The Stress Phenotyping Framework: A multidisciplinary biobehavioral approach for assessing and therapeutically targeting maladaptive stress physiology.

Although dysregulated stress biology is becoming increasingly recognized as a key driver of lifelong disparities in chronic disease, we presently have no validated biomarkers of toxic stress physiology; no biological, behavioral, or cognitive treatments specifically focused on normalizing toxic stress processes; and no agreed-upon guidelines for treating stress in the clinic or evaluating the efficacy of interventions that seek to reduce toxic stress and improve human functioning. We address these critical issues by (a) systematically describing key systems and mechanisms that are dysregulated by stress; (b) summarizing indicators, biomarkers, and instruments for assessing stress response systems; and (c) highlighting therapeutic approaches that can be used to normalize stress-related biopsychosocial functioning. We also present a novel multidisciplinary Stress Phenotyping Framework that can bring stress researchers and clinicians one step closer to realizing the goal of using precision medicine-based approaches to prevent and treat stress-associated health problems.

Association of chronotropic incompetence with reduced cardiorespiratory fitness in older adults with HIV.

OBJECTIVE: Understanding the physiological drivers of reduced cardiorespiratory fitness in people with HIV (PWH) will inform strategies to optimize healthspan. Chronotropic incompetence is common in heart failure and associated with low cardiorespiratory fitness yet is understudied in PWH. The objective was to determine the prevalence of chronotropic incompetence and its relationship with cardiorespiratory fitness. DESIGN: Participants were PWH at least 50 years of age with no prior history of heart failure or coronary heart disease who were enrolled in a randomized exercise trial. Baseline cardiopulmonary exercise testing (CPET) was used to measure cardiorespiratory fitness as peak oxygen consumption (VO2peak) and calculate the chronotropic index from heart rate values. Chronotropic incompetence was defined as an index less than 80%. RESULTS: The 74 participants were on average 61 years old, 80% Black or African American, and 93% men. Chronotropic incompetence was present in 31.1%. VO2peak was significantly lower among participants with chronotropic incompetence compared with participants without chronotropic incompetence [mean (SD) ml/min/kg: 20.9 (5.1) vs. 25.0 (4.5), P = 0.001]. Linear regression showed that chronotropic incompetence and age were independent predictors of VO2peak, but smoking and comorbidity were not. The chronotropic index correlated with VO2peak (r = 0.48, P < 0.001). CONCLUSION: Among older PWH without heart failure or coronary heart disease, chronotropic incompetence was present in approximately one-third of individuals and was associated with clinically relevant impaired cardiorespiratory fitness. Investigation of chronotropic incompetence in large cohorts which includes PWH and heart failure may contribute to strategies that promote healthy aging with HIV infection and offer a preclinical window for intervention.

Adverse Childhood Experiences and Related Events are Associated with Asthma Symptoms in Children.

OBJECTIVE: To examine the association between adverse childhood experiences (ACEs) and related events and asthma symptom burden in children. METHODS: This is a cross-sectional study of baseline data from 147 participants with asthma from a cohort of children enrolled in the Pediatric ACEs Screening and Resiliency Study. Participants completed the PEdiatric ACEs and Related Life Events Screener (PEARLS) tool, a 17-item questionnaire, capturing 3 domains of childhood adversity-child maltreatment, household challenges, and social context. Asthma symptom burden was assessed using the International Study of Asthma and Allergies in Childhood core questionnaire, which asks participants to identify the presence and frequency of severe wheezing that limits speech, wheezing with exercise, nocturnal wheezing, and nocturnal cough in the last 12 months. Using multivariable logistical regression models, we examined the relationship between reported PEARLS and asthma symptoms. RESULTS: Of children with asthma, 86% reported at least 1 adversity, with 48% reporting 4 or more. The odds of severe wheeze limiting speech increased by 19% with each additional reported adversity captured by the PEARLS tool (95% confidence intervals (CI) 1.01-1.41). Increasing PEARLS scores were also associated with 16% increased odds of reporting wheeze with exercise (95% CI 1.03-1.31). Wheezing with exercise was associated with the household challenges domain (odds ratio (OR) 1.34; 95% CI 1.05-1.72), while severe wheeze limiting speech was associated with the social context domain (OR 1.75; 95%CI 1.02-3.02). CONCLUSIONS: Childhood adversities are associated with increased asthma symptom burden, suggesting the tool may be helpful in identifying children at risk for poorly controlled asthma.

A telehealth-delivered intervention to extend the veteran HIV treatment cascade for cardiovascular disease prevention: V-EXTRA-CVD study protocol for a randomized controlled trial.

Background: Veterans living with HIV have up to twice the risk of atherosclerotic cardiovascular disease (ASCVD) compared to those without HIV.Objective: Our study seeks to test a non-physician led virtual self-management implementation strategy to reduce ASCVD risk among people living with HIV (PWH). We aim to conduct a randomized control trial among PWH (n = 300) with a diagnosis of hypertension (HTN) who are enrolled in Veterans Health Administration (VHA) clinics, on suppressive antiretroviral therapy (ART), randomized 1:1 to intervention vs. education control for a 12-month duration.Methods: Using human centered design approach, we have adapted a previous 5-component telehealth focused, non-physician led intervention to a Veteran population. The education control arm receives enhanced education in addition to usual care. The primary outcome is 6 mmHg reduction in systolic BP over 12-month in the intervention arm compared to the control arm. The secondary outcome is a 12-month difference in non-HDL cholesterol. While each component of our intervention has an evidence base, they have not been tested together in an HIV context.Conclusion: The proposed multicomponent intervention has the potential to improve cardiovascular outcomes in PWH using novel virtual care methods in a patient centered care approach.

Pediatric ACEs and related life event screener (PEARLS) latent domains and child health in a safety-net primary care practice.

BACKGROUND: Research examining the connections between individual adverse childhood experiences (ACEs) and how groupings of interrelated adversities are linked with subsequent health is scarce, limiting our understanding of risk during a period of rapid expansion of ACE screening in clinical practice. The study objective was to conduct a psychometric analysis to derive latent domains of ACEs and related life events and assess the association between each domain and health outcome. METHODS: Participants (3 months-11 years) were recruited from the University of California San Francisco Benioff's Children Hospital Oakland Primary Care Clinic. Children were screened with the Pediatric ACEs and Related Life Events Screener (PEARLS) (n = 340), which assessed 17 total ACEs and related life events, including forms of abuse, household challenges, and social risks. Domains were constructed using confirmatory factor analysis and associations between the three identified domains and 14 health outcomes were assessed using multivariable linear and logistic regression models. RESULTS: Three PEARLS domains were identified: Maltreatment (ω = 0.73, ɑ=0.87), Household Challenges (ω = 0.70, ɑ=0.82), and Social Context (ω = 0.55, ɑ=0.70). Measurement invariance was supported across both gender and screening format. All domains were associated with poorer general and behavioral health and stomachaches. Maltreatment and Social Context were additionally associated with eczema while only Social Context was associated with increased odds of reporting headaches and somatic symptoms. CONCLUSION: In an underserved, urban west-coast pediatric population, the PEARLS found three adversity domains of Maltreatment, Household Challenges, and Social Context that all had an independent statistically significant association with poorer child health. The results provide a timely and more nuanced representation of risk that can inform clinical practice and policy using more targeted resources and interventions.

Using Active Surveillance to Identify Monoclonal Antibody Candidates Among COVID-19-Positive Veterans in the Atlanta VA Health Care System.

Background: Strategies for optimizing identification and outreach to potential candidates for monoclonal antibody (Mab) therapy for COVID-19 are not clear. Using a centralized, active surveillance system, the Atlanta Veterans Affairs Health Care System (AVAHCS) infectious disease (ID) team identified candidates for Mab infusion and provided treatment. Observations: As part of a quality improvement project from December 28, 2020, to August 31, 2021, a clinical team consisting of ID pharmacists and physicians reviewed each outpatient with a positive COVID-19 polymerase chain reaction test daily at the AVAHCS. The clinical team used Emergency Use Authorization (EUA) criteria to determine eligibility. Eligible patients were contacted on the same day of review via telephone to confirm eligibility and obtain verbal consent. Telehealth follow-up occurred on day 1 and day 7 postinfusion to assess for adverse events. In total, 2028 patients with COVID-19 were identified; 289 patients (14%) were eligible, and 132 (46%) received Mab therapy. Similar to AVAHCS demographics, a majority of those who received Mab therapy were non-Hispanic Black patients (65%). The most common comorbidities were hypertension (59%) and diabetes (37%). The median time from symptom onset to positive COVID-19 polymerase chain reaction (PCR) test result was 6 days (range, 0-9), and the median time from positive COVID-19 PCR test result to Mab infusion was 2 days (range, 0-8). Twelve patients (9%) required hospitalization for worsening COVID-19 symptoms postinfusion. No deaths occurred. Conclusions: Combining laboratory surveillance and active screening led to high uptake of Mab therapy and minimized delay from symptom onset to Mab infusion, thereby optimizing outpatient treatment of COVID-19. This approach also successfully screened and treated Black patients in the AVAHCS population.

Screening for adverse childhood experiences in pediatrics: A randomized trial of aggregate-level versus item-level response screening formats.

BACKGROUND: While there is growing support for screening for Adverse Childhood Experiences (ACEs), rigorous evidence on the efficacy and preference of screening methods is needed. OBJECTIVE: To examine caregiver: (1) rates of disclosure of their child's exposure to ACEs using item-level response (each item can be endorsed) versus aggregate-level response (only total score reported) screening format, (2) associations between family demographic factors and disclosure by screening format, and (3) emotional reaction and experience of screening formats in a diverse, low-income pediatric population. METHODS: Caregiver participants (n = 367) were randomized to complete the Pediatric ACEs and Related Life Events Screener (PEARLS) tool, in an aggregate-level response vs item-level response format from 2016-2019. Select caregivers (n = 182) participated in debriefing interviews. T-test and chi-square analyses in 2019 compared PEARLS disclosure rates and reactions between the screening modalities. Regression models explored interactions with child characteristics. Thematic analysis of interview notes captured caregiver screening experience. RESULTS: PEARLS disclosure rates were significantly higher in the aggregate-level response compared to the item-level response screening arm (p <0.05). This difference was accentuated for children identified as black and/or male (p <0.05). Caregiver reactions to PEARLS screening were rarely negative in either screening format. Qualitative data demonstrated strong caregiver preference for the item-level response format; additional themes include provider relationship, fear with disclosure, and screening outcome expectations. CONCLUSION: While caregivers reported a preference for the item-level response format, the aggregate-level response screening format elicited higher disclosures rates particularly for children who are black or ma. TRIAL REGISTRATION: Clinical trial registry: NCT04182906.

A Caregiver-Child Intervention for Mitigating Toxic Stress ("The Resiliency Clinic"): A Pilot Study.

INTRODUCTION: Primary care-based interventions that promote nurturing caregiving relationships and early relational health may help mitigate toxic stress and promote resilience in children. This pilot study aims to: (1) describe a novel group-based, psychoeducational primary care intervention for children experiencing adverse childhood experiences (ACEs) ("The Resiliency Clinic"), (2) assess program feasibility and acceptability, and (3) explore effects on child/caregiver behavioral health. METHODS: Intervention design centered on promoting supportive caregiving, caregiver/child self-regulation and co-regulation and teaching evidence-based stress management tools. Program feasibility and acceptability were assessed through attendance data and caregiver focus groups. Behavioral health measures were obtained at baseline and 8-month follow-up. RESULTS: Of 101 eligible families, 38 (37.6%) enrolled and attended a median of 3.00 (mean = 2.95, sd = 1.75) out of 6 sessions. Caregivers reported high satisfaction and benefits including stress management tools and connection with staff and other parents. There were modest, statistically non-significant improvements in caregiver stress (d = 0.23) and child executive functioning (d = 0.27). DISCUSSION: In conclusion, a group intervention teaching supportive caregiving and stress mitigation is feasible and acceptable for many families in an urban federally qualified health center (FQHC) with a signal for modest improvements in behavioral health. Future program iterations will seek to address participation barriers and expand the intervention's capacity to promote early relational health.

Clinical characteristics and social determinants of health associated with 30-day hospital readmissions of patients with COVID-19.

COVID-19 readmissions are associated with increased patient mortality and healthcare system strain. This retrospective cohort study of PCR-confirmed COVID-19 positive adults (>18 years) hospitalized and readmitted within 30 days of discharge from index admission was performed at eight Atlanta hospitals from March to December 2020. The objective was to describe COVID-19 patient-level demographics and clinical characteristics, and community-level social determinants of health (SDoH) that contribute to 30-day readmissions. Demographics, comorbidities, COVID-19 treatment, and discharge disposition data were extracted from the index admission. ZIP codes were linked to a demographic/lifestyle database interpolating to community-level SDoH. Of 7155 patients with COVID-19, 463 (6.5%) had 30-day, unplanned, all-cause hospital readmissions. Statistically significant differences were not found in readmissions stratified by age, sex, race, or ethnicity. Patients with a high-risk Charlson Comorbidity Index had higher odds of readmission (OR 4.8 (95% CI: 2.1 to 11.0)). Remdesivir treatment and intensive care unit (ICU) care were associated with lower odds of readmission (OR 0.5 (95% CI: 0.4 to 0.8) and OR 0.5 (95% CI: 0.4 to 0.7), respectively). Patients residing in communities with larger average household size were less likely to be readmitted (OR 0.7 (95% CI: 0.5 to 0.9). In this cohort, patients who received remdesivir, were cared for in an ICU, and resided in ZIP codes with higher proportions of residents with increased social support had lower odds of readmission. These patient-level factors and community-level SDoH may be used to identify patients with COVID-19 who are at increased risk of readmission.

Pediatrics adverse childhood experiences and related life events screener (PEARLS) and health in a safety-net practice.

BACKGROUND: Adverse Childhood Experiences (ACEs) are associated with behavioral, mental, and clinical outcomes in children. Tools that are easy to incorporate into pediatric practice, effectively screen for adversities, and identify children at high risk for poor outcomes are lacking. OBJECTIVE: To examine the relationship between caregiver-reported child ACEs and related life events with health outcomes. PARTICIPANTS AND SETTING: Participants (0-11 years) were recruited from the University of California San Francisco Benioff's Children Hospital Oakland Primary Care Clinic. There were 367 participants randomized. METHODS: Participants were randomized 1:1:1 to item-level (item response), aggregate-level (total number of exposures), or no screening for ACEs (control arm) with the PEdiatric ACEs and Related Life Event Screener (PEARLS). We assessed 10 ACE categories capturing abuse, neglect, and household challenges, as well as 7 additional categories. Multivariable regression models were conducted. RESULTS: Participants reported a median of 2 (IQR 1-5) adversities with 76 % (n = 279) reporting at least one adversity; participants in the aggregate-level screening arm, on average, disclosed 1 additional adversity compared to item-level screening (p = 0.01). Higher PEARLS scores were associated with poorer perceived child general health (adjusted B = -0.94, 95 %CI: -1.26, -0.62) and Global Executive Functioning (adjusted B = 1.99, 95 %CI: 1.51, 2.46), and greater odds of stomachaches (aOR 1.14; 95 %CI: 1.04-1.25) and asthma (aOR 1.08; 95 %CI 1.00, 1.17). Associations did not differ by screening arm. CONCLUSION: In a high-risk pediatric population, ACEs and other childhood adversities remain an independent predictor of poor health. Increased efforts to screen and address early-life adversity are necessary.

Disease burden of adverse childhood experiences across 14 states.

OBJECTIVE: To examine whether the relationship between Adverse Childhood Experiences (ACEs) and health outcomes is similar across states and persists net of ACEs associations with smoking, heavy drinking, and obesity. METHODS: We use data from the Behavioral Risk Factor Surveillance System for 14 states. Logistic regressions yield estimates of the direct associations of ACEs exposure with health outcomes net of health risk factors, and indirect ACEs-health associations via health risk factors. Models were estimated for California (N = 22,475) and pooled data from 13 states (N = 110,076), and also separately by state. RESULTS: Exposure to ACEs is associated with significantly higher odds of smoking, heavy drinking, and obesity. Net of these health risk factors, there was a significant and graded relationship in California and the pooled 13-state data between greater ACEs exposure and odds of depression, asthma, COPD, arthritis, and cardiovascular disease. Four or more ACEs were less consistently associated across states with cancer and diabetes and a dose-response relationship was also not present. There was a wide range across individual states in the percentage change in health outcomes predicted for exposure to 4+ ACEs. ACEs-related smoking, heavy drinking, and obesity explain a large and significant proportion of 4+ ACEs associations with COPD and cardiovascular disease, however some effect, absent of risk behavior, remained. CONCLUSIONS: ACE's associations with most of the health conditions persist independent of behavioral pathways but only asthma, arthritis, COPD, cardiovascular disease, and depression consistently exhibit a dose-response relationship. Our results suggest that attention to child maltreatment and household dysfunction, mental health treatment, substance abuse prevention and promotion of physical activity and healthy weight outcomes might mitigate some adverse health consequences of ACEs. Differences across states in the pattern of ACEs-health associations may also indicate fruitful areas for prevention.

Adult health burden and costs in California during 2013 associated with prior adverse childhood experiences.

OBJECTIVES: To estimate the adult health burden and costs in California during 2013 associated with adults' prior Adverse Childhood Experiences (ACEs). METHODS: We analyzed five ACEs-linked conditions (asthma, arthritis, COPD, depression, and cardiovascular disease) and three health risk factors (lifetime smoking, heavy drinking, and obesity). We estimated ACEs-associated fractions of disease risk for people aged 18+ for these conditions by ACEs exposure using inputs from a companion study of California Behavioral Risk Factor Surveillance System data for 2008-2009, 2011, and 2013. We combined these estimates with published estimates of personal healthcare spending and Disability-Adjusted-Life-Years (DALYs) in the United States by condition during 2013. DALYs captured both the years of healthy life lost to disability and the years of life lost to deaths during 2013. We applied a published estimate of cost per DALY. RESULTS: Among adults in California, 61% reported ACEs. Those ACEs were associated with $10.5 billion in excess personal healthcare spending during 2013, and 434,000 DALYs valued at approximately $102 billion dollars. During 2013, the estimated health burden per exposed adult included $589 in personal healthcare expenses and 0.0224 DALYs valued at $5,769. CONCLUSIONS: Estimates of the costs of childhood adversity are far greater than previously understood and provide a fiscal rationale for prevention efforts.

Development and implementation of a pediatric adverse childhood experiences (ACEs) and other determinants of health questionnaire in the pediatric medical home: A pilot study.

Adverse Childhood Experiences (ACEs) are associated with poor health outcomes, underlining the significance of early identification and intervention. Currently, there is no validated tool to screen for ACEs exposure in childhood. To fill this gap, we designed and implemented a pediatric ACEs questionnaire in an urban pediatric Primary Care Clinic. Questionnaire items were selected and modified based on literature review of existing childhood adversity tools. Children twelve years and under were screened via caregiver report, using the developed instrument. Cognitive interviews were conducted with caregivers, health providers, and clinic staff to assess item interpretation, clarity, and English/Spanish language equivalency. Using a rapid cycle assessment, information gained from the interviews were used to iteratively change the instrument. Additional questions assessed acceptability of screening within primary care and preferences around administration. Twenty-eight (28) caregivers were administered the questionnaire. Cognitive interviews conducted among caregivers and among 16 health providers and clinic staff resulted in the changes in wording and addition of examples in the items to increase face validity. In the final instrument, no new items were added; however, two items were merged and one item was split into three separate items. While there was a high level of acceptability of the overall questionnaire, some caregivers reported discomfort with the sexual abuse, separation from caregiver, and community violence items. Preference for methods of administration were split between tablet and paper formats. The final Pediatric ACE and other Determinants of Health Questionnaire is a 17-item instrument with high face validity and acceptability for use within primary care settings. Further evaluation on the reliability and construct validity of the instrument is being conducted prior to wide implementation in pediatric practice.

Review of Tools for Measuring Exposure to Adversity in Children and Adolescents.

Exposure to childhood adversity can result in negative behavioral and physical health outcomes due to potential long-term embedding into regulatory biological processes. Screening for exposure to adversity is a critical first step in identifying children at risk for developing a toxic stress response. We searched PubMed, PsycArticles, and CINAHL for studies published between January 1, 2012, and December 31, 2016, as well as other sources, to identify potential tools for measuring cumulative adversity in children and adolescents. We identified 32 tools and examined them for adversity categories, target population, administration time, administration qualifications and method, and reliability and validity. We also created a list of recommended tools that would be feasible for use by pediatric practitioners in most types of practice. This review provides a starting point for mobilizing screening in pediatric settings, highlighting the challenges with existing tools, and potential issues in the development and evaluation of future tools.

Ameliorating the biological impacts of childhood adversity: A review of intervention programs.

Childhood adversity negatively impacts the biological development of children and has been linked to poor health outcomes across the life course. The purpose of this literature review is to explore and evaluate the effectiveness of interventions that have addressed an array of biological markers and physical health outcomes in children and adolescents affected by adversity. PubMed, CINAHL, PsychInfo, Sociological Abstracts databases and additional sources (Cochrane, WHO, NIH trial registries) were searched for English language studies published between January 2007 and September 2017. Articles with a childhood adversity exposure, biological health outcome, and evaluation of intervention using a randomized controlled trial study design were selected. The resulting 40 intervention studies addressed cortisol outcomes (n = 20) and a range of neurological, epigenetic, immune, and other outcomes (n = 22). Across institutional, foster care, and community settings, intervention programs demonstrated success overall for improving or normalizing morning and diurnal cortisol levels, and ameliorating the impacts of adversity on brain development, epigenetic regulation, and additional outcomes in children. Factors such as earlier timing of intervention, high quality and nurturant parenting traits, and greater intervention engagement played a role in intervention success. This study underlines progress and promise in addressing the health impacts of adversity in children. Ongoing research efforts should collect baseline data, improve retention, replicate studies in additional samples and settings, and evaluate additional variables, resilience factors, mediators, and long-term implications of results. Clinicians should integrate lessons from the intervention sciences for preventing and treating the health effects of adversity in children and adolescents.