Chondroitin 4-O-sulfation regulates hippocampal perineuronal nets and social memory.

Glycan alterations are associated with aging, neuropsychiatric, and neurodegenerative diseases, although the contributions of specific glycan structures to emotion and cognitive functions remain largely unknown. Here, we used a combination of chemistry and neurobiology to show that 4-O-sulfated chondroitin sulfate (CS) polysaccharides are critical regulators of perineuronal nets (PNNs) and synapse development in the mouse hippocampus, thereby affecting anxiety and cognitive abilities such as social memory. Brain-specific deletion of CS 4-O-sulfation in mice increased PNN densities in the area CA2 (cornu ammonis 2), leading to imbalanced excitatory-to-inhibitory synaptic ratios, reduced CREB activation, elevated anxiety, and social memory dysfunction. The impairments in PNN densities, CREB activity, and social memory were recapitulated by selective ablation of CS 4-O-sulfation in the CA2 region during adulthood. Notably, enzymatic pruning of the excess PNNs reduced anxiety levels and restored social memory, while chemical manipulation of CS 4-O-sulfation levels reversibly modulated PNN densities surrounding hippocampal neurons and the balance of excitatory and inhibitory synapses. These findings reveal key roles for CS 4-O-sulfation in adult brain plasticity, social memory, and anxiety regulation, and they suggest that targeting CS 4-O-sulfation may represent a strategy to address neuropsychiatric and neurodegenerative diseases associated with social cognitive dysfunction.

Oscillatory Coupling Between Neural and Cardiac Rhythms.

Oscillations serve a critical role in organizing biological systems. In the brain, oscillatory coupling is a fundamental mechanism of communication. The possibility that neural oscillations interact directly with slower physiological rhythms (e.g., heart rate, respiration) is largely unexplored and may have important implications for psychological functioning. Oscillations in heart rate, an aspect of heart rate variability (HRV), show remarkably robust associations with psychological health. Mather and Thayer proposed coupling between high-frequency HRV (HF-HRV) and neural oscillations as a mechanism that partially accounts for such relationships. We tested this hypothesis by measuring phase-amplitude coupling between HF-HRV and neural oscillations in 37 healthy adults at rest. Robust coupling was detected in all frequency bands. Granger causality analyses indicated stronger heart-to-brain than brain-to-heart effects in all frequency bands except gamma. These findings suggest that cardiac rhythms play a causal role in modulating neural oscillations, which may have important implications for mental health.

Responsive parental support buffers the link between chronic stress and cardiometabolic risk among adolescents.

Youth exposed to chronic stress exhibit increased cardiometabolic risk which parental social support may attenuate. Notably, theories emphasize that support should be delivered responsively for it to exert buffering effects, but this has not been thoroughly tested empirically. This study examined whether timing of support is an important but unrecognized element of responsiveness during adolescence in buffering the link between chronic stress and cardiometabolic risk. Participants were 242 adolescents aged 15 years (63 % female, 38 % Black). Adolescents completed assessments of chronic stress (Life Stress Interview), and trained personnel collected anthropometric measures and blood samples to assess cardiometabolic risk (reflected in low-grade inflammation and metabolic syndrome). Adolescents also completed an eight-day diary assessment to report daily stressor exposure and parental support. Using the diary data, responsiveness of parental support was operationalized as the within-individual difference in parental support received on stressor (vs. non-stressor) days, such that increased parental support on stressor days reflected more timely support. Results suggest that responsive parental support buffered the link between chronic stress and cardiovascular risk. Specifically, chronic stress was associated with greater risk only when parental support was not temporally aligned with stress exposure, but this association was not observed among adolescents who received timely parental support. These findings shed light on why parental support may not always exert buffering effects during adolescence, highlighting the importance of taking a developmental approach to understanding protective effects.

Higher substance use is associated with low executive control neural activity and higher inflammation.

Individuals with substance use problems show lower executive control and alterations in prefrontal brain systems supporting emotion regulation and impulse control. A separate literature suggests that heightened inflammation also increases risk for substance use, in part, through targeting brain systems involved in executive control. Research on neural and inflammatory signaling in substance use, however, has occurred in parallel. Drawing on recent neuroimmune network models, we used fMRI to examine the relationships between executive control-related brain activity (as elicited by an n-back working memory task), peripheral inflammation, as quantified by inflammatory cytokines and C-reactive protein (CRP), and substance use for the past month in 93 participants [mean age = 24.4 (SD = 0.6)]. We operationalized low executive control as a neural inefficiency during the n-back task to achieve normative performance, as reflected in higher working memory-related brain activity and lower activity in the default mode network (DMN). Consistent with prediction, individuals with low executive control and high inflammation reported more substance use over the past month, controlling for behavioral performance on the n-back, sex, time between assessments, body-mass-index (BMI), and personal socioeconomic status (SES) (interaction between inflammation and working memory-related brain activity, b = 0.210, p = 0.005; interaction between inflammation and DMN, b = -0.219, p < 0.001). Findings suggest that low executive control and high inflammation may be associated with higher substance use. This has implications for understanding psychological, neural, and immunological risk for substance use problems and the development of interventions to target each of these components.

Exposure to parental depression in adolescence and proinflammatory phenotypes 20 years later.

Although the biological embedding model of adversity proposes that stressful experiences in childhood create a durable proinflammatory phenotype in immune cells, research to date has relied on study designs that limit our ability to make conclusions about whether the phenotype is long-lasting. The present study leverages an ongoing 20-year investigation of African American youth to test research questions about the extent to which stressors measured in childhood forecast a proinflammatory phenotype in adulthood, as indicated by exaggerated cytokine responses to bacterial stimuli, monocyte insensitivity to inhibitory signals from hydrocortisone, and low-grade inflammation. Parents reported on their depressive symptoms and unsupportive parenting tendencies across youths' adolescence. At age 31, youth participants (now adults) completed a fasting blood draw. Samples were incubated with lipopolysaccharide and doses of hydrocortisone to evaluate proinflammatory processes. Additionally, blood samples were tested for indicators of low-grade inflammation, including IL-6, IL-8, IL-10, and TNF-α, and soluble urokinase plasminogen activator receptor. Analyses revealed that parental depression across youths' adolescence prospectively predicted indicators of proinflammatory phenotypes at age 31. Follow-up analyses suggested that unsupportive parenting mediated these associations. These findings suggest that exposure to parental depression in adolescence leaves an imprint on inflammatory activity that can be observed 20 years later.

Major stress in early childhood strengthens the association between peripheral inflammatory activity and corticostriatal responsivity to reward.

BACKGROUND: Severe, chronic stress during childhood accentuates vulnerability to mental and physical health problems across the lifespan. To explain this phenomenon, the neuroimmune network hypothesis proposes that childhood stressors amplify signaling between peripheral inflammatory cells and developing brain circuits that support processing of rewards and threats. Here, we conducted a preliminary test of the basic premises of this hypothesis. METHODS: 180 adolescents (mean age = 19.1 years; 68.9 % female) with diverse racial and ethnic identities (56.1 % White; 28.3 % Hispanic; 26.1 % Asian) participated. The Childhood Trauma Interview was administered to quantify early adversity. Five inflammatory biomarkers were assayed in antecubital blood - C-reactive protein, tumor necrosis factor-a, and interleukins-6, -8, and -10 - and were averaged to form a composite score. Participants also completed a functional MRI task to measure corticostriatal responsivity to the anticipation and acquisition of monetary rewards. RESULTS: Stress exposure and corticostriatal responsivity interacted statistically to predict the inflammation composite. Among participants who experienced major stressors in the first decade of life, higher inflammatory activity covaried with lower corticostriatal responsivity during acquisition of monetary rewards. This relationship was specific to participants who experienced major stress in early childhood, implying a sensitive period for exposure, and were evident in both the orbitofrontal cortex and the ventral striatum, suggesting the broad involvement of corticostriatal regions. The findings were independent of participants' age, sex, racial and ethnic identity, family income, and depressive symptoms. CONCLUSIONS: Collectively, the results are consistent with hypotheses suggesting that major stress in childhood alters brain-immune signaling.

Annual Research Review: Neuroimmune network model of depression: a developmental perspective.

Depression is a serious public health problem, and adolescence is an 'age of risk' for the onset of Major Depressive Disorder. Recently, we and others have proposed neuroimmune network models that highlight bidirectional communication between the brain and the immune system in both mental and physical health, including depression. These models draw on research indicating that the cellular actors (particularly monocytes) and signaling molecules (particularly cytokines) that orchestrate inflammation in the periphery can directly modulate the structure and function of the brain. In the brain, inflammatory activity heightens sensitivity to threats in the cortico-amygdala circuit, lowers sensitivity to rewards in the cortico-striatal circuit, and alters executive control and emotion regulation in the prefrontal cortex. When dysregulated, and particularly under conditions of chronic stress, inflammation can generate feelings of dysphoria, distress, and anhedonia. This is proposed to initiate unhealthy, self-medicating behaviors (e.g. substance use, poor diet) to manage the dysphoria, which further heighten inflammation. Over time, dysregulation in these brain circuits and the inflammatory response may compound each other to form a positive feedback loop, whereby dysregulation in one organ system exacerbates the other. We and others suggest that this neuroimmune dysregulation is a dynamic joint vulnerability for depression, particularly during adolescence. We have three goals for the present paper. First, we extend neuroimmune network models of mental and physical health to generate a developmental framework of risk for the onset of depression during adolescence. Second, we examine how a neuroimmune network perspective can help explain the high rates of comorbidity between depression and other psychiatric disorders across development, and multimorbidity between depression and stress-related medical illnesses. Finally, we consider how identifying neuroimmune pathways to depression can facilitate a 'next generation' of behavioral and biological interventions that target neuroimmune signaling to treat, and ideally prevent, depression in youth and adolescents.

Socioeconomic disadvantage and high-effort coping in childhood: evidence of skin-deep resilience.

BACKGROUND: Low socioeconomic status (SES) is a risk factor for poor outcomes across development. Recent evidence suggests that, although psychosocial resilience among youth living in low-SES households is common, such expressions of resilience may not extend to physical health. Questions remain about when these diverging mental and physical health trajectories emerge. The current study hypothesized that skin-deep resilience - a pattern wherein socioeconomic disadvantage is linked to better mental health but worse physical health for individuals with John Henryism high-effort coping - is already present in childhood. METHODS: Analyses focus on 165 Black and Latinx children (Mage = 11.5) who were free of chronic disease and able to complete study procedures. Guardians provided information about their SES. Children reported on their John Henryism high-effort coping behaviors. They also provided reports of their depressed and anxious mood, which were combined into a composite of internalizing symptoms. Children's cardiometabolic risk was captured as a composite reflecting high levels of systolic or diastolic blood pressure, waist circumference, HbA1c, triglycerides, and low high-density lipoprotein cholesterol. RESULTS: Among youth who reported using John Henryism high-effort coping, SES risk was unrelated to internalizing symptoms and was positively associated with cardiometabolic risk. In contrast, for youth who did not engage in high-effort coping, SES risk was positively associated with internalizing symptoms and was unrelated to cardiometabolic risk. CONCLUSIONS: For youth with high-effort coping tendencies, socioeconomic disadvantage is linked to cardiometabolic risk. Public health efforts to support at-risk youth must consider both mental and physical health consequences associated with striving in challenging contexts.

Task-based default mode network connectivity predicts cognitive impairment and negative symptoms in first-episode schizophrenia.

Individuals diagnosed with schizophrenia (SZ) demonstrate difficulty distinguishing between internally and externally generated stimuli. These aberrations in "source monitoring" have been theorized as contributing to symptoms of the disorder, including hallucinations and delusions. Altered connectivity within the default mode network (DMN) of the brain has been proposed as a mechanism through which discrimination between self-generated and externally generated events is disrupted. Source monitoring abnormalities in SZ have additionally been linked to impairments in selective attention and inhibitory processing, which are reliably observed via the N100 component of the event-related brain potential elicited during an auditory paired-stimulus paradigm. Given overlapping constructs associated with DMN connectivity and N100 in SZ, the present investigation evaluated relationships between these measures of disorder-related dysfunction and sought to clarify the nature of task-based DMN function in SZ. DMN connectivity and N100 measures were assessed using EEG recorded from SZ during their first episode of illness (N = 52) and demographically matched healthy comparison participants (N = 25). SZ demonstrated less evoked theta-band connectivity within DMN following presentation of pairs of identical auditory stimuli than HC. Greater DMN connectivity among SZ was associated with better performance on measures of sustained attention (p = .03) and working memory (p = .09), as well as lower severity of negative symptoms, though it was not predictive of N100 measures. Together, present findings provide EEG evidence of lower task-based connectivity among first-episode SZ, reflecting disruptions of DMN functions that support cognitive processes. Attentional processes captured by N100 appear to be supported by different neural mechanisms.

Ambient PM2.5 and specific sources increase inflammatory cytokine responses to stimulators and reduce sensitivity to inhibitors.

Ambient exposure to fine particulate matter (PM2.5) is associated with increased morbidity and mortality from multiple diseases. Recent observations suggest the hypothesis that trained immunity contributes to these risks, by demonstrating that ambient PM2.5 sensitizes innate immune cells to mount larger inflammatory response to subsequent bacterial stimuli. However, little is known about how general and durable this sensitization phenomenon is, and whether specific sources of PM2.5 are responsible. Here we consider these issues in a longitudinal study of children. The sample consisted of 277 children (mean age 13.92 years; 63.8% female; 38.4% Black; 32.2% Latinx) who completed baseline visits and were re-assessed two years later. Fasting whole blood was ex vivo incubated with 4 stimulating agents reflecting microbial and sterile triggers of inflammation, and with 2 inhibitory agents, followed by assays for IL-1ß, IL-6, IL-8, and TNF-α. Blood also was assayed for 6 circulating biomarkers of low-grade inflammation: C-reactive protein, interleukin-6, -8, and -10, tumor necrosis factor-α, and soluble urokinase-type plasminogen activator receptor. Using machine learning, levels of 15 p.m.2.5 constituents were estimated for a 50 m grid around children's homes. Models were adjusted for age, sex, race, pubertal status, and household income. In cross-sectional analyses, higher neighborhood PM2.5 was associated with larger cytokine responses to the four stimulating agents. These associations were strongest for constituents released by motor vehicles and soil/crustal dust. In longitudinal analyses, residential PM2.5 was associated with declining sensitivity to inhibitory agents; this pattern was strongest for constituents from fuel/biomass combustion and motor vehicles. By contrast, PM2.5 constituents were not associated with the circulating biomarkers of low-grade inflammation. Overall, these findings suggest the possibility of a trained immunity scenario, where PM2.5 heightens inflammatory cytokine responses to multiple stimulators, and dampens sensitivity to inhibitors which counter-regulate these responses.

Reflections on resilience.

Resilience research has long sought to understand how factors at the child, family, school, community, and societal levels shape adaptation in the face of adversities such as poverty and war. In this article we reflect on three themes that may prove to be useful for future resilience research. First is the idea that mental and physical health can sometimes diverge, even in response to the same social process. A better understanding of explanations for this divergence will have both theoretical and public health implications when it comes to efforts to promote resilience. Second is that more recent models of stress suggest that stress can accelerate aging. Thus, we suggest that research on resilience may need to also consider how resilience strategies may need to be developed in an accelerated fashion to be effective. Third, we suggest that if psychological resilience interventions can be conducted in conjunction with efforts to enact system-level changes targeted at adversities, this may synergize the impact that any single intervention can have, creating a more coordinated and effective set of approaches for promoting resilience in young people who confront adversity in life.

The balance of giving versus receiving social support and all-cause mortality in a US national sample.

While numerous studies exist on the benefits of social support (both receiving and giving), little research exists on how the balance between the support that individuals regularly give versus that which they receive from others relates to physical health. In a US national sample of 6,325 adults from the National Survey of Midlife Development in the United States, participants were assessed at baseline on hours of social support given and received on a monthly basis, with all-cause mortality data collected from the National Death Index over a 23-y follow-up period. Participants who were relatively balanced in the support they gave compared to what they received had a lower risk of all-cause mortality than those who either disproportionately received support from others (e.g., received more hours of support than they gave each month) or disproportionately gave support to others (e.g., gave many more hours of support a month than they received). These findings applied to instrumental social support (e.g., help with transportation, childcare). Additionally, participants who gave a moderate amount of instrumental social support had a lower risk of all-cause mortality than those who either gave very little support or those who gave a lot of support to others. Associations were evident over and above demographic, medical, mental health, and health behavior covariates. Although results are correlational, one interpretation is that promoting a balance, in terms of the support that individuals regularly give relative to what they receive in their social relationships, may not only help to strengthen the social fabric of society but may also have potential physical health benefits.

The human gut microbiome and health inequities.

Individuals who are minoritized as a result of race, sexual identity, gender, or socioeconomic status experience a higher prevalence of many diseases. Understanding the biological processes that cause and maintain these socially driven health inequities is essential for addressing them. The gut microbiome is strongly shaped by host environments and affects host metabolic, immune, and neuroendocrine functions, making it an important pathway by which differences in experiences caused by social, political, and economic forces could contribute to health inequities. Nevertheless, few studies have directly integrated the gut microbiome into investigations of health inequities. Here, we argue that accounting for host-gut microbe interactions will improve understanding and management of health inequities, and that health policy must begin to consider the microbiome as an important pathway linking environments to population health.

Skin-deep Resilience and Early Adolescence: Neighborhood Disadvantage, Executive Functioning, and Pubertal Development in Minority Youth.

Skin-deep resilience, in which youth overcome adversity and achieve success in psychological and academic domains but at a cost to their physiological well-being, has been documented in late adolescence and adulthood. However, its potential to emerge at earlier developmental stages is unknown. To address this gap, secondary data analyses were executed using waves 1 and 2 of the Adolescent Brain Cognitive Development study (n = 7712; ages 9-10 years at baseline [mean: 9.92; SD = 0.63]; 47.1% female; 66.1% White, 13.4% Black, and 20.6% Hispanic). The results indicated high levels of executive functioning were associated with improved psychological and behavioral outcomes at one-year follow-up. However, for racial and ethnic minority (i.e., Black or Hispanic) youth from disadvantaged neighborhoods, high levels of executive functioning were also associated with accelerated pubertal development. No significant interaction was observed among White youth. The findings suggest the skin-deep resilience pattern may be evident in early adolescence.

Multi-omics approach to socioeconomic disparity in metabolic syndrome reveals roles of diet and microbiome.

The epidemy of metabolic syndrome (MetS) is typically preceded by adoption of a "risky" lifestyle (e.g., dietary habit) among populations. Evidence shows that those with low socioeconomic status (SES) are at an increased risk for MetS. To investigate this, we recruited 123 obese subjects (body mass index [BMI] ≥ 30) from Chicago. Multi-omic data were collected to interrogate fecal microbiota, systemic markers of inflammation and immune activation, plasma metabolites, and plasma glycans. Intestinal permeability was measured using the sugar permeability testing. Our results suggest a heterogenous metabolic dysregulation among obese populations who are at risk of MetS. Systemic inflammation, linked to poor diet, intestinal microbiome dysbiosis, and gut barrier dysfunction may explain the development of MetS in these individuals. Our analysis revealed 37 key features associated with increased numbers of MetS features. These features were used to construct a composite metabolic-inflammatory (MI) score that was able to predict progression of MetS among at-risk individuals. The MI score was correlated with several markers of poor diet quality as well as lower levels of gut microbial diversity and abnormalities in several species of bacteria. This study reveals novel targets to reduce the burden of MetS and suggests access to healthy food options as a practical intervention.

Sulfated glycans engage the Ang-Tie pathway to regulate vascular development.

The angiopoietin (Ang)-Tie pathway is essential for the proper maturation and remodeling of the vasculature. Despite its importance in disease, the mechanisms that control signal transduction through this pathway are poorly understood. Here, we demonstrate that heparan sulfate glycosaminoglycans (HS GAGs) regulate Ang-Tie signaling through direct interactions with both Ang ligands and Tie1 receptors. HS GAGs formed ternary complexes with Ang1 or Ang4 and Tie2 receptors, resulting in potentiation of endothelial survival signaling. In addition, HS GAGs served as ligands for the orphan receptor Tie1. The HS-Tie1 interaction promoted Tie1-Tie2 heterodimerization and enhanced Tie1 stability within the mature vasculature. Loss of HS-Tie1 binding using CRISPR-Cas9-mediated mutagenesis in vivo led to decreased Tie protein levels, pathway suppression and aberrant retinal vascularization. Together, these results reveal that sulfated glycans use dual mechanisms to regulate Ang-Tie signaling and are important for the development and maintenance of the vasculature.

What Are the Health Consequences of Upward Mobility?

Health disparities by socioeconomic status (SES) have been extensively documented, but less is known about the physical health implications of achieving upward mobility. This article critically reviews the evolving literature in this area, concluding that upward mobility is associated with a trade-off, whereby economic success and positive mental health in adulthood can come at the expense of physical health, a pattern termed skin-deep resilience. We consider explanations for this phenomenon, including prolonged high striving, competing demands between the environments upwardly mobile individuals seek to enter and their environments of origin, cultural mismatches between adaptive strategies from their childhood environments and those that are valued in higher-SES environments, and the sense of alienation, lack of belonging, and discrimination that upwardly mobile individuals face as they move into spaces set up by and for high-SES groups. These stressors are hypothesized to lead to unhealthy behaviors and a dysregulation of biological systems, with implications for cardiometabolic health.

Resilience in children with chronic illness: Tests of the shift-and-persist and skin-deep resilience theories.

This study investigated, and discusses the integration of, the shift-and-persist (SAP) and skin-deep resilience (SDR) theories. The SAP theory states that the combination of shifting (adjusting oneself to stressful situations through strategies like emotion regulation) and persisting (enduring adversity with strength by finding meaning and maintaining optimism) will be beneficial to physical health in children experiencing adversity. The SDR theory states that high striving/self-control will be beneficial to mental health but detrimental to physical health among those confronting adversity. This study investigated 308 children ages 8-17 experiencing the adversity of a chronic illness (asthma). SAP and SDR (striving/self-control) were assessed via questionnaires, and physical health (asthma symptoms, inflammatory profiles), mental health (anxiety/depression, emotional functioning), and behavioral (medication adherence, activity limitations, collaborative relationships with providers) outcomes were measured cross-sectionally. SAP was associated with better physical health, whereas SDR was associated with worse physical health. Both were associated with better mental health. Only SDR was associated with better behavioral outcomes. Implications of findings and discussion of how to integrate these theories are provided. We suggest that future interventions might seek to cultivate both SAP and SDR to promote overall better health and well-being across multiple domains in children experiencing adversity.

Low Socioeconomic Status Is Associated with a Greater Neural Response to Both Rewards and Losses.

Low socioeconomic status (SES) has been associated with distinct patterns of reward processing, which appear to have adverse implications for health outcomes, well-being, and human capital. However, most studies in this literature have used complex tasks that engage more than reward processing and/or retrospectively studied childhood SES in samples of adults. To clarify how SES relates to the development of reward processing tendencies, we measured income-to-poverty ratio (IPR) in 172 youth who subsequently underwent functional MRI while completing a passive avoidance task to assess neural responses to reward and loss information. Participants were 12-15 years old (mean = 13.94, SD = .52; 65.7% female) from a sample broadly representative of the Chicago area in terms of SES (IPR range = 0.1-34.53; mean = 3.90; SD = 4.15) and racial makeup (40.1% White 30.8% Black; 29.1% Hispanic). To the extent they had lower IPR, children displayed a trend toward worse behavioral performance on the passive avoidance task. Lower IPR also was associated with a greater response in attention brain regions to reward and loss cues and to reward and loss feedback. Lower IPR also was associated with reduced differentiation between reward and loss feedback in the ventromedial prefrontal and parietal cortex. The current data suggest that both increased salience of reward/loss information and reduced discrimination between reward and loss feedback could be factors linking SES with the development of human capital and health outcomes.

Violence-related distress and lung function in two longitudinal studies of youth.

BACKGROUND: Exposure to violence has been associated with lower lung function in cross-sectional studies. METHODS: We examined whether increasing violence-related distress over time is associated with worse lung function and worse asthma control or quality of life in a secondary analysis of a 48-week randomised clinical trial in 98 youth with asthma (aged 9-16 years) treated with low-dose inhaled corticosteroids (Vitamin D Kids Asthma Study (VDKA)). We then replicated our findings for lung function in a prospective study of 232 Puerto Rican youth followed for an average of 5.4 years. Violence-related distress was assessed using the Checklist of Children's Distress Symptoms (CCDS) scale. Our outcomes of interest were percent predicted lung function measures and (in VDKA only) asthma control (assessed using the Asthma Control Test) and asthma-related quality of life (assessed using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ)). RESULTS: In a multivariable analysis in VDKA, each 1-point increment in CCDS score was associated with decrements of 3.27% in forced expiratory volume in 1 s (FEV1) % pred (95% CI -6.44- -0.22%; p=0.04), 2.65% in forced vital capacity (FVC) % pred (95% CI -4.86- -0.45%; p=0.02) and 0.30 points in the overall PAQLQ score (95% CI -0.50- -0.10 points; p<0.01). Similar findings for FEV1 and FVC were obtained in the prospective study of Puerto Rican youth. CONCLUSIONS: Our findings suggest that violence-related distress may worsen lung function and quality of life in youth with asthma (even those treated with low-dose inhaled corticosteroids), and further support policies to reduce exposure to violence among children in the USA and Puerto Rico.