Tai Chi compared with cognitive behavioral therapy and the reversal of systemic, cellular and genomic markers of inflammation in breast cancer survivors with insomnia: A randomized clinical trial.

BACKGROUND: Insomnia contributes to inflammation in breast cancer survivors. This study evaluates whether insomnia treatment reverses inflammation in breast cancer survivors with insomnia. METHODS: Participants (n = 90) were randomized to 3 months of Tai Chi (n = 45) or cognitive behavioral therapy for insomnia (CBT-I)(n = 45), and followed for one year post-intervention to 15 month endpoint. Our previous report found that Tai Chi as compared to CBT-I resulted in similar rates of insomnia response and remission over 15 months. Here, we analyze changes in plasma C-reactive protein and pro- and anti-inflammatory cytokines, Toll-like receptor (TLR)-4 stimulated monocyte production of interleukin (IL)-6 and tumor necrosis factor-α (TNF), and cellular pro-inflammatory and anti-viral gene expression (Conserved Transcriptional Response to Adversity RNA profile; CTRA) over 15 months. RESULTS: Insomnia treatment resulted in decreases in the TLR-4 stimulated monocyte production of IL-6, TNF, and their co-expression, as well as decreases in the CTRA profile, decreases inflammatory gene transcripts, and increases in anti-viral gene transcripts over 15 months (all P's < 0.01). In addition, as compared to CBT-I, Tai Chi resulted in greater decreases in plasma IL-6 (P < 0.05), and greater decreases in TLR-4 activated monocyte production of IL-6 and co-expression of IL-6 and TNF at 15 month endpoint. CBT-I resulted in greater increases in anti-viral gene transcripts. CONCLUSIONS: Administration of either CBT-I or Tai Chi effectively treats insomnia, and shows additional benefits of reducing cellular and genomic markers of inflammation, and increasing anti-viral genomic markers in breast cancer survivors with insomnia. Tai Chi, as compared to CBT-I, yields greater and more durable decreases in systemic- and cellular inflammation. Targeting insomnia might mitigate the risk of inflammation-related co-morbidities in breast cancer survivors.

Prenatal maternal Inflammation, childhood cognition and adolescent depressive symptoms.

BACKGROUND: Accumulating evidence indicates that higher prenatal maternal inflammation is associated with increased depression risk in adolescent and adult-aged offspring. Prenatal maternal inflammation (PNMI) may increase the likelihood for offspring to have lower cognitive performance, which, in turn, may heighten risk for depression onset. Therefore, this study explored the potential mediating role of childhood cognitive performance in the relationship between PNMI and adolescent depressive symptoms in offspring. METHODS: Participants included 696 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Biomarkers of maternal inflammation [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1RA) and soluble TNF receptor-II (sTNF-RII)] were assayed from first (T1) and second trimester (T2) sera. Childhood (ages 9-11) cognitive performance was assessed via standardized Peabody Picture Vocabulary Test (PPVT), a measure of receptive vocabulary correlated with general intelligence. Adolescent (ages 15-17) depressive symptoms were assessed via self-report. RESULTS: There were no significant associations between T1 biomarkers and childhood PPVT or adolescent depressive symptoms. Higher T2 IL1-RA was directly associated with lower childhood PPVT (b = -0.21, SE = 0.08, t = -2.55, p = 0.01), but not with adolescent depressive symptoms. T2 IL-6 was not directly associated with childhood PPVT, but higher T2 IL-6 was directly associated at borderline significance with greater depressive symptoms in adolescence (b = 0.05, SE = 0.03, t = 1.96, p = 0.05). Lower childhood PPVT predicted significantly higher adolescent depressive symptoms (b = -0.07, SE = 0.02, t = -2.99, p < 0.01). There was a significant indirect effect of T2 IL-1RA on adolescent depressive symptoms via childhood PPVT (b = 0.03, 95 % CI = 0.002-0.03) indicating a partially mediated effect. No significant associations were found with T2 sTNF-RII nor IL-8. CONCLUSIONS: Lower childhood cognitive performance, such as that indicated by a lower PPVT score, represents a potential mechanism through which prenatal maternal inflammation contributes to adolescent depression risk in offspring.

Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis.

Although prediagnostic circulating concentrations of the immune activation markers soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) have been associated with non-Hodgkin lymphoma (NHL) risk, studies have been limited by sample size in associations with NHL subtypes. We pooled data from eight nested case-control studies to investigate subtype-specific relationships for these analytes. Using polytomous regression, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific analyte tertiles to selected subtypes vs controls (n = 3310): 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). We observed associations with DLBCL for elevated sCD27 [OR for third vs first tertile (ORT3 ) = 2.2, 95% CI = 1.6-3.1], sCD30 (ORT3  = 2.0, 95% CI = 1.6-2.5) and CXCL13 (ORT3  = 2.3, 95% CI = 1.8-3.0). We also observed associations with sCD27 for CLL/SLL (ORT3  = 3.3, 95% CI = 2.4-4.6), MZL (ORT3  = 7.7, 95% CI = 3.0-20.1) and TCL (ORT3  = 3.4, 95% CI = 1.5-7.7), and between sCD30 and FL (ORT3  = 2.7, 95% CI = 2.0-3.5). In analyses stratified by time from phlebotomy to case diagnosis, the sCD27-TCL and all three DLBCL associations were equivalent across both follow-up periods (<7.5, ≥7.5 years). For other analyte-subtype comparisons, associations were stronger for the follow-up period closer to phlebotomy, particularly for indolent subtypes. In conclusion, we found robust evidence of an association between these immune markers and DLBCL, consistent with hypotheses that mechanisms related to immune activation are important in its pathogenesis. Our other findings, particularly for the rarer subtypes MZL and TCL, require further investigation.

Epigenetic aging in older breast cancer survivors and noncancer controls: preliminary findings from the Thinking and Living with Cancer Study.

BACKGROUND: Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes. METHODS: Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency-matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy-Cognitive Function) and physical (Medical Outcomes Study Short Form-12) function assessments at approximately 24 to 36 and 60 months after enrollment. Mixed-effects models tested survivor-control differences in epigenetic aging, adjusting for age and comorbidities; models for functional outcomes also adjusted for racial group, site, and cognitive reserve. RESULTS: Survivors were 1.04 to 2.22 years biologically older than controls on Horvath, EEA, GrimAge, and DunedinPACE measures (p = .001-.04) at approximately 24 to 36 months after enrollment. Survivors exposed to chemotherapy were 1.97 to 2.71 years older (p = .001-.04), and among this group, an older EEA related to worse self-reported cognition (p = .047) relative to controls. An older epigenetic age related to worse physical function in all women (p < .001-.01). Survivors and controls showed similar epigenetic aging over time, but Black survivors showed accelerated aging over time relative to non-Hispanic White survivors. CONCLUSION: Older breast cancer survivors, particularly those exposed to chemotherapy, showed greater epigenetic aging than controls that may relate to worse outcomes. If replicated, measurement of biological aging could complement geriatric assessments to guide cancer care for older women.

Plasma levels of interleukin-6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study.

BACKGROUND: Immune activation/inflammation markers (immune markers) were tested to explain differences in neurocognition among older breast cancer survivors versus noncancer controls. METHODS: Women >60 years old with primary breast cancer (stages 0-III) (n = 400) were assessed before systemic therapy with frequency-matched controls (n = 329) and followed annually to 60 months; blood was collected during annual assessments from 2016 to 2020. Neurocognition was measured by tests of attention, processing speed, and executive function (APE). Plasma levels of interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor α (TNF-α), and interferon γ were determined using multiplex testing. Mixed linear models were used to compare results of immune marker levels by survivor/control group by time and by controlling for age, racial/ethnic group, cognitive reserve, and study site. Covariate-adjusted multilevel mediation analyses tested whether survivor/control group effects on cognition were explained by immune markers; secondary analyses examined the impact of additional covariates (e.g., comorbidity and obesity) on mediation effects. RESULTS: Participants were aged 60-90 years (mean, 67.7 years). Most survivors had stage I (60.9%) estrogen receptor-positive tumors (87.6%). Survivors had significantly higher IL-6 levels than controls before systemic therapy and at 12, 24, and 60 months (p ≤ .001-.014) but there were no differences for other markers. Survivors had lower adjusted APE scores than controls (p < .05). Levels of IL-6, IL-10, and TNF-α were related to APE, with IL-6 explaining part of the relationship between survivor/control group and APE (p = .01). The magnitude of this mediation effect decreased but remained significant (p = .047) after the consideration of additional covariates. CONCLUSIONS: Older breast cancer survivors had worse long-term neurocognitive performance than controls, and this relationship was explained in part by elevated IL-6.

The Presence of Implicit Gender Bias in Colon and Rectal Surgery Residency Letters of Recommendation.

BACKGROUND: Selection for colorectal surgery residency relies on letters of recommendation for assessment of candidates' strengths and weaknesses. It is unclear whether this process incorporates implicit gender bias. OBJECTIVE: This study aimed to assess the presence of gender bias in letters of recommendation for colorectal surgery residency. DESIGN: Mixed methods assessment of the characteristics described within the blinded letters of the 2019 application cycle to a single academic residency. SETTINGS: Academic medical center. PATIENTS: Blinded letters from the 2019 colorectal surgery residency application cycle. INTERVENTIONS: Characteristics of the letters were qualitatively and quantitatively analyzed. MAIN OUTCOME MEASURES: Association of gender with the presence of descriptors within the letters. RESULTS: A total of 111 applicants, 409 letter writers, and 658 letters were analyzed. Forty-three percent of applicants were female. Female and male applicants had an equal mean number of positive (5.4 vs 5.8; p = 0.10) and negative (0.5 vs 0.4; p = 0.07) attributes represented. Female applicants were more likely to be described as having poor academic skills (6.0 vs 3.4%; p = 0.04) and possessing negative leadership qualities (5.2% vs 1.4%; p < 0.01) than male applicants. Male applicants were more likely to be described as kind (36.6% vs 28.3%; p = 0.03), curious (16.4% vs 9.2%; p = 0.01), possessing positive academic skills (33.7% vs 20.0%; p < 0.01), and possessing positive teaching skills (23.5% vs 17.0%; p = 0.04). LIMITATIONS: This study analyzed a single year of applications to an academic center and may not be generalizable. CONCLUSIONS: There are differences in the qualities used to describe female versus male applicants in colorectal surgery residency application letters of recommendation. Female applicants were more often described in negative academic terms and possessing negative leadership qualities. Males were more likely to be described as kind, curious, academically impressive, and possessing good teaching skills. The field may benefit from educational initiatives to reduce implicit gender bias in letters of recommendation. See Video Abstract at http://links.lww.com/DCR/C191 . LA PRESENCIA DE SESGO DE GNERO IMPLCITO EN LAS CARTAS DE RECOMENDACIN DE RESIDENCIA EN CIRUGA DE COLON Y RECTO: ANTECEDENTES:La selección para la residencia en cirugía colorrectal se basa en cartas de recomendación para la evaluación subjetiva de las fortalezas y debilidades de los candidatos. No está claro si este proceso incorpora un sesgo de género implícito.OBJETIVO:Evaluar la presencia de sesgo de género en las cartas de recomendación para la residencia en cirugía colorrectal.DISEÑO:Evaluación de métodos mixtos de las características descritas dentro de las cartas selladas del ciclo de solicitud de 2019 a una sola residencia académica.ENTORNO CLÍNICO:Centro médico académico.PACIENTES:Cartas selladas del ciclo de solicitud de residencia en cirugía colorrectal de 2019.INTERVENCIONES:Las características de las cartas se determinaron utilizando medidas cualitativas y cuantitativas.PRINCIPALES MEDIDAS DE VALORACIÓN:Asociación del género con la presencia de descriptores dentro de las cartas.RESULTADOS:Hubo 111 solicitantes, 409 escritores de cartas y se analizaron 658 cartas. El 43% de los solicitantes eran mujeres. Los solicitantes masculinos y femeninos tenían el mismo promedio de atributos positivos (5,4 frente a 5,8; p = 0,10) y negativos (0,5 frente a 0,4; p = 0,07) representados. Las solicitantes femeninas tenían más probabilidades de ser descritas como con deficientes habilidades académicas (6,0 frente a 3,4%, p = 0,04) y poseían cualidades de liderazgo negativas (5,2% frente a 1,4%; p < 0,01) en comparacion con los solicitantes masculinos. Los solicitantes masculinos tenían más probabilidades de ser descritos como amables (36,6 % frente a 28,3%; p = 0,03), curiosos (16,4% frente a 9,2%; p = 0,01), que poseían habilidades académicas positivas (33,7 % frente a 20,0%; p < 0,01), y habilidades docentes positivas (23,5% vs 17,0%; p = 0,04).LIMITACIONES:Este estudio analizó un solo año de solicitudes a un centro académico y puede no ser generalizable.CONCLUSIÓN:Existen diferencias en las cualidades utilizadas para describir a los solicitantes femeninos versus masculinos en las cartas de recomendación de solicitud de residencia en cirugía colorrectal. Las candidatas femeninas se describieron con mayor frecuencia en términos académicos negativos y poseían cualidades de liderazgo negativas. Los hombres eran más propensos a ser descritos como amables, curiosos, académicamente impresionantes y con buenas habilidades docentes. El campo puede beneficiarse de iniciativas educativas para reducir el sesgo de género implícito en las cartas de recomendación. Consulte Video Resumen en http://links.lww.com/DCR/C191 . (Traducción-Dr. Ingrid Melo ).

A Growing Divide? Social Determinants of the Use of Nonoperative Management of Rectal Cancer and Its Impact on Survival.

INTRODUCTION: Nonoperative management (NOM) of locally advanced rectal cancer was described as early as 2004. Initial national data demonstrated increase in utilization of NOM from 1998 to 2010, but newer national utilization data are not available. METHODS: We performed a retrospective cohort study using the National Cancer Database to assess utilization and 5-y overall survival (OS) of NOM of locally advanced rectal cancer. All patients had American Joint Committee on Cancer stage 2 or 3 rectal cancer, were over 40 y old, received both chemotherapy and radiation therapy, and were not being treated with palliative intent. RESULTS: 74,780 patients were analyzed. 64,540 (86.2%) underwent a definitive resection, 10,330 (13.8%) had NOM. Utilization of NOM steadily increased from 11.3% in 2010 to 18.6% in 2018. Multivariate regression identified the highest predictors of utilization of NOM to be uninsured status, government insurance, Black race, and treatment at a community cancer center. Multivariate regression identified NOM as the highest hazard for mortality (hazard ratio = 2.286, confidence interval 2.209-2.366). After propensity score matching, the mean estimated 5-y OS was 52.0% for those managed operatively compared to 39.8% for those managed nonoperatively. CONCLUSIONS: From 2004 to 2018, the utilization of NOM of locally advanced rectal cancer significantly increased. However, there was a significant discrepancy in OS in comparison to surgical resection for these patients. Further study is needed to determine the long-term oncologic safety of NOM.

Inflammatory and immune marker trajectories from pregnancy to one-year post-birth.

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.

Association of interleukin-8 and risk of incident and recurrent depression in long-term breast cancer survivors.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Ventromedial prefrontal cortex activity differentiates sick from healthy faces: Associations with inflammatory responses and disease avoidance motivation.

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 an 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.

Socioeconomic Status and Inflammation in Women with Early-stage Breast Cancer: Mediation by Body Mass Index.

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.

What Can an Aging Pouch Tell Us? Outcomes of Ileoanal Pouches Over 20 Years Old.

BACKGROUND: Little is known about the long-term functional outcomes of restorative proctocolectomy. OBJECTIVE: The aim of this study was to examine ileoanal pouch outcomes 20 and 30 years postoperatively. DESIGN: This is a retrospective case series. SETTING: This study was conducted at a tertiary care referral center. PATIENTS: Patients who underwent restorative proctocolectomy between 1980 and 1994 were identified. Those with ≥20 years of in-person follow-up were included. MAIN OUTCOMES MEASURES: Pouch function, pouchitis, anal stricture, and pouch failure rates were analyzed. RESULTS: A total of 203 patients had ≥20 years of follow-up. Of those, 71 had ≥30 years of follow-up. Initial diagnoses included ulcerative colitis (83%), indeterminate colitis (9%), familial adenomatous polyposis (4%), and Crohn's disease (3%). Twenty-one percent of those with ulcerative or indeterminate colitis later transitioned to Crohn's disease. Mean daily stool frequency was 7 (IQR 6-8), 38% experienced seepage, 31% had anal stenosis, 47% experienced pouchitis, and 18% had pouch failure. Over time, stool frequency increased in 41% of patients, stayed the same in 43%, and decreased in 16%. Patients older than 50 years at the time of construction had more daily bowel movements (median 8 vs 6; p = 0.02) and more seepage (77% vs 35%; p = 0.005) than those younger than 50 years. Patients with Crohn's disease had higher stool frequency (median 8 vs 6; p < 0.001) and higher rates of anal stenosis (44% vs 26%; p = 0.02), pouchitis (70% vs 40%; p < 0.001), and pouch failure (38% vs 12%; p < 0.001) compared to non-Crohn's patients. Patients with ≥30 years of follow-up had similar function as those with 20-30 years of follow-up. LIMITATIONS: This was a retrospective, single-institution study. Only 35% of pouches created during the study period had >20 years of follow-up. CONCLUSIONS: Most patients maintain reasonably good function and retain their pouches after 20 years. Over time, stool frequency and seepage increase. Older age and Crohn's disease are associated with worse outcomes. See Video Abstract at http://links.lww.com/DCR/B801. QU NOS DICE UN RESERVORIO A LARGO PLAZO RESULTADOS DE LOS RESERVORIOS ILEOANALES MAYORES DE AOS: ANTECEDENTES:se sabe poco sobre los resultados funcionales a largo plazo de la proctocolectomía restauradora.OBJETIVO:El objetivo de este estudio fue examinar los resultados del reservorio ileoanal 20 y 30 años después de la operación.DISEÑO:Serie de casos retrospectiva.ENTORNO CLÍNICO:Centro de referencia de atención terciariaPACIENTES:Se identificaron pacientes que se sometieron a proctocolectomía restauradora entre 1980 y 1994. Se incluyeron aquellos con ≥20 años de seguimiento en persona.PRINCIPALES MEDIDAS DE VALORACIÓN:Se analizaron la función, inflamación, tasas de falla del reservorio y estenosis anal.RESULTADOS:Un total de 203 pacientes tuvieron ≥20 años de seguimiento. De ellos, 71 tenían ≥30 años de seguimiento. Los diagnósticos iniciales incluyeron colitis ulcerosa (83%), colitis indeterminada (9%), poliposis adenomatosa familiar (4%) y enfermedad de Crohn (3%). El 21% de las personas con colitis ulcerosa o indeterminada pasaron posteriormente a la enfermedad de Crohn. La frecuencia promedio de las deposiciones diarias fue de 7 (rango intercuartil 6-8), el 38% experimentó filtración, el 31% tuvo estenosis anal, el 47% experimentó pouchitis y el 18% tuvo falla del reservorio. Con el tiempo, la frecuencia de las deposiciones aumentó en el 41% de los pacientes, se mantuvo igual en el 43% y disminuyó en el 16%. Los pacientes mayores de 50 años en el momento de la construcción tenían más evacuaciones intestinales diarias (media 8 vs 6, p = 0,02) y más filtraciones (77% vs 35%, p = 0,005) que los menores de 50 años. Los pacientes con enfermedad de Crohn tenían mayor frecuencia de deposiciones (media 8 vs 6, p < 0,001) y tasas más altas de estenosis anal (44% vs 26%, p = 0,02), inflamacion (70% vs 40%, p <0,001) y falla del reservorio (38% frente a 12%, p <0,001) en comparación con pacientes que tenian enfermedad de Crohn. Los pacientes con ≥30 años de seguimiento tuvieron una función similar a aquellos con 20-30 años de seguimiento.LIMITACIONES:Este fue un estudio retrospectivo de una sola institución. Solo el 35% de los reservorios creados durante el período de estudio tuvieron más de 20 años de seguimiento.CONCLUSIONES:La mayoría de los pacientes mantienen una función razonablemente buena y conservan el reservorio después de 20 años. Con el tiempo, la frecuencia de las deposiciones y la filtración aumentan. La vejez y la enfermedad de Crohn se asocian con peores resultados. Consulte Video Resumen en http://links.lww.com/DCR/B801. (Traducción - Dr. Ingrid Melo).

Systemic inflammation and symptomatology in patients with prostate cancer treated with androgen deprivation therapy: Preliminary findings.

BACKGROUND: Increases in fatigue, depressive symptomatology, and cognitive impairment are common after the initiation of androgen deprivation therapy (ADT) for prostate cancer. To date, no studies have examined the potential role of inflammation in the development of these symptoms in ADT recipients. The goal of the current study was to examine circulating markers of inflammation as potential mediators of change in fatigue, depressive symptomatology, and cognitive impairment related to the receipt of ADT. METHODS: Patients treated with ADT for prostate cancer (ADT+; n = 47) were assessed around the time of the initiation of ADT and 6 and 12 months later. An age- and education-matched group of men without a history of cancer (CA-; n = 82) was assessed at comparable time points. Fatigue, depressive symptomatology, and cognitive impairment were assessed with the Fatigue Symptom Inventory, the Center for Epidemiological Studies Depression Scale, and a battery of neuropsychological tests, respectively. Circulating markers of inflammation included interleukin 1 receptor antagonist (IL-1RA), interleukin 6 (IL-6), soluble tumor necrosis factor receptor II (sTNF-RII), and C-reactive protein (CRP). RESULTS: Fatigue, depressive symptomatology, and serum IL-6 increased significantly over time in the ADT+ group versus the CA- group; rates of cognitive impairment also changed significantly between the groups. No significant changes in IL-1RA, sTNF-RII, or CRP over time were detected. Treatment-related increases in IL-6 were associated with worsening fatigue but not depressive symptomatology or cognitive impairment. CONCLUSIONS: Results of this preliminary study suggest that increases in circulating IL-6, perhaps due to testosterone inhibition, may play a role in fatigue secondary to receipt of ADT. Additional research is needed to determine whether interventions to reduce circulating inflammation improve fatigue in this population.

Exploring neural mechanisms of the health benefits of gratitude in women: A randomized controlled trial.

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.

Sleep, inflammation, and perception of sad facial emotion: A laboratory-based study in older adults.

BACKGROUND: Facial emotion perception (FEP) is pivotal for discriminating salient emotional information. Accumulating data indicate that FEP responses, particularly to sad emotional stimuli, are impaired in depression. This study tests whether sleep disturbance and inflammation, two risk factors for depression, contribute to impaired FEP to sad emotional stimuli. METHODS: In older adults (n = 40, 71.7 ± 6.8y, 56.4% female), disturbance of sleep maintenance (i.e., wake time after sleep onset [WASO]) was evaluated by polysomnography. In the morning, plasma concentrations of two markers of systemic inflammation were evaluated (i.e., interleukin [IL]-6, tumor necrosis factor [TNF]-α), followed by two FEP tasks, which assessed delays in emotion recognition (ER) and ratings of perceived emotion intensity (EI) in response to sad facial emotional stimuli, with exploration of FEP responses to happiness and anger. Linear regression models tested whether WASO, IL-6, and TNF-α would be associated with impaired FEP to sad emotional stimuli. In addition, moderation tests examined whether inflammation would moderate the link between sleep disturbance and impaired FEP to sad emotional stimuli. RESULTS: Longer WASO predicted longer ER delays (p < 0.05) and lower EI ratings in response to sad faces (p < 0.01). Further, higher TNF-α (p < 0.05) but not IL-6 predicted longer ER delays for sad faces, whereas higher IL-6 (p < 0.01) but not TNF-α predicted lower EI ratings for sad faces. Finally, TNF-α moderated the relationship between longer WASO and longer ER delays to sad faces (p < 0.001), while IL-6 moderated the relationship between longer WASO and lower EI ratings to sad faces (p < 0.01). Neither sleep nor inflammatory measures were associated with FEP responses to happiness or anger. CONCLUSION: In older adults, disturbance of sleep maintenance is associated with impaired FEP to sad emotion, a relationship that appears to be moderated by inflammation. These data indicate that sleep disturbance and inflammation converge and contribute to impaired FEP with implications for risk for late-life depression.

Feeling needed: Effects of a randomized generativity intervention on well-being and inflammation in older women.

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.

Inflammation and Risk of Depression in HIV: Prospective Findings From the Multicenter AIDS Cohort Study.

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.

Worsening cognitive performance is associated with increases in systemic inflammation following hematopoietic cell transplantation.

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.

Pre-diagnosis plasma immune markers and risk of non-Hodgkin lymphoma in two prospective cohort studies.

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 (<5, 5 to <10, ≥10) after blood draw. Soluble interleukin-2 receptor-α, CXC chemokine ligand 13, soluble CD30, and soluble tumor necrosis factor receptor-2 were individually positively associated, and B-cell activating factor of the tumor necrosis factor family inversely associated, with all non-Hodgkin lymphoma and one or more subtypes. The biomarker combinations associated independently with lymphoma varied somewhat by subtype and years after blood draw. Of note, the unexpected inverse association between B-cell activating factor and chronic lymphocytic leukemia/small lymphocytic lymphoma risk (OR: 95%CI: 0.51, 0.43-0.62) persisted more than ten years after blood draw (OR: 0.70; 95%CI: 0.52-0.93). In conclusion, immune activation precedes non-Hodgkin lymphoma diagnosis by several years. Decreased B-cell activating factor levels may denote nascent chronic lymphocytic leukemia many years pre-diagnosis.

Increased Central Nervous System Interleukin-8 in a Majority Postlaminectomy Syndrome Chronic Pain Population.

Background and Objectives: Multiple processes have been identified as potential contributors to chronic pain, with increasing evidence illustrating an association with aberrant levels of neuroimmune mediators. The primary objectives of the present study were to examine central nervous system cytokines, chemokines, and growth factors present in a chronic pain population and to explore patterns of the same mediator molecules over time. Secondary objectives explored the relationship of central and peripheral neuroimmune mediators while examining the levels of anxiety, depression, sleep quality, and perception of pain associated with the chronic pain patient experience. Methods: Cerebrospinal fluid (CSF) from a population of majority postlaminectomy syndrome patients (N = 8) was compared with control CSF samples (N = 30) to assess for significant differences in 10 cytokines, chemokines, and growth factors. The patient population was then followed over time, analyzing CSF, plasma, and psychobehavioral measures. Results: The present observational study is the first to demonstrate increased mean CSF levels of interleukin-8 (IL-8; P < 0.001) in a small population of majority postlaminectomy syndrome patients, as compared with a control population. Over time in pain patients, CSF levels of IL-8 increased significantly (P < 0.001). Conclusions: These data indicate that IL-8 should be further investigated and psychobehavioral components considered in the overall chronic pain paradigm. Future studies examining the interactions between these factors and IL-8 may identify novel targets for treatment of persistent pain states.