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.

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.

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.

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.

Systematic review of pediatric health outcomes associated with childhood adversity.

BACKGROUND: Early detection of and intervention in childhood adversity has powerful potential to improve the health and well-being of children. A systematic review was conducted to better understand the pediatric health outcomes associated with childhood adversity. METHODS: PubMed, PsycArticles, and CINAHL were searched for relevant articles. Longitudinal studies examining various adverse childhood experiences and biological health outcomes occurring prior to age 20 were selected. Mental and behavioral health outcomes were excluded, as were physical health outcomes that were a direct result of adversity (i.e. abusive head trauma). Data were extracted and risk of bias was assessed by 2 independent reviewers. RESULTS: After identifying 15940 records, 35 studies were included in this review. Selected studies indicated that exposure to childhood adversity was associated with delays in cognitive development, asthma, infection, somatic complaints, and sleep disruption. Studies on household dysfunction reported an effect on weight during early childhood, and studies on maltreatment reported an effect on weight during adolescence. Maternal mental health issues were associated with elevated cortisol levels, and maltreatment was associated with blunted cortisol levels in childhood. Furthermore, exposure to childhood adversity was associated with alterations of immune and inflammatory response and stress-related accelerated telomere erosion. CONCLUSION: Childhood adversity affects brain development and multiple body systems, and the physiologic manifestations can be detectable in childhood. A history of childhood adversity should be considered in the differential diagnosis of developmental delay, asthma, recurrent infections requiring hospitalization, somatic complaints, and sleep disruption. The variability in children's response to adversity suggests complex underlying mechanisms and poses a challenge in the development of uniform diagnostic guidelines. More large longitudinal studies are needed to better understand how adversity, its timing and severity, and the presence of individual genetic, epigenetic, and protective factors affects children's health and development.

Self-reported racial/ethnic discrimination and bronchodilator response in African American youth with asthma.

IMPORTANCE: Asthma is a multifactorial disease composed of endotypes with varying risk profiles and outcomes. African Americans experience a high burden of asthma and of psychosocial stress, including racial discrimination. It is unknown which endotypes of asthma are vulnerable to racial/ethnic discrimination. OBJECTIVE: We examined the association between self-reported racial/ethnic discrimination and bronchodilator response (BDR) among African American youth with asthma ages 8 to 21 years (n = 576) and whether this association varies with tumor necrosis factor alpha (TNF-α) level. MATERIALS AND METHODS: Self-reported racial/ethnic discrimination was assessed by a modified Experiences of Discrimination questionnaire as none or any. Using spirometry, BDR was specified as the mean percentage change in forced expiratory volume in one second before and after albuterol administration. TNF-α was specified as high/low levels based on our study population mean. Linear regression was used to examine the association between self-reported racial/ethnic discrimination and BDR adjusted for selected characteristics. An interaction term between TNF-α levels and self-reported racial/ethnic discrimination was tested in the final model. RESULTS: Almost half of participants (48.8%) reported racial/ethnic discrimination. The mean percent BDR was higher among participants reporting racial/ethnic discrimination than among those who did not (10.8 versus 8.9, p = 0.006). After adjustment, participants reporting racial/ethnic discrimination had a 1.7 (95% CI: 0.36-3.03) higher BDR mean than those not reporting racial/ethnic discrimination. However, we found heterogeneity of this association according to TNF-α levels (p-interaction = 0.040): Among individuals with TNF-α high level only, we observed a 2.78 higher BDR mean among those reporting racial/ethnic discrimination compared with those not reporting racial/ethnic discrimination (95%CI: 0.79-4.77). CONCLUSIONS: We found BDR to be increased in participants reporting racial/ethnic discrimination and this association was limited to African American youth with TNF-α high asthma, an endotype thought to be resistant to traditional asthma medications. These results support screening for racial/ethnic discrimination in those with asthma as it may reclassify disease pathogenesis.