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In cancer patients, an interleukin (IL)-8 gene variant that leads to higher production of IL-8, is associated with lower risk of depressive symptoms. In non-cancer adults, higher levels of IL-8 correlate with lower severity of depressive symptoms, decreased risk of suicide, and improved treatment response in females, but not males. This study evaluates the prospective association between circulating levels IL-8 and incident and recurrent major depressive disorder in breast cancer survivors.In this single site, prospective cohort study with protocol modification extending follow-up from 24- to 32 months, recruitment occurred between September 2013 and January 2018, and follow-up was completed February 2021. Participants were identified from a Kaiser Permanente of Southern California health plan-based sample of 219 breast cancer survivors, who were two or more years since diagnosis of early stage breast cancer (TNM 0-II), aged 55 to 85 years, with no major depression or health events in last year. Circulating levels of IL-8 were obtained at enrollment. Primary outcome was time to incident or recurrent major depressive disorder as diagnosed by interview and DSM-5 criteria.Among 219 participants (mean age, 70 years; 100% female; 16 [7.3%] Asian, 42 [19.2%] Black, 161 [73.5%] White), 84% completed 24 months follow-up. After protocol modification, 59% completed 32 months follow-up. Median follow-up was 28.5 months. The primary endpoint occurred in 27 participants (12.4%, 5.7 events /100 person years; 95% CI 2.7 - 8.8). Higher IL-8 was associated with lower risk of incident and recurrent depression (hazard ratio, HR, 0.52, 95% CI 0.26 - 1.05). Among those with levels of IL-8 in the highest quartile, the primary endpoint occurred in 2 participants (3.6%; 1.6 events/100 person years; 95% CI 1.3 - 1.9), as compared to 25 participants in the pooled lower quartiles (15.2%; 7.2 events/100 persons years; 95%CI 7.0 - 7.4; rate difference, 5.6 per 100 person years, 95%CI 5.2 - 5.9; HR, 0.21, 95%CI 0.05 - 90, multivariable adjusted HR, 0.20, 95%CI 0.05 - 0.88).Among breast cancer survivors, higher IL-8 at enrollment was associated with a decreased risk of incident and recurrent major depression. These findings provide insights into mechanisms of depression risk and development of novel therapies for depression prevention, and suggest that testing for IL-8 may have prognostic value in identifying resilience or risk of depression.

Background Humans are able to discern the health status of others using olfactory and visual cues, and subsequently shift behavior to make infection less likely. However, little is known about how this process occurs. The present study examined the neural regions involved in differentiating healthy from sick individuals using visual cues. Methods While undergoing a functional magnetic resonance imaging scan, participants (N=42) viewed facial photos of 30 individuals (targets) who had been injected with inflammatory challenge, low-dose endotoxin (i.e., sick) or placebo (i.e., healthy), and rated how much they liked each face. We examined regions implicated in processing either threat (amygdala, anterior insula) or cues that signal safety (ventromedial prefrontal cortex [VMPFC]), and how this activity related to their liking of targets and cytokine levels (interleukin-6, tumor necrosis factor-α) exhibited by the targets. Results Photos of sick faces were rated as less likeable compared to healthy faces, and the least liked faces were those individuals with the greatest inflammatory response. While threat-related regions were not significantly active in response to viewing sick faces, the VMPFC was more active in response to viewing healthy (vs. sick) faces. Follow-up analyses revealed that participants tended to have lower VMPFC activity when viewing the least liked faces and the faces of those with the greatest inflammatory response. Conclusions This work builds on prior work implicating the VMPFC in signaling the presence of safe, non-threatening visual stimuli, and suggests the VMPFC may be sensitive to cues signaling relative safety in the context of pathogen threats.

Background Breast cancer is the most common cancer among women in the US, and women of low socioeconomic status (SES) show markedly poorer outcomes than those of high SES. SES may influence health through inflammation, although links between SES and inflammatory biomarkers have not been investigated in women with breast cancer. This study tested the hypothesis that breast cancer patients of lower SES would show higher levels of inflammation than those of higher SES. BMI was examined as a mediator of this association. Methods Women recently diagnosed with early-stage breast cancer (N = 194) were recruited before neoadjuvant or adjuvant therapy. Participants completed questionnaires and provided blood samples for immune assessment. SES was indexed by participants’ self-reported education and annual household income, BMI was determined by height and weight measurements, and blood was assayed for inflammatory biomarkers linked with cancer outcomes: IL-6, CRP, TNF-α, and sTNF-RII. General linear models tested associations between SES and inflammation, and mediation models examined indirect effects through BMI. Results Consistent with hypotheses, education status was associated with CRP, (F(2,185) = 4.72, p = 0.001), and sTNF-RII, (F(2,185) = 4.19, p = 0.02), such that lower education was associated with higher levels of both biomarkers. Further, BMI mediated the associations between education and CRP, (95% CIs [-0.62, −0.11; −0.76, −0.21]), sTNF-RII, (95% CIs [−0.09, −0.01; −0.10, −0.02]), and IL-6, (95% CIs [−0.32, −0.05; −0.38, −0.09]). Annual household income was not significantly associated with inflammation (ps > 0.25), and indirect effects on inflammation through BMI were not significant. Conclusions Lower education was associated with higher levels of inflammation in this sample, which may presage poor breast cancer-related and clinical outcomes. SES should inform the development of interventions targeting BMI and inflammation in breast cancer.

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, p16INK4a. In the present study, we determine whether treatment of insomnia in older adults with cognitive behavioral therapy for insomnia (CBT-I) would reduce p16INK4a 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 p16INK4a. 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 p16INK4a. Compared to baseline, expression of p16INK4a 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 p16INK4a expression by 24 months compared to baseline (P = 0.02). Individuals not sustaining remission of insomnia exhibited overall increase expression of p16INK4a by 24 months (P = 0.03). In older adults with insomnia, p16INK4a increases over 24 months, while CBT-I treatment of insomnia mitigates the increase in p16INK4a. Further, sustained remission of insomnia using CBT-I leads to a decrease in p16INK4a. These results suggest that behavioral interventions that are effective at treating insomnia might reduce the population of senescent cells in circulating blood.

OBJECTIVE. Research has established links between social isolation and heightened levels of proinflammatory cytokines (e.g., interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-α]). Recent advances allow for the examination of cytokines that may also play a role in antiviral immunity (interferon-gamma [IFN-γ]). The present work explored how various features of social experience relate to circulating cytokines in breast cancer survivors, as inflammation has been tied to cancer recurrence and mortality. DESIGN. Female breast cancer survivors (N=43) completed a blood draw to assess circulating levels of proinflammatory cytokines (IL-6, TNF-α) and levels of a cytokine that also relates to antiviral immunity (IFN-γ). MAIN OUTCOME MEASURES. We examined associations between cytokines and different aspects of social experience, including household size, psychosocial well-being, and social threat anxiety. RESULTS. Circulating levels of IFN-γ were associated with larger household size (r=0.32, p=0.04) and higher levels of psychosocial well-being (r=0.33, p=0.04). Additionally, heightened levels of IL-6 were associated with social threat anxiety (r=0.38, p=0.01). Heightened IL-6 was also associated with household size (r=0.33, p=0.03). CONCLUSION. These findings are consistent with work suggesting that antiviral immunity and inflammation may have distinct contributions to the links between social experience and health, particularly for those previously diagnosed with breast cancer.

Background: To examine the contribution of B-cell activation molecules to B-cell follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), a prospective study was conducted using pre-diagnosis serial serum samples from the US Department of Defense Serum Repository. Methods: Each case (n = 142 FL, n = 211 DLBCL) was matched to two controls on age, gender, race, military branch, and blood collection dates. Immune activation molecules (IL1β, IL2, IL4, IL5, IL6, IL10, IL12, CXCL13, IL8, TNFα, IFNγ, GM-CSF, VEGF, sCD30, IgE) were quantified using ELISA or multiplex immunometric (Luminex) assay. Longitudinal data were analyzed using linear mixed modeling. As serial specimens were collected over several years before diagnosis, we evaluated the temporal dynamics of these markers. Results: Increased serum levels of sCD30, CXCL13, and to a lesser extent IL10, were associated with both FL and DLBCL in cases compared with controls, with a median follow-up of 5.5 years from the earliest specimen collection to diagnosis date. Significant increasing sCD30 and CXCL13 trajectories for FL and DLBCL subtypes were noted starting at the earliest time points and with IL10 levels increasing significantly at time points closer to diagnosis. Conclusions: These results suggest that sCD30, CXCL13, and IL10 may contribute to the etiology of FL and DLBCL and are potential biomarkers for these non–Hodgkin lymphoma subtypes. Impact: The increasing trajectories of the B-cell activation molecules, sCD30, CXCL13, and to a lesser extent IL10, may indicate early disease-induced effects or reflect the chronic stimulation of B-cells that promotes the development of FL and DLBCL subtypes.

Background: There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors. Methods: Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ (N = 325) and age-, racial/ethnic group-, and education-matched controls (N = 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition. Results: Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 (HMCN1) gene (p = 1.624 × 10−8), and rs78786199 (chromosome 2, p = 1.925 × 10−8) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. Conclusions: The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD.

Purpose: Cancer-related cognitive problems may result from peripheral inflammation effects on the brain. We tested whether differences in cognitive performance between breast cancer survivors and non-cancer controls was explained by elevated inflammatory cytokines. Methods: We enrolled women >60 years, newly diagnosed with primary breast cancer (stage 0-III) (n=400) and frequency-matched non-cancer controls (n=329) from six national centers from 2010- 2020, with blood collection beginning in 2016. Baseline assessments occurred pre-systemic therapy (or enrollment for controls) with annual follow-up to 60-months. The primary outcome was the score on neurocognitive tests of the attention, processing speed and executive function (APE) domain. Plasma levels of IL-6, IL-10, and TNF-alpha were determined using multiplex testing and mixed linear models compared results for each marker across all timepoints by survivor/control group, adjusting for age, race, WRAT scores, recruitment site, comorbidities, and BMI. Multi-level mediation analyses tested the simultaneous direct effects of survivor/control group on cognition and indirect effects of group on each immune marker and the effect of the marker on cognition, controlling for covariates. Results: Participants had an average age of 67.7 years (range: 60-90). Most survivors had stage I (60.9%) estrogen-receptor positive (87.6%) tumors. Survivors had significantly higher adjusted IL-6 levels than controls at baseline, 12-, 24- and 60-months (p=< 0.001 to 0.014), but there were no differences for other markers. Survivors had lower adjusted APE scores than controls, and this effect was due to the indirect effects of being a survivor vs. control on IL-6 (p=0.047). Conclusion: Cancer and its treatments were related to poorer attention, processing speed, and executive function compared to non-cancer frequency matched controls, and this difference was partially explained by elevated IL-6. Citation Format: Jeanne S. Mandelblatt, Brent J. Small, Xingtao Zhou, Zev M. Nakamura, Harvey J. Cohen, Tim A. Ahles, Jaeil Ahn, Traci N. Bethea, Martine Extermann, Heather S.L. Jim, Brenna C. McDonald, Sunita K. Patel, Kelly Rentscher, James Root, Andrew J. Saykin, Kathleen Van Dyk, Wanting Zhai, Elizabeth C. Breen, Judith E. Carroll. Differences in attention, processing speed, and executive function in older breast cancer survivors compared to controls is partially explained by plasma IL-6: The Thinking and Living with Cancer (TLC) Study [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A012.

Cancer and its treatments are thought to increase risk for accelerated aging in survivors, and biological aging may be a key mechanism; however, no research to date has examined epigenetic markers of aging in long-term breast cancer survivors. We used data from the Thinking and Living with Cancer (TLC) study to examine whether older breast cancer survivors have accelerated epigenetic aging compared to non-cancer controls several years after treatment completion and whether epigenetic aging related to cognitive and physical function. Non-metastatic breast cancer survivors ages 62–84 years (n=89) and frequency-matched controls (n=101) provided two blood samples between 24- and 60-months post-diagnosis. DNA methylation profiling (Illumina Infinium EPIC array) derived epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging Methylation. Participants completed neuropsychological testing and questionnaires to assess cognitive and physical function at each visit. Mixed-effects models adjusted for chronological age and comorbidities and applied false discovery rate correction for multiple testing. Survivors were 1.04–2.22 years older biologically than controls at the first blood sample based on Horvath, Hannum, and GrimAge measures (corrected ps=.025, .025, and .058, respectively), with marginal differences for Dunedin Pace of Aging (corrected p=.096); however, survivors and controls showed similar changes in epigenetic aging over time. Exposure to prior chemotherapy (with or without hormonal therapy; n=29) was associated with an epigenetic age 1.97–2.71 years older than controls (corrected ps=.005 to .065). Among survivors who received chemotherapy, an older Hannum epigenetic age was associated with poorer self-reported cognition relative to controls (coeff=-0.64, uncorrected p=.047; n.s. after correction). Older breast cancer survivors, particularly those receiving chemotherapy, showed an accelerated epigenetic aging profile compared to their peers without cancer at 24 months or more post-diagnosis, following the completion of active therapy. This study also provides preliminary evidence that survivors who received chemotherapy may be at increased risk for poorer age-related survivorship outcomes. Citation Format: Kelly E. Rentscher, Wanting Zhai, Brent J. Small, Jaeil Ahn, Tim A. Ahles, Traci N. Bethea, Elizabeth C. Breen, Harvey J. Cohen, Martine Extermann, Deena M.A. Graham, Paul B. Jacobsen, Heather S.L. Jim, Brenna C. McDonald, Zev M. Nakamura, Sunita K. Patel, James C. Root, Andrew J. Saykin, Danielle B. Tometich, Kathleen M. Van Dyk, Xingtao Zhou, Jeanne S. Mandelblatt, Judith E. Carroll. Long-term epigenetic aging in older breast cancer survivors and non-cancer controls: Preliminary findings from the Thinking and Living with Cancer (TLC) Stud [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B018.

Despite the substantial adverse psychological impact of testicular cancer, few interventions have sought to improve psychosocial functioning and stress-related biomarkers in young adult survivors. Goal-focused Emotion-regulation Therapy (GET) is designed to improve distress symptoms, emotion regulation, and goal navigation skills, which would be expected to improve regulation of stress-sensitive biomarkers. The aim was to examine the effects of GET versus an active control intervention on salivary stress and circulating inflammatory markers in young adult survivors of testicular cancer. Young adult men with testicular cancer ( N = 44) who had undergone chemotherapy within the last 2 years were randomized to GET or individual supportive therapy (ISP) delivered over 8 weeks. Saliva samples were collected for 2 consecutive days at baseline and post-intervention (awakening, 8 hr later, bedtime) to measure diurnal rhythm. Circulating plasma levels of CRP, IL-6, IL-1ra, TNFαRII, and VEGF were measured at baseline and post-intervention. Regression modeling demonstrated a significant group effect on daily output of salivary cortisol (area under the curve) (β = −57, p < .05), with cortisol output decreasing from baseline to post-intervention for those receiving GET (Cohen’s d = 0.45). There were no significant intervention effects in salivary alpha-amylase. Plasma levels of IL-1ra were significantly lower post-intervention in GET compared to ISP; no other significant plasma effects were observed. GET, an intervention designed to promote goal-related and emotion-focused self-regulation, has potential to mitigate stress-related processes and inflammation in this young adult survivor group. More research is needed to determine efficacy.

Chronic inflammation in women diagnosed with breast cancer is critically linked with tumor progression, metastasis and survival. C-reactive protein (CRP)—a circulating marker of inflammation—is an important prognostic marker for cancer-related outcomes in breast cancer survivors (e.g. recurrence, fatigue). Psychological stress, which increases circulating markers of inflammation following sympathetic nervous system (SNS) activation, may modulate tumor-relevant inflammatory processes. However, little is known about neural mechanisms that might link stress and downstream SNS-initiated proinflammatory processes, such as elevated CRP. Past work suggests that threat-related neural regions, such as the amygdala, may be key in translating psychological stress into SNS activity and subsequent peripheral inflammation. Thus, we examined amygdala reactivity to socially threatening stimuli in association with perceived stress and plasma CRP levels to further elucidate neuro-immune pathways of social threat processing within breast cancer survivors (N = 37). Significant positive correlations were found between left amygdala reactivity in response to socially threatening stimuli (e.g. angry/fearful faces vs happy faces) and perceived stress in the previous month (r = 0.32, P = 0.025) and between left amygdala reactivity and CRP (r = 0.33, P = 0.025). This work builds on prior research implicating the amygdala as a key structure in crosstalk between threat-related neural circuitries and peripheral inflammation, particularly within cancer survivors.

Studies suggest that inflammation might be involved in the pathogenesis of depression. Individuals with human immunodeficiency virus (HIV) have a higher risk of depression and elevated inflammatory profiles. Despite this, research on the link between inflammation and depression among this high-risk population is limited. We examined a sample of men who have sex with men from the Multicenter AIDS Cohort Study in prospective analyses of the association between inflammation and clinically relevant depression symptoms, defined as scores >20 on Center for Epidemiological Studies Depression Scale. We included 1,727 participants who contributed 9,287 person-visits from 1984 to 2010 (8,218 with HIV (HIV+) and 1,069 without (HIV−)). Exploratory factor analysis (EFA) was used to characterize underlying inflammatory processes from 19 immune markers. Logistic regression with generalized estimating equations was used to evaluate associations between inflammatory processes and depressive symptoms stratified by HIV serostatus. Three EFA-identified inflammatory processes (EIPs) were identified. EIP-1 scores—described by soluble tumor necrosis factor receptor 2 (sTNF-R2), soluble interleukin-2 receptor α (sIL-2Rα), sCD27, B-cell activating factor, interferon γ-induced protein 10 (IP-10), soluble interleukin-6 receptor (sIL-6R), sCD14, and sGP130—were significantly associated with 9% higher odds of depressive symptoms in HIV+ participants (odds ratio = 1.09; 95% confidence interval: 1.03, 1.16) and 33% higher odds in HIV− participants (odds ratio = 1.33; 95% confidence interval: 1.09, 1.61). Findings suggest that immune activation might be involved in depression risk among both HIV+ and HIV− men who have sex with men.

Objectives: Circulating cytokines have been associated with depression, but their detection has limitations, which may be overcome by direct detection of intracellular cytokines (ICCs) after lipopolysaccharide (LPS) stimulation in vitro. This study compared circulating versus LPS-induced inflammatory markers as correlates of subthreshold depressive symptoms.Methods: Secondary data analysis of a cross-sectional insomnia study in healthy community-dwelling older adults was conducted. In 117 participants (≥55 years), plasma tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP) and in vitro LPS-induced monocyte production of IL-6 and TNF-α were assayed. Depressive symptoms were assessed using the clinician-rated Inventory of Depressive Symptomatology (IDS-C). Multivariate linear regression was conducted to test the associations between inflammatory markers and subthreshold depressive symptoms in the entire sample as well as in subgroups stratified into higher and lower inflammation levels.Results: LPS-induced TNF-α (adjusted β = 0.28, p = .04), IL-6 (0.29, p = .03) and TNF-α + IL-6 (0.43, p = .001) significantly positively correlated with subthreshold depressive symptoms only in higher inflammation subgroups. No circulating biomarkers positively correlated in any subgroups. In the entire sample, no biomarkers were significantly associated with subthreshold depressive symptoms.Conclusions: LPS-induced cytokines may be more sensitive correlates of subthreshold depressive symptoms than circulating cytokines, particularly in older adults with higher systemic inflammation.Clinical Trials Registry: ClinicalTrials.gov NCT00280020.

Background There are robust sex differences in the prevalence of depression. Inflammation and anhedonia may play a role in understanding these sex differences. Indeed, sex differences in inflammation-induced neural responses to reward may provide insight into the sex gaps in depression, but no study has examined this question. Methods As such, the current study examined whether there were sex differences in reward-related neural activity (i.e., ventral striatum [VS] activity) in response to an experimental inflammatory challenge. Human participants ( N = 115; 69 female) were randomly assigned to receive either placebo or low-dose endotoxin, which increases inflammation in a safe, time-limited manner. Two hours after receiving placebo or endotoxin (the height of the inflammatory response to endotoxin), participants completed a task in which they anticipated monetary reward in a functional magnetic resonance imaging scanner. Results Results demonstrated that endotoxin (vs. placebo) led to reduced VS activity in anticipation of reward and that there were sex differences in this effect. Specifically, in female participants, endotoxin (vs. placebo) led to decreased VS activity in anticipation of reward, but this effect was not present in male participants. In addition, within the endotoxin condition, decreases in VS activity in anticipation of reward were related to increases in inflammation for female but not male participants. Conclusions These findings may have implications for understanding how inflammation may contribute to sex differences in rates of depression.

Systemic inflammation is associated with increasing age. Yet, there are limited data about the association between age and systemic inflammation within older adults, and whether older age is also associated with cellular and nuclear signaling markers of inflammation. In community-dwelling older adults (N = 262, 60–88 years), systemic levels of C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor II; levels of toll-like receptor-4–stimulated monocytic production of interleukin-6 and tumor necrosis factor α; and resting nuclear levels of activated nuclear factor kappa B and signal transducer and activator of transcription (STAT1, STAT3, STAT5) were evaluated. Adjusting for demographic and clinical factors, multivariate linear regression tested the association between age and each inflammatory marker. Age was positively associated with increased levels of interleukin-6 and soluble tumor necrosis factor receptor II (p’s < .05) and with increases in STAT1, STAT3, and STAT5 activation (p’s < .05). However, no relationship was found between age and C-reactive protein, toll-like receptor-4–stimulated interleukin-6/tumor necrosis factor alpha α production, or nuclear factor kappa B. Within a community-dwelling sample of older adults, older age is associated with increases in STAT activation, along with increases of systemic inflammatory cytokines. In older adults, heterogeneity in age-related increases in inflammatory disease risk may be related to individual variability in inflammation.

Background C-reactive protein (CRP) is an inflammatory biomarker associated with all-cause mortality and morbidities such as cardiovascular disease. CRP is increased with HIV infection and thought to increase with age, though trajectories of CRP with aging have not been well characterized. We investigated trajectories of CRP in men from the Multicenter AIDS Cohort Study, according to HIV infection and HIV viral load status. Methods CRP measurements from 12 250 serum samples, provided by 2132 men over a span of 30 years, were categorized by HIV status at sample collection: HIV uninfected (HIV−, n = 1717), HIV infected with undetectable RNA (HIV+ suppressed, n = 4075), and detectable HIV RNA (HIV+ detectable, n = 6458). Age-related trajectories of CRP were fit to multivariable linear mixed models; we tested for differences in trajectories by HIV status. Results CRP increased with age in all sample groups. HIV+ detectable and HIV+ suppressed samples had higher CRP than HIV− samples throughout the observed age range of 20–70 years (p < .05). CRP concentrations at age 45 years were 38% (95% CI: 26%–50%) and 26% (15%–38%) higher in HIV+ detectable and HIV+ suppressed samples, respectively, relative to HIV− samples. HIV+ detectable samples showed more rapid linear increases with age (8% higher/decade, 0.3%–16%) than HIV− samples. Conclusions We observed higher concentrations of CRP across 5 decades of age in men living with HIV, and steeper increases with age in men with detectable HIV RNA, relative to HIV− men. These results are consistent with a contribution of inflammation to the higher risk of age-related comorbidities with HIV infection.

Introduction In cross-sectional studies of depressed patients, relationships between depression and levels of IL-8 are inconsistent, and have not been examined in relation to sex. Given identified sex differences in longitudinal data, it is important to evaluate sex-specific cross-sectional relationships between IL-8 and depressive symptoms, which may explain some inconsistency in the extant literature. It is further unknown whether IL-8 levels may relate to specific symptom profiles among depressed patients, with or without regard to sex. Methods Among 108 patients with treatment resistant depression (50 females), we evaluated cross-sectional relationships between IL-8 and depression severity, as measured by the Hamilton Depression Rating Scale [HAM-D] Score, and examined sex-specific relationships, as well as relationships with depressive symptom profiles. Other inflammatory markers (IL-6, IL-10, TNF-α, CRP) were also explored in relation to HAM-D. Results Higher IL-8 was associated with lower total HAM-D score (standardized β = −0.19, p = 0.049). Sex-specific effects were identified (IL-8 x sex interaction: p = 0.03), in which higher IL-8 related to lower HAM-D score in females (standardized β = −0.41, p = 0.004, effect size (sr2) = 0.17), but not males (standardized β = 0.02, p = 0.91). Among a subset of 94 patients (41 females) who had individual HAM-D items available, we evaluated relationships between IL-8 and HAM-D factor subscores. Across sexes, higher IL-8 was associated with lower anxiety/hypochondriasis subscores (standardized β = −0.31, p = 0.002; sex interaction: p = 0.99). Sex differences were identified for relationships between IL-8 and two other HAM-D factor subscores. Conclusions IL-8 may be related to anxiety symptoms across sexes, but may have a sex-specific relationship with other depressive symptoms. Further evaluation of sex-specific relationships between IL-8, depression symptom profiles, treatment response, and potential neurobiological correlates, may inform mechanisms of depression pathophysiology and aid in development of precision medicine strategies.

Inflammation plays a role in depression pathophysiology and treatment response, with effects varying by sex and therapeutic modality. Lower levels of interleukin(IL)-8 predict depression response to antidepressant medication and to electroconvulsive therapy (ECT), although ECT effects are specific to females. Whether IL-8 predicts depression response to ketamine and in a sex-specific manner is not known. Here, depressed patients (n = 46; female, n = 17) received open label infusion of ketamine (0.5 mg/kg over 40 min; NCT02165449). Plasma levels of IL-8 were evaluated at baseline and post-treatment. Baseline levels of IL-8 had a trending association with response to ketamine, depending upon sex (responder status × sex interaction: p = 0.096), in which lower baseline levels of IL-8 in females (p = 0.095) but not males (p = 0.96) trended with treatment response. Change in levels of IL-8 from baseline to post-treatment differed significantly by responder status (defined as ≥50% reduction in Hamilton Depression Rating Scale [HAM-D] Score), depending upon sex (responder status × sex × time interaction: F(1,42)=6.68, p = 0.01). In addition, change in IL-8 interacted with sex to predict change in HAM-D score (β = -0.63, p = 0.003); increasing IL-8 was associated with decreasing HAM-D score in females (p = 0.08) whereas the inverse was found in males (p = 0.02). Other inflammatory markers (IL-6, IL-10, tumor necrosis factor-α, C-reactive protein) were explored with no significant relationships identified. Given these preliminary findings, further evaluation of sex differences in the relationship between IL-8 and treatment response is warranted to elucidate mechanisms of response and aid in the development of personalized approaches to depression treatment.

Background: Peripheral blood levels of soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) are proposed markers of immune activation, the effects of which may influence the development of non-Hodgkin lymphoma (NHL). Pre-diagnostic circulating levels of sCD27, sCD30 and CXCL13 have been associated with NHL, although individual studies have typically been underpowered to assess associations for individual NHL subtypes. We pooled data from eight case-control studies nested within general-population cohorts to investigate subtype-specific relationships with these immune markers. Methods: After pooling, immune marker data for 2,455 cases diagnosed >2 years after blood collection and 3,310 controls were available for analysis. Using polytomous regression models, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific tertiles of each immune marker to the following subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n=623), diffuse large B-cell lymphoma (DLBCL; n=621), follicular lymphoma (FL; n=398), marginal zone lymphoma (MZL; n=138), mantle cell lymphoma (MCL; n=82) and T-cell lymphoma (TCL; n=92). Results: We observed associations with DLBCL for elevated levels of sCD27 [OR for 3rd vs. 1st tertile (ORT3) = 2.2, 95% CI = 1.6-3.1; Ptrend = 9.3x10-6), sCD30 (ORT3 = 2.0, 95% CI 1.6-2.5; Ptrend = 6.5 x10-10) and CXCL-13 (ORT3 = 2.3, 95% CI 1.8-3.0; Ptrend = 3.9 x10-12). These associations remained in a model simultaneously adjusting for all three markers. We also observed associations with sCD27 for CLL/SLL (ORT3 = 3.3, 95% CI = 2.4-4.6; Ptrend = 1.6x10-13), MZL (ORT3 =7.7, 95% CI 3.0-20.1; Ptrend = 2.3x10-6) and TCL (ORT3 = 3.4, 95% CI 1.5-7.7; Ptrend = 0.003), and between sCD30 and FL (ORT3 = 2.7, 95% CI 2.0-3.5; Ptrend = 1.7x10-12), all of which remained after adjustment for the other immune markers. In analyses stratified by follow-up time from blood collection to case diagnosis, the sCD27-TCL association and all three DLBCL associations were equivalent across both follow-up periods (>2- Citation Format: Jongeun Rhee, Brenda M. Birmann, Anneclaire J. De Roos, Mara M. Epstein, Otoniel Martinez-Maza, Elizabeth C. Breen, Lynn I. Levin, Kala Visvanathan, H Dean Hosgood, Thomas Rohan, Lihong Qi, Qing Lan, Nathaniel Rothman, Mark P. Purdue. Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 685.

Background Gratitude has received growing interest as an emotion that can bring greater happiness and health. However, little is known about the effects of gratitude on objective measures of physical health or the neural mechanisms that underlie these effects. Given strong links between gratitude and giving behavior, and giving and health, it is possible that gratitude may benefit health through the same mechanisms as giving to others. Thus, this study investigated whether gratitude activates a neural ‘caregiving system’ (e.g., ventral striatum (VS), septal area (SA)), which can downregulate threat responding (e.g., amygdala) and possibly cellular inflammatory responses linked to health. Methods A parallel group randomized controlled trial examined the effect of a six-week online gratitude (n = 31) vs. control (n = 30) writing intervention on neural activity and inflammatory outcomes. Pre- and post-intervention, healthy female participants (ages 35–50) reported on support-giving behavior and provided blood samples to assess circulating plasma levels and stimulated monocytic production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)). Post-intervention, participants completed a gratitude task and a threat reactivity task in an fMRI scanner. Results There were no significant group differences (gratitude vs. control intervention) in neural responses (VS, SA, or amygdala) to the gratitude or threat tasks. However, across the entire sample, those who showed larger pre- to- post-intervention increases in self-reported support-giving showed larger reductions in amygdala reactivity following the gratitude task (vs. control task). Additionally, those who showed larger reductions in amygdala reactivity following the gratitude task showed larger pre-to-post reductions in the stimulated production of TNF-α and IL-6. Importantly, gratitude-related reductions in amygdala reactivity statistically mediated the relationship between increases in support-giving and decreases in stimulated TNF-α production. Conclusion The observed relationships suggest that gratitude may benefit health (reducing inflammatory responses) through the threat-reducing effects of support-giving.

ObjectiveSleep disturbance is a known risk factor for depression, but it is not known whether sleep disturbance contributes to greater risk of depression in those infected with human immunodeficiency virus (HIV+) as compared to those uninfected with HIV (HIV-).MethodsUsing data from the Multicenter AIDS Cohort Study, a population-based prospective study of men who have sex with men (MSM), self-reported sleep disturbance (>2 weeks) and depressive symptoms (Clinical Epidemiologic Scale for Depression, CES-D) were assessed every 6 months over 12 years of follow-up. Adjusted mixed effects logistic regression analyses tested whether sleep disturbance predicted depression (CES-D ≥ 16) at the immediate subsequent visit, and so on over 12 years, in non-depressed HIV+(N = 1054; 9556 person-visits) and non-depressed HIV- (N = 1217; 12,680 person-visits). In HIV+ vs. HIV- MSM, linearly estimated average incidence of depression and normalized cumulative rate of depression over 12 years were compared.ResultsIn the HIV+ MSM, sleep disturbance was associated with a significant increase in depression 6 months later (OR = 1.6; 95% CI, 1.30, 1.96), which was significantly greater (P

Background: Men who have sex with men (MSM) are at increased risk for anal cancer. In cervical cancer screening, patterns of repeated cytology results are used to identify low- and high-risk women, but little is known about these patterns for anal cytology among MSM. Methods: We analyzed Multicenter AIDS Cohort Study (MACS) data for MSM who were offered anal cytology testing annually (HIV-positive) or every 2 years (HIV-negative) for 4 years. Results: Following an initial negative (normal) cytology, the frequency of a second negative cytology was lower among HIV-positive MSM with CD4 ≥ 500 (74%) or CD4

Background Pregnancy is an immunomodulatory state, with reported systematic changes in inflammatory and immune activity by pregnancy stage. Published data are inconsistent as to how inflammatory and immune markers change and recover across pregnancy and the postpartum period, or the sociodemographic, health and pregnancy-related factors that could affect biomarker trajectories. The purpose of this study is to describe inflammatory and immune marker trajectories from pregnancy to a year post-birth, and to test associations with sociodemographic, health and pregnancy-related variables. Methods A sample of 179 pregnant women were assessed three times during pregnancy (between 8 and 36 weeks gestation) and three times during the postpartum period (between 1 and 12 months). Maternal sociodemographic characteristics, health, and pregnancy factors were obtained at study entry. Blood samples from each assessment were assayed for interleukin(IL)-6, tumor necrosis factor(TNF)α, IL-8, IL-10, and interferon(IFN)γ. Multilevel modelling was used to characterize biomarker trajectories and associations with sociodemographic and health variables. Results Distinct trajectories over time emerged for each biomarker. Male pregnancies were associated with higher TNFα, IL-10, and IFNγ; higher pre-pregnancy BMI was associated with higher IL-6 and IFNγ. Nulliparity was associated with greater increases in IL-6 and TNFα. Conclusions Patterns observed for inflammatory and immune markers from pregnancy to a year postpartum support the hypothesis that the maternal immune system changes systematically across pregnancy and through an extended postpartum period. Parity, pre-pregnancy BMI and child sex are associated with inflammatory marker patterns over time. These results contribute to our understanding of how immune system activity changes from pregnancy to the post-birth period, and the factors that could affect those changes.

Importance Older adults with insomnia have a high risk of incident and recurrent depression. Depression prevention is urgently needed, and such efforts have been neglected for older adults. Objective To examine whether treatment of insomnia disorder with cognitive behavioral therapy for insomnia (CBT-I) compared with an active comparator condition, sleep education therapy (SET), prevents major depressive disorder in older adults. Design, setting, and participants This assessor-blinded, parallel-group, single-site randomized clinical trial assessed a community-based sample of 431 people and enrolled 291 adults 60 years or older with insomnia disorder who had no major depression or major health events in past year. Study recruitment was performed from July 1, 2012, to April 30, 2015. The trial protocol was modified to extend follow-up from 24 to 36 months, with follow-up completion in July 2018. Data analysis was performed from March 1, 2019, to March 30, 2020. Interventions Participants were randomized to 2 months of CBT-I (n = 156) or SET (n = 135). Main outcomes and measures The primary outcome was time to incident major depressive disorder as diagnosed by interview and Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria. Secondary outcome was sustained remission of insomnia disorder before depression event or duration of follow-up. Results Among 291 randomized participants (mean [SD] age, 70.1 [6.7] years; 168 [57.7%] female; 7 [2.4%] Asian, 32 [11.0%] Black, 3 [1.0%] Pacific Islander, 241 [82.8%] White, 6 [2.1%] multiracial, and 2 [0.7%] unknown), 156 were randomized to CBT-I and 135 to SET. A total of 140 participants (89.7%) completed CBT-I and 130 (96.3%) participants completed SET (χ2 = 4.9, P = .03), with 114 (73.1%) completing 24 months of follow-up in the CBT-I group and 117 (86.7%) in the SET group (χ2 = 8.4, P = .004). After protocol modification, 92 (59.0%) of the CBT-I participants and 86 (63.7%) of the SET participants agreed to extended follow-up (χ2 = 0.7, P = .41), with 81 (51.9%) of the CBT-I participants and 77 (57.0%) of the SET group completing 36 months of follow-up (χ2 = 0.8; P = .39). Incident or recurrent major depression occurred in 19 participants (12.2%) in the CBT-I group and in 35 participants (25.9%) in the SET group, with an overall benefit (hazard ratio, 0.51; 95%, CI 0.29-0.88; P = .02) consistent across subgroups. Remission of insomnia disorder continuously sustained before depression event or during follow-up was more likely in CBT-I participants (41 [26.3%]) compared with the SET participants (26 [19.3%], P = .03). Those in the CBT-I group with sustained remission of insomnia disorder had an 82.6% decreased likelihood of depression (hazard ratio, 0.17; 95%, CI 0.04-0.73; P = .02) compared with those in the SET group without sustained remission of insomnia disorder. Conclusions and relevance The findings of this randomized clinical trial indicate that treatment of insomnia with CBT-I has an overall benefit in the prevention of incident and recurrent major depression in older adults with insomnia disorder. Community-level screening for insomnia concerns in older adults and wide delivery of CBT-I-based treatment for insomnia could substantially advance public health efforts to treat insomnia and prevent depression in this vulnerable older adult population. Trial registration ClinicalTrials.gov Identifier: NCT01641263.

Inflammation and B-cell hyperactivation have been associated with non-Hodgkin lymphoma development. This prospective analysis aimed to further elucidate pre-diagnosis plasma immune marker profiles associated with non-Hodgkin lymphoma risk. We identified 598 incident lymphoma cases and 601 matched controls in Nurses' Health Study and Health Professionals Follow-up Study participants with archived pre-diagnosis plasma samples and measured 13 immune marker levels with multiplexed immunoassays. Using multivariable logistic regression we calculated Odds Ratios (OR) and 95% Confidence Intervals (CI) per standard deviation unit increase in biomarker concentration for risk of non-Hodgkin lymphoma and major histological subtype, stratifying additional models by years (

Generativity, or concern for and contribution to the well-being of younger generations, plays an important role in successful aging. The purpose of this study was to develop a novel, writing-based intervention to increase feelings of generativity and test the effect of this intervention on well-being and inflammation in a sample of older women. Participants in this study (n=73; mean age = 70.9 years, range 60–86 years) were randomly assigned to a 6-week generativity writing condition (writing about life experiences and sharing advice with others) or a control writing condition (neutral, descriptive writing). Self-reported measures of social well-being, mental health, and physical health, as well as objective measures of systemic and cellular levels of inflammation (plasma pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α; genome-wide RNA transcriptional profiling), were assessed pre- and post-intervention. The generativity intervention led to significant improvements across multiple domains, including increases in participation in social activities, decreases in psychological distress, more positive expectations regarding aging in the physical health domain, and decreases in pro-inflammatory gene expression. Thus, this study provides preliminary evidence for the ability of a novel, low-cost, low-effort intervention to favorably impact inflammation and well-being in older women. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov

Although there has been much interest in understanding the effect of gratitude on health-related outcomes, this remains an understudied area of research, particularly regarding mechanisms and measurement of biological outcomes. The present study explored whether a gratitude intervention could reduce inflammatory outcomes and whether this occurred through increased support-giving. Healthy women (n = 76) were randomly assigned to a 6-week gratitude intervention (i.e., writing on topics intended to induce gratitude) or a control condition (i.e., neutral writing). Support-giving and markers of inflammation were measured pre- and postintervention. Those in the gratitude intervention (vs. control) reported higher postintervention levels of support-giving. Moreover, those with lower levels of psychological distress gave more support as a function of the gratitude intervention. Regarding inflammatory outcomes, although there was no effect of the gratitude intervention on postintervention inflammatory markers, increases in support-giving across the entire sample were related to decreases in inflammatory markers. These results, along with a scarcity of work in this area, suggest that further work is needed to more fully understand the relationships between gratitude and biological markers relevant to health. Finally, these novel findings linking support-giving and decreases in inflammation also indicate that the mammalian caregiving system, associated with enhanced support-giving and reduced physiological stress responding, is a mechanism worth further examination to elucidate the links between social support and health. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Racial disparities in health outcomes between African Americans and European Americans have been well-documented, but not fully understood. Chronic inflammation contributes to several of the diseases showing racial disparities (e.g., Human Immunodeficiency Virus [HIV]), and racial differences in stress exposure (e.g., experiences of racial discrimination) that stimulate pro-inflammatory processes that may contribute to differential health outcomes. We performed a cross-sectional bioinformatic analyses relating perceived discrimination (as measured by the Perceived Ethnic Discrimination Questionnaire [PED-Q]) to the activity of pro-inflammatory, neuroendocrine, and antiviral transcription control pathways relevant to the conserved transcriptional response to adversity (CTRA) in peripheral blood leukocytes. Subjects were 71 individuals (37 HIV-seropositive (HIV+); 34 HIV-seronegative (HIV-)) (mean age = 53 years, range 27-63), who self-identified either as African American/Black (n = 48) or European American/White (n = 23). This provided the opportunity to examine the independent effects of race and HIV, as well as the modifying role of perceived discrimination on pathways involved in CTRA. Exploratory analysis examined the interactive effects of HIV and race on pathways involved in CTRA. Relative to European Americans, African Americans showed increased activity of two key pro-inflammatory transcription control pathways (NF- кB and AP-1) and two stress-responsive signaling pathways (CREB and glucocorticoid receptor); these effects did not differ significantly as a function of HIV infection (HIV x Race interaction, all p > .10). Results suggested that differences in experiences of racial discrimination could potentially account for more than 50% of the total race-related difference in pro-inflammatory transcription factor activity. In sum, differential exposure to racial discrimination may contribute to racial disparities in health outcomes in part by activating threat-related molecular programs that stimulate inflammation and contribute to increased risk of chronic illnesses.

Purpose Breast cancer diagnosis and treatment are associated with increased inflammatory activity, which can induce sickness symptoms. We examined whether emotional acceptance moderates the association between proinflammatory cytokines and self-reported sickness symptoms in women recently diagnosed with breast cancer. Methods Women ( N = 136) diagnosed with stage 0-III breast cancer within the previous 6 months provided plasma samples and completed the FACT: Physical Well-Being Scale, as well as the Acceptance of Emotion Scale every 3 months for 2 years. At each time point, we quantified interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α using a high sensitivity multiplex assay. Results Higher within-subject mean TNF-α across all time-points predicted higher mean sickness symptoms. At individual time-points, higher IL-6 and IL-8 levels were associated with higher sickness symptoms. Mean emotional acceptance across all time-points moderated the relationship between mean IL-8 and sickness symptoms, with sickness symptoms remaining persistently high in women with low emotional acceptance even when IL-8 levels were low. At individual time-points, emotional acceptance positively moderated the correlations of IL-8 and TNF-α with sickness symptoms, such that the associations between higher levels of these proinflammatory cytokines and higher sickness symptoms were attenuated when emotional acceptance was high. Conclusion Emotional acceptance was shown for the first time to moderate the associations of cytokines with sickness symptoms in breast cancer patients over time following diagnosis and treatment. The association between emotional acceptance and sickness symptoms was significantly different from zero but relatively small in comparison to the range of sickness symptoms. Results suggest that targeting emotion regulation may help to break the cycle between inflammation and sickness symptoms in women with breast cancer.

Study objectives Insomnia, particularly in later life, may raise the risk for chronic diseases of aging and mortality through its effect on cellular aging. The current study examines the effects of insomnia on telomere length, a measure of cellular aging, and tests whether insomnia interacts with chronological age to increase cellular aging. Methods A total of 126 males and females (60-88 y) were assessed for insomnia using the Diagnostic and Statistical Manual IV criterion for primary insomnia and the International Classification of Sleep Disorders, Second Edition for general insomnia (45 insomnia cases; 81 controls). Telomere length in peripheral blood mononuclear cells (PBMC) was determined using real-time quantitative polymerase chain reaction (qPCR) methodology. Results In the analysis of covariance model adjusting for body mass index and sex, age (60-69 y versus 70-88 y) and insomnia diagnosis interacted to predict shorter PBMC telomere length (P = 0.04). In the oldest age group (70-88 y), PBMC telomere length was significantly shorter in those with insomnia, mean (standard deviation) M(SD) = 0.59(0.2) compared to controls with no insomnia M(SD) = 0.78(0.4), P = 0.04. In the adults aged 60-69 y, PBMC telomere length was not different between insomnia cases and controls, P = 0.44. Conclusions Insomnia is associated with shorter PBMC telomere length in adults aged 70-88 y, but not in those younger than 70 y, suggesting that clinically severe sleep disturbances may increase cellular aging, especially in the later years of life. These findings highlight insomnia as a vulnerability factor in later life, with implications for risk for diseases of aging.

BackgroundChronic inflammation and immune activation are reported to play a key role in the etiology of non-Hodgkin lymphoma (NHL). We conducted a meta-analysis on the associations between prediagnosis circulating levels of immune stimulatory markers, interleukin 6 (IL-6), IL-10, tumor necrosis factor α (TNF-α), CXCL13, soluble CD23 (sCD23), sCD27, sCD30, and the risk of NHL.MethodsRelevant studies were identified from PubMed, EMBASE, and Web of Science up to January 1, 2017. We calculated summary odds ratio (OR) estimates for the association between one natural log increase in concentration of each biomarker and NHL using random-effects models for NHL as a composite outcome and for several histological subtypes of NHL.ResultsSeventeen nested case control studies were included. Elevated levels of several biomarkers were more strongly associated with increased odds of NHL: TNF-α, OR = 1.18 (95% confidence interval [CI] = 1.04 to 1.34); CXCL13, OR = 1.47 (95% CI = 1.03 to 2.08); sCD23, OR = 1.57 (95% CI = 1.21 to 2.05); sCD27, OR = 2.18 (95% CI = 1.20 to 3.98); sCD30, OR = 1.65 (95% CI = 1.22 to 2.22). In stratified analyses, IL-6, TNF-α, sCD27, and sCD30 were more strongly associated with NHL in HIV-infected individuals compared to HIV-uninfected individuals. Between-study heterogeneity was observed across multiple biomarkers for overall NHL and by subtypes.ConclusionThis meta-analysis provides evidence that elevated circulating levels of TNF-α, CXCL13, sCD23, sCD27, and sCD30 are consistently associated with an increased risk of NHL, suggesting the potential utility of these biomarkers in population risk stratification and prediction.

Activation of the innate immune system is thought to contribute to depression. Multiple social and behavioral factors are also known to instigate depression. Whether these socio-behavioral factors interact with inflammatory stimuli to alter proinflammatory responses and depressed mood is not known. In 115 healthy adults, social, emotional, and behavioral factors were assessed at baseline. A single infusion of endotoxin (Escherichia coli; 0.8 ng/kg of body weight) or placebo (0.9% saline) was administered with hourly assessment of depressed mood and proinflammatory cytokines (interleukin-6 (IL-6); tumor necrosis factor-α (TNF)). Inflammatory gene expression was examined at 30 min after infusion, prior to increase of inflammatory cytokines. As compared to placebo, endotoxin-induced increases of depressed mood were moderated by baseline levels of perceived stress, trait sensitivity to social disconnection, and severity of symptoms of anxiety and depression (all Ps

Purpose To determine treatment and aging-related effects on longitudinal cognitive function in older breast cancer survivors. Methods Newly diagnosed nonmetastatic breast cancer survivors (n = 344) and matched controls without cancer (n = 347) 60 years of age and older without dementia or neurologic disease were recruited between August 2010 and December 2015. Data collection occurred during presystemic treatment/control enrollment and at 12 and 24 months through biospecimens; surveys; self-reported Functional Assessment of Cancer Therapy-Cognitive Function; and neuropsychological tests that measured attention, processing speed, and executive function (APE) and learning and memory (LM). Linear mixed-effects models tested two-way interactions of treatment group (control, chemotherapy with or without hormonal therapy, and hormonal therapy) and time and explored three-way interactions of ApoE (ε4+ v not) by group by time; covariates included baseline age, frailty, race, and cognitive reserve. Results Survivors and controls were 60 to 98 years of age, were well educated, and had similar baseline cognitive scores. Treatment was related to longitudinal cognition scores, with survivors who received chemotherapy having increasingly worse APE scores ( P = .05) and those initiating hormonal therapy having lower LM scores at 12 months ( P = .03) than other groups. These group-by-time differences varied by ApoE genotype, where only ε4+ survivors receiving hormone therapy had short-term decreases in adjusted LM scores (three-way interaction P = .03). For APE, the three-way interaction was not significant ( P = .14), but scores were significantly lower for ε4+ survivors exposed to chemotherapy (−0.40; 95% CI, −0.79 to −0.01) at 24 months than ε4+ controls (0.01; 95% CI, 0.16 to 0.18; P < .05). Increasing age was associated with lower baseline scores on all cognitive measures ( P < .001); frailty was associated with baseline APE and self-reported decline ( P < .001). Conclusion Breast cancer systemic treatment and aging-related phenotypes and genotypes are associated with longitudinal decreases in cognitive function scores in older survivors. These data could inform treatment decision making and survivorship care planning.

Objective Maternal infection during pregnancy has been associated with increased risk of offspring psychopathology, including depression. As most infections do not cross the placenta, maternal immune responses to infection have been considered as potentially contributing to this relationship. This study examined whether gestational timing of maternal inflammation during pregnancy is associated with offspring internalizing and/or externalizing symptoms during childhood and, further, whether fetal sex moderated this relationship. Method Participants were 737 pregnant women and their offspring who were continuously followed through late childhood. Archived first and second trimester sera were analyzed for markers of inflammation [interleukin 8 (IL-8), IL-6, IL-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor-II (sTNF-RII)]. When offspring were aged 9–11, mothers completed a questionnaire assessing psychological symptoms. Results Multivariate regression analyses indicated that elevated IL-8 in the first trimester was associated with significantly higher levels of externalizing symptoms in offspring. Higher IL-1ra in the second trimester was associated with higher offspring internalizing symptoms. Further, second trimester IL-1ra was associated with increased internalizing symptoms in females only. Conclusion These findings demonstrate that elevated maternal inflammation during pregnancy is associated with the emergence of separate psychological phenotypes and that timing of exposure and fetal sex matter for offspring outcomes. Given that internalizing and externalizing symptoms in childhood increase risk for a variety of mental disorders later in development, these findings potentially have major implications for early intervention and prevention work.

Background Cognitive decline is a frequently cited concern among patients receiving hematopoietic cell transplantation (HCT), and patients often experience neurocognitive deficits (i.e., stable or worsening neurocognitive performance) throughout the transplant course. Deficits can be most severe during the acute transplant period (i.e., 90 days after transplantation), when patients also typically experience elevated systemic levels of inflammation. Previous studies have identified inflammation as a likely mechanism underlying neurocognitive deficits, primarily in women with breast cancer; however, longitudinal studies have been limited. In this study, our aim was to evaluate the relationship between changes in systemic inflammation and changes in cognition from pre- to post-transplant in patients receiving allogeneic HCT. Methods Patients scheduled for allogeneic HCT (n = 85) were assessed prior to HCT and 90 days after HCT. Biomarkers of inflammation included IL-6, sTNF-RII, CRP, and IL-1ra, which have been previously associated with neurocognitive deficits in cancer patients. Patients completed neuropsychological testing and self-report questionnaires. Results Mixed models demonstrated that from pre- to post-HCT, increases in IL-6 and sTNF-RII were associated with neurocognitive deficits, and decreases in CRP were associated with better neurocognitive performance. There were no significant associations between changes in inflammation and self-reported cognitive performance. Conclusions Our findings are the first to our knowledge to report a robust relationship between increasing inflammation and neurocognitive deficits from pre- to post-HCT. Additional studies are needed to confirm these findings in a larger sample.

BACKGROUND: Clinicians often use population-based reference intervals (RIs) when interpreting patient results. However, this method can present problems if the analyte in question has wide variability from person to person. METHODS: We examined the biological variation of routine hematologic markers in 82 white non-Hispanic men every 6 months during a 30-year period, to determine the usefulness of population-based RIs and age-related decline of hematological markers. RESULTS: Many of these markers showed significant person-to-person differences (index of individuality