Anger, agency, risk and action: a neurobehavioral model with proof-of-concept in healthy young adults.

Introduction: Anger can engender action by individuals and groups. It is thus important to understand anger's behavioral phenotypes and their underlying neural substrates. Here, we introduce a construct we term agentic anger, a negatively valenced internal state that motivates action to achieve risky goals. We evaluate our neurobehavioral model via testable hypotheses in two proof-of-concept studies. Study 1 Methods: Study 1 used the Incentive Balloon Analogue Risk Task in a within-subjects, repeated measures design in 39 healthy volunteers to evaluate: (a) impact of blockade of reward on agentic anger, assessed by self-reports of negative activation (NA), (b) impact of achievement of reward on exuberance, assessed by self-reports of positive activation (PA), (c) the interrelationship of these valenced states, and (d) their relationship with personality. Study 1 Results: Task-induced NA was positively correlated with task-induced PA, risk-taking on the task and trait Social Potency (SP), a measure of trait agency and reward sensitivity on the Multidimensional Personality Questionnaire Brief-Form. Study 2 Methods: Study 2 assessed functional MRI response to stakes for risk-taking in healthy volunteers receiving 20 mg d-amphetamine in a double-blinded, placebo-controlled crossover design (N = 10 males), providing preliminary information on ventral striatal response to risky rewards during catecholamine activation. Study 2 Results: Trait SP and task-induced PA were strongly positively related to catecholamine-facilitated BOLD response in the right nucleus accumbens, a brain region where DA prediction error signal shapes action value and selection. Participants' task-induced NA was strongly positively related with trait SP and task-induced PA, replicating the findings of Study 1. Discussion: Together these results inform the phenomenology and neurobiology of agentic anger, which recruits incentive motivational circuitry and motivates personal action in response to goals that entail risk (defined as exposure to uncertainty, obstacles, potential harm, loss and/or financial, emotional, bodily, or moral peril). Neural mechanisms of agency, anger, exuberance, and risk-taking are discussed, with implications for personal and group action, decision-making, social justice, and behavior change.

A Randomized Controlled Pilot Trial Comparing Effects of Qigong and Exercise/Nutrition Training on Fatigue and Other Outcomes in Female Cancer Survivors.

Cancer-related fatigue (CRF) is a common and burdensome, often long-term side effect of cancer and its treatment. Many non-pharmacological treatments have been investigated as possible CRF therapies, including exercise, nutrition, health/psycho-education, and mind-body therapies. However, studies directly comparing the efficacy of these treatments in randomized controlled trials are lacking. To fill this gap, we conducted a parallel single blind randomized controlled pilot efficacy trial with women with CRF to directly compare the effects of Qigong (a form of mind-body intervention) (n = 11) to an intervention that combined strength and aerobic exercise, plant-based nutrition and health/psycho-education (n = 13) in a per protocol analysis. This design was chosen to determine the comparative efficacy of 2 non-pharmacologic interventions, with different physical demand intensities, in reducing the primary outcome measure of self-reported fatigue (FACIT "Additional Concerns" subscale). Both interventions showed a mean fatigue improvement of more than double the pre-established minimal clinically important difference of 3 (qigong: 7.068 ± 10.30, exercise/nutrition: 8.846 ± 12.001). Mixed effects ANOVA analysis of group × time interactions revealed a significant main effect of time, such that both groups significantly improved fatigue from pre- to post-treatment (F(1,22) = 11.898, P = .002, generalized eta squared effect size = 0.116) There was no significant difference between fatigue improvement between groups (independent samples t-test: P = .70 ), suggesting a potential equivalence or non-inferiority of interventions, which we could not definitively establish due to our small sample size. This study provides evidence from a small sample of n = 24 women with CRF that qigong improves fatigue similarly to exercise-nutrition courses. Qigong additionally significantly improved secondary measures of mood, emotion regulation, and stress, while exercise/nutrition significantly improved secondary measures of sleep/fatigue. These findings provide preliminary evidence for divergent mechanisms of fatigue improvement across interventions, with qigong providing a gentler and lower-intensity alternative to exercise/nutrition.

"Honorable Toward Your Whole Self": Experiences of the Body in Fatigued Breast Cancer Survivors.

INTRODUCTION: Cancer Related Fatigue (CRF) is one of the most common and detrimental side effects of cancer treatment. Despite its increasing prevalence and severity CRF remains dismissed by the majority of clinicians. One reason for the apparent gap between clinical need and clinical undertaking is the penchant toward reductionist accounts of the disorder: a tendency to discount the interface between the lived experience of sufferers and the multi-dimensional etiology of CRF as it manifests adversely on a day-to-day basis. METHODS: In order to better understand the interplay between social, bodily, and emotional components of the disorder we undertook semi-structured interviews with thirteen Breast Cancer survivors suffering from CRF, and then subsequently analyzed their responses using Team Based Qualitative Analysis. RESULTS: Our analysis revealed multiple dimensions of the social and bodily underpinnings of fatigue. Most relevantly we found a consistent change in the level and quality of attention to bodily signals. This shift in awareness appeared to be directly connected to the experience of CRF and a newfound, "respect," for the needs of the body. Furthermore, we found that many of the practices that were described as helpful in alleviating fatigue were oriented around eliciting a sense of embodied awareness, examples being: dance, yoga, and shamanic ritual. This relationship with bodily sensations existed in conjunction with the anxiety and trauma that arose as a result of cancer treatment. CONCLUSION: Our analysis suggests that the quality of awareness and relationship to bodily experience in CRF is a functionally relevant component of the disorder and should be considered as an experiential target moving forward.

Distinct Insular Functional Connectivity Changes Related to Mood and Fatigue Improvements in Major Depressive Disorder Following Tai Chi Training: A Pilot Study.

Objective: Tai chi (TC), a contemplative practice combining slow movements and deep breathing, has been shown to be clinically effective in alleviating depressive symptoms. Feelings of fatigue or low vitality often accompany major depressive disorder (MDD) though they are commonly overlooked and not well understood neurologically. By using resting state functional connectivity (rs-FC) using the insula as the seed, this study examines the relationship between mood and vitality symptoms in MDD and how they are impacted by TC training. Methods: Patients (N = 16) with MDD participated in a 10-week TC intervention. Self-report scores of vitality (using the SF-36 scale) and depressed mood (using the Beck Depression Inventory) as well as rs-fMRI were collected pre- and post-intervention. A seed-to-voxel approach was used to test whether changes in insular rs-FC were related to therapeutic improvement in MDD-related symptoms resulting from TC practice. Results: We found decreased self-reported depressed mood and increased vitality following the TC intervention. Furthermore, decreases in depressed mood were associated with increased rs-FC between the right anterior insula (AIC) and superior temporal gyrus and caudate (cluster-corrected p < 0.05). Increased vitality was associated with increased rs-FC between the right posterior insula (PIC) and regions associated with sensorimotor processes (cluster-corrected p < 0.05). Conclusion: These results provide support for differential changes in insula connectivity as neural correlates of symptom improvement in MDD.

Admission diagnoses among patients with heart failure: Variation by ACO performance on a measure of risk-standardized acute admission rates.

BACKGROUND: A key quality metric for Accountable Care Organizations (ACOs) is the rate of hospitalization among patients with heart failure (HF). Among this patient population, non-HF-related hospitalizations account for a substantial proportion of admissions. Understanding the types of admissions and the distribution of admission types across ACOs of varying performance may provide important insights for lowering admission rates. METHODS: We examined admission diagnoses among 220 Medicare Shared Savings Program ACOs in 2013. ACOs were stratified into quartiles by their performance on a measure of unplanned risk-standardized acute admission rates (RSAARs) among patients with HF. Using a previously validated algorithm, we categorized admissions by principal discharge diagnosis into: HF, cardiovascular/non-HF, and noncardiovascular. We compared the mean admission rates by admission type as well as the proportion of admission types across RSAAR quartiles (Q1-Q4). RESULTS: Among 220 ACOs caring for 227,356 patients with HF, the median (IQR) RSAARs per 100 person-years ranged from 64.5 (61.7-67.7) in Q1 (best performers) to 94.0 (90.1-99.9) in Q4 (worst performers). The mean admission rates by admission types for ACOs in Q1 compared with Q4 were as follows: HF admissions: 9.8 (2.2) vs 14.6 (2.8) per 100 person years (P < .0001); cardiovascular/non-HF admissions: 11.1 (1.6) vs 15.9 (2.6) per 100 person-years (P < .0001); and noncardiovascular admissions: 42.7 (5.4) vs 69.6 (11.3) per 100 person-years (P < .0001). The proportion of admission due to HF, cardiovascular/non-HF, and noncardiovascular conditions was 15.4%, 17.5%, and 67.1% in Q1 compared with 14.6%, 15.9%, and 69.4% in Q4 (P < .007). CONCLUSIONS: Although ACOs with the best performance on a measure of all-cause admission rates among people with HF tended to have fewer admissions for HF, cardiovascular/non-HF, and noncardiovascular conditions compared with ACOs with the worst performance (highest admission rates), the largest difference in admission rates were for noncardiovascular admission types. Across all ACOs, two-thirds of admissions of patients with HF were for noncardiovascular causes. These findings suggest that comprehensive approaches are needed to reduce the diverse admission types for which HF patients are at risk.

Age of Data at the Time of Publication of Contemporary Clinical Trials.

Importance: As medical knowledge and clinical practice rapidly evolve over time, there is an imperative to publish results of clinical trials in a timely way and reduce unnecessary delays. Objectives: To characterize the age of clinical trial data at the time of publication in journals with a high impact factor and highlight the time from final data collection to publication. Design and Setting: A cross-sectional analysis was conducted of all randomized clinical trials published from January 1 through December 31, 2015, in the Annals of Internal Medicine, BMJ, JAMA, JAMA Internal Medicine, Lancet, and New England Journal of Medicine. Multivariable linear regression analyses were conducted to assess whether data age (adjusted for follow-up duration) and publication time were associated with trial characteristics. Main Outcomes and Measures: The outcome measures were the midpoint of data collection until publication (data age), the time from first participant enrollment to last participant enrollment (enrollment time), and the time from final data collection to publication (publication time). Results: There were 341 clinical trials published in 2015 by the 6 journals. For assessment of the primary end point, 37 trials (10.9%) had a follow-up period of less than 1 month, 172 trials (50.4%) had a follow-up period of 1 month to 1 year, and 132 trials (38.7%) had a follow-up period of more than 1 year. For all trials, the median data age at publication was 33.9 months (interquartile range, 23.5-46.3 months). Among trials with a follow-up period of 1 month or less, the median data age was 30.6 months (interquartile range, 18.6-39.0 months). A total of 68 trials (19.9%) required more than 4 years to complete enrollment. The median time from the completion of data collection to publication was 14.8 months (interquartile range, 7.4-22.2 months); publication time was 2 or more years in 63 trials (18.5%). In multivariable regression analyses adjusted for follow-up time, inconclusive or unfavorable trial results were significantly associated with older data age (>235 days). Compared with trials funded only by private industry, trials funded by government were associated with a significantly longer time to publication (>180 days). Conclusions and Relevance: Clinical trials in journals with a high impact factor were published with a median data age of nearly 3 years. For a substantial proportion of studies, time for enrollment and time from completion of data collection to publication were quite long, indicating marked opportunities for improvement in clinical trials to reduce data age.

Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing.

Wnt/ß-catenin signal transduction directs intestinal stem cell (ISC) proliferation during homeostasis. Hyperactivation of Wnt signaling initiates colorectal cancer, which most frequently results from truncation of the tumor suppressor Adenomatous polyposis coli (APC). The ß-catenin-TCF transcription complex activates both the physiological expression of Wnt target genes in the normal intestinal epithelium and their aberrantly increased expression in colorectal tumors. Whether mechanistic differences in the Wnt transcription machinery drive these distinct levels of target gene activation in physiological versus pathological states remains uncertain, but is relevant for the design of new therapeutic strategies. Here, using a Drosophila model, we demonstrate that two evolutionarily conserved transcription cofactors, Earthbound (Ebd) and Erect wing (Ewg), are essential for all major consequences of Apc1 inactivation in the intestine: the hyperactivation of Wnt target gene expression, excess number of ISCs, and hyperplasia of the epithelium. In contrast, only Ebd, but not Ewg, mediates the Wnt-dependent regulation of ISC proliferation during homeostasis. Therefore, in the adult intestine, Ebd acts independently of Ewg in physiological Wnt signaling, but cooperates with Ewg to induce the hyperactivation of Wnt target gene expression following Apc1 loss. These findings have relevance for human tumorigenesis, as Jerky (JRK/JH8), the human Ebd homolog, promotes Wnt pathway hyperactivation and is overexpressed in colorectal, breast, and ovarian cancers. Together, our findings reveal distinct requirements for Ebd and Ewg in physiological Wnt pathway activation versus oncogenic Wnt pathway hyperactivation following Apc1 loss. Such differentially utilized transcription cofactors may offer new opportunities for the selective targeting of Wnt-driven cancers.

Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: HIV-infected patients have a high risk of myocardial infarction. We aimed to assess the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in this population. METHODS: In a randomised, double-blind, placebo-controlled trial, 40 HIV-infected participants with subclinical coronary atherosclerosis, evidence of arterial inflammation in the aorta by fluorodeoxyglucose (FDG)-PET, and LDL-cholesterol concentration of less than 3.37 mmol/L (130 mg/dL) were randomly assigned (1:1) to 1 year of treatment with atorvastatin or placebo. Randomisation was by the Massachusetts General Hospital (MGH) Clinical Research Pharmacy with a permuted-block algorithm, stratified by sex with a fixed block size of four. Study codes were available only to the MGH Research Pharmacy and not to study investigators or participants. The prespecified primary endpoint was arterial inflammation as assessed by FDG-PET of the aorta. Additional prespecified endpoints were non-calcified and calcified plaque measures and high risk plaque features assessed with coronary CT angiography and biochemical measures. Analysis was done by intention to treat with all available data and without imputation for missing data. The trial is registered with ClinicalTrials.gov, number NCT00965185. FINDINGS: The study was done from Nov 13, 2009, to Jan 13, 2014. 19 patients were assigned to atorvastatin and 21 to placebo. 37 (93%) of 40 participants completed the study, with equivalent discontinuation rates in both groups. Baseline characteristics were similar between groups. After 12 months, change in FDG-PET uptake of the most diseased segment of the aorta was not different between atorvastatin and placebo, but technically adequate results comparing longitudinal changes in identical regions could be assessed in only 21 patients (atorvastatin Δ -0.03, 95% CI -0.17 to 0.12, vs placebo Δ -0.06, -0.25 to 0.13; p=0.77). Change in plaque could be assessed in all 37 people completing the study. Atorvastatin reduced non-calcified coronary plaque volume relative to placebo: median change -19.4% (IQR -39.2 to 9.3) versus 20.4% (-7.1 to 94.4; p=0.009, n=37). The number of high-risk plaques was significantly reduced in the atorvastatin group compared with the placebo group: change in number of low attenuation plaques -0.2 (95% CI -0.6 to 0.2) versus 0.4 (0.0, 0.7; p=0.03; n=37); and change in number of positively remodelled plaques -0.2 (-0.4 to 0.1) versus 0.4 (-0.1 to 0.8; p=0.04; n=37). Direct LDL-cholesterol (-1.00 mmol/L, 95% CI -1.38 to 0.61 vs 0.30 mmol/L, 0.04 to 0.55, p<0.0001) and lipoprotein-associated phospholipase A2 (-52.2 ng/mL, 95% CI -70.4 to -34.0, vs -13.3 ng/mL, -32.8 to 6.2; p=0.005; n=37) decreased significantly with atorvastatin relative to placebo. Statin therapy was well tolerated, with a low incidence of clinical adverse events. INTERPRETATION: No significant effects of statin therapy on arterial inflammation of the aorta were seen as measured by FDG-PET. However, statin therapy reduced non-calcified plaque volume and high-risk coronary plaque features in HIV-infected patients. Further studies should assess whether reduction in high-risk coronary artery disease translates into effective prevention of cardiovascular events in this at-risk population. FUNDING: National Institutes of Health, Harvard Clinical and Translational Science Center, National Center for Research Resources.

High-density lipoprotein-mediated cholesterol efflux capacity is improved by treatment with antiretroviral therapy in acute human immunodeficiency virus infection.

BACKGROUND: Individuals infected with human immunodeficiency virus (HIV) have decreased high-density lipoprotein (HDL)-cholesterol and increased cardiovascular disease (CVD). Reverse cholesterol transport from macrophages may be inhibited by HIV and contribute to increased CVD. Human studies have not investigated longitudinal effects of HIV and antiretroviral therapy (ART) on cholesterol efflux. METHODS: Subjects with acute HIV infection were randomized to ART or not. Cholesterol efflux capacity was determined ex vivo after exposure of murine macrophages to apolipoprotein B-depleted patient sera obtained at baseline and after 12 weeks. RESULTS: After 12 weeks, HIV RNA decreased most in subjects randomized to ART. Available data on cholesterol demonstrated that efflux capacity from Abca1(+/+) macrophages was increased most by sera obtained from ART-treated subjects (20.5% ± 5.0% to 24.3 % ± 6.9%, baseline to 12 weeks, P = .007; ART group [n = 6] vs 18.0 % ± 3.9% to 19.1 % ± 2.9%, baseline to 12 weeks, P = .30; untreated group [n = 6] [P = .04 ART vs untreated group]). Change in HIV RNA was negatively associated with change in Abca1(+/+) macrophage cholesterol efflux (r = - 0.62, P = .03), and this finding remained significant (P = .03) after controlling for changes in HDL-cholesterol, CD4(+) cells, and markers of monocyte or macrophage activation. CONCLUSIONS: In subjects acutely infected with HIV, ATP-binding cassette transporter A1-mediated cholesterol efflux was stimulated to a greater degree over time by apolipoprotein B-depleted serum from subjects randomized to ART. The improvement in cholesterol efflux capacity is independently related to reduction in viral load.