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.

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.

Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress ß-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

Multiomic foundations of human prefrontal cortex tissue function.

The prefrontal cortex (PFC) is a region of the brain that in humans is involved in the production of higher-order functions such as cognition, emotion, perception, and behavior. Neurotransmission in the PFC produces higher-order functions by integrating information from other areas of the brain. At the foundation of neurotransmission, and by extension at the foundation of higher-order brain functions, are an untold number of coordinated molecular processes involving the DNA sequence variants in the genome, RNA transcripts in the transcriptome, and proteins in the proteome. These "multiomic" foundations are poorly understood in humans, perhaps in part because most modern studies that characterize the molecular state of the human PFC use tissue obtained when neurotransmission and higher-order brain functions have ceased (i.e., the postmortem state). Here, analyses are presented on data generated for the Living Brain Project (LBP) to investigate whether PFC tissue from individuals with intact higher-order brain function has characteristic multiomic foundations. Two complementary strategies were employed towards this end. The first strategy was to identify in PFC samples obtained from living study participants a signature of RNA transcript expression associated with neurotransmission measured intracranially at the time of PFC sampling, in some cases while participants performed a task engaging higher-order brain functions. The second strategy was to perform multiomic comparisons between PFC samples obtained from individuals with intact higher-order brain function at the time of sampling (i.e., living study participants) and PFC samples obtained in the postmortem state. RNA transcript expression within multiple PFC cell types was associated with fluctuations of dopaminergic, serotonergic, and/or noradrenergic neurotransmission in the substantia nigra measured while participants played a computer game that engaged higher-order brain functions. A subset of these associations - termed the "transcriptional program associated with neurotransmission" (TPAWN) - were reproduced in analyses of brain RNA transcript expression and intracranial neurotransmission data obtained from a second LBP cohort and from a cohort in an independent study. RNA transcripts involved in TPAWN were found to be (1) enriched for RNA transcripts associated with measures of neurotransmission in rodent and cell models, (2) enriched for RNA transcripts encoded by evolutionarily constrained genes, (3) depleted of RNA transcripts regulated by common DNA sequence variants, and (4) enriched for RNA transcripts implicated in higher-order brain functions by human population genetic studies. In PFC excitatory neurons of living study participants, higher expression of the genes in TPAWN tracked with higher expression of RNA transcripts that in rodent PFC samples are markers of a class of excitatory neurons that connect the PFC to deep brain structures. TPAWN was further reproduced by RNA transcript expression patterns differentiating living PFC samples from postmortem PFC samples, and significant differences between living and postmortem PFC samples were additionally observed with respect to (1) the expression of most primary RNA transcripts, mature RNA transcripts, and proteins, (2) the splicing of most primary RNA transcripts into mature RNA transcripts, (3) the patterns of co-expression between RNA transcripts and proteins, and (4) the effects of some DNA sequence variants on RNA transcript and protein expression. Taken together, this report highlights that studies of brain tissue obtained in a safe and ethical manner from large cohorts of living individuals can help advance understanding of the multiomic foundations of brain function.

The future of psychophysiology, then and now.

Since its founding in 1973, Biological Psychology has showcased and provided invaluable support to psychophysiology, a field that has grown and changed enormously. This article discusses some constancies that have remained fundamental to the journal and to the field as well as some important trends. Some aspects of our science have not received due consideration, affecting not only the generalizability of our findings but the way we develop and evaluate our research questions and the potential of our field to contribute to the common good. The article offers a number of predictions and recommendations for the next period of growth of psychophysiology.

Racial Discrimination and Metabolic Syndrome in Young Black Adults.

Importance: Metabolic syndrome (MetS) is a common health condition that predisposes individuals to cardiovascular disease (CVD) and disproportionately affects Black and other racially and ethnically minoritized people. Concurrently, Black individuals also report more exposure to racial discrimination compared with White individuals; however, the role of discrimination in the development of MetS over time and associated mediators in these pathways remain underexplored. Objective: To evaluate the association between racial discrimination and MetS in rural Black individuals transitioning from late adolescence into early adulthood and to identify potential mediating pathways. Design, Setting, and Participants: This longitudinal cohort study included Black adolescents enrolled in the Strong African American Families Healthy Adults (SHAPE) Project between June 2009 and May 2021. Families resided in rural counties of Georgia, where poverty rates are among the highest in the nation. Analyses included 322 of the 500 participants who originally enrolled in SHAPE and who were eligible to participate. Guardians provided information about socioeconomic disadvantage. Analyses were conducted in April 2023. Exposures: Youths reported exposure to racial discrimination annually from ages 19 to 21 years. Main Outcomes and Measures: MetS was the main health outcome and was measured at ages 25 and 31 years. MetS was diagnosed according to the International Diabetes Federation guidelines, which requires central adiposity (ie, waist circumference ≥94 cm for males and ≥80 cm for females) and at least 2 of the 4 additional components: signs of early hypertension (ie, systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg); elevated triglyceride levels (ie, >150 mg/dL); elevated fasting glucose level (ie, ≥100 mg/dL); or lowered high-density lipoprotein levels (ie, <40 mg/dL in men and <50 mg/dL in women). At age 25 years, markers of inflammatory activity (ie, soluble urokinase plasminogen activator receptor [suPAR]) and sleep problems were collected to consider as potential mediators. Results: In 322 participants (210 [65.2%] female) ages 19 to 21 years, more frequent exposure to racial discrimination was associated with higher suPAR levels (b = 0.006; 95% CI, 0.001-0.011; P = .01) and more sleep problems at age 25 years (b = 0.062; 95% CI, 0.028-0.097; P < .001) as well as a 9.5% higher risk of MetS diagnosis at age 31 years (odds ratio [OR], 1.10; 95% CI, 1.01-1.20; P = .03). Both suPAR (b = 0.015; 95% CI, 0.002-0.037) and sleep problems (b = 0.020; 95% CI, 0.002-0.047) at age 25 years were significant indirect pathways. No significant interactions between sex and discrimination emerged. Conclusions and Relevance: This study suggests that racial discrimination in late adolescence is associated with MetS among Black young adults through biobehavioral pathways. Thus, health interventions for MetS in Black adults will need to contend with sleep behaviors and inflammatory intermediaries as well as address and reduce exposure to racial discrimination to narrow disparities and promote health equity.

Association between Maternal Perinatal Stress and Depression on Infant DNA Methylation in the First Year of Life.

Maternal stress and depression during pregnancy and the first year of the infant's life affect a large percentage of mothers. Maternal stress and depression have been associated with adverse fetal and childhood outcomes as well as differential child DNA methylation (DNAm). However, the biological mechanisms connecting maternal stress and depression to poor health outcomes in children are still largely unknown. Here we aim to determine whether prenatal stress and depression are associated with changes in cord blood mononuclear cell DNAm (CBMC-DNAm) in newborns (n = 119) and whether postnatal stress and depression are associated with changes in peripheral blood mononuclear cell DNAm (PBMC-DNAm) in children of 12 months of age (n = 113) from the Canadian Healthy Infant Longitudinal Development (CHILD) cohort. Stress was measured using the 10-item Perceived Stress Scale (PSS) and depression was measured using the Center for Epidemiologic Studies Depression Questionnaire (CESD). Both stress and depression were measured at 18 weeks and 36 weeks of pregnancy and six months and 12 months postpartum. We conducted epigenome-wide association studies (EWAS) using robust linear regression followed by a sensitivity analysis in which we bias-adjusted for inflation and unmeasured confounding using the bacon and cate methods. To investigate the cumulative effect of maternal stress and depression, we created composite prenatal and postnatal adversity scores. We identified a significant association between prenatal stress and differential CBMC-DNAm at 8 CpG sites and between prenatal depression and differential CBMC-DNAm at 2 CpG sites. Additionally, we identified a significant association between postnatal stress and differential PBMC-DNAm at 8 CpG sites and between postnatal depression and differential PBMC-DNAm at 11 CpG sites. Using our composite scores, we further identified 2 CpG sites significantly associated with prenatal adversity and 7 CpG sites significantly associated with postnatal adversity. Several of the associated genes, including PLAGL1, HYMAI, BRD2, and ERC2 have been implicated in adverse fetal outcomes and neuropsychiatric disorders. This suggested that differential DNAm may play a role in the relationship between maternal mental health and child health.

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.

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.

Family Disadvantage, Education, and Health Outcomes Among Black Youths Over a 20-Year Period.

Importance: Upward mobility (via educational attainment) is highly valued, but longitudinal associations with mental and physical health among Black youths are less understood. Objective: To examine associations of childhood family disadvantage and college graduation with adult mental and physical health in Black youths followed up into adulthood. Design, Setting, and Participants: This longitudinal, prospective cohort study of Black youths from the state of Georgia who were studied for 20 years (ages 11 to 31 years) was conducted between 2001 and 2022. Participants for this study were drawn from the Strong African American Healthy Adults Program. Data analysis was conducted from April 2023 to January 2024. Exposures: Family economic disadvantage (measured during the adolescent years) and college graduation (indicating upward mobility). Main Outcomes and Measures: Primary outcomes included mental health, substance use, and physical health. Mental health included a composite of internalizing and disruptive problems (anxiety, depression, anger, aggressive behaviors, and emotional reactivity). Substance use included a composite of smoking, drinking, and drug use. Physical health included metabolic syndrome (MetS) and proinflammatory phenotypes (immune cells mounting exaggerated cytokine responses to bacterial challenge and being insensitive to inhibitory signals from glucocorticoids). Mental and physical health measures were taken at age 31 and during the adolescent years. Linear and logistic regression analyses, as well as mediated moderation analyses, were conducted. Results: The study population consisted of 329 Black youths (212 women [64%]; 117 men [36%]; mean [SD] age at follow-up, 31 [1] years). Compared with those who did not graduate college, those who graduated from college had 0.14 SD fewer mental health problems (b = -1.377; 95% CI, -2.529 to -0.226; ß = -0.137; P = .02) and 0.13 SD lower levels of substance use (b = -0.114; 95% CI, -0.210 to -0.018; ß = -0.131; P = .02). Residualized change scores revealed that college graduates showed greater decreases from age 16 to 31 years in mental health problems (b = -1.267; 95% CI, -2.360 to -0.174; ß = -0.133; P = .02) and substance use problems (b = -0.116; 95% CI, -0.211 to -0.021; ß = -0.136; P = .02). For physical health, significant interactions between childhood family disadvantage and college completion emerged in association with MetS (OR, 1.495; 95% CI, 1.111-2.012; P = .008) and proinflammatory phenotype (b = 0.051; 95% CI, 0.003 to 0.099; ß = 0.131; P = .04). Among youths growing up in disadvantaged households, college completion was associated with a 32.6% greater likelihood of MetS (OR, 3.947; 95% CI, 1.003-15.502; P = .049) and 0.59 SD more proinflammatory phenotype (mean difference, 0.249, 95% CI, 0.001 to 0.497; P = .049). Conversely, among those from economically advantaged backgrounds, college completion was correlated with lower MetS and less proinflammatory phenotype. Findings held after controlling for body mass index at age 19 years. Conclusions and Relevance: In this longitudinal cohort study of Black youths, graduating from college was associated with an adult profile of better mental health but poorer physical health among those from economic disadvantage. These findings suggest that developing interventions that foster healthy outcomes across multiple life domains may be important for ensuring that striving for upward mobility is not accompanied by unintended cardiometabolic risk.

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.

Interpersonal violence exposure and inflammation during adolescence and young adulthood.

Exposure to violence increases young peoples' risk of developing mental and physical health problems. Chronic stress-related upregulation of innate immune system activity and the development of low-grade inflammation may partially underlie this health risk. However, much of the previous research has been limited to cross-sectional studies utilizing between-person analytic designs, susceptible to confounding by unmeasured factors. In this six-wave panel study of N=157 female adolescents and young adults, we tested within-person associations between interpersonal violence exposure and multiple measures of inflammatory activity. Ex vivo culture studies suggested that participants' immune cells were more reactive to microbial stimulation and less sensitive to inhibition by glucocorticoids after violence. Numbers of circulating monocyte cells increased after violence, but serum levels of interleukin-6 and c-reactive protein did not. Findings from this within-person analysis suggest that violence exposure up-regulates innate immune system activity during adolescence and young adulthood in ways that may increase mental and physical health risk.

Filamin A Is a Prognostic Serum Biomarker for Differentiating Benign Prostatic Hyperplasia from Prostate Cancer in Caucasian and African American Men.

Prostate cancer represents a significant health risk to aging men, in which diagnostic challenges to the identification of aggressive cancers remain unmet. Prostate cancer screening is driven by the prostate-specific antigen (PSA); however, in men with benign prostatic hyperplasia (BPH) due to an enlarged prostate and elevated PSA, PSA's screening utility is diminished, resulting in many unnecessary biopsies. To address this issue, we previously identified a cleaved fragment of Filamin A (FLNA) protein (as measured with IP-MRM mass spectrometry assessment as a prognostic biomarker for stratifying BPH from prostate cancer and subsequently evaluated its expanded utility in Caucasian (CA) and African American (AA) men. All men had a negative digital rectal examination (DRE) and PSA between 4 and 10 ng/mL and underwent prostate biopsy. In AA men, FLNA serum levels exhibited diagnostic utility for stratifying BPH from patients with aggressive prostate cancer (0.71 AUC and 12.2 OR in 48 men with BPH and 60 men with PCa) and outperformed PSA (0.50 AUC, 2.2 OR). In CA men, FLNA serum levels also exhibited diagnostic utility for stratifying BPH from patients with aggressive prostate cancer (0.74 AUC and 19.4 OR in 191 men with BPH and 109 men with PCa) and outperformed PSA (0.46 AUC, 0.32 OR). Herein, we established FLNA alone as a serum biomarker for stratifying men with BPH vs. those with high Gleason (7-10) prostate cancers compared to the current diagnostic paradigm of using PSA. This approach demonstrates clinical actionability of FLNA alone without the requirement of prostate volume measurement as a test with utility in AA and CA men and represents a significant opportunity to decrease the number of unnecessary biopsies in aggressive prostate cancer diagnoses.

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.

Prenatal exposure to maternal disadvantage-related inflammatory biomarkers: associations with neonatal white matter microstructure.

Prenatal exposure to heightened maternal inflammation has been associated with adverse neurodevelopmental outcomes, including atypical brain maturation and psychiatric illness. In mothers experiencing socioeconomic disadvantage, immune activation can be a product of the chronic stress inherent to such environmental hardship. While growing preclinical and clinical evidence has shown links between altered neonatal brain development and increased inflammatory states in utero, the potential mechanism by which socioeconomic disadvantage differentially impacts neural-immune crosstalk remains unclear. In the current study, we investigated associations between socioeconomic disadvantage, gestational inflammation, and neonatal white matter microstructure in 320 mother-infant dyads over-sampled for poverty. We analyzed maternal serum levels of four cytokines (IL-6, IL-8, IL-10, TNF-α) over the course of pregnancy in relation to offspring white matter microstructure and socioeconomic disadvantage. Higher average maternal IL-6 was associated with very low socioeconomic status (SES; INR < 200% poverty line) and lower neonatal corticospinal fractional anisotropy (FA) and lower uncinate axial diffusivity (AD). No other cytokine was associated with SES. Higher average maternal IL-10 was associated with lower FA and higher radial diffusivity (RD) in corpus callosum and corticospinal tracts, higher optic radiation RD, lower uncinate AD, and lower FA in inferior fronto-occipital fasciculus and anterior limb of internal capsule tracts. SES moderated the relationship between average maternal TNF-α levels during gestation and neonatal white matter diffusivity. When these interactions were decomposed, the patterns indicated that this association was significant and positive among very low SES neonates, whereby TNF-α was inversely and significantly associated with inferior cingulum AD. By contrast, among the more advantaged neonates (lower-to-higher SES [INR ≥ 200% poverty line]), TNF-α was positively and significantly associated with superior cingulum AD. Taken together, these findings suggest that the relationship between prenatal cytokine exposure and white matter microstructure differs as a function of SES. These patterns are consistent with a scenario where gestational inflammation's effects on white matter development diverge depending on the availability of foundational resources in utero.

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.

Registry-derived stage (RD-Stage) for capturing stage at diagnosis for pancreatic carcinoma in Australia.

INTRODUCTION: Stage of pancreatic carcinoma at diagnosis is a strong prognostic indicator of morbidity and mortality, yet is poorly notified to population-based cancer registries ("cancer registries"). Registry-derived stage (RD-Stage) provides a method for cancer registries to use available data sources to compile and record stage in a consistent way. This project describes the development and validation of rules to capture RD-Stage (pancreatic carcinoma) and applies the rules to data currently captured in each Australian cancer registry. MATERIALS AND METHODS: Rules for deriving RD-stage (pancreatic carcinoma) were developed using the American Joint Commission on Cancer (AJCC) Staging Manual 8th edition and endorsed by an Expert Working Group comprising specialists responsible for delivering care to patients diagnosed with pancreatic carcinoma, cancer registry epidemiologists and medical coders. Completeness of data fields required to calculate RD-Stage (pancreatic carcinoma) and an overall proportion of cases for whom RD stage could be assigned was assessed using data collected by each Australian cancer registry, for period 2018-2019. A validation study compared RD-Stage (pancreatic carcinoma) calculated by the Victorian Cancer Registry with clinical stage captured by the Upper Gastro-intestinal Cancer Registry (UGICR). RESULTS: RD-Stage (pancreatic carcinoma) could not be calculated in 4/8 (50%) of cancer registries; one did not collect the required data elements while three used a staging system not compatible with RD-Stage requirements. Of the four cancer registries able to calculate RD-Stage, baseline completeness ranged from 9% to 76%. Validation of RD-Stage (pancreatic carcinoma) with UGICR data indicated that there was insufficient data available in VCR to stage 174/457 (38%) cases and that stage was unknown in 189/457 (41%) cases in the UGICR. Yet, where it could be derived, there was very good concordance at stage level (I, II, III, IV) between the two datasets. (95.2% concordance], Kendall's coefficient = 0.92). CONCLUSION: There is a lack of standardisation of data elements and data sources available to cancer registries at a national level, resulting in poor capacity to currently capture RD-Stage (pancreatic carcinoma). RD-Stage provides an excellent tool to cancer registries to capture stage when data elements required to calculate it are available to cancer registries.

Vibrational manipulation of dry granular materials in lab-on-a-chip devices.

We present vibrational techniques to pump, mix, and separate dry granular materials using multifrequency vibrations applied to a solid substrate with a standard audio system. The direction and velocity of the granular flow are tuned by modulating the sign and amplitude, respectively, of the vibratory waveform, with typical pumping velocities of centimeters per second. Different granular materials are mixed by combining them at Y-shaped junctions, and mixtures of granules with different friction coefficients are separated along straight channels by judicious choice of the vibratory waveform. We demonstrate that the observed velocities accord with a theory valid for sufficiently large or fast vibrations, and we discuss the implications for using vibrational manipulation in conjunction with established microfluidic technologies to combine liquid and dry solid handling operations at sub-millimeter length scales.

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.