore conducted a cross-sectional logistic regression analysis of the 2018 Behavioral Risk Factor Surveillance System among 16 US states/territories with data on past 30-day marijuana use to describe the emerging dual nicotine and marijuana vaping population. We additionally examined trends in marijuana use, including marijuana vaping, from 2016 to 2018. Of the 131,807 participants studied, 3068 were current e-cigarette users, among whom 7.1% also vaped marijuana. Prevalence of nicotine-predominant, dual nicotine marijuana, and marijuana-predominant vaping was 3.36%, 0.38% and 1.09%, respectively. Compared to nicotine-predominant vapers, dual and marijuana-predominant vapers were older, had greater proportions of non-Whites, particularly Hispanics, and less likely to be current smokers (nicotine-predominant vs dual vs marijuana-predominant vaping: current tobacco use 44.7 vs 23.7 vs 11.1%). Proportion of dual vapers among current e-cigarette users was 8.6%, 2.6% and 7.1% for 2016, 2017 and 2018, respectively. Prevalence of marijuana use increased from 8.97% (2016) to 13.1% (2018) while no clear trend was observed for marijuana vaping. Dual nicotine and marijuana vaping is prevalent in the US, and compared to predominantly nicotine vapers such users have higher mean ages, and are more likely to be Blacks, Hispanics, and never cigarette smokers. Marijuana use overall increased from 2016 to 2018. Dual vapers represent a large and important emerging population that will require dedicated study of health effects and tailored regulatory strategies.

The chapters and reports in this book explore a wide variety of topics related to how health literacy can impact clinical practice and public health. While health literacy is relevant to healthcare issues across populations, it has unique implications in the field of pediatrics, where parents and other caregivers are responsible for managing their child's healthcare. Younger children have varying roles and involvement; over time, as children reach adolescence, they have an increasing understanding of and participation in their healthcare. This chapter will review the epidemiology of health literacy in parents, adolescents, and children, and how this compares to the general adult population. It will highlight unique considerations regarding health literacy and pediatric health. The chapter will then focus on the impact of health literacy and relevant health literacy-informed interventions on pediatric health. Finally, the chapter will discuss gaps in the literature and future directions.

Patient nonadherence to healthy lifestyle behaviors and medical treatments (like medication adherence) accounts for a significant portion of chronic disease burden. Despite the plethora of behavioral interventions to overcome key modifiable/nonmodifiable barriers and enable facilitators to adherence, short- and long-term adherence to healthy lifestyle behaviors and medical treatments is still poor. To optimize adherence, we aimed to provide a novel mobile health solution steeped in precision and personalized population health and a pantheoretical approach that increases the likelihood of adherence. We have described the stages of a pantheoretical approach utilizing tailoring, clustering/profiling, personalizing, and optimizing interventions/strategies to obtain adherence and highlight the minimal engineering needed to build such a solution.

Higher serum 6-bromotryptophan has been associated with lower risk of chronic kidney disease (CKD) progression, implicating mechanisms beyond renal clearance. We studied genetic determinants of urine 6-bromotryptophan and its association with CKD risk factors and incident end-stage kidney disease (ESKD) in 4,843 participants of the German Chronic Kidney Disease (GCKD) study. 6-bromotryptophan was measured from urine samples using mass spectrometry. Patients with higher levels of urine 6-bromotryptophan had higher baseline estimated glomerular filtration rate (eGFR, p < 0.001). A genome-wide association study of urine 6-bromotryptophan identified two significant loci possibly related to its tubular reabsorption, SLC6A19, and its production, ERO1A, which was also associated with serum 6-bromotryptophan in an independent study. The association between urine 6-bromotryptophan and time to ESKD was assessed using Cox regression. There were 216 ESKD events after four years of follow-up. Compared with patients with undetectable levels, higher 6-bromotryptophan levels were associated with lower risk of ESKD in models unadjusted and adjusted for ESKD risk factors other than eGFR (<median level: cause-specific hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.51 to 0.97; ≥median level: HR 0.50, 95% CI 0.34 to 0.74). Upon adjustment for baseline eGFR, this association became attenuated, suggesting that urine 6-bromotryptophan may represent a correlated marker of kidney health.

SARS-CoV-2 is the virus that causes coronavirus disease (COVID-19) which has reached pandemic levels resulting in significant morbidity and mortality affecting every inhabited continent. The large number of patients requiring intensive care threatens to overwhelm healthcare systems globally. Likewise, there is a compelling need for a COVID-19 disease severity test to prioritize care and resources for patients at elevated risk of mortality. Here, an integrated point-of-care COVID-19 Severity Score and clinical decision support system is presented using biomarker measurements of C-reactive protein (CRP), N-terminus pro B type natriuretic peptide (NT-proBNP), myoglobin (MYO), D-dimer, procalcitonin (PCT), creatine kinase-myocardial band (CK-MB), and cardiac troponin I (cTnI). The COVID-19 Severity Score combines multiplex biomarker measurements and risk factors in a statistical learning algorithm to predict mortality. The COVID-19 Severity Score was trained and evaluated using data from 160 hospitalized COVID-19 patients from Wuhan, China. Our analysis finds that COVID-19 Severity Scores were significantly higher for the group that died versus the group that was discharged with median (interquartile range) scores of 59 (40-83) and 9 (6-17), respectively, and area under the curve of 0.94 (95% CI 0.89-0.99). Although this analysis represents patients with cardiac comorbidities (hypertension), the inclusion of biomarkers from other pathophysiologies implicated in COVID-19 (e.g., D-dimer for thrombotic events, CRP for infection or inflammation, and PCT for bacterial co-infection and sepsis) may improve future predictions for a more general population. These promising initial models pave the way for a point-of-care COVID-19 Severity Score system to impact patient care after further validation with externally collected clinical data. Clinical decision support tools for COVID-19 have strong potential to empower healthcare providers to save lives by prioritizing critical care in patients at high risk for adverse outcomes.

World Trade Center particulate matter (WTC-PM)-exposed firefighters with metabolic syndrome (MetSyn) have a higher risk of WTC lung injury (WTC-LI). Since macrophages are crucial innate pulmonary mediators, we investigated WTC-PM/lysophosphatidic acid (LPA) co-exposure in macrophages. LPA, a low-density lipoprotein metabolite, is a ligand of the advanced glycation end-products receptor (AGER or RAGE). LPA and RAGE are biomarkers of WTC-LI. Human and murine macrophages were exposed to WTC-PM, and/or LPA, and compared to controls. Supernatants were assessed for cytokines/chemokines; cell lysate immunoblots were assessed for signaling intermediates after 24 h. To explore the translatability of our in-vitro findings, we assessed serum cytokines/chemokines and metabolites of symptomatic, never-smoking WTC-exposed firefighters. Agglomerative hierarchical clustering identified phenotypes of WTC-PM-induced inflammation. WTC-PM induced GM-CSF, IL-8, IL-10, and MCP-1 in THP-1-derived macrophages and induced IL-1α, IL-10, TNF-α, and NF-κB in RAW264.7 murine macrophage-like cells. Co-exposure induced synergistic elaboration of IL-10 and MCP-1 in THP-1-derived macrophages. Similarly, co-exposure synergistically induced IL-10 in murine macrophages. Synergistic effects were seen in the context of a downregulation of NF-κB, p-Akt, -STAT3, and -STAT5b. RAGE expression after co-exposure increased in murine macrophages compared to controls. In our integrated analysis, the human cytokine/chemokine biomarker profile of WTC-LI was associated with discriminatory metabolites (fatty acids, sphingolipids, and amino acids). LPA synergistically elaborated WTC-PM's inflammatory effects in vitro and was partly RAGE-mediated. Further research will focus on the intersection of MetSyn/PM exposure.

The COVID-19 pandemic is causing world-wide social dislocation, operational and economic dysfunction, and high rates of morbidity and mortality. Medical practices are responding by developing, disseminating and implementing unprecedented changes in health care delivery. Telemedicine has rapidly moved to the frontline of clinical practice due to the need for prevention and mitigation strategies; these have been encouraged, facilitated, and enabled by changes in government rules and regulations and payer-driven reimbursement policies.We describe our neurology department's situational transformation from in-person outpatient visits to a largely virtual neurology practice in response to the COVID-19 pandemic. Two key factors enabled our rapid deployment of virtual encounters in neurology and its subspecialties. The first was a well-established robust information technology infrastructure supporting virtual urgent care services at our institution; this connected physicians directly to patients using both the physician's and the patient's own mobile devices. The second is the concept of one patient, one chart, facilitated by a suite of interconnected electronic medical record (EMR) applications on several different device types.We present our experience with conducting general teleneurology encounters using secure synchronous audio and video connections integrated with an EMR. This report also details how we perform virtual neurological examinations that are clinically meaningful, and how we document, code and bill for these virtual services. Many of these processes can be used by other neurology providers, regardless of their specific practice model. We then discuss potential roles for teleneurology after the COVID-19 global pandemic has been contained.