A dyadic longitudinal analysis of parent-adolescent inflammation trends and the role of shared socioeconomic characteristics on family inflammation.

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 (bint = - 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.

Sleep Disturbance as a Mediator of Lung Cancer Stigma on Psychological Distress and Physical Symptom Burden.

OBJECTIVE: This study tested sleep disturbance as a mediator through which stigma and discrimination predict psychological distress and physical symptom burden in adults with lung cancer. METHODS: Lung cancer patients on active oncological treatment ( N = 108; 74.1% stage IV) completed questionnaires on lung cancer stigma, sleep, distress, and physical symptoms at study entry and at 6- and 12-week follow-up. Mediation analyses were conducted to investigate whether stigma and discrimination predicted distress and physical symptoms at study entry and across 12 weeks through disrupted sleep. RESULTS: Higher discrimination ( b = 5.52, 95% confidence interval [CI] = 2.10-8.94) and constrained disclosure ( b = 0.45, 95% CI = 0.05-0.85) were associated significantly with higher sleep disruption at study entry. Sleep disruption, in turn, was associated with higher distress ( b = 0.19, 95% CI = 0.09-0.29) and physical symptoms ( b = 0.28, 95% CI = 0.17-0.40) at study entry. Sleep disruption significantly mediated relationships between higher discrimination and the outcomes of distress (indirect effect = 1.04, 95% CI = 0.13-1.96) and physical symptoms (indirect effect = 1.58, 95% CI = 0.37-2.79) at study entry. Sleep disruption also mediated relationships between constrained disclosure and the outcomes of distress (indirect effect = 0.85, 95% CI = < 0.01-0.17) and physical symptoms (indirect effect = 0.13, 95% CI = 0.01-0.25). CONCLUSIONS: Lung cancer patients evidenced pronounced sleep disruption, which mediated relationships between indicators of lung cancer stigma and distress and physical symptoms at study entry. Research is needed to test additional mechanisms through which lung cancer stigma predicts these outcomes longitudinally.

Sleep-wake behavioral characteristics associated with depression symptoms: findings from the Multi-Ethnic Study of Atherosclerosis.

STUDY OBJECTIVES: To help prioritize target/groups for experimental intervention studies, we characterized cross-sectional associations between 24-hour sleep-wake measures and depression symptoms, and evaluated if similar sleep-wake-depression relationships existed in people with and without higher insomnia severity. METHODS: Participants had ≥3 days of actigraphy data (n = 1884; mean age = 68.6/SD = 9.1; 54.1% female). We extracted 18 sleep, activity, timing, rhythmicity, and fragmentation measures from actigraphy. We used individual and multivariable regressions with the outcome of clinically significant depression symptoms (Center for Epidemiologic Studies Depression Scale ≥ 16). We conducted sensitivity analyses in people with higher insomnia severity (top quartile of the Women's Health Initiative Insomnia Rating Scale total score). RESULTS: From separate models in the overall sample, the odds of having depression symptoms were higher with: later timing (e.g. activity onset time odds ratio [OR]/1 SD = 1.32; 95% confidence interval [CI]: 1.16 to 1.50), lower rhythmicity (e.g. pseudo-F OR/1 SD = 0.75; 95% CI: 0.66 to 0.85), less activity (e.g. amplitude OR/1 SD = 0.83; 95% CI: 0.72 to 0.95), and worse insomnia (OR/1 SD = 1.48, 95% CI: 1.31 to 1.68). In multivariable models conducted among people with lower insomnia severity, later timing, lower rhythmicity, and higher insomnia severity were independent correlates of depression. In people with higher insomnia symptom severity, measures of later timing were most strongly associated with depression symptoms. CONCLUSIONS: These correlative observations suggest that experimental studies are warranted to test if: broadly promoting 24-hour sleep-wake functioning reduces depression even in people without severe insomnia, and if advancing timing leads to depression symptom reductions in people with insomnia.

Type I interferons, inflammation, and fatigue in a longitudinal RNA study of women with breast cancer.

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.

IL-6 predicts non-suicidal self-injury over 3 months in high-risk adolescents.

BACKGROUND: Suicide is the second leading cause of death in 12- to 17-year-old adolescents in the USA. Research on biological mechanisms contributing to self-harm risk that could be targeted in treatment could help to prevent suicide and self-harm episodes. AIMS: We aimed to evaluate whether markers of inflammation, interleukin-6 (IL-6) and C-reactive protein (CRP), predict self-harm over 3 months within a sample selected for elevated suicide/self-harm risk at project entry. METHOD: Fifty-one adolescents aged 12-19 years selected for elevated suicide/self-harm risk completed three clinical interviews about suicide attempts and non-suicidal self-injury, 3 months apart. At baseline and 3 months, youth also provided blood samples, from which we assayed levels of IL-6 and CRP. RESULTS: Using generalised mixed models, we found that greater levels of IL-6 predicted more self-harm episodes (odds ratio [OR] = 3.3, 95% CI: 1.1, 10.0) and specifically, non-suicidal self-injury (OR = 3.5, 95% CI: 1.1, 11.2), over 3 months. CONCLUSIONS: The study findings increase our understanding of whether and how inflammation may be implicated in risk of self-harm. IL-6 may be a viable biological marker of short-term risk for self-harm.

The feasibility of a sleep education program for informal dementia care dyads: A pilot randomized controlled trial.

BACKGROUND: Untreated sleep problems in both persons living with dementia (PLWD) and their family care partners (CP) impact their health and quality of life. This pilot study tested a sleep intervention program for both dyad members. METHODS: Thirty dyads were randomized to a 5-session Care2Sleep intervention (n = 15 dyads) or an information-only control group (n = 15 dyads) delivered in-person or by video-telehealth by trained sleep educators. Care2Sleep is a manual-based program, incorporating key components of cognitive behavioral therapy for insomnia, daily light exposure and walking, and problem-solving for dementia-related behaviors. Adherence with Care2Sleep recommendations was assessed. Sleep outcomes included actigraphy-measured sleep efficiency (SE) and total wake time (TWT) for dyads, and the Pittsburgh Sleep Quality Index (PSQI) for CP. Other outcomes for CP included the Zarit Burden Interview (ZBI) and positive aspects of caregiving (PAC). Outcomes were measured at baseline, posttreatment, and 3-month follow-up. A 2 (group) by 3 (time) mixed model analysis of variance tested treatment effects. RESULTS: Study feasibility was demonstrated, with 13 dyads completing all five sessions of Care2Sleep program and 14 completing the control condition. In the Care2Sleep group, the dyads adhered to recommended sleep schedules of 76% for bedtime and 72% for get-up time for PLWD, and 69% for bedtime and 67% for get-up time for CP. There were several nonsignificant trends in outcomes from baseline to 3-month follow-up between the two groups. For example, SE increased by 3.2% more for PLWD and 3.2% more for CP with Care2Sleep versus control. TWT decreased by 14 min more for PLWD and 12 min more for CP with Care2Sleep versus control at the 3-month follow-up. CP in Care2Sleep also showed improvement in the PSQI, ZBI, and PAC scores. CONCLUSIONS: A dyadic approach to sleep improvement is feasible. Larger trials are needed to test effects of this intervention for PLWD and their family CP. CLINICALTRIALS: gov: NCT03455569.

Structural brain plasticity and inflammation are independently related to changes in depressive symptoms six months after an index ECT course.

BACKGROUND: Electroconvulsive therapy (ECT) is effective for treatment-resistant depression and leads to short-term structural brain changes and decreases in the inflammatory response. However, little is known about how brain structure and inflammation relate to the heterogeneity of treatment response in the months following an index ECT course. METHODS: A naturalistic six-month study following an index ECT course included 20 subjects with treatment-resistant depression. Upon conclusion of the index ECT course and again after six months, structural magnetic resonance imaging scans and peripheral inflammation measures [interleukin-6 (IL-6), IL-8, tumor necrosis factor (TNF-α), and C-reactive protein] were obtained. Voxel-based morphometry processed with the CAT-12 Toolbox was used to estimate changes in gray matter volume. RESULTS: Between the end of the index ECT course and the end of follow-up, we found four clusters of significant decreases in gray matter volume (p < 0.01, FWE) and no regions of increased volume. Decreased HAM-D scores were significantly related only to reduced IL-8 level. Decreased volume in one cluster, which included the right insula and Brodmann's Area 22, was related to increased HAM-D scores over six months. IL-8 levels did not mediate or moderate the relationship between volumetric change and depression. CONCLUSIONS: Six months after an index ECT course, multiple regions of decreased gray matter volume were observed in a naturalistic setting. The independent relations between brain volume and inflammation to depressive symptoms suggest novel explanations of the heterogeneity of longer-term ECT treatment response.

Efficacy of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction for Depression Symptoms and Sleep-Wake Disruption in Older and Younger Adults: Secondary Age-Stratified Analysis of a Randomized Controlled Trial.

OBJECTIVE: Perform a secondary analysis examining the efficacy of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for depression symptom responses, and explore changes in potential target mechanisms. DESIGN: Secondary analysis of a randomized controlled trial with convenience age subsamples (younger (20-49 year; n = 52) versus and older (50-71 years; n = 35)). SETTING: Community mental health clinics. PARTICIPANTS: Eighty-seven adults with serious mental illness. INTERVENTION: TranS-C versus treatment as usual (TAU). MEASUREMENTS: Outcomes were depression symptoms (Quick Inventory of Depression Symptoms), insomnia symptoms (Insomnia Severity Index), and objective sleep-wake rhythm measures (interdaily stability and relative amplitude). RESULTS: Depression response rates (≥50% symptom reductions) were higher in the TranS-C (35.0%) than the TAU (8.8%) group 6-months postintervention (χ2 = 10.3, p = 0.001). There was a medium effect of TranS-C versus TAU on depression symptoms 6-months postintervention (Cohen's d = -0.40, 95% confidence interval (CI): -0.81, 0.01). In both age groups, there were large treatment effects on insomnia symptoms post-treatment (Cohen's d >0.90). In the older subsample, there were additionally medium treatment effects on post-treatment interdaily stability (Cohen's d = 0.60, 95% CI: -0.11, 1.61). Post-treatment reductions in insomnia symptoms correlated with depression symptom reduction 6-months later in the younger subsample (Spearman rho = 0.59, n = 20, p = 0.008). In older adults, postintervention increases in interdaily stability correlated with depression symptom reductions 6-months later (Spearman rho = -0.52, n = 15, p = 0.049). CONCLUSION: Confirmatory trials are needed, given the low age-specific sample sizes here, to determine if TranS -C's produces durable depression responses by increasing sleep-wake rhythm stability in older adults and improving insomnia symptoms in younger adults. BRIEF ARTICLE SUMMARY: The authors evaluated preliminary efficacy of a behavioral intervention that targets sleep/sleep-wake rhythms, the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C), for depression symptoms in people with serious mental illness. TranS-C was associated with higher depression response rates than treatment as usual 6-months postintervention. The degree of depression symptom response 6-months later was related to the degree of treatment phase improvements in interdaily stability (in older adults) and reduction in insomnia severity (in younger adults). A pragmatic nonpharmacologic intervention, the Transdiagnostic Intervention for Sleep and Circadian Dysfunction, has preliminary efficacy for improving sleep-wake factors and depression symptoms.

Everyday discrimination, emotion, and daily interactions during adolescence.

The present study examined whether everyday discrimination relates to the frequency of adolescents' positive and negative daily social interactions and whether these associations are driven by anger and positive emotion. Adolescents (N = 334) participated in a three-wave longitudinal study, in which they completed surveys regarding everyday discrimination, anger, and positive emotion, as well as 15 daily reports of conflict and getting along with friends and family. Higher everyday discrimination was related to more daily conflicts and fewer experiences of getting along with other people. Longitudinal models also provided preliminary evidence that everyday discrimination was associated with daily conflicts 4 years later indirectly through anger. Overall, results suggest everyday discrimination relates to adolescents' daily experiences, potentially through differences in emotion.

Work Productivity Among Younger Breast Cancer Survivors: The Impact of Behavioral Interventions for Depression.

OBJECTIVES: The Pathways to Wellness randomized controlled trial found that 2 behavioral interventions, mindfulness awareness practices and survivorship education, reduced depressive symptoms in younger breast cancer survivors (BCSs) compared with wait-list control. This secondary analysis examines whether the interventions led to reduced loss of work productivity among younger BCSs and whether such reductions were mediated by reductions in depressive symptoms. METHODS: The Work Productivity and Activity Impairment scale was used to measure work productivity loss at 4 assessment time points. Correlates of productivity loss at enrollment were examined using multivariable linear regression. Differences in change over time in productivity loss between each intervention group and control were assessed using linear mixed models. Reduced depressive symptoms were tested as a mediator of reduced productivity loss. RESULTS: Of 247 trial participants, 199 were employed and included in the analyses. At enrollment, higher productivity loss was associated with chemotherapy receipt (P = .003), younger age (P = .021), more severe cognitive problems (P = .002), higher musculoskeletal pain severity (P = .002), more depressive symptoms (P = .016), and higher fatigue severity (P = .033). The mindfulness intervention led to significantly less productivity loss compared with control at all 3 postintervention assessment points (all P < .05), with about 54% of the effect mediated by reduction in depressive symptoms. Survivorship education was not associated with reduced loss of productivity. CONCLUSIONS: These findings suggest that addressing depressive symptoms through behavioral interventions, such as mindfulness, may mitigate impacts on work productivity in younger BCSs.

Heightened neural activity and functional connectivity responses to social rejection in female adolescents at risk for depression: Testing the Social Signal Transduction Theory of Depression.

BACKGROUND: Although social rejection is among the strongest proximal precipitants of major depressive disorder (MDD), little is known about the underlying neurobiological mechanisms and whether neural sensitivity to social rejection may help explain differences in MDD risk. To address this issue, we tested whether neural responses to social threat differed in female adolescents at high vs. low maternal risk for MDD. METHOD: Female adolescents with (high-risk; n = 22, Mage = 14.68) and without (low-risk; n = 30, Mage = 15.07) a maternal history of depression were experimentally exposed to negative and neutral social evaluation while undergoing an fMRI scan. Neural responses were assessed by event-related activity and functional connectivity, as well as multivoxel pattern analysis. Activity and functional connectivity analyses focused on a priori-selected regions of interest implicated in self-referential processing and emotion regulation. RESULTS: Compared to low-risk female adolescents, high-risk female adolescents exhibited greater increases in self-reported depression and social disconnection following social evaluation. Moreover, compared to low-risk female adolescents, high-risk female adolescents exhibited greater amygdala responses to negative social evaluation and a differential pattern of functional connectivity in brain regions related to emotion regulation, self-referential processing, and negative affect. Additionally, these markers of neural threat reactivity were related to depressive symptoms. LIMITATIONS: A cross-sectional study design and relatively small, Western sample. CONCLUSIONS: These results suggest that exaggerated neural reactivity to social threat-and an atypical pattern of related functional connectivity-is evident in individuals with a preclinical risk factor for depression. Targeting such responding may thus be a fruitful strategy for preventing depression in at-risk youth.

Executive functioning trajectories and their prospective association with inflammatory biomarkers in schizophrenia and non-psychiatric comparison participants.

BACKGROUND AND HYPOTHESIS: Cognitive change in people with schizophrenia (PwS) is challenging to assess, but important to understand. Previous studies with limited age ranges and follow-up were subject to practice effects. Controlling for practice effects in a well-established cohort, we examined executive functioning trajectories and their association with inflammatory biomarkers, hypothesizing that PwS will have worsening executive functioning over time compared to non-psychiatric comparison participants (NCs), predicted by higher baseline inflammation with a stronger relationship in PwS than NCs. STUDY DESIGN: Executive functioning was assessed in 350 participants (n = 186 PwS, 164 NCs) at 12-16-month intervals (0 to 7 follow-up visits). Inflammatory biomarkers at baseline included high sensitivity C-Reactive Protein (hs-CRP), Interferon-gamma, Tumor Necrosis Factor (TNF)-alpha, and Interleukin(IL)-6, -8, and - 10. Executive functioning trajectories across diagnostic groups were estimated using a linear mixed-effects model controlling for age, sex, race/ethnicity, and education level, with additional models to assess prediction by baseline inflammation. STUDY RESULTS: Over 4.4 years average follow-up, improvements in executive functioning were attenuated in PwS and older participants. Controlling for practice effects negated improvements, revealing declines among highly educated participants regardless of diagnosis. Higher baseline hs-CRP predicted worse executive functioning only among NCs, while TNF-alpha was predictive of change in all participants only after controlling for practice effects. Only the main effect of hs-CRP on executive function was significant after adjusting for multiple comparisons. None of the other inflammatory biomarkers predicted executive functioning or trajectories of performance among study participants. CONCLUSIONS: Systemic inflammation as reflected by baseline inflammatory biomarker levels did not predict longitudinal declines in executive functioning. Additional studies examining the temporal dynamics of inflammation and cognition in PwS will help further clarify their relationship and associated mechanisms.

Depressive symptom trajectories in older breast cancer survivors: the Thinking and Living with Cancer Study.

PURPOSE: To identify trajectories of depressive symptoms in older breast cancer survivors and demographic, psychosocial, physical health, and cancer-related predictors of these trajectories. METHODS: Recently diagnosed nonmetastatic breast cancer survivors (n = 272), ages 60-98 years, were evaluated for depressive symptoms (Center for Epidemiological Studies Depression Scale, CES-D; scores ≥16 suggestive of clinically significant depressive symptoms). CES-D scores were analyzed in growth-mixture models to determine depression trajectories from baseline (post-surgery, pre-systemic therapy) through 3-year annual follow-up. Multivariable, multinomial logistic regression was used to identify baseline predictors of depression trajectories. RESULTS: Survivors had three distinct trajectories: stable (84.6%), emerging depressive symptoms (10.3%), and recovery from high depressive symptoms at baseline that improved slowly over time (5.1%). Compared to stable survivors, those in the emerging (OR = 1.16; 95% CI = 1.08-1.23) or recovery (OR = 1.26; 95% CI = 1.15-1.38) groups reported greater baseline anxiety. Greater baseline deficit accumulation (frailty composite measure) was associated with emerging depressive symptoms (OR = 3.71; 95% CI = 1.90-7.26). Less social support at baseline (OR = 0.38; 95% CI = 0.15-0.99), but greater improvement in emotional (F = 4.13; p = 0.0006) and tangible (F = 2.86; p = 0.01) social support over time, was associated with recovery from depressive symptoms. CONCLUSIONS: Fifteen percent of older breast cancer survivors experienced emerging or recovery depressive symptom trajectories. Baseline anxiety, deficit accumulation, and lower social support were associated with worse outcomes. IMPLICATIONS FOR CANCER SURVIVORS: Our results emphasize the importance of depression screening throughout the course of cancer care to facilitate early intervention. Factors associated with depressive symptoms, including lower levels of social support proximal to diagnosis, could serve as intervention levers.

Alcohol use disorder (AUD) is associated with enhanced sensitivity to cellular lipopolysaccharide challenge.

BACKGROUND: Inflammation has been associated with alcohol use disorder (AUD). A novel method to characterize AUD-related immune signaling involves probing Toll-like receptor (TLR)-4 stimulated monocyte production of intracellular cytokines (ICCs) via lipopolysaccharide (LPS). We evaluated relationships between AUD and ICC production at rest and after LPS stimulation. METHODS: We analyzed blood samples from 36 participants (AUD N = 14; Controls N = 22), collected across time, with ICC expression assessed at rest (i.e., unstimulated) and following stimulation with LPS (i.e., a total of 5 repeated unstimulated or stimulated measures/participant). Markers assessed included tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), TNF-α and IL-6 co-expression, and interferon (IFN). For each marker, we constructed linear mixed models with AUD, LPS, and timepoint as fixed effects (BMI as covariate), allowing for random slope and intercept. AUD × LPS was included as an interaction. RESULTS: For TLR4-stimulated monocyte production of TNF-α, there were effects of AUD (p < 0.01), LPS (p < 0.001), and AUD × LPS interaction (p < 0.05), indicating that individuals with AUD showed greater unstimulated- and stimulated monocyte expression of TNF-α. Similarly, for TLR4-stimulated monocyte co-expression of TNF-α and IL-6, there were effects of AUD (p < 0.01), LPS (p < 0.001), and AUD × LPS interaction (p < 0.05). No AUD or LPS effects were found for IL-6. Timepoint effects were observed on IL-6 and TNF-α/IL-6 co-expression (p < 0.001). Finally, for IFN there were also effects of AUD (p < 0.05), LPS (p < 0.001), and AUD × LPS (p < 0.001). CONCLUSIONS: Individuals with AUD showed greater resting or unstimulated levels of intracellular monocyte expression of TNF-α and IL-6/TNF-α co-expression than controls. AUD was associated with increases in TLR4-stimulated monocyte production of TNF-α and co-production of IL-6 and TNF-α. This is, to our knowledge, the first study to investigate relationships between AUD and monocyte production of proinflammatory cytokines, at rest and in response to TLR4 stimulation with LPS. The study extends previous findings on the roles of proinflammatory cytokines in AUD and serves as a critical proof of concept for the use of this method to probe neuroimmune mechanisms underlying AUD.

Inflammation-related proteins as biomarkers of treatment-related behavioral symptoms: A longitudinal study of breast cancer patients and age-matched controls.

Background: Behavioral symptoms in breast cancer (BC) survivors have been attributed to cancer treatment and resulting inflammation. However, studies linking behavioral symptoms to BC treatment have observed patients only after some treatment. Our prospective study with pre-treatment baseline investigates post-treatment changes in inflammation-related biomarkers and whether those changes correlate with changes in symptoms. Methods: Participants were postmenopausal women, newly-diagnosed with stage 0-3 BC before any treatment (n = 173 "patients"), and age-matched women without cancer (n = 77 "controls"), who were assessed on plasma markers [soluble tumor necrosis factor receptor type 2 (sTNF-RII), interleukin (IL)-6, IL-1 receptor antagonist (IL-1RA), C-reactive protein (CRP)]) and symptoms (Physical Functioning, Pain, Attention/concentration, Perceived Cognitive Problems, Fatigue, Sleep Insufficiency, Depression). Participants were assessed again 1 month, 1 year, and 2 years after completing primary treatment or similar interval in controls. Generalized linear mixed models tested 4 treatments (surgery alone or with chemotherapy, radiation, or both) for association with change per marker. Joint models tested change per marker for association with change per symptom. Models considered demographic, socioeconomic, and clinical covariates. False Discovery Rate method controlled risk of error from multiple hypotheses. Results: At one month post-completion of treatment, sTNF-RII and IL-6 were elevated by all BC treatments, as were IL-1RA and CRP after surgery alone (all, p < 0.05). By 1 year, markers' average values returned to baseline. Throughout 2-year follow-up, increase-from-baseline in sTNF-RII, IL-1RA, and IL-6 coincided with worsened Physical Functioning, and increase-from-baseline in sTNF-RII coincided with increased Pain (all, p < 0.01). These biomarker-symptom associations (excepting IL-6) were exclusive to patients. No other symptoms worsened, and baseline Fatigue and Depression improved in all participants. Conclusions: BC treatment, even surgery, is associated with transient elevation in inflammatory markers. In patients post-treatment, increase-from-baseline in sTNF-RII accompanies increased Pain and decreased Physical Functioning, suggesting that sTNF-RII merits development as a clinical biomarker in BC patients.

Heat of the night: sleep disturbance activates inflammatory mechanisms and induces pain in rheumatoid arthritis.

Sleep has a homeostatic role in the regulation of the immune system and serves to constrain activation of inflammatory signalling and expression of cellular inflammation. In patients with rheumatoid arthritis (RA), a misaligned inflammatory profile induces a dysregulation of sleep-wake activity, which leads to excessive inflammation and the induction of increased sensitivity to pain. Given that multiple biological mechanisms contribute to sleep disturbances (such as insomnia), and that the central nervous system communicates with the innate immune system via neuroendocrine and neural effector pathways, potential exists to develop prevention opportunities to mitigate the risk of insomnia in RA. Furthermore, understanding these risk mechanisms might inform additional insomnia treatment strategies directed towards steering and reducing the magnitude of the inflammatory response, which together could influence outcomes of pain and disease activity in RA.

Stress to inflammation and anhedonia: Mechanistic insights from preclinical and clinical models.

Anhedonia, as evidenced by impaired pleasurable response to reward, reduced reward motivation, and/or deficits in reward-related learning, is a common feature of depression. Such deficits in reward processing are also an important clinical target as a risk factor for depression onset. Unfortunately, reward-related deficits remain difficult to treat. To address this gap and inform the development of effective prevention and treatment strategies, it is critical to understand the mechanisms that drive impairments in reward function. Stress-induced inflammation is a plausible mechanism of reward deficits. The purpose of this paper is to review evidence for two components of this psychobiological pathway: 1) the effects of stress on reward function; and 2) the effects of inflammation on reward function. Within these two areas, we draw upon preclinical and clinical models, distinguish between acute and chronic effects of stress and inflammation, and address specific domains of reward dysregulation. By addressing these contextual factors, the review reveals a nuanced literature which might be targeted for additional scientific inquiry to inform the development of precise interventions.

Sleep disruption induces activation of inflammation and heightens risk for infectious disease: Role of impairments in thermoregulation and elevated ambient temperature.

Thermoregulation and sleep are tightly coordinated, with evidence that impairments in thermoregulation as well as increases in ambient temperature increase the risk of sleep disturbance. As a period of rest and low demand for metabolic resources, sleep functions to support host responses to prior immunological challenges. In addition by priming the innate immune response, sleep prepares the body for injury or infection which might occur the following day. However when sleep is disrupted, this phasic organization between nocturnal sleep and the immune system becomes misaligned, cellular and genomic markers of inflammation are activated, and increases of proinflammatory cytokines shift from the nighttime to the day. Moreover, when sleep disturbance is perpetuated due to thermal factors such as elevated ambient temperature, the beneficial crosstalk between sleep and immune system becomes further imbalanced. Elevations in proinflammatory cytokines have reciprocal effects and induce sleep fragmentation with decreases in sleep efficiency, decreases in deep sleep, and increases in rapid eye movement sleep, further fomenting inflammation and inflammatory disease risk. Under these conditions, sleep disturbance has additional potent effects to decrease adaptive immune response, impair vaccine responses, and increase vulnerability to infectious disease. Behavioral interventions effectively treat insomnia and reverse systemic and cellular inflammation. Further, insomnia treatment redirects the misaligned inflammatory- and adaptive immune transcriptional profiles with the potential to mitigate risk of inflammation-related cardiovascular, neurodegenerative, and mental health diseases, as well as susceptibility to infectious disease.

Null results of oxytocin and vasopressin administration on mentalizing in a large fMRI sample: evidence from a randomized controlled trial.

BACKGROUND: Although potential links between oxytocin (OT), vasopressin (AVP), and social cognition are well-grounded theoretically, most studies have included all male samples, and few have demonstrated consistent effects of either neuropeptide on mentalizing (i.e. understanding the mental states of others). To understand the potential of either neuropeptide as a pharmacological treatment for individuals with impairments in social cognition, it is important to demonstrate the beneficial effects of OT and AVP on mentalizing in healthy individuals. METHODS: In the present randomized, double-blind, placebo-controlled study (n = 186) of healthy individuals, we examined the effects of OT and AVP administration on behavioral responses and neural activity in response to a mentalizing task. RESULTS: Relative to placebo, neither drug showed an effect on task reaction time or accuracy, nor on whole-brain neural activation or functional connectivity observed within brain networks associated with mentalizing. Exploratory analyses included several variables previously shown to moderate OT's effects on social processes (e.g., self-reported empathy, alexithymia) but resulted in no significant interaction effects. CONCLUSIONS: Results add to a growing literature demonstrating that intranasal administration of OT and AVP may have a more limited effect on social cognition, at both the behavioral and neural level, than initially assumed. Randomized controlled trial registrations: ClinicalTrials.gov; NCT02393443; NCT02393456; NCT02394054.

A randomized, placebo-controlled, double-blinded mechanistic clinical trial using endotoxin to evaluate the relationship between insomnia, inflammation, and affective disturbance on pain in older adults: A protocol for the sleep and Healthy Aging Research for pain (SHARE-P) study.

Chronic pain is prevalent in older adults. Treatment, especially with opioids, is often ineffective and poses considerable negative consequences in this population. To improve treatment, it is important to understand why older adults are at a heightened risk for developing chronic pain. Insomnia is a major modifiable risk factor for chronic pain that is ubiquitous among older adults. Insomnia can also lead to heightened systemic inflammation and affective disturbance, both of which may further exacerbate pain conditions in older adults. Endotoxin exposure can be used as an experimental model of systemic inflammation and affective disturbance. The current study aims to understand how insomnia status and endotoxin-induced changes in inflammation and affect (increased negative affect and decreased positive affect) may interact to impact pain facilitatory and inhibitory processes in older adults. Longitudinal data will also assess how pain processing, affective, and inflammatory responses to endotoxin may predict the development of pain and/or depressive symptoms. The current study is a randomized, double-blinded, placebo-controlled, mechanistic clinical trial in men and women, with and without insomnia, aged 50 years and older. Participants were randomized to either 0.8ng/kg endotoxin injection or saline placebo injection. Daily diaries were used to collect variables related to sleep, mood, and pain at two-week intervals during baseline and 3-, 6-, 9-, and 12-months post-injection. Primary outcomes during the experimental phase include conditioned pain modulation, temporal summation, and affective pain modulation ∼5.5 hours after injection. Primary outcomes for longitudinal assessments are self-reported pain intensity and depressive symptoms. The current study uses endotoxin as an experimental model for pain. In doing so, it aims to extend the current literature by: (1) including older adults, (2) investigating insomnia as a potential risk factor for chronic pain, (3) evaluating the role of endotoxin-induced affective disturbances on pain sensitivity, and (4) assessing sex differences in endotoxin-induced hyperalgesia. Clinicaltrialsgov: NCT03256760. Trial sponsor: NIH R01AG057750-01.