Association of psychological well-being with gene expression: Generalization Study.

<p>¹. Partial regression coefficients relating centered log₂ gene expression values to standardized scores on 1- or 6-d representations of psychological well-being. All associations are adjusted for age, sex, race, BMI, smoking, alcohol consumption, and gene transcript covariates marking major leukocyte subsets.</p><p>². Variance Inflation Factor. Values > 10 indicate significant multicollinearity.</p><p>Association of psychological well-being with gene expression: Generalization Study.</p

Psychological Well-Being and the Human Conserved Transcriptional Response to Adversity

<div><p>Research in human social genomics has identified a conserved transcriptional response to adversity (CTRA) characterized by up-regulated expression of pro-inflammatory genes and down-regulated expression of Type I interferon- and antibody-related genes. This report seeks to identify the specific aspects of positive psychological well-being that oppose such effects and predict reduced CTRA gene expression. In a new confirmation study of 122 healthy adults that replicated the approach of a previously reported discovery study, mixed effect linear model analyses identified a significant inverse association between expression of CTRA indicator genes and a summary measure of eudaimonic well-being from the Mental Health Continuum – Short Form. Analyses of a 2- representation of eudaimonia converged in finding correlated psychological and social subdomains of eudaimonic well-being to be the primary carriers of CTRA associations. Hedonic well-being showed no consistent CTRA association independent of eudaimonic well-being, and summary measures integrating hedonic and eudaimonic well-being showed less stable CTRA associations than did focal measures of eudaimonia (psychological and social well-being). Similar results emerged from analyses of pooled discovery and confirmation samples (n = 198). Similar results also emerged from analyses of a second new generalization study of 107 healthy adults that included the more detailed Ryff Scales of Psychological Well-being and found this more robust measure of eudaimonic well-being to also associate with reduced CTRA gene expression. Five of the 6 major sub-domains of psychological well-being predicted reduced CTRA gene expression when analyzed separately, and 3 remained distinctively prognostic in mutually adjusted analyses. All associations were independent of demographic characteristics, health-related confounders, and RNA indicators of leukocyte subset distribution. These results identify specific sub-dimensions of eudaimonic well-being as promising targets for future interventions to mitigate CTRA gene expression, and provide no support for any independent favorable contribution from hedonic well-being.</p></div

Well-being and CTRA gene expression.

<p>(A) Relationship between MHC-SF hedonic and eudaimonic well-being domain scores (2-d representation). (B) Relationship between psychological well-being and social well-being scores (the 2-d eudaimonic domain within the 3-d well-being representation). (C) Point estimates of average association coefficients relating range-spanning variations in hedonic and eudaimonic well-being scores [-2 SD, +2 SD] to unstandardized (log₂ metric) gene expression values for 52 CTRA indicator genes (reverse scoring 34 inverse components) in the discovery study (n = 76) and confirmation study (n = 122). Log₂ association coefficients are transformed to % difference in average CTRA transcript abundance to facilitate interpretation.</p

Association of well-being with gene expression: pooled Discovery and Confirmation Studies.

<p>¹. Partial regression coefficients relating standardized gene expression values to standardized scores on 1-, 2-, and 3-d representations of well-being (A, B, C) or a categorical representation of flourishing mental health (D). All associations are adjusted for age, sex, race, BMI, smoking, alcohol consumption, illness symptoms, and gene transcript covariates marking major leukocyte subsets.</p><p>². Variance Inflation Factor. Values > 10 indicate significant multicollinearity.</p><p>Association of well-being with gene expression: pooled Discovery and Confirmation Studies.</p

Generalization Study Sample Characteristics.

<p>¹. Simple (unadjusted) association with psychological well-being: <i>r</i> point estimate or ANOVA effect size <i>r</i> (<i>p</i>-value).</p><p>². Ryff-PWB item responses range from 1 = Strongly disagree to 6 = Strongly agree, yielding 9-item scale scores ranging from 9–54.</p><p>Generalization Study Sample Characteristics.</p

Confirmation Study Sample Characteristics.

<p>¹. Simple (unadjusted) association with well-being: <i>r</i> point estimate or ANOVA effect size <i>r</i> (<i>p</i>-value).</p><p>². Flourishing: ≥ 1 of 3 hedonic well-being signs and ≥ 6 of 11 eudaimonic well-being signs experienced “5–6 times a week” or “every day”.</p><p>³. Frequency of 13 minor illness symptoms over the past 2 weeks, scaled from 0 = not at all to 8 = very frequently.</p><p>⁴. CES-D</p><p>⁵. MHC-SF well-being scores scale from 0 = “never” to 5 = “every day”</p><p>Confirmation Study Sample Characteristics.</p

Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn\u27s Disease: A Pragmatic Randomized Trial

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn\u27s disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn\u27s disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn\u27s disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965