Effects of highly active antiretroviral therapy initiation on epigenomic DNA methylation in persons living with HIV.

Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood. Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2-3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT). Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10-7) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis. Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.

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.

Alzheimer's disease-related biomarkers and cancer-related cognitive decline: the thinking and living with cancer study.

PURPOSE: We evaluated whether plasma Alzheimer's Disease (AD)-related biomarkers were associated with cancer-related cognitive decline (CRCD) among older breast cancer survivors. METHODS: We included survivors 60-90 years with primary stage 0-III breast cancers (n = 236) and frequency-matched non-cancer controls (n = 154) who passed a cognitive screen and had banked plasma specimens. Participants were assessed at baseline (pre-systemic therapy) and annually for up to 60-months. Cognition was measured using tests of attention, processing speed and executive function (APE) and learning and memory (LM); perceived cognition was measured by the FACT-Cog PCI. Baseline plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), beta-amyloid 42/40 (Aß42/40) and phosphorylated tau (p-tau181) were assayed using single molecule arrays. Mixed models tested associations between cognition and baseline AD-biomarkers, time, group (survivor vs control) and their two- and three-way interactions, controlling for age, race, WRAT4 Word Reading score, comorbidity and BMI; two-sided 0.05 p-values were considered statistically significant. RESULTS: There were no group differences in baseline AD-related biomarkers except survivors had higher baseline NfL levels than controls (p = .013). Survivors had lower adjusted longitudinal APE than controls starting from baseline and continuing over time (p = <0.002). However, baseline AD-related biomarker levels were not independently associated with adjusted cognition over time, except controls had lower APE scores with higher GFAP levels (p = .008). CONCLUSION: The results do not support a relationship between baseline AD-related biomarkers and CRCD. Further investigation is warranted to confirm the findings, test effects of longitudinal changes in AD-related biomarkers and examine other mechanisms and factors affecting cognition pre-systemic therapy.

Sex-Specific Pathways From Prenatal Maternal Inflammation to Adolescent Depressive Symptoms.

Importance: Prenatal maternal inflammation has been associated with major depressive disorder in offspring in adulthood as well as with internalizing and externalizing symptoms in childhood; however, the association between prenatal inflammation and offspring depression in adolescence has yet to be examined. Objective: To determine whether maternal levels of inflammatory biomarkers during pregnancy are associated with depressive symptomatology in adolescent-aged offspring and to examine how gestational timing, offspring sex, and childhood psychiatric symptoms impact these associations. Design, Setting, and Participants: This was an observational study of a population-based birth cohort from the Child Health and Development Studies (CHDS), which recruited almost all mothers receiving obstetric care from the Kaiser Foundation Health Plan (KFHP) in Alameda County, California, between June 1959 and September 1966. Pregnancy data and blood sera were collected from mothers, and offspring psychiatric symptom data were collected in childhood (ages 9-11 years) and adolescence (ages 15-17 years). Mother-offspring dyads with available maternal prenatal inflammatory biomarkers during first and/or second trimesters and offspring depressive symptom data at adolescent follow-up were included. Data analyses took place between March 2020 and June 2023. Exposures: Levels of inflammatory biomarkers (interleukin 6 [IL-6], IL-8, IL-1 receptor antagonist [IL-1RA], and soluble tumor necrosis factor receptor-II) assayed from maternal sera in the first and second trimesters of pregnancy. Main Outcomes and Measures: Self-reported depressive symptoms at adolescent follow-up. Results: A total of 674 mothers (mean [SD] age, 28.1 [5.9] years) and their offspring (350 male and 325 female) were included in this study. Higher second trimester IL-6 was significantly associated with greater depressive symptoms in offspring during adolescence (b, 0.57; SE, 0.26); P = .03). Moderated mediation analyses showed that childhood externalizing symptoms significantly mediated the association between first trimester IL-6 and adolescent depressive symptoms in male offspring (b, 0.18; 95% CI, 0.02-0.47), while childhood internalizing symptoms mediated the association between second trimester IL-1RA and adolescent depressive symptoms in female offspring (b, 0.80; 95% CI, 0.19-1.75). Conclusions and Relevance: In this study, prenatal maternal inflammation was associated with depressive symptoms in adolescent-aged offspring. The findings of the study suggest that pathways to adolescent depressive symptomatology from prenatal risk factors may differ based on both the timing of exposure to prenatal inflammation and offspring sex.

Quality assurance standards and their use in the preparation of parenteral systemic anticancer therapy products in healthcare establishments: a scoping review.

OBJECTIVES: The use of parenteral systemic anticancer therapy (SACT) has led to improved cancer survival. A quality assurance (QA) system of the aseptic compounding process is necessary to ensure safe and consistent production of parenteral SACT. This scoping review identifies international evidence and practice relating to QA standards in the preparation of parenteral SACT in healthcare establishments. METHODS: Standards relating to aseptic compounding in hospital pharmacies and literature exploring the aseptic compounding of parenteral SACT were included. Literature relating to the non-aseptic compounding of medicines and records specific to sterile manufacturing in industrial settings were excluded. A search of several electronic databases, trial registries, the grey literature and websites of key European hospital pharmacy groups and accreditation bodies was conducted on 16 March 2022. A narrative discussion was performed by country, and content analysis of articles was conducted. RESULTS: Thirty-seven records were included. Standards reviewed covered the work environment, the preparation process and the safety of the workers who are potentially exposed to hazardous chemicals. It was a common practice to include frequent audits to ensure adherence to standards. Some standards also recommended external inspections to allow for further learnings. Periodic reviews are encouraged to ensure standards maintain relevance. National standards of the countries reviewed were based on international standards, with minor adaptations for local conditions. CONCLUSIONS: The main limitation of this review is that it is limited to countries with a high human development index. The review shows that the use of an internationally recognised standard as a basis for national standards is best practice, and will allow for relevance into the future.

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.

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.

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.

Genetic Variants Associated with Longitudinal Cognitive Performance in Older Breast Cancer Patients and Controls.

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.

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 ).

Remission of insomnia in older adults treated with cognitive behavioral therapy for insomnia (CBT-I) reduces p16INK4a gene expression in peripheral blood: secondary outcome analysis from a randomized clinical trial.

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.

Plasma and cerebrospinal fluid inflammatory markers and human aggression.

A growing body of work suggests that individuals with aggressive behavior and/or aggressive tendencies have evidence of chronic, low level, inflammation as manifested by elevated circulating levels of acute phase reactant proteins and pro-inflammatory cytokines. While animal studies report that direct application of pro-inflammatory proteins in brain increase aggressive behavior, there is no data on the relationship of central levels of these proteins and aggression in human subjects. We simultaneously measured levels of both plasma and lumbar cerebrospinal fluid (CSF) C-Reactive Protein (CRP) and IL-6, IL-8, and TNF-α in 77 medically healthy, drug-free, individuals with varying degrees of aggression including 22 individuals with DSM-5 Intermittent Explosive Disorder (IED). Aggression was assessed using the Life History of Aggression (LHA) and the Buss-Perry Aggression Questionnaire (BPAQ). Plasma and CSF levels of CRP, IL-8, and TNF-α, but not IL-6, correlated significantly with each other. Aggressive individuals with IED displayed elevated plasma, but not CSF, levels of proinflammatory markers and this relationship was specific to IED. Similarly, composite aggression scores correlated significantly with plasma, but not CSF, pro-inflammatory markers. Aggressive behavior in humans is correlated with Plasma, but not CSF, proinflammatory markers despite the observation that these two sets of markers are significantly correlated. Since the direct application of proinflammatory proteins in brains of animals increase aggressive behavior, proinflammatory proteins likely influence brain-based behavior in a manner not reflected in lumbar CSF.

Associations between psychosocial factors and circulating cytokines in breast cancer survivors.

OBJECTIVE: Research has established links between social isolation and heightened levels of proinflammatory cytokines (e.g., interleukin-6 [IL-6], tumour 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.

Elevated C-Reactive Protein and Subsequent Patient-Reported Cognitive Problems in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study.

PURPOSE: To examine longitudinal relationships between levels of C-reactive protein (CRP) and cognition in older breast cancer survivors and noncancer controls. METHODS: English-speaking women age ≥ 60 years, newly diagnosed with primary breast cancer (stage 0-III), and frequency-matched controls were enrolled from September 2010 to March 2020; women with dementia, neurologic disorders, and other cancers were excluded. Assessments occurred presystemic therapy/enrollment and at annual visits up to 60 months. Cognition was measured using the Functional Assessment of Cancer Therapy-Cognitive Function and neuropsychological testing. Mixed linear effect models tested for survivor-control differences in natural log (ln)-transformed CRP at each visit. Random effect-lagged fluctuation models tested directional effects of ln-CRP on subsequent cognition. All models controlled for age, race, study site, cognitive reserve, obesity, and comorbidities; secondary analyses evaluated if depression or anxiety affected results. RESULTS: There were 400 survivors and 329 controls with CRP specimens and follow-up data (average age of 67.7 years; range, 60-90 years). The majority of survivors had stage I (60.9%), estrogen receptor-positive (87.6%) tumors. Survivors had significantly higher adjusted mean ln-CRP than controls at baseline and 12-, 24-, and 60-month visits (all P < .05). Higher adjusted ln-CRP predicted lower participant-reported cognition on subsequent visits among survivors, but not controls (P interaction = .008); effects were unchanged by depression or anxiety. Overall, survivors had adjusted Functional Assessment of Cancer Therapy-Cognitive Function scores that were 9.5 and 14.2 points lower than controls at CRP levels of 3.0 and 10.0 mg/L. Survivors had poorer neuropsychological test performance (v controls), with significant interactions with CRP only for the Trails B test. CONCLUSION: Longitudinal relationships between CRP and cognition in older breast cancer survivors suggest that chronic inflammation may play a role in development of cognitive problems. CRP testing could be clinically useful in survivorship care.

Longitudinal Changes in Immune Activation Serum Biomarkers Prior to Diagnosis and Risk of B-cell NHL Subtypes.

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 (IL1ß, 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.

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.