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Objective: To determine the association between objective (geospatial) and subjective (perceived) measures of neighborhood disadvantage (ND) and aggressive breast cancer tumor biology, defined using validated social adversity-associated transcription factor (TF) activity and clinical outcomes., Background: ND is associated with shorter breast cancer recurrence-free survival (RFS), independent of individual, tumor, and treatment characteristics, suggesting potential unaccounted biological mechanisms by which ND influences RFS., Methods: We quantified TF-binding motif prevalence within promoters of differentially expressed genes for 147 tissue samples prospectively collected on the protocol. Covariate-adjusted multivariable regression analyzed objective and subjective ND scores with 5 validated TFs of social adversity and aggressive biology-pro-inflammatory activity [nuclear factor-κB ( NF-kB ), activator protein 1 ( AP-1 )], sympathetic nervous system (SNS) activity [cyclic 3'-5' adenosine monophosphate response element-binding protein ( CREB )], and protective cellular responses [interferon-regulatory factor ( IRF ) and signal transducer and activator of transcription ( STAT )]. To clinically validate these TFs as prognostic biomarkers of aggressive biology, logistic regression and multivariable Cox proportional-hazards models analyzed their association with Oncotype DX scores and RFS, respectively., Results: Increasing objective ND was associated with aggressive tumor biology (up-regulated NF-kB , activator protein 1, down-regulated IRF , and signal transducer and activator of transcription) and SNS activation (up-regulated CREB ). Increasing subjective ND (eg, threat to safety) was associated with up-regulated NF-kB and CREB and down-regulated IRF . These TF patterns were associated with high-risk Oncotype DX scores and shorter RFS., Conclusions: In the largest human social genomics study, objective and subjective ND were significantly associated with TFs of aggressive biology and SNS activation. These TFs also correlated with worse clinical outcomes, implicating SNS activation as one potential mechanism behind ND survival disparities. These findings remain to be validated in a national cohort., Competing Interests: N.G. is funded by an Breast Cancer Research Foundation, Paul Calabresi Award, American Surgical Association Fellowship Award, American Society of Clinical Oncology (ASCO) Career Development Award, and an NIH P50 Transdisciplinary Cancer Control Support Grant. Also, she is a paid technical consultant for the World Health Organization. M.A. is funded by the Florida Breast Cancer Foundation; NIH grants R01CA206456, UG3 CA260317, R61 CA263335, R37 CA255875; a PCORI grant AD-2020C3-21171; and an NIH P50 Transdisciplinary Cancer Control Support Grant. Also, he is a paid consultant for Blue Note Therapeutics and Atlantis Healthcare. He is also the inventor of Cognitive Behavioral Stress Management, filed with the University of Miami as UMIP-483, which is licensed to Blue Note Therapeutics. S.C. is funded by the NIH K12 and NIA P30-AG017265. A.E.H. is funded by the Ruth L. Kirschstein Institutional National Research Service Award, T32CA211034. The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Aging is associated with increased proinflammatory gene expression and systemic inflammation, and psychosocial stress may accelerate these changes. Mindfulness interventions show promise for reducing psychosocial stress and extending healthspan. Inflammatory pathways may play a role. In a sample of lonely older adults, we tested whether mindfulness training reduces proinflammatory gene expression and protein markers of systemic inflammation., Methods: Lonely older adults (65-85 years; N = 190) were randomly assigned to an 8-week Mindfulness-Based Stress Reduction (MBSR) or matched Health Enhancement Program (HEP). Blood was drawn before and after the intervention and at 3-month follow-up. In peripheral blood mononuclear cells, RNA profiling was used to assess transcriptional regulation by proinflammatory nuclear factor κB (NF-κB) as well as β-adrenergic cAMP response element-binding protein (CREB), antiviral interferon regulatory factor (IRF), and glucocorticoid receptor (GR) transcription factors. Plasma was assayed for proinflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP). Analyses tested time (pre, post, follow-up) by condition (MBSR versus HEP) effects., Results: MBSR reduced NF-κB ( d = 0.17, p = .028) but did not alter CREB ( d = 0.10, p = .20), IRF ( d = 0.13, p = .086), or GR activity ( d = 0.14, p = .063) relative to HEP over time. Contrary to predictions, there were no time by condition effects of MBSR compared with HEP on reducing circulating IL-6 or CRP., Conclusions: In lonely older adults, MBSR reduced cellular proinflammatory gene regulation in ways that would predict reduced disease risk. However, no similar effect was observed for circulating protein markers of inflammation. These results provide specificity about how mindfulness interventions may impact distinct inflammatory markers among aging adults in ways that may have important implications for healthspan., Trial Registration: Clinical Trials identifier NCT02888600., (Copyright © 2023 by the American Psychosomatic Society.)

Previous research has shown that adverse social conditions may promote a conserved transcriptional response to adversity (CTRA) involving up-regulation of proinflammatory gene expression and down-regulation of Type I interferon anti-viral genes in circulating blood cells. However, the impact of social conditions on lymphoid tissue gene regulation remains largely unexplored. This project assessed how social instability in adult male rhesus macaques (N=10, 5 in unstable, and 5 in stable social conditions) might regulate gene expression within secondary lymphoid tissue (lymph nodes; LN). Unstable social conditions down-regulated axillary LN expression of genes involved in Type I interferon anti-viral responses. Transcript origin analyses implicated monocytes and B cells as cellular mediators of these effects, and promoter-based bioinformatics analyses indicated reduced activity of AP-1, NF-κB, IRF, and CREB transcription factors within the axillary LN microenvironment. Although the current study is limited in sample size, these results suggest that social influences on immune cell gene regulation extend beyond the circulating leukocyte pool to alter generalized transcriptome profiles in secondary lymphoid tissue, and they do so in a regulatory program that resembles the pattern of antiviral inhibition previously observed in circulating leukocytes.

Background: Depression risk increases dramatically for adolescent females following the pubertal transition. Although chronic early-life stressor exposure and a maternal history of depression are established risk factors for depression onset in this population, we know little about the biological mechanisms underlying these associations., Method: To investigate, we examined how chronic early-life stressor exposure and maternal depression history were associated with stress-related gene expression patterns, using a high-risk family design in 48 psychiatrically healthy adolescent females, 20 of whom had a mother with a lifetime history of depression. Lifetime chronic stressor exposure was assessed using the STRAIN and gene expression patterns were estimated using transcriptional profiling of whole blood., Results: Consistent with hypotheses, we found that adolescent females with greater chronic stressor exposure had higher NR3C1 expression levels compared to those with less chronic stressor exposure. Additionally, youth with a depressed mother had lower levels of FKBP5 expression compared to those without a depressed mother. Levels of FKBP5 expression, in turn, interacted with chronic stressor exposure to predict NR3C1 expression. Specifically, for those with low chronic stressor exposure, levels of FKBP5 and NR3C1 expression were strongly interrelated, whereas for those with high chronic stressor exposure, NR3C1 expression was high regardless of levels of FKBP5 expression., Limitations: This study was correlational, the sample size was limited, and additional research is needed to elucidate the underlying mechanisms and predict who subsequently develops depression., Conclusions: Notwithstanding these limitations, these data indicate that having low FKBP5 expression, alongside high NR3C1 expression, may be a potential preclinical marker of depression risk in adolescent females that warrants additional investigation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest with respect to this work., (Copyright © 2024. Published by Elsevier B.V.)

Altered activity of major immunoregulatory pathways has been reported in major depressive disorder (MDD) and is thought to underlie the elevations in circulating inflammatory mediators present in a subgroup of patients. However, the drivers of these changes in gene expression remain unclear. One potential modulator of immune function is viral infection. Here we examined the relationship between cytomegalovirus (CMV), a common herpesvirus, that has been shown to be a pathological cofactor in inflammatory disorders, and activity of key coordinators of the innate inflammatory response in MDD. We used RNAseq to characterize gene expression differences in in 79 unmedicated individuals with MDD and 80 healthy controls (HCs). A well-established bioinformatic strategy was used to quantify transcription control pathway activity based on the relative prevalence of pre-specified transcription factor-binding motifs in the promoters of differentially expressed genes. The main aim was to characterize diagnostic differences in immunoregulatory pathway activity and determine if these were related to CMV serostatus or antibody titer (viral reactivation). Significantly increased activity of interferon regulatory factor 1 (IRF1) and nuclear factor kappa-B cell (NF-κB) pathways was observed in the MDD group compared with HCs. Transcript Origin Analyses using cell-specific reference transcriptomes indicated that the MDD-associated transcriptome changes derived primarily from myeloid lineage immune cells (classical and non-classical monocytes). A more modest MDD-associated upregulation of glucocorticoid receptor (GR) pathway activity was also present. CMV infection/activity across the combined MDD and HC groups was weakly related to GR pathway activation but not to IRF1 and NF-κB activity; the most salient signature of CMV was activation and/or expansion of the CD8+ T-cell population. The elevated MDD-associated NF-κB (but not IRF1) activity was markedly attenuated after controlling for CMV antibody titer or for CD8+ T-cell prevalence. At least some of the NF-κB signal in MDD may be attributable to the cellular immune response to CMV, suggesting that CMV infection may be one of several pathways contributing to inflammation in depression. The pronounced activation of the antiviral IRF-1 pathway in MDD suggests the contribution of viral processes although this specific antiviral effect was not specific to CMV.CMV may indirectly drive interferon responses by impairing T-cell control of other viral infections., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TBM received compensation as a member of the Clinical and Scientific Advisory Board for Quadrant Biosciences Inc, unrelated to the current work. All other authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: High-grade (HGOC) and low-grade ovarian carcinoma (LGOC) are distinct malignancies with different biological features, treatment paradigms, and life expectancies. However, differences in quality of life (QOL), sleep, and depressive symptoms have not been examined by grade, and neither have inflammatory profiles associated with these symptoms. We aim to characterize QOL and biomarkers by OC grade., Methods: Participants included patients with HGOC (N = 578) or LGOC (N = 85). Participants completed baseline assessments of psychosocial factors prior to primary surgery or neoadjuvant chemotherapy and contributed saliva for cortisol and blood for interleukin-6 (IL-6) quantification. Samples were collected intraoperatively to quantify tumor cortisol. General linear models were used to examine differences in biological and psychological variables by grade., Results: At baseline, patients with LGOC reported less depression (p = 0.018) and sleep disturbances (p = 0.014), but no significant difference in depressive mood (p = 0.11) or QOL (p = 0.51) compared to patients with HGOC, adjusting for age and disease stage. There were trends towards lower tumor cortisol levels (p = 0.078) in LGOC compared to HGOC. One-year post-diagnosis, we found a significant improvement in QOL and fatigue, and a decrease in vegetative depression and IL-6 levels irrespective of grade., Conclusions: We present the first characterization of psychosocial experiences of patients with LGOC. Despite having a better disease prognosis, patients with LGOC were just as likely to have mood disturbances as those with HGOC. There was a trend towards differences in tumor cortisol by grade. Our findings highlight the need to address well-being in patients with both low- and high-grade ovarian malignancies., Competing Interests: Declaration of competing interest Dr. Thaker has done consulting for Iovance Biotherapeutics, Imunon, Merck, Eisai, Agenus, Immunogen, R-Pharm, Astra Zeneca, Clovis Oncology. Aadi Biosciences, Glaxo Smith Kline, Relacorilant, Seagen, Mersana, Novocure, and Verastem. Merck and Glaxo Smith Kline have provided institutional research grants. Immunon has provided shares to Dr. Thaker. Dr. Sood has done consulting for Merck, GSK, ImmunoGen, Astra Zeneca, Kiyatec, Iylon, Onxeo and is a shareholder for BioPath. Dr. Lutgendorf is a shareholder for AbbVie., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Psychosocial stress and adversity have been linked to accelerated aging and increased risk for age-related diseases. Animal and in vitro studies have shown that exposure to stress hormones (catecholamines, glucocorticoids) can impact biological aging processes such as DNA damage and cellular senescence, suggesting they play a key role in links between stress and aging; however, these associations have not been well investigated in humans. We examined cross-sectional associations between chronic stress exposures, stress hormones, and biological aging markers in midlife adults and whether stress hormones mediated associations between stress and aging. Participants were 531 adults aged 26-78 years (M age  = 53.9, 50.1 % female) in the nationally representative Midlife in the United States Refresher cohort. They reported chronic stress exposures in childhood and adulthood (Stressful Life Event Inventory) and provided 12-hour urine samples used to assess norepinephrine, epinephrine, and cortisol. RNA sequencing of peripheral blood mononuclear cells derived aging biomarkers: the DNA damage response (DDR; 30-gene composite), cellular senescence signal p16 INK4a (CDKN2A), and the pro-inflammatory senescence-associated secretory phenotype (SASP; 57-gene composite). Regression models adjusting for age, sex, race/ethnicity, BMI, smoking status, alcohol use, and medications revealed that more childhood exposures were associated with higher norepinephrine (β = 0.09, p = 0.04), independent from adult exposures. Higher norepinephrine was associated with elevated DDR expression (β = 0.17, p < 0.001). Higher norepinephrine (β = 0.14, p = 0.003) and epinephrine (β = 0.10, p = 0.02) were both associated with elevated SASP expression. Statistical mediation analyses implicated elevated norepinephrine as a plausible mediator of associations between childhood exposures and both DDR (unstandardized b = 0.005, 95 % CI [0.0002, 0.011]) and SASP (b = 0.002, 95 % CI [0.0001, 0.05]). Findings provide preliminary evidence in humans that stress hormones may impact key biological aging processes and may be a mechanism linking chronic stress exposures in childhood to accelerated aging later in life., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Adverse psychosocial exposure is associated with increased pro-inflammatory gene expression and reduced type-1 interferon gene expression known as the conserved transcriptional response to adversity (CTRA). CTRA is not well-studied in cognitive impairment but may contribute to late-life cognitive decline., Methods: We examined perceived stress, loneliness, well-being, and the impact of coronavirus disease 2019 (COVID-19) and the relationship to the expression of genes associated with the CTRA. Mixed-effect linear models were used to quantify associations between psychosocial variables and CTRA gene expression., Results: Eudaimonic well-being (EWB) was inversely associated with CTRA gene expression in participants with both normal cognition (NC) and mild cognitive impairment (MCI). Self-reported coping strategies differed by cognitive status and variably impacted CTRA gene expression., Discussion: EWB is an important correlate of stress, even in people with MCI. The prodromal cognitive decline appears to moderate the significance of coping strategies as a correlate of CTRA gene expression., Highlights: Conserved transcriptional response to adversity (CTRA) gene expression is higher with lower eudaimonic well-being.Eudaimonic well-being was important in both participants with normal cognition and those with mild cognitive impairment.Coping strategies and impact on CTRA gene expression differed by cognitive status.Loneliness in a population with relatively low loneliness scores did not impact CTRA gene expression., Competing Interests: All authors report no conflicts of interest. Author disclosures are available in the Supporting Information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: Neighborhoods represent complex environments with unique social, cultural, physical, and economic attributes that have major impacts on disparities in health, disease, and survival. Neighborhood disadvantage is associated with shorter breast cancer recurrence-free survival (RFS) independent of individual-level (race, ethnicity, socioeconomic status, insurance, tumor characteristics) and health system-level determinants of health (receipt of guideline-concordant treatment). This persistent disparity in RFS suggests unaccounted mechanisms such as more aggressive tumor biology among women living in disadvantaged neighborhoods compared with advantaged neighborhoods. The objective of this article was to provide a clear framework and biological mechanistic explanation for how neighborhood disadvantage affects cancer survival., Methods: Development of a translational epidemiological framework that takes a translational disparities approach to study cancer outcome disparities through the lens of social genomics and social epigenomics., Results: The social genomic determinants of health, defined as the physiological gene regulatory pathways (ie, neural/endocrine control of gene expression and epigenetic processes) through which contextual factors, particularly one's neighborhood, can affect activity of the cancer genome and the surrounding tumor microenvironment to alter disease progression and treatment outcomes., Conclusion: We propose a novel, multilevel determinants of health model that takes a translational epidemiological approach to evaluate the interplay between political, health system, social, psychosocial, individual, and social genomic determinants of health to understand social disparities in oncologic outcomes. In doing so, we provide a concrete biological pathway through which the effects of social processes and social epidemiology come to affect the basic biology of cancer and ultimately clinical outcomes and survival.

Accumulating evidence indicates that social isolation (SI) in humans and rodents is associated with increased cancer incidence and mortality, yet mediating mechanisms remain elusive. Here, we examine the neuroendocrine and immunological consequences of SI and its short- and long-term physiological impacts in naïve and cancer-bearing rats. Findings indicate that isolated animals experienced a significant decrease in weight compared to controls. Specifically, females showed a marked weight decrease during the first week of isolation. Isolated rats had significantly higher numbers of MADB106 experimental pulmonary metastases. Although mortality rates were higher in isolated tumor-bearing rats, unexpectedly, they exhibited a reduced growth rate of orthotopically implanted MADB106 tumors. Transcriptomic analyses of these excised tumors indicated a major downregulation in the expression of various genes, including those associated with pro-metastatic processes (e.g., EMT). In naïve rats (no cancer), levels of IL-6 increased, and total IgG levels decreased under SI conditions. A mixed effect was found for TNFα, which increased in females and decreased in males. In the central nervous system, isolated rats showed altered gene expression in key brain regions associated with stress responses and social behavior. The paraventricular nucleus of the thalamus emerged as a significantly affected region, along with the bed nucleus of the stria terminalis. Changes were observed in the expression of oxytocin, serotonin, and dopamine receptors. Isolated rats also exhibited greater alterations in hypothalamic-pituitary-adrenal (HPA) axis-related regulation and an increase in plasma CORT levels. Our study highlights the profound impact of SI on metastatic processes. Additionally, the potential detrimental effects of SI on thermoregulation were discussed, emphasizing the importance of social thermoregulation in maintaining physiological stability and highlighting the need to avoid single-caging practices in research. We report neuro-immune interactions and changes in brain gene expression, highlighting the need for further research into these underlying processes to improve outcomes in animal models and potential interventions for cancer patients through increased social support., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

To address the challenge of predicting psychological response to a psychosocial intervention we tested the possibility that baseline gene expression profiles might provide information above and beyond baseline psychometric measures. The genomics strategy utilized individual level inferences of transcription factor activity to predict changes in loneliness and affect in response to two well-established meditation interventions. Initial algorithm development analyses focused on three a-priori defined stress-related gene regulation pathways (CREB, GR, and NF-ĸB) as inferred from TELiS promoter-based bioinformatic analysis of basal (pre-intervention) blood samples from a randomized-controlled trial comparing a compassion-based meditation (CM, n = 45) with mindfulness meditation (MM, n = 44). Greater baseline CREB activity (but not GR or NF-ĸB) predicted greater reductions from pre- to post-intervention in loneliness (b = -0.24, p = 0.016) and negative emotions (b = -0.23, p = 0.017) for CM, but not for MM. A second algorithm validation analysis applied the same approach to another randomized controlled trial comparing CM (n = 42) with MM (n = 38) and a health education control condition (n = 41). Similarly, greater baseline CREB activity predicted greater pre- to post-intervention decreases in loneliness (b = -0.24, p = 0.029) and greater increases in satisfaction with life (b = 0.21, p = 0.046) for the CM condition only. Baseline CREB activity was not associated with baseline psychometric measures in either study. Results raise the possibility that pre-intervention gene expression profiles may reflect non-conscious psychobiological states that affect psychological responses to distinct psychosocial interventions, and thereby help personalize intervention selection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Overactivation of the stress response can influence cancer outcomes through immune-related pathways. Adolescents and young adults (AYAs) undergoing hematopoietic cell transplantation (HCT) are at risk for poor outcomes, yet there are limited behavioral interventions and no psychosocial biomarker data for this population. The Conserved Transcriptional Response to Adversity (CTRA) is an inflammation-related pattern observed in conditions of heightened stress and is associated with HCT outcomes. The objective of the current study was to explore the CTRA gene regulatory impact of Promoting Resilience in Stress Management (PRISM) intervention among AYAs receiving HCT. We hypothesized that patients who received the intervention would have favorable gene expression signatures compared to those in the control arm. This was an ancillary study within a randomized trial testing the PRISM intervention on psychosocial outcomes among AYAs aged 12 to 24 years receiving HCT (NCT03640325). CTRA was quantified through genome-wide transcriptional profiles obtained from whole blood collected at baseline, 1-, and 3-month post-HCT. Group differences in CTRA gene expression were estimated using mixed-effect linear models. There were no baseline group differences in CTRA expression, but PRISM participants showed a greater decline in CTRA at 1 month compared to controls (β -0.301 ± SE 0.114, P = .016), even when controlling for demographic (Group × Time interaction: F(2, 18) = 7.41, P = .004; β -0.386 ± 0.127, P = .007) and clinical covariates (Group × Time interaction: F(2, 20) = 7.03, P = .005; β -0.480 ± 0.144, P = .003). These differences were not detectable at 3 months (β -0.147 ± SE 0.120, P = .235). There was a change in stress-related gene expression among AYAs randomized to a psychosocial intervention. The stress-inflammation axis may be a targetable pathway in the AYA HCT population., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.

This study employs multi-level and mixed-methods approaches to examine how structural violence affects the health of low-income, single Black mothers. We use multilevel regression models to examine how feeling "trapped" in racially segregated neighborhoods with high levels of violence on the South Side of Chicago affects mothers' (N = 69) reports of posttraumatic stress disorder and depressive symptoms. The relationship between feeling "trapped" and variations in expression of mRNA for the glucocorticoid receptor gene NR3C1 using microarray assays was also examined. The regression models revealed that feeling "trapped" significantly predicted increased mental distress in the form of PTSD, depressive symptoms, and glucocorticoid receptor gene regulation. The mothers' voices revealed a nuanced understanding about how a lack of financial resources to move out of the neighborhood creates feelings of being "trapped" in dangerous situations., (© 2022. W. Montague Cobb-NMA Health Institute.)

Objectives: Loneliness is a pressing public health concern, but the mechanisms by which it leads to declining physical health are uncertain. Prior work has begun to explore epigenetic pathways, with some evidence suggesting a link between loneliness and DNA methylation, though it is unclear whether epigenetic variation can help explain loneliness-health associations., Methods: Associations between loneliness and epigenetic age acceleration (EAA) were estimated, as well as the degree to which EAA mediated and moderated the association between loneliness and the development of chronic physical health conditions (multimorbidity) in older adulthood. The sample consisted of Health and Retirement Study participants who provided blood draws and consented to methylation profiling (n = 4,018)., Results: Baseline loneliness was associated with greater EAA in the GrimAge measure net of demographic and behavioral covariates (β = 0.07, p = .003). Loneliness and GrimAge each predicted increasing condition counts, but there was no evidence of an interactive effect. The association between loneliness and increasing condition counts was, however, significantly mediated by GrimAge (indirect path β = 0.020, p = .003)., Discussion: These results suggest that the impact of loneliness on multimorbidity may, in part, operate through DNA methylation. The specific intermediary, physiological mechanisms that are involved will require further research, but EAA measures like GrimAge are promising in helping to understand the health impacts of loneliness., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Sex differences in immune-based disorders are well-established, with female sex associated with a markedly heightened risk of autoimmune disease. Female sex is also overrepresented in other conditions associated with elevated inflammation, including depression, chronic pain, and chronic fatigue. The mechanisms underlying these disparities are unclear. This study used an experimental model of inflammatory challenge to interrogate molecular mechanisms that may contribute to female vulnerability to disorders with an inflammatory basis., Method: In this analysis of a secondary outcome from a randomized controlled trial, 111 participants (67 female) received either a bolus injection of endotoxin (n = 59) or placebo (n = 52). Participants provided blood samples before and 0.5 h post-injection for assessment of differential activation of key pro-inflammatory (i.e., activator protein (AP)-1; nuclear factor (NF)-κB) and immunoregulatory (i.e., glucocorticoid receptor (GR); cAMP response element binding protein (CREB)) signaling pathways via genome-wide expression profiling and promoter-based bioinformatics analyses., Results: Relative to males, females exhibited greater endotoxin-induced increases in bioinformatic measures of CREB transcription factor activity ( p's  < 0.01). However, contrary to hypotheses, female vs. male sex was not associated with greater increases in activation of NF-κB, AP-1, or GR in response to endotoxin vs. placebo administration., Conclusions: This work suggests CREB signaling as a critical upstream biological pathway that should be further interrogated as a mechanism of female vulnerability to immune-related disorders. Future work should clarify whether increased CREB signaling indicates sex differences in activity of the sympathetic nervous system or other physiological pathways that signal through CREB, such as prostaglandin release., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Low socioeconomic status (SES) is a risk factor for mortality and immune dysfunction across a wide range of diseases, including cancer. However, cancer is distinct in the use of allogeneic hematopoietic cell transplantation (HCT) as a treatment for hematologic malignancies to transfer healthy hematopoietic cells from one person to another. This raises the question of whether social disadvantage of an HCT cell donor, as assessed by low SES, might impact the subsequent health outcomes of the HCT recipient. To evaluate the cellular transplantability of SES-associated health risk, we analyzed the health outcomes of 2,005 HCT recipients who were transplanted for hematologic malignancy at 125 United States transplant centers and tested whether their outcomes differed as a function of their cell donor's SES (controlling for other known HCT-related risk factors). Recipients transplanted with cells from donors in the lowest quartile of SES experienced a 9.7% reduction in overall survival ( P = 0.001) and 6.6% increase in treatment-related mortality within 3 y ( P = 0.008) compared to those transplanted from donors in the highest SES quartile. These results are consistent with previous research linking socioeconomic disadvantage to altered immune cell function and hematopoiesis, and they reveal an unanticipated persistence of those effects after cells are transferred into a new host environment. These SES-related disparities in health outcomes underscore the need to map the biological mechanisms involved in the social determinants of health and develop interventions to block those effects and enhance the health of both HCT donors and recipients., Competing Interests: Competing interests statement:The authors declare no competing interest.

Female sex workers (FSW) are highly mobile, which may result in reduced access to and use of health services and increased risk for poor health outcomes, particularly for those living with HIV. Mobility includes spatial, temporal, and social elements that are not fully captured by quantitative measures. We conducted two rounds of in-depth interviews with FSW living with HIV in Iringa, Tanzania (n = 20), and Santo Domingo, Dominican Republic (n = 20), to describe mobility experiences and compare mobility narratives across settings. We integrated a thematic analysis of all interviews with a narrative analysis of a subset of 10 information-rich interviews (five in each country) with women who had recently traveled, for sex work or another reason, outside of their hometown. Across narratives, FSW living with HIV traveled locally or to seasonal destinations, for short and long periods. Social factors influencing mobility included economic drivers; risk of arrest, harassment, or violence; anonymity and/or familiarity; social relationships; and clients' mobility. Spatial, temporal, and social factors intersected in unique ways in FSW's mobility experiences, yet distinct mobility typologies were evident across settings and destinations. Together, mobility narratives of FSW living with HIV can inform quantitative research on mobility typologies in Tanzania, the Dominican Republic, and elsewhere. With the potential for economic circumstances, climate change, and other emergencies to increase people's mobility around the world, researchers and practitioners can learn from the lived experiences of FSW to inform whether and how to tailor and improve the accessibility of HIV care and treatment interventions based on spatial, temporal, and social characteristics of mobility., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hendrickson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Multiple myeloma (MM) is an incurable cancer and is the leading indication for autologous hematopoietic stem cell transplantation (HSCT). To be eligible for HSCT, a patient must have a caregiver, as caregivers play a central role in HSCT preparation and recovery. MM patients remain on treatment indefinitely, and thus patients and their caregivers face long-term challenges including the intensity of HSCT and perpetual therapy after transplant. Importantly, both patients and their caregivers show heightened depressive and anxiety symptoms, with dyadic correspondence evidenced and caregivers' distress often exceeding that of patients. An extensive psychoneuroimmunology (PNI) literature links distress with health via immune and neuroendocrine dysregulation as well as biological aging. However, data on PNI in the context of multiple myeloma - in patients or caregivers - are remarkably limited. Distress in MM patients has been associated with poorer outcomes including higher inflammation, greater one year post-HSCT hospital readmissions, and worse overall survival. Further, anxiety and depression are linked to biological aging and may contribute to the poor long-term health of both patients and caregivers. Because MM generally affects older adults, individual differences in biological aging may represent an important modifier of MM biology and HSCT treatment outcomes. There are a number of clinical scenarios in which biologically younger people could be prescribed more intensive therapies, with potential for greater benefit, by using a personalized cancer therapy approach based on the quantification of physiologic reserve. Further, despite considerable psychological demands, the effects of distress on health among MM caregivers is largely unexamined. Within this context, the current critical review highlights gaps in knowledge at the intersection of HSCT, inflammation, and biological aging in the context of MM. Research in this area hold promise for opportunities for novel and impactful psychoneuroimmunology (PNI) research to enhance health outcomes, quality of life, and longevity among both MM patients and their caregivers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Marital quality shares ties to inflammatory conditions like cardiovascular disease and diabetes. For decades, research has focused on marital conflict as a primary mechanism given its potential to trigger inflammatory responses. However, longitudinal evidence suggests that marital conflict declines over time, and little attention has been paid to the inflammatory aftermath of other types of marital exchanges. A spouse's emotional distress is an important but overlooked marital context, as partners are exposed to each other's upsetting emotions throughout adulthood. To directly compare reactivity in proinflammatory gene expression to these two marital stressors and to examine differences by age and marital satisfaction, 203 community adults ages 25-90 (N = 102 couples) provided blood samples and rated their negative mood before and after they 1) watched their partner relive an upsetting personal memory and, in a separate visit 1-2 weeks later, 2) discussed a conflictual topic in their relationship. Controlling for age, sex, race/ethnicity, BMI, alcohol use, smoking, and comorbidities, increases in proinflammatory gene expression were significantly larger after the partner's upsetting disclosure than after marital conflict (B = 0.073, SE = 0.031, p = .018). This pattern paralleled emotional reactivity to the tasks, wherein negative mood rose more in response to the partner's disclosure than to marital conflict (B = 4.305, SE = 1.468, p = .004). In sum, proinflammatory and mood reactivity to spousal distress exceeded reactivity to marital conflict, a well-established marital stressor. Findings reveal spousal distress as a novel mechanism that may link marriage to inflammation-related diseases, and even pose risks for both happy and unhappy couples across adulthood., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Accurately measuring gender and sex is crucial in public health and epidemiology. Iteratively reexamining how variables-including gender and sex-are conceptualized and operationalized is necessary to achieve impactful research. Reexamining gender and sex advances epidemiology toward its goals of health promotion and disease elimination. While we cannot reduce the complexities of sex and gender to simply an issue of measurement, striving to capture these concepts and experiences accurately must be an ongoing dialogue and practice-to the benefit of the field and population health. We assert that epidemiology must counteract misconceptions and accurately measure gender and sex in epidemiology. We aim to summarize existing critiques and guiding principles in measuring gender and sex that can be applied in practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Multiple sclerosis (MS) is a chronic neurological disease frequently associated with significant fatigue, anxiety, depression, and stress. These symptoms are difficult to treat, and prominently contribute to the decreases in quality of life observed with MS. The underlying mechanisms of these "silent" symptoms are not well understood and include not just the psychological responses to a chronic disease, but also biological contributions from bidirectional psycho-neuro-immune (dys)regulation of systemic inflammatory biology. To address these issues, we conducted a prospective, observational pilot study to investigate the psychological, biological, and neuroarchitecture changes associated with a mindfulness-based stress reduction (MBSR) program in MS. The overarching hypothesis was that MBSR modulates systemic and central nervous system inflammation via top-down neurocognitive control over forebrain limbic areas responsible for the neurobiological stress response. 23 patients were enrolled in MBSR and assessed pre/post-program with structural 3 T MRI, behavioral measures, hair cortisol, and blood measures of peripheral inflammation, as indexed by the Conserved Transcriptional Response to Adversity (CTRA) profile. MBSR was associated with improvements across a variety of behavioral outcomes, as well as on-study enlargement of the head of the right hippocampus. The CTRA analyses revealed that greater inflammatory gene expression was related to worse patient-reported anxiety, depression, stress, and loneliness, in addition to lower eudaimonic well-being. Hair cortisol did not significantly change from pre- to post-MBSR. These results support the use of MBSR in MS and elucidate inflammatory mechanisms related to key patient-reported outcomes in this population., (© 2024. The Author(s).)

Having associations with a range of adverse physical health outcomes including mortality, loneliness is increasingly recognized as a pressing public health concern, but the mechanisms studied to date do not yet explain all loneliness-related health risk. We sought to evaluate whether epigenetic influences on DNA methylation could help explain the relationship between loneliness and health. To do so, we first estimated associations between loneliness and epigenetic age acceleration (EAA) in a subsample of participants in the study of midlife in the United States ( n = 1,310), before testing whether EAA mediated and/or moderated the association between loneliness and the onset of chronic health conditions in older adulthood ( n = 445 completing longitudinal follow-ups). Greater loneliness was weakly associated with greater EAA in the Horvath, DunedinPACE, and GrimAge measures after accounting for demographic (0.08 ≤ β ≤ 0.11) and behavioral (0.06 ≤ β ≤ 0.08) covariates. Loneliness also predicted increases in chronic condition counts and these effects were more pronounced for individuals with higher DunedinPACE EAA values (interaction term β = 0.09, p = .009), suggesting possible synergistic impacts. EAA measures appear to be promising in helping to understand individual variations in the health impacts of loneliness, but the specific mechanisms involved require further research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Discrimination is a social determinant of health and health disparities for which the biological mechanisms remain poorly understood. This study investigated the hypothesis that discrimination contributes to poor health outcomes by accelerating biological processes of aging. We analyzed survey and blood DNA methylation data from the Midlife in the United States (MIDUS) study (N = 1967). We used linear regression analysis to test associations of everyday, major, and workplace discrimination with biological aging measured by the DunedinPACE, PhenoAge, and GrimAge2 epigenetic clocks. MIDUS participants who reported more discrimination tended to exhibit a faster pace of aging and older biological age as compared to peers who reported less discrimination. Effect-sizes for associations tended to be larger for the DunedinPACE pace-of-aging clock (effect-size range r = 0.1-0.2) as compared with the PhenoAge and GrimAge2 biological-age clocks (effect-sizes r < 0.1) and for experiences of everyday and major discrimination as compared with workplace discrimination. Smoking status and body-mass index accounted for roughly half of observed association between discrimination and biological aging. Reports of discrimination were more strongly associated with accelerated biological aging among White as compared with Black participants, although Black participants reported more discrimination overall and tended to exhibit older biological age and faster biological aging. Findings support the hypothesis that experiences of interpersonal discrimination contribute to accelerated biological aging and suggest that structural and individual-level interventions to reduce discrimination and promote adaptive coping have potential to support healthy aging and build health equity., Competing Interests: DWB is listed as an inventor on the Duke University and University of Otago invention DunedinPACE, which is licensed to TruDiagnostic., (© 2024 The Authors.)

Experimental activation of the innate immune system has contributed significantly to both our understanding of how psychological factors influence immune function as well as how immune activity influences the brain and behavior. The annual influenza vaccine can be used to interrogate the effects of mild immune stimulation on day-to-day changes in psychological processes in human subjects that range across the lifespan and in both clinical and non-clinical populations. Yet, the immune response to the influenza vaccine in the days immediately following its administration are not well characterized. The present study describes changes in inflammatory and antiviral gene expression within circulating immune cells, plasma cytokines, and C-reactive protein (CRP) following receipt of the flu vaccine, and further reports the association between several common behavioral health factors and the acute immune response. Participants were 65 adults (mean age 18.81 ± 1.03 years; 66.2% female) who provided a blood sample immediately before and then 24 h after receiving the vaccine. A subsample also provided additional blood samples at 48 and 72 h. Plasma was assayed for CRP, IL-6, IL-10, IL-8, TNF-α, and IFN-γ, and peripheral blood mononuclear cell RNA was sequenced for evidence of change in expression of an a priori set of type 1 interferon (IFN) and inflammatory response genes (INFLAM). Plasma cytokines, CRP, and IFN response genes increased 24 h after vaccination, all ps < .001. The increase in IFN gene expression correlated with the observed increase in plasma cytokines and CRP, p < .0001. The immune response to influenza vaccination at 24-hours was moderated by anxiety symptoms, BMI, being female, sleep, and history of influenza vaccination. These factors and their associations with common immune challenges may be useful in studies interrogating the origins of immune dysregulation. The annual influenza vaccine is an accessible and reliable exogenous activator of both circulating and transcriptional markers of innate immune reactivity, with sensitivity to behavioral health factors relevant for psychoneuroimmunology research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Fatigue is a common side effect of cancer and its treatment and is thought to be driven in part by activation of the proinflammatory cytokine network. However, the cellular and molecular underpinnings of cancer-related fatigue (CRF) have not been determined, nor have immune pathways beyond inflammation been carefully investigated. The goal of this study was to examine the association between CRF and activation of canonical proinflammatory gene regulation pathways and Type I interferon (IFN) signaling pathways in breast cancer patients during and after treatment., Methods: Women diagnosed with early-stage breast cancer (n = 181) completed assessments before and after treatment with radiation and/or chemotherapy and at 6, 12, and 18-month post-treatment follow-ups. Assessments included self-reported fatigue (Multidimensional Fatigue Symptom Inventory - Short Form) and expression of pre-specified sets of Type I IFN and pro-inflammatory immune response genes determined from mRNA sequencing of PBMCs. Mixed effect linear models examined changes in fatigue and immune gene expression over time and tested the hypothesis that fatigue would be associated with increased expression of Type I IFN and inflammatory response genes., Results: There were significant changes in fatigue and immune gene expression across the assessment period; all measures increased from pre- to post-treatment but showed diverging patterns over the follow-up, with declines in fatigue and persistent elevations in Type I IFN and proinflammatory gene expression. In mixed effect linear models, expression of Type I IFN response genes was elevated in association with fatigue across the assessment period, from pre-treatment to 18-month follow-up. In contrast, pro-inflammatory gene expression was associated with fatigue only at 6, 12, and 18-month follow-ups. Analyses controlling for changes in leukocyte subsets continued to show a significant association between fatigue and Type I IFN gene expression but reduced the time-dependent association with pro-inflammatory gene expression to non-significant., Conclusions: Results revealed unexpected complexity in the immune underpinnings of CRF and identify a novel role for IFN signaling as a robust contributor to this symptom before, during, and after treatment. Pro-inflammatory gene expression emerged as a predictor of fatigue later in the cancer trajectory, and that effect was primarily accounted for by a concurrent increase in monocyte prevalence., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Although rural residence has been related to health disparities in cancer patients, little is known about how rural residence impacts mental health and quality of life (QOL) in ovarian cancer patients over time. This prospective longitudinal study investigated mental health and QOL of ovarian cancer patients in the first-year post-diagnosis., Method: Women with suspected ovarian cancer completed psychosocial surveys pre-surgery, at 6 months and one-year; clinical data were obtained from medical records. Histologically confirmed high grade epithelial ovarian cancer patients were eligible. Rural/urban residence was categorized from patient counties using the USDA Rural-Urban Continuum Codes. Linear mixed effects models examined differences in psychosocial measures over time, adjusting for covariates., Results: Although disparities were not observed at study entry for any psychosocial variable (all p-values >0.22), urban patients showed greater improvement in total distress over the year following diagnosis than rural patients (p = 0.025) and were significantly less distressed at one year (p = 0.03). Urban patients had a more consistent QOL improvement than their rural counterparts (p = 0.006). There were no differences in the course of depressive symptoms over the year (p = 0.17). Social support of urban patients at 12 months was significantly higher than that of rural patients (p = 0.04)., Conclusion: Rural patients reported less improvement in psychological functioning in the year following diagnosis than their urban counterparts. Clinicians should be aware of rurality as a potential risk factor for ongoing distress. Future studies should examine causes of these health disparities and potential long-term inequities and develop interventions to address these issues., Competing Interests: Declaration of competing interest Dr. Thaker has done consulting for, Zentalis, Verastem, Immunon, Seagen, Novocure, Caris, R-Pharm, Merck, and Glaxo Smith Kline and Astra Zeneca, has research funding from Merck and Glaxo Smith Kline, and is a Immunon shareholder; Dr. Sood has done consulting for Merck and Kiyatec, has had research funding from M-Trap, and is a Biopath shareholder; Dr. Lutgendorf is a shareholder of Abbvie; other authors declare no potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way., Methods: Primary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells., Results: PKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines., Conclusions: Although PKC modulators have some significant effects on NK cells, their contribution in "kick and kill" strategies is likely due to upregulating HIV expression in CD4 + T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the "kick" rather than the "kill" arm of this HIV cure approach., Competing Interests: Stanford University has filed patent applications on SUW133 and related technology, which has been licensed by Neurotrope BioScience (Synaptogenix, Inc.) for the treatment of neurological disorders and by BryoLogyx, Inc. for use in HIV/AIDS eradication and cancer immunotherapy. P.A.W. is an adviser to both companies and a cofounder of the latter. J.A.Z. is on the scientific advisory board for BryoLogyx, Inc. and is a cofounder of CDR3 Therapeutics. The remaining authors declare no competing interests., (Copyright © 2024 Pathogens and Immunity.)

Introduction: Cabotegravir long-acting injectable HIV pre-exposure prophylaxis (LA-PrEP) was shown to be safe and effective in multiple clinical trials. Increasing uptake and persistence among populations with elevated risk for HIV acquisition, especially among men who have sex with men (MSM), is critical to HIV prevention., Objective: This analysis aims to understand potential users' preferences for LA-PrEP, with audience segmentation., Design: Willingness to use and preferences for LA-PrEP were measured in HIV-negative, sexually active MSM in the 2020 American Men's Internet Survey. Respondents answered a discrete choice experiment with paired profiles of hypothetical LA-PrEP characteristics with an opt-out option (no LA-PrEP). Conditional and mixed logit models were run; the final model was a dummy-coded mixed logit that interacted with the opt-out., Setting: US national online sample., Results: Among 2506 MSM respondents, most (75%) indicated a willingness to use LA-PrEP versus daily oral PrEP versus no PrEP. Respondents were averse to side effects and increasing costs and preferred increasing levels of protection. Respondents preferred a 2-hour time to obtain LA-PrEP vs 1 hour, with a strong aversion to 3 hours. Overall, there was an aversion to opting out of LA-PrEP, with variations: those with only one partner, no/other insurance or who were Black, Indigenous or People of Colour were significantly less likely to prefer LA-PrEP, while those who were Hispanic/Latino, college educated and <40 years significantly preferred LA-PrEP., Conclusions: A large proportion of MSM expressed a preference for LA-PrEP over daily oral pills. Most respondents chose LA-PrEP regardless of cost, clinic time, side effects or protection level; however, preferences varied by sociodemographics. These varied groups likely require tailored intervention strategies to achieve maximum LA-PrEP uptake and persistence., Competing Interests: Competing interests: JG and Johns Hopkins University and THS and PSS and Emory University receive grant funding from ViiV Healthcare to conduct pre-exposure prophylaxis-related research. JFPB holds an Innovation in Regulatory Science Award from the Burroughs Wellcome Fund., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The objective of this study was to understand at what level of the Autonomous Pharmacy Framework facilities are operating, in terms of the current state of data collection and analysis in the medication-use process, and to gather insights about systems integration and automation use., Methods: The Autonomous Pharmacy Advisory Board, a group of chief pharmacy officers and operational leaders, developed a self-assessment instrument based on the previously published Autonomous Pharmacy Framework, made the self-assessment instrument available via the internet, and reviewed respondents' self-reported results. The data collection period for the survey started in March of 2021 and ended in January of 2023., Results: A total of 119 facility-level self-assessments were completed and analyzed. On a scale of 1 to 5, where 1 represented little or no data-driven automation with lots of manual tasks and 5 represented the utmost data-driven automation with few manual tasks, the average overall facility-level score was 2.77 (range, 1.38-4.41). Results revealed slight variance by facility bed capacity. Much more variation was found in the degrees to which individual facilities have automated core processes like inventory management, intravenous medication preparation, and financial reporting., Conclusion: As a baseline, this automation-focused facility self-assessment suggests that for essentially all health-system pharmacy facilities and their larger organizations, a substantial body of work needs to be done to further develop and upgrade technology and practice in tandem, greatly expand data collection and analysis, and thereby achieve better operational, financial, and clinical outcomes. Significant advancements are needed to arrive at the highly reliable, highly automated, data-driven medication-use process involving few repetitive manual tasks envisioned in the Autonomous Pharmacy Framework., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The objective of the present study was to evaluate the interdependency of parent-adolescent inflammation trends across time and to examine whether shared family socioeconomic characteristics explained between-family differences in parents' and adolescents' risk for inflammation. A total of N = 348 families, consisting of one parent and one adolescent child, were followed every two years in a three-wave longitudinal study. Sociodemographic questionnaires were used to determine parental educational attainment and family income-to-needs ratio (INR). At each time point, parents and adolescents collected dried blood spot (DBS) samples that were assayed for circulating CRP and log-transformed prior to analysis by longitudinal dyadic models. Models revealed significant differences in parents' and adolescents' inflammation trends over time (b int  = - 0.13, p < 0.001). While parental CRP levels remained relatively stable across the study period, adolescent CRP increased by approximately 38% between study waves. Parents' average CRP levels were positively correlated with adolescents' average CRP (r = 0.32, p < 0.001), but parental change in CRP over time was not significantly related to change in adolescents' CRP over time. Family dyads with higher parental educational attainment had lower average CRP (b = -0.08, p = 0.01), but parental education did not predict change in dyads' inflammation over time. Study findings suggest that shared family socioeconomic characteristics contribute to baseline similarities in parents' and adolescents' inflammation and potentially point to adolescence as a period of inflammatory change where youth may diverge from parental inflammation trends., Competing Interests: None., (© 2024 The Authors.)

Perioperative stress and inflammatory signaling can invigorate pro-metastatic molecular processes in patients' tumors, potentially worsening long-term survival. Yet, it is unknown whether pre-operative psychotherapeutic interventions can attenuate such effects. Herein, three weeks before surgery, forty women diagnosed with stage I-III invasive ductal/lobular breast carcinoma were randomized to a 6-week one-on-one psychological intervention (6 meetings with a medical psychologist and bi-weekly phone calls) versus standard nursing-staff-attention. The intervention protocol was individually tailored based on evaluation of patients' emotional, cognitive, physiological, and behavioral stress response-patterns, and also included psychoeducation regarding medical treatments and recruitment of social support. Resected primary tumors were subjected to whole-genome RNA sequencing and bioinformatic analyses, assessing a priori hypothesized cancer-relevant molecular signatures. Self-report questionnaires (BSI-18, Hope-18, MSPSS, and a stress-scale) were collected three (T1) and one (T2) week before surgery, a day before (T3) and after (T4) surgery, and three weeks (T5) and 3-months (T6) following surgery. The intervention reduced distress (GSI), depression, and somatization scores (BSI-18: p < 0.01, p < 0.05, p < 0.05; T5 vs. T1). Additionally, tumors from treated patients (vs. controls) showed: (i) decreased activity of transcription control pathways involved in adrenergic and glucocorticoid signaling (CREB, GR) (p < 0.001), pro-inflammatory signaling (NFkB) (p < 0.01), and pro-malignant signaling (ETS1, STAT and GATA families) (p < 0.001, p < 0.01, p < 0.005); (ii) increased M1 macrophage polarization (p < 0.05), and CD4 + T cell activity (p < 0.01); and an unexpected increase in epithelial-to-mesenchymal-transition (EMT) signature (p < 0.005). This is the first randomized controlled trial to show beneficial effects of a psychological perioperative intervention on tumor pro-metastatic molecular biomarkers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Childhood maltreatment has been repeatedly linked to a higher incidence of health conditions with an underlying proinflammatory component, such as asthma, chronic obstructive pulmonary disease, stroke, and cardiovascular disease. Childhood maltreatment has also been linked to elevated systemic inflammation prior to the onset of disease. However, childhood maltreatment is highly comorbid with other risk factors which have also been linked to inflammation, namely major depression. The present analysis addresses this issue by assessing the association of maltreatment with genome-wide transcriptional profiling of immune cells collected from four orthogonal groups of adolescents (aged 13-17): maltreated and not maltreated in childhood, with and without major depressive disorder. Maltreatment and psychiatric history were determined using semi-structured clinical interviews and cross-validated using self-report questionnaires. Dried whole blood spots were collected from each participant ( n = 133) and assayed to determine the extent to which maltreatment in childhood was associated with a higher prevalence of transcriptional activity among differentially expressed genes, specific immune cell subtypes, and up- or down-regulation of genes involved in immune function after accounting for current major depression. Maltreatment was associated with increased interferon regulatory factor (IRF) transcriptional activity ( p = 0.03), as well as nuclear factor erythroid-2 related factor 1 (NRF1; p = 0.002) and MAF ( p = 0.01) among up-regulated genes, and increased activity of nuclear factor kappa beta (NF-κB) among down-regulated genes ( p = 0.01). Non-classical CD16+ monocytes were implicated in both the up- and down-regulated genes among maltreated adolescents. These data provide convergent evidence supporting the role of maltreatment in altering intracellular and molecular markers of immune function, as well as implicate monocyte/macrophage functions as mechanisms through which childhood maltreatment may shape lifelong immune development and function.

Up to 40 % of individuals who sustain traumatic injuries are at risk for posttraumatic stress disorder (PTSD) and the conditional risk for developing PTSD is even higher for Black individuals. Exposure to racial discrimination, including at both interpersonal and structural levels, helps explain this health inequity. Yet, the relationship between racial discrimination and biological processes in the context of traumatic injury has yet to be fully explored. The current study examined whether racial discrimination is associated with a cumulative measure of biological stress, the gene expression profile conserved transcriptional response to adversity (CTRA), in Black trauma survivors. Two-weeks (T1) and six-months (T2) post-injury, Black participants (N = 94) provided a blood specimen and completed assessments of lifetime racial discrimination and PTSD symptoms. Mixed effect linear models evaluated the relationship between change in CTRA gene expression and racial discrimination while adjusting for age, gender, body mass index (BMI), smoking history, heavy alcohol use history, and trauma-related variables (mechanism of injury, lifetime trauma). Results revealed that for individuals exposed to higher levels of lifetime racial discrimination, CTRA significantly increased between T1 and T2. Conversely, CTRA did not increase significantly over time in individuals exposed to lower levels of lifetime racial discrimination. Thus, racial discrimination appeared to lead to a more sensitized biological profile which was further amplified by the effects of a recent traumatic injury. These findings replicate and extend previous research elucidating the processes by which racial discrimination targets biological systems., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Although the concept of hope is highly relevant for cancer patients, little is known about its association with cancer-relevant biomarkers. Here we examined how hope was related to diurnal cortisol and interleukin-6 (IL-6), a pro-inflammatory cytokine previously associated with tumor biology and survival in ovarian cancer. Secondly, we examined whether hope and hopelessness are distinctly associated with these biomarkers., Method: Participants were 292 high-grade ovarian cancer patients who completed surveys and provided saliva samples 4x/daily for 3 days pre-surgery to assess diurnal cortisol. Blood (pre-surgery) and ascites were assessed for IL-6. Hope and hopelessness were assessed using standardized survey items from established scales (Center for Epidemiological Studies Depression Scale; Profile of Mood States, Functional Assessment of Cancer Therapy). Two hopeless items were z-scored and combined into a composite for analysis. Regression models related these variables to nocturnal cortisol, cortisol slope, plasma and ascites IL-6, adjusting for cancer stage, BMI, age, and depression., Results: Greater hope was significantly related to a steeper cortisol slope, β = -0.193, p = 0.046, and lower night cortisol, β = -0.227, p = 0.018, plasma IL-6, β = -0.142, p = 0.033, and ascites IL-6, β = -0.290, p = 0.002. Secondary analyses including both hope and hopelessness showed similar patterns, with distinct relationships of hope with significantly lower nocturnal cortisol β = -0.233,p = 0.017 and ascites IL-6, β = -0.282,p = 0.003, and between hopelessness and a flatter cortisol slope, β = 0.211, p = 0.031., Conclusions: These data suggest a biological signature of hope associated with less inflammation and more normalized diurnal cortisol in ovarian cancer. These findings have potential clinical utility but need replication with more diverse samples and validated assessments of hope., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Thaker has served as a consultant for Immunon, has been on advisory boards for Astra Zeneca, Clovis Oncology, Glaxo Smith Kline, Seagen, Agenus, Immunon, Immunogen, Mersana, Novocure R-Pharm, Zentalis, Aadi Pharmaceuticals, Merck, Caris, and Iovance Biotherapeutics, and has had research funding from Merck and Glaxo Smith Kline, and is a Immunon shareholder; Dr. Lutgendorf is an Abbvie shareholder; Dr. Sood has done consulting for Merck, Astra Zeneca, Kiyatec, Glaxo Smith Kline, Onexo, ImmunoGen, Iylon, has a patent planned/pending for EGFL6 antibody, and is a Biopath shareholder; Dr. Corn is the Chief Medical Officer of Lutris-Pharma. All other authors report no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Disparities in socio-economic status (SES) predict many immune system-related diseases, and previous research documents relationships between SES and the immune cell transcriptome. Drawing on a bioinformatically-informed network approach, we situate these findings in a broader molecular framework by examining the upstream regulators of SES-associated transcriptional alterations. Data come from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally representative sample of 4543 adults in the United States. Results reveal a network-of differentially expressed genes, transcription factors, and protein neighbors of transcription factors-that shows widespread SES-related dysregulation of the immune system. Mediational models suggest that body mass index (BMI) plays a key role in accounting for many of these associations. Overall, the results reveal the central role of upstream regulators in socioeconomic differences in the molecular basis of immunity, which propagate to increase risk of chronic health conditions in later-life., (© 2024. The Author(s).)

Affective reactivity to stress is a person-level measurement of how well an individual copes with daily stressors. A common method of measuring affective reactivity entails the estimation of within-person differences of either positive or negative affect on days with and without stressors present. Individuals more reactive to common stressors, as evidenced by affective reactivity measurements, have been shown to have increased levels of circulating pro-inflammatory markers. While affective reactivity has previously been associated with inflammatory markers, the upstream mechanistic links underlying these associations are unknown. Using data from the Midlife in the United States (MIDUS) Refresher study (N = 195; 52% female; 84% white), we quantified daily stress processes over 10 days and determined individuals' positive and negative affective reactivities to stressors. We then examined affective reactivity association with peripheral blood mononuclear cell (PBMC) gene expression of the immune-related conserved transcriptional response to adversity. Results indicated that individuals with a greater decrease in positive affect to daily stressors exhibited heightened PBMC JUNB expression after Bonferroni corrections (p-adjusted < 0.05). JUNB encodes a protein that acts as a transcription factor which regulates many aspects of the immune response, including inflammation and cell proliferation. Due to its critical role in the activation of macrophages and maintenance of CD4+ T-cells during inflammation, JUNB may serve as a potential upstream mechanistic target for future studies of the connection between affective reactivity and inflammatory processes. Overall, our findings provide evidence that affective reactivity to stress is associated with levels of immune cell gene expression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Patient-reported outcomes (PROs) capture subjective social determinants of health (SDOHs), which can affect health outcomes through the stress response pathway. The conserved transcriptional response to adversity (CTRA) is a stress-mediated proinflammatory transcriptomic pattern that has been linked to adverse hematopoietic cell transplant (HCT) outcomes. This study examined the association of pretransplant CTRA with patient-reported SDOHs in allogeneic HCT recipients. In this cross-sectional study, pre-HCT SDOH-related PROs included the 36-Item Short Form Health Survey and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). CTRA was assessed by RNA sequencing of whole blood specimens, with mixed effects linear regression models relating CTRA expression to PRO scores while controlling for age, sex, race, disease, and performance status. Among 121 patients, the median age was 54 years, 42% were female, and 91% were White. CTRA was elevated in participants reporting lower scores on the FACT-BMT (P = .003), including the general (P = .003) and BMT-specific (P = .014) components. Effects were driven by the social well-being domain (P = .0001). This corresponded to an 8% to 15% difference in CTRA RNA expression across a 4 standard deviation range in patient-reported SDOHs. Ancillary bioinformatics analyses confirmed the association of well-being with reduced proinflammatory transcription pathway activity [cyclic AMP response element-binding protein, (CREB), NF-κB, and activating protein-1 (AP-1)]. In conclusion, HCT-treated patients who experience unfavorable social conditions show elevated CTRA expression in pretransplant blood samples. These data highlight the biologic sequelae of social well-being and community context and suggest a potential molecular mechanism for the impact of social gradients in HCT outcomes. Targeting this pathway could optimize outcomes in this high-risk population., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Diverse manifestations of biological aging often reflect disparities in socioeconomic status (SES). In this paper, we examine associations between indicators of SES and an mRNA-based aging signature during young adulthood, before clinical indications of aging are common. We use data from wave V (2016-2018) of the National Longitudinal Study of Adolescent to Adult Health, a nationally representative study of adults aged 33-43 years, with transcriptomic data from a subset of 2,491 participants. Biological aging is measured using 1) a composite transcriptomic aging signature previously identified by Peters et al.'s out-of-sample meta-analysis (Nat Commun. 2015;6:8570) and 2) 9 subsets that represent functional pathways of coexpressed genes. SES refers to income, education, occupation, subjective social status, and a composite measure combining these 4 dimensions. We examine hypothesized mechanisms through which SES could affect aging: body mass index, smoking, health insurance status, difficulty paying bills, and psychosocial stress. We find that SES-especially the composite measure and income-is associated with transcriptomic aging and immune, mitochondrial, ribosomal, lysosomal, and proteomal pathways. Counterfactual mediational models suggest that the mediators partially account for these associations. The results thus reveal that numerous biological pathways associated with aging are already linked to SES in young adulthood., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Growing evidence suggests that social relationship quality can influence age-related health outcomes, although how the quality of one's relationships directly relates to the underlying aging process is less clear. We hypothesized that the absence of close relationships as well as lower support and higher strain within existing relationships would be associated with an accelerated epigenetic aging profile among older adults in the Health and Retirement Study. Adults (N = 3,647) aged 50-100 years completed ratings of support and strain in relationships with their spouse, children, other family members, and friends. They also provided a blood sample that was used for DNA methylation profiling to calculate a priori-specified epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging methylation (DunedinPoAm38). Generalized linear models that adjusted for chronological age, sex, and race/ethnicity and applied a false discovery rate correction revealed that the absence of marital and friend relationships related to an older GrimAge and faster DunedinPoAm38. Among those with existing relationships, lower support from a spouse, child, other family, and friends and higher strain with friends related to an older PhenoAge and GrimAge and faster DunedinPoAm38. In secondary analyses that further adjusted for socioeconomic and lifestyle factors, lower support from other family members and friends was associated with greater epigenetic aging. Findings suggest that the absence of close relationships and lower support within existing relationships-particularly with family members and friends-relate to accelerated epigenetic aging in older adulthood, offering one mechanism through which social relationships might influence risk for age-related declines and disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Social connections are crucial to human health and well-being. Previous research on molecular mechanisms in health has focused primarily on the individual-level perception of social connections (e.g., loneliness). This study adopted socio-centric social network analysis that includes all social ties from the entire population of interest to examine the group-level social connections and their association with a molecular genomic measure of health., Methods: Using socio-centric (global) social network data from an entire village in Korea, we investigated how social network characteristics are related to immune cell gene expression among older adults. Blood samples were collected (N = 53, 65-79 years) and mixed effect linear model analyses were performed to examine the association between social network characteristics and Conserved Transcriptional Response to Adversity (CTRA) RNA expression patterns., Results: Social network positions measured by k-core score, the degree of cohesive core positions in an entire village, were significantly associated with CTRA downregulation. Such associations emerged above and beyond the effects of perceived social isolation (loneliness) and biobehavioral risk factors (smoking, alcohol, BMI, etc.). Social network size, defined as degree centrality, was also associated with reduced CTRA gene expression, but its association mimicked that of perceived social isolation (loneliness)., Conclusions: The current findings implicate community-level social network characteristics in the regulation of individual human genome function above and beyond individual-level perceptions of connectedness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Inflammation has been shown to predict depression, but sensitivity to inflammation varies across individuals. Experimental studies administering potent pro-inflammatory agents have begun to characterize this sensitivity. However, risk factors for inflammation-associated depression in naturalistic contexts have not been determined. The present study examined key psychological and behavioral risk factors (state anxiety, perceived stress, negative affect, disturbed sleep, and childhood adversity) as potential moderators of the relationship between inflammation and depressive symptoms in a prospective longitudinal study of breast cancer survivors. Women with early stage breast cancer were recruited after completing primary cancer treatment (n final  = 161). Depressive symptoms, inflammatory markers (CRP, IL-6, and sTNF-RII), and key risk factors were assessed post treatment (T1), at 6 and 12-month follow-ups (T2 and T3), and during a final follow-up (TF) 3-6 years after T1; childhood adversity was measured only at T3. Inflammatory markers were combined into a single inflammatory index prior to analyses. Women who reported higher levels of state anxiety, perceived stress, negative affect, and/or sleep disturbance at T1 (post-treatment) exhibited higher depressive symptoms at times when inflammation was higher than typical (interaction βs ranged from .06 to .08; all ps < .014). Results demonstrate the relevance of these risk factors for understanding inflammation-associated depression in a clinical context and could inform targeted strategies for prevention and treatment among at-risk populations., (© 2021. The Author(s).)

Lisa M Lundquist1, Sabrina W Cole2, Jill M Augustine11Mercer University College of Pharmacy and Health Sciences, Atlanta, GA, 2Wingate University School of Pharmacy, Wingate, NC, USAAbstract: Rheumatoid arthritis is a chronic, progressive, autoimmune disease that leads to significant disability and premature mortality. Various treatment options are available, but the foundation of treatment includes nonbiologic and biologic disease-modifying antirheumatic drugs. The incidence of patients with rheumatoid arthritis refractory to first-line agents is estimated to be at least 20%. Abatacept, a T cell costimulation modulator, is the first agent to interfere with full T cell activation by competing with CD28 for binding of CD80 and CD86, which results in decreased secretion of proinflammatory cytokines and autoantibody production. Current American College of Rheumatology treatment guidelines recommend abatacept for patients with at least moderate disease activity and a poor prognosis demonstrating an inadequate response to other agents. Several key Phase III trials have been conducted to evaluate the efficacy and safety of abatacept in patients with an inadequate response to methotrexate or anti-tumor necrosis factor alpha therapy. Response rates in all trials showed statistically significant improvements compared with placebo according to American College of Rheumatology criteria for disease improvement. The most common adverse event report in patients receiving abatacept was infection; however, the frequency of adverse events was similar to placebo. Abatacept is a safe and effective rheumatoid arthritis treatment for patients with an inadequate response to methotrexate or anti-tumor necrosis factor alpha therapy.Keywords: abatacept, rheumatoid arthritis, treatment refractory, biologic, disease-modifying antirheumatic drugs

Background and Objectives: A recent exploratory study of transcriptional effects of long-term practice of Transcendental Meditation (TM) technologies found evidence for altered expression of genes associated with health and disease. In the present secondary analysis of those data, we test the more specific hypothesis that this sample of long-term practitioners shows a significant reduction in markers of the "Conserved Transcriptional Response to Adversity" (CTRA), an RNA profile characterized by up-regulated inflammation and down-regulated Type I interferon (IFN) activity., Materials and Methods: Data come from a previously published study providing genome-wide transcriptional profiles of peripheral blood mononuclear cells (PBMC) from healthy, 38-year practitioners of TM technologies and matched controls ( n  = 12, mean age 65). The current analysis specifically tests for differential expression of a previously established CTRA indicator gene score, with cross-validation by promoter-based bioinformatic analysis of CTRA-typical differences in transcription factor activity and monocyte subset cellular origins., Results: Compared to controls, the TM group showed lower expression of a pre-specified set of CTRA indicator genes. These effects were accompanied by genome-wide indications of down-regulated pro-inflammatory transcription factor activity (NF-κB, AP-1), up-regulated activity of Interferon Response Factors (IRF) and reduced transcriptional activity of classical monocytes. Conclusions : A sample of long-term practitioners of TM showed reduced CTRA gene expression in PBMC compared to matched controls, supporting the likely value of further research to evaluate causality and specificity of this potential mechanism of health benefits in meditators., Competing Interests: None., (© 2023 Published by Elsevier Inc.)

Late life insomnia may increase risk for accelerated biological aging. Intervening to treat insomnia may provide protection from biological aging by reducing the prevalence of senescent cells in the immune system, as indicated by gene expression of a marker of cellular senescence, p16 INK4a . In the present study, we determine whether treatment of insomnia in older adults with cognitive behavioral therapy for insomnia (CBT-I) would reduce p16 INK4a gene expression in peripheral blood mononuclear cells (PBMC), compared to a sleep education therapy (SET), an active comparator condition. Secondly, we investigate the relationship between sustained insomnia remission and reduced expression of p16 INK4a . Participants 60 + years old with insomnia were enrolled in a randomized controlled trial and assigned to CBT-I or SET. Analyses of 231 older adults (CBT-I = 119; SET = 112) examine baseline, post (2 months), and 24 months gene expression of p16 INK4a . Compared to baseline, expression of p16 INK4a increased in the SET group over 24 months (P = 0.03), but showed no change in the CBT-I group. Those who received CBT-I and experienced sustained remission of insomnia had a significant decline in p16 INK4a expression by 24 months compared to baseline (P = 0.02). Individuals not sustaining remission of insomnia exhibited overall increase expression of p16 INK4a by 24 months (P = 0.03). In older adults with insomnia, p16 INK4a increases over 24 months, while CBT-I treatment of insomnia mitigates the increase in p16 INK4a . Further, sustained remission of insomnia using CBT-I leads to a decrease in p16 INK4a . These results suggest that behavioral interventions that are effective at treating insomnia might reduce the population of senescent cells in circulating blood., (© 2023. The Author(s).)

Psychosocial risk factors have been linked with accelerated epigenetic aging, but little is known about whether psychosocial resilience factors (eg, Sense of Purpose in Life) might reduce epigenetic age acceleration. In this study, we tested if older adults who experience high levels of Purpose might show reduced epigenetic age acceleration. We evaluated the relationship between Purpose and epigenetic age acceleration as measured by 13 DNA methylation (DNAm) "epigenetic clocks" assessed in 1 572 older adults from the Health and Retirement Study (mean age 70 years). We quantified the total association between Purpose and DNAm age acceleration as well as the extent to which that total association might be attributable to demographic factors, chronic disease, other psychosocial variables (eg, positive affect), and health-related behaviors (heavy drinking, smoking, physical activity, and body mass index [BMI]). Purpose in Life was associated with reduced epigenetic age acceleration across 4 "second-generation" DNAm clocks optimized for predicting health and longevity (false discovery rate [FDR] q < 0.0001: PhenoAge, GrimAge, Zhang epigenetic mortality index; FDR q < 0.05: DunedinPoAm). These associations were independent of demographic and psychosocial factors, but substantially attenuated after adjusting for health-related behaviors (drinking, smoking, physical activity, and BMI). Purpose showed no significant association with 9 "first-generation" DNAm epigenetic clocks trained on chronological age. Older adults with greater Purpose in Life show "younger" DNAm epigenetic age acceleration. These results may be due in part to associated differences in health-related behaviors. Results suggest new opportunities to reduce biological age acceleration by enhancing Purpose and its behavioral sequelae in late adulthood., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alterations in immune system gene expression have been implicated in psychopathology, but it remains unclear whether similar associations occur for intraindividual variations in emotion. The present study examined whether positive emotion and negative emotion were related to expression of pro-inflammatory and antiviral genes in circulating leukocytes from a community sample of 90 adolescents (M age = 16.3 years, SD = 0.7; 51.1% female). Adolescents reported their positive emotion and negative emotion and provided blood samples twice, five weeks apart. Using a multilevel analytic framework, we found that within-individual increases in positive emotion were associated with reduced expression of both pro-inflammatory and Type I interferon (IFN) response genes, even after adjusting for demographic and biological covariates, and for leukocyte subset abundance. By contrast, increases in negative emotion were related to higher expression of pro-inflammatory and Type I IFN genes. When tested in the same model, only associations with positive emotion emerged as significant, and increases in overall emotional valence were associated with both lower pro-inflammatory and antiviral gene expression. These results are distinct from the previously observed Conserved Transcriptional Response to Adversity (CTRA) gene regulation pattern characterized by reciprocal changes in pro-inflammatory and antiviral gene expression and may reflect alterations in generalized immunologic activation. These findings highlight one biological pathway by which emotion may potentially impact health and physiological function in the context of the immune system, and future studies can investigate whether fostering positive emotion may promote adolescent health through changes in the immune system., Competing Interests: Declarations of interest None., (Copyright © 2023. Published by Elsevier Ltd.)