Dopamine and Norepinephrine Differentially Mediate the Exploration-exploitation Tradeoff.

Dopamine (DA) and norepinephrine (NE) have been repeatedly implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision making processes. Although two neuromodulators share a synthesis pathway and are co-activated under states of arousal, they engage in distinct circuits and modulatory roles. However, the specific role of each neuromodulator in decision making, in particular the exploration-exploitation tradeoff, remains unclear. Revealing how each neuromodulator contributes to exploration-exploitation tradeoff is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of these two catecholamine systems in regulating exploration, a direct comparison using the same dynamic decision making task is needed. Here, we ran male and female mice in a restless two-armed bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol), and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine on exploration. Increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulatory effect of beta-noradrenergic receptor activity on exploration was mediated by sex. Reinforcement learning model parameters suggested that dopamine modulation affected exploration via decision noise and norepinephrine modulation affected exploration via sensitivity to outcome. Together, these findings suggested that the mechanisms that govern the exploration-exploitation transition are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration.Significance Statement Both dopamine (DA) and norepinephrine (NE) have been implicated in the decision making process. Although these two catecholamines have shared aspects of their biosynthetic pathways and projection targets, they are thought to exert many core functions via distinct neural targets and receptor subtypes. However, the computational neuroscience literature often ascribes similar roles to these catecholamines, despite the above evidence. Resolving this discrepancy is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. This study examines the role of dopamine and norepinephrine on the explore-exploit tradeoff. By testing mice, we were able to compare multiple pharmacological agents within subjects, and examine sources of individual differences, allowing direct comparison between the effects of these two catecholamines in modulating decision making.

Dose Reduction of Edoxaban in Patients 80 Years and Older With Atrial Fibrillation: Post Hoc Analysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial.

Importance: In older patients with atrial fibrillation who take anticoagulants for stroke prevention, bleeding is increased compared with younger patients, thus, clinicians frequently prescribe lower than recommended doses in older patients despite limited randomized data. Objective: To evaluate ischemic and bleeding outcomes in patients 80 years and older with atrial fibrillation receiving edoxaban, 60 mg vs 30 mg, and edoxaban, 30 mg vs warfarin. Design, Setting, and Participants: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a parallel-design, double-blind, global clinical trial that randomized patients with atrial fibrillation to either one of 2 edoxaban dosing regimens or warfarin. This secondary analysis focused on patients 80 years or older without dose-reduction criteria receiving edoxaban, 60 mg vs 30 mg, as well as patients with or without dose-reduction criteria receiving edoxaban, 30 mg, vs warfarin. Study data were analyzed between October 2022 and December 2023. Interventions: Oral edoxaban, 30 mg once daily; edoxaban, 60 mg once daily; or warfarin. Main Outcomes and Measures: Primary net clinical outcome of death, stroke or systemic embolism, and major bleeding and each individual component. Results: The current analysis included 2966 patients 80 years and older (mean [SD] age, 83 [2.7] years; 1671 male [56%]). Among 1138 patients 80 years and older without dose-reduction criteria, those receiving edoxaban, 60 mg vs 30 mg, had more major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03), particularly gastrointestinal hemorrhage (HR, 2.24; 95% CI, 1.29-3.90; P = .004), with no significant difference in efficacy end points. Findings were supported by analyses of endogenous factor Xa inhibition, a marker of anticoagulant effect, which was comparable between younger patients receiving edoxaban, 60 mg, and older patients receiving edoxaban, 30 mg. In 2406 patients 80 years and older with or without dose-reduction criteria, patients receiving edoxaban, 30 mg, vs warfarin had lower rates of the primary net clinical outcome (HR, 0.78; 95% CI, 0.68-0.91; P = .001), major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001), and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046), whereas rates of stroke or systemic embolism were comparable. Conclusions and Relevance: In this post hoc analysis of the ENGAGE AF-TIMI 48 randomized clinical trial, in patients 80 years and older with atrial fibrillation, major bleeding events were lower in patients randomized to receive edoxaban, 30 mg per day, compared with either edoxaban, 60 mg per day (in patients without dose-reduction criteria), or warfarin (irrespective of dose-reduction status), without an offsetting increase in ischemic events. These data support the concept that lower-dose anticoagulants, such as edoxaban, 30 mg, may be considered in older patients with atrial fibrillation even in the absence of dose-reduction criteria. Trial Registration: ClinicalTrials.gov Identifier: NCT00781391.

Periprocedural Edoxaban Management and Clinical Outcomes in Patients Undergoing Transcatheter Cardiovascular Procedures in the EMIT-AF/VTE Program.

Clinical trial registration number: NCT02950168, NCT02951039.

Personalized Cognitive Health in Psychiatry: Current State and the Promise of Computational Methods.

BACKGROUND: Decades of research have firmly established that cognitive health and cognitive treatment services are a key need for people living with psychosis. However, many current clinical programs do not address this need, despite the essential role that an individual's cognitive and social cognitive capacities play in determining their real-world functioning. Preliminary practice-based research in the Early Psychosis Intervention Network early psychosis intervention network shows that it is possible to develop and implement tools that delineate an individuals' cognitive health profile and that help engage the client and the clinician in shared decision-making and treatment planning that includes cognitive treatments. These findings signify a promising shift toward personalized cognitive health. STUDY DESIGN: Extending upon this early progress, we review the concept of interindividual variability in cognitive domains/processes in psychosis as the basis for offering personalized treatment plans. We present evidence from studies that have used traditional neuropsychological measures as well as findings from emerging computational studies that leverage trial-by-trial behavior data to illuminate the different latent strategies that individuals employ. STUDY RESULT: We posit that these computational techniques, when combined with traditional cognitive assessments, can enrich our understanding of individual differences in treatment needs, which in turn can guide evermore personalized interventions. CONCLUSION: As we find clinically relevant ways to decompose maladaptive behaviors into separate latent cognitive elements captured by model parameters, the ultimate goal is to develop and implement approaches that empower clients and their clinical providers to leverage individual's existing learning capacities to improve their cognitive health and well-being.

Sex mechanisms as nonbinary influences on cognitive diversity.

Essentially all neuropsychiatric diagnoses show some degree of sex and/or gender differences in their etiology, diagnosis, or prognosis. As a result, the roles of sex-related variables in behavior and cognition are of strong interest to many, with several lines of research showing effects on executive functions and value-based decision making in particular. These findings are often framed within a sex binary, with behavior of females described as less optimal than male "defaults"-- a framing that pits males and females against each other and deemphasizes the enormous overlap in fundamental neural mechanisms across sexes. Here, we propose an alternative framework in which sex-related factors encompass just one subset of many sources of valuable diversity in cognition. First, we review literature establishing multidimensional, nonbinary impacts of factors related to sex chromosomes and endocrine mechanisms on cognition, focusing on value- based decision-making tasks. Next, we present two suggestions for nonbinary interpretations and analyses of sex-related data that can be implemented by behavioral neuroscientists without devoting laboratory resources to delving into mechanisms underlying sex differences. We recommend (1) shifting interpretations of behavior away from performance metrics and towards strategy assessments to avoid the fallacy that the performance of one sex is worse than another; and (2) asking how much variance sex explains in measures and whether any differences are mosaic rather than binary, to avoid assuming that sex differences in separate measures are inextricably correlated. Nonbinary frameworks in research on cognition will allow neuroscience to represent the full spectrum of brains and behaviors.

Edoxaban for stroke prevention in atrial fibrillation and factors associated with dosing: patient characteristics from the prospective observational ETNA-AF-China registry.

Real-world data on effectiveness and safety of a single non-vitamin K antagonist oral anticoagulant in the Chinese population with atrial fibrillation (AF) are limited. This study reports characteristics of patients treated with edoxaban and factors associated with dosing patterns from routine care in China. ETNA-AF-China (NCT04747496) is a multicentre, prospective, observational study enrolling edoxaban-treated patients from four economic regions with a targeted 2-year follow-up. Of the 4930 patients with AF (mean age: 70.2 ± 9.5 years; male, 57.1%), the mean creatinine clearance (CrCl), CHA2DS2-VASc, and HAS-BLED scores were 71.2 mL/min, 2.9, and 1.6. Overall, 6.4% of patients were perceived as frail by investigators. Available label dose reduction criteria (N = 4232) revealed that 3278 (77.5%) patients received recommended doses and 954 (22.5%) non-recommended doses. Northeast (53.0%) and West (43.1%) regions had the highest prescriptions of 60 mg and 30 mg recommended doses, respectively. Non-recommended 30 mg doses were more frequently prescribed in patients with antiplatelet use and history of heart failure than recommended 60 mg. Multivariate analysis identified advanced age as the strongest associated factor with non-recommended doses. Frailty had the strongest association with 30 mg except for age, and history of TIA was the most relevant factor associated with 60 mg. In conclusion, patients in the ETNA-AF-China study were predominantly aged 65 years and older, had mild-to-moderate renal impairment and good label adherence. Advanced age was associated with non-recommended doses, with frailty most common for non-recommended 30 mg and a history of TIA for the non-recommended 60 mg dose.

Change in Weight Status Among Children Who Do and Do Not Participate in Intensive Health Behavior and Lifestyle Treatment for Obesity.

Background: Primary care providers (PCPs) are expected to provide weight management counseling despite having low confidence in their ability to be effective. This analysis examined change in weight status between children who received usual care from their PCP and those who received one of two structured weight management programs in a randomized control trial. Methods: Data from parent-child dyads who were referred to the Guided Self-Help Obesity Treatment in the Doctor's Office study, but did not participate, were examined to determine change in weight status compared with those who participated in the trial. Families were divided into four groups: Group 1, structured treatment with high attendance; Group 2, structured treatment with low attendance; Group 3, PCP/usual care with some weight management counseling; and Group 4, PCP/usual care with no counseling. Anthropometric data and PCP delivery of weight management counseling were abstracted from the electronic health record. Main outcomes were changes in child BMI z-scores, BMI as a percentage relative to the 95th percentile, and BMI as a difference relative to the 95th percentile at the end of treatment and 6-month follow-up for each group. Results: Groups 1 and 2 showed significant decreases in weight status over time, with Group 1 showing the greatest decrease. Groups 3 and 4 remained relatively stable. Changes in weight status in Groups 2, 3, and 4 were significantly different from Group 1 at post-treatment. Conclusions: While structured weight management programs have a significant impact on weight status, those who received some counseling by their PCP did not show significant increases in weight status and were relatively weight stable. Efforts should be broadened to support PCPs as they provide weight management counseling in the office.

Management of edoxaban therapy and clinical outcomes in patients undergoing major or nonmajor surgery: a subanalysis of the EMIT-AF/VTE study.

BACKGROUND: Optimising periprocedural management of direct oral anticoagulation in patients with atrial fibrillation on chronic treatment undergoing major surgeries is an important aspect of balancing the risk of surgery-related bleeding with the risk of thromboembolic events, which may vary by surgery type. METHODS: This subanalysis of the prospective EMIT-AF/VTE programme assessed periprocedural-edoxaban management, according to physicians' decisions, and bleeding and thromboembolic event rates in patients who underwent major vs. nonmajor surgeries. Edoxaban interruption and clinical outcomes were compared between major vs. nonmajor surgeries and between renal function subgroups (creatinine clearance [CrCL] ≤ 50 mL/min vs. > 50 mL/min). RESULTS: We included 276 major and 512 nonmajor surgeries. The median pre- and postprocedural duration of edoxaban interruption in major vs. nonmajor surgeries was 4 vs. 1 days, whereas median duration of interruption for those with preprocedural-only and postprocedural-only interruption was 2 vs. 1 days and 2 vs. 0 days, respectively (P < 0.0001). Rates of all bleeding and clinically relevant nonmajor bleeding were numerically higher in major vs. nonmajor surgeries. Event rates (number of events per 100 surgeries) were low overall (< 6 events per 100 surgeries), independent of renal function subgroups. CONCLUSION: In this subanalysis of the EMIT-AF/VTE programme, periprocedural-edoxaban interruption was significantly longer in patients undergoing major vs. nonmajor surgery. This clinician-driven approach was associated with low rates of bleeding and thromboembolic events following both major and nonmajor surgeries. TRIAL REGISTRATION: NCT02950168, registered October 31, 2016; NCT02951039, registered November 1, 2016.

Investigation of the human metabolism and disposition of the prolyl hydrolase inhibitor daprodustat using IV microtracer with Entero-Test bile string.

Daprodustat is an oral small molecule hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI) approved in Japan and the United States for the treatment of anemia associated with chronic kidney disease. This phase 1, nonrandomized, 2-period, crossover study in 6 healthy men characterized and quantified the metabolites generated after a microtracer IV infusion of 50 µg (125 nCi) [14 C]-daprodustat administered concomitantly with a nonradiolabeled therapeutic dose of a 6-mg daprodustat tablet, followed by a single oral solution dose of 25 mg (62.5 µCi) [14 C]-daprodustat. High-performance liquid chromatography (HPLC) coupled with radioactivity detection (TopCount or AMS) and HPLC-tandem mass spectrometry (HPLC-MSn ) were used for quantitative measurement and structural identification of radioactive metabolites in plasma, urine, feces, and bile. Following oral administration of [14 C]-daprodustat, unchanged daprodustat was the principal circulating drug-related component, accounting for 40% of plasma radioactivity. Predominant oxidative metabolites M2, M3, M4, and M13 individually represented 6-8% of the plasma radioactivity and together accounted for the majority of radioactivity in urine and feces (53% in both matrices; 12% and 41% of dose, respectively). Unchanged daprodustat was not detected in urine and was only 0.7% of total radioactivity in feces (<0.5% of dose), with the remainder of the dose accounted for by oxidative metabolites. The radio-metabolic profile of duodenal bile following IV infusion of [14 C]-daprodustat was similar to that observed in feces after oral administration. The data suggested that oral daprodustat was extensively absorbed, cleared exclusively by oxidative metabolism, and eliminated via hepatobiliary (primary) and urinary (secondary) excretion.

Treatment Satisfaction and Convenience for Patients With Atrial Fibrillation on Edoxaban or Vitamin K Antagonists After Transcatheter Aortic Valve Replacement: A Post Hoc Analysis from the ENVISAGE-TAVI AF Trial.

ENVISAGE-TAVI AF (Edoxaban versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation-Atrial Fibrillation; NCT02943785) was a prospective, randomized, open-label trial comparing non-vitamin K oral anticoagulant (NOAC) edoxaban with vitamin K antagonists (VKAs) in patients with atrial fibrillation after successful transcatheter aortic valve replacement (TAVR). The effect of edoxaban- or VKA-based therapy on patient-reported outcomes remains unknown, as most studies focus on efficacy and safety. Pre-TAVR patient-reported expectations and post-TAVR Treatment Satisfaction and Convenience with edoxaban or VKA treatment (at months 3 and 12) were analyzed using the Perception of Anticoagulation Treatment Questionnaire (PACT-Q). This analysis included randomized and dosed patients with an evaluable PACT-Q1 assessment at baseline and ≥1 postbaseline assessment (PACT-Q2). Subanalyses included patients stratified by pre-TAVR anticoagulant (NOAC, VKA, no NOAC/VKA). Edoxaban- (n = 585) and VKA-treated (n = 522) patients had similar baseline characteristics and treatment expectations. Pre-TAVR anticoagulant use did not affect treatment expectations. After TAVR, edoxaban-treated patients had significantly higher Treatment Satisfaction and Convenience scores compared with VKA-treated patients at all time points (p <0.001 for all). Among edoxaban-treated patients, those who received VKAs pre-TAVR were significantly more satisfied with treatment than those who received NOACs (p <0.001) or no NOACs/VKAs (p = 0.003); however, there was no significant difference in the perception of convenience (p = 0.927 and p = 0.092, respectively). Conversely, among VKA-treated patients, the type of anticoagulant used pre-TAVR did not affect Treatment Satisfaction or Convenience scores post-TAVR. In conclusion, patients with atrial fibrillation who received edoxaban post-TAVR reported significantly higher Treatment Satisfaction and Convenience scores compared with those who received VKAs, resulting in a clinically meaningful difference between treatment groups.

Predictors of All-Cause Mortality After Successful Transcatheter Aortic Valve Implantation in Patients With Atrial Fibrillation.

Prevalent and incident atrial fibrillation are common in patients who undergo transcatheter aortic valve implantation and are associated with impaired postprocedural outcomes, including mortality. We determined predictors of long-term mortality in patients with atrial fibrillation after successful transcatheter aortic valve implantation. The EdoxabaN Versus standard of care and theIr effectS on clinical outcomes in pAtients havinG undergonE Transcatheter Aortic Valve Implantation-Atrial Fibrillation (ENVISAGE-TAVI AF) trial (NCT02943785) was a multicenter, prospective, randomized controlled trial in patients with prevalent or incident atrial fibrillation after successful transcatheter aortic valve implantation who received edoxaban or vitamin K antagonists. A Cox proportional hazard model was performed to identify predictors of all-cause mortality using a stepwise approach for multiple regression analysis. In addition, we assessed the performance of different risk scores and prediction models using ENVISAGE-TAVI AF data. Of 1,426 patients in ENVISAGE-TAVI AF, 178 (12.5%) died during the follow-up period (median 548 days). Our stepwise approach identified greater risk of mortality with older age, impaired renal function, nonparoxysmal atrial fibrillation, excessive alcohol use, New York Heart Association heart failure class III/IV, peripheral artery disease, and history of major bleeding or predisposition to bleeding. The present model (concordance statistic [c-statistic] 0.67) was a better discriminator than were other frequently used risk scores, such as the Society of Thoracic Surgeons score (c-statistic 0.56); Congestive heart failure, Hypertension, Age ≥75, Diabetes, Stroke, Vascular disease, Age 65 to 74 years, and Sex category (CHA2DS2-VASc) score (c-statistic 0.54); or Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, and Drugs/alcohol concomitantly (HAS-BLED) score (c-statistic 0.58). In ENVISAGE-TAVI AF, several modifiable and nonmodifiable clinical characteristics were significantly associated with greater long-term all-cause mortality. Improved risk stratification to estimate the probability of mortality after successful transcatheter aortic valve implantation in patients with atrial fibrillation may improve long-term patient prognosis.

Predictive Factors and Clinical Events Associated with Edoxaban Interruption and Heparin Bridging Strategy: EMIT-AF/VTE.

Patients treated with edoxaban may require diagnostic and therapeutic procedures that involve edoxaban interruption. Although heparin bridging strategies are not recommended, heparin is frequently used in clinical practice. However, whether heparin use decreases thromboembolic risk remains unclear, and the potential for increased periprocedural bleeding remains a concern. Here, we report factors predicting edoxaban interruption and the use of heparin bridging strategies and associated clinical events from Global EMIT-AF/VTE, a multicenter, prospective, noninterventional study (Clinicaltrials.gov NCT02950168). Eligible patients are adults with atrial fibrillation or venous thromboembolism treated with edoxaban who underwent a diagnostic or therapeutic procedure. Edoxaban interruption, heparin bridging strategies, and clinical event data were collected from 5 days before procedure through 29 days afterwards. Edoxaban was interrupted in 1222/2089 procedures (58.5%); a heparin bridging strategy was used during 178 (14.6%) of these interruptions. Patients who received periprocedural heparin had higher baseline HAS-BLED (2.4±1.0 vs 1.9±1.1, P <0.0001) scores and similar CHA2DS2-VASc (3.6±1.6 vs 3.4±1.6, P = 0.09) scores versus patients who did not. HAS-BLED score >3 and high EHRA procedural risk predicted both edoxaban interruption and the use of a heparin bridging strategy, whereas CHA2DS2-VASc scores did not predict either. Bleeding and ischemic event rates were low; the all-bleeding rate was higher with the use of a heparin bridging strategy versus without (6.2% vs 3.1%, P = 0.04). Periprocedural heparin use was associated with higher bleeding rates, but not with lower thromboembolic risk. Individual patient and procedural bleeding risks appear to contribute more than stroke risk to clinicians' consideration of a heparin bridging strategy.

Edoxaban use in the context of dental procedures: analysis from the EMIT-AF/VTE database.

INTRODUCTION: Literature reviews support continuing anticoagulation during dental procedures. However, studies often present grouped anticoagulation data, and information on individual anticoagulant management would be helpful to dentists. The Edoxaban Management in Diagnostic and Therapeutic Procedures (EMIT-AF/VTE) programme (NCT02950168; NCT02951039) demonstrated low periprocedural bleeding and thrombotic event rates in patients with atrial fibrillation receiving edoxaban. AIMS: To report periprocedural edoxaban interruption and clinical events in patients from EMIT-AF/VTE who underwent dental procedures. METHODS: Dental procedures were categorised by type (cleaning/noncleaning). Edoxaban interruption, bleeding events, and thrombotic events were observed 5 days preprocedure through 29 days postprocedure. RESULTS: Overall, 196 patients underwent 350 cleaning and/or noncleaning procedures; most patients (171/196 [87.2%]) underwent noncleaning procedures (282/350 [80.6%]), whereas 48/196 (24.5%) underwent 68/350 (19.4%) cleaning procedures. Edoxaban was uninterrupted for most cleanings (53/68 [77.9%]). Preprocedural interruption was common for single and multiple tooth extractions (single, 67/100 [67.0%]; multiple, 16/30 [53.3%]). The only major bleeding occurred after an unrelated cleaning. Minor bleeding occurred in 1/68 (1.5%) cleaning and 4/282 (1.4%) noncleaning procedures. There were no thrombotic events. CONCLUSIONS: For most cleanings, edoxaban was not interrupted, whereas preprocedural interruption was more common for tooth extractions. Overall, bleeding rates were low, and no thrombotic events occurred.

Neutrophil-lymphocyte ratio and clinical outcomes in 19,697 patients with atrial fibrillation: Analyses from ENGAGE AF- TIMI 48 trial.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is the ratio between neutrophil and lymphocyte counts measured in peripheral blood. NLR is easily calculable based on a routine blood test available worldwide and may reflect systemic inflammation. However, the relationship between NLR and clinical outcomes in atrial fibrillation (AF) patients is not well-described. METHODS: We calculated NLR at baseline in ENGAGE AF-TIMI 48, a randomized trial comparing edoxaban versus warfarin in patients with AF followed for 2.8 years (median). The association of baseline NLR with major bleeding events, major adverse cardiac events (MACE), cardiovascular death, stroke/systemic embolism, and all-cause mortality were calculated. RESULTS: The median baseline NLR in 19,697 patients was 2.53 (interquartile range 1.89-3.41). NLR was associated with major bleeding events (HR 1.60; 95% CI 1.41-1.80), stroke/systemic embolism (HR 1.25; 95% CI, 1.09-1.44), MI (HR 1.73; 95% CI 1.41-2.12), MACE (HR 1.70; 95% CI 1.56-1.84), CV (HR 1.93; 95% CI 1.74-2.13) and all-cause mortality (HR 2.00; 95% CI 1.83-2.18). The relationships between NLR and outcomes remained significant after adjustment for risk factors. Edoxaban consistently reduced major bleeding. MACE, and CV death across NLR groups vs. warfarin. CONCLUSIONS: NLR represents a widely available, simple, arithmetic calculation that could be immediately and automatically reported during a white blood cell differential measurement to identify patients with AF at increased risk of bleeding, CV events, and mortality.

Risks of Heart Failure, Stroke, and Bleeding in Atrial Fibrillation According to Heart Failure Phenotypes.

BACKGROUND: The risks of heart failure (HF) events compared with stroke/systemic embolic events (SEE) or major bleeding (MB) in heart failure with reduced ejection fraction (HFrEF) vs heart failure with preserved ejection fraction (HFpEF) in a large atrial fibrillation (AF) population have not been well-studied. OBJECTIVES: This study sought to assess HF outcomes, according to HF history and HF phenotypes (HFrEF vs HFpEF), and compare these events with SEE and MB, among patients with AF. METHODS: We analyzed patients enrolled in the ENGAGE-AF TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48) trial. Cumulative incidence of heart failure hospitalization (HHF) or HF death was assessed and compared with the rates of fatal and nonfatal stroke/SEE and MB over a median follow-up of 2.8 years. RESULTS: Overall, 12,124 (57.4%) had a history of HF (37.7% HFrEF, 40.1% HFpEF, 22.1% with unknown ejection fraction). The rate per 100 person-years (py) of HHF or HF death (4.95; 95% CI: 4.70-5.20) was higher than of fatal and nonfatal stroke/SEE (1.77; 95% CI: 1.63-1.92) and MB (2.66; 95% CI: 2.47-2.86) among patients with HF history. HFrEF patients experienced a higher rate of HHF or HF death compared with HFpEF patients (7.15 vs 3.65; P < 0.001), while the rates of fatal and nonfatal stroke/SEE and MB were similar by HF phenotype. Patients with HF history had a higher rate of mortality after a HHF (1.29; 95% CI: 1.17-1.42) than after a stroke/SEE (0.69; 95% CI: 0.60-0.78) or after MB (0.61; 95% CI: 0.53-0.70). Overall, patients with nonparoxysmal AF had a higher rate of HF and stroke/SEE events regardless of HF history. CONCLUSIONS: Patients with AF and HF, regardless of ejection fraction, are at a higher risk of HF events with higher subsequent mortality rates than of stroke/SEE or MB. While HFrEF is associated with a higher risk of HF events than HFpEF, the risk of stroke/SEE and MB is similar between HFrEF and HFpEF.

Prolonged Physiological Stress Is Associated With a Lower Rate of Exploratory Learning That Is Compounded by Depression.

BACKGROUND: Stress is a major risk factor for depression, and both are associated with important changes in decision-making patterns. However, decades of research have only weakly connected physiological measurements of stress to the subjective experience of depression. Here, we examined the relationship between prolonged physiological stress, mood, and explore-exploit decision making in a population navigating a dynamic environment under stress: health care workers during the COVID-19 pandemic. METHODS: We measured hair cortisol levels in health care workers who completed symptom surveys and performed an explore-exploit restless-bandit decision-making task; 32 participants were included in the final analysis. Hidden Markov and reinforcement learning models assessed task behavior. RESULTS: Participants with higher hair cortisol exhibited less exploration (r = -0.36, p = .046). Higher cortisol levels predicted less learning during exploration (ß = -0.42, false discovery rate [FDR]-corrected p [pFDR] = .022). Importantly, mood did not independently correlate with cortisol concentration, but rather explained additional variance (ß = 0.46, pFDR = .022) and strengthened the relationship between higher cortisol and lower levels of exploratory learning (ß = -0.47, pFDR = .022) in a joint model. These results were corroborated by a reinforcement learning model, which revealed less learning with higher hair cortisol and low mood (ß = -0.67, pFDR = .002). CONCLUSIONS: These results imply that prolonged physiological stress may limit learning from new information and lead to cognitive rigidity, potentially contributing to burnout. Decision-making measures link subjective mood states to measured physiological stress, suggesting that they should be incorporated into future biomarker studies of mood and stress conditions.

Prescribing Patterns and Outcomes of Edoxaban in Atrial Fibrillation: One-Year Data from the Global ETNA-AF Program.

Non-recommended dosing occurs in ~25-50% of non-vitamin K antagonist oral anticoagulant prescriptions, with limited data for edoxaban. We analyzed edoxaban dosing patterns in atrial fibrillation patients from the Global ETNA-AF program, relating patterns to baseline characteristics and 1-year clinical outcomes. The following dosing groups were compared: non-recommended 60 mg ("overdosed") vs. recommended 30 mg; non-recommended 30 mg ("underdosed") vs. recommended 60 mg. Most (22,166/26,823; 82.6%) patients received recommended doses. Non-recommended dosing was more frequent near label-specified dose-reduction thresholds. Ischemic stroke (IS; HR 0.85, 95% CI 0.50-1.47; p = 0.6) and major bleeding (MB; HR 1.47, 95% CI 0.97-2.71; p = 0.07) did not differ between recommended 60 mg and "underdosed" groups, whereas all-cause (HR 1.61, 95% CI 1.23-2.08; p = 0.0003) and cardiovascular deaths (HR 1.61, 95% CI 1.11-2.38; p = 0.01) were higher in the "underdosed" group. Compared with recommended 30 mg, the "overdosed" group had lower IS (HR 0.51, 95% CI 0.28-0.98; p = 0.04) and all-cause death (HR 0.74, 95% CI 0.55-0.98; p = 0.03) without higher MB (HR 0.74, 95% CI 0.46-1.22; p = 0.2). In conclusion: non-recommended dosing was infrequent, but more common near dose-reduction thresholds. "Underdosing" was not associated with better clinical outcomes. The "overdosed" group had lower IS and all-cause death without higher MB.

Dopamine and norepinephrine differentially mediate the exploration-exploitation tradeoff.

The catecholamines dopamine (DA) and norepinephrine (NE) have been repeatedly implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision making processes. Although the two neuromodulators share a synthesis pathway and are co-activated under states of arousal, they engage in distinct circuits and roles in modulating neural activity across the brain. However, in the computational neuroscience literature, they have been assigned similar roles in modulating the latent cognitive processes of decision making, in particular the exploration-exploitation tradeoff. Revealing how each neuromodulator contributes to this explore-exploit process will be important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of these two catecholamine systems in regulating exploration and exploitation, a direct comparison using the same dynamic decision making task is needed. Here, we ran mice in a restless two-armed bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA receptor antagonist (flupenthixol), a nonselective DA receptor agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol), and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine receptor activity on the level of exploration. Increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. Beta-noradrenergic receptor activity also modulated exploration, but the modulatory effect was mediated by sex. Reinforcement learning model parameters suggested that dopamine modulation affected exploration via decision noise and norepinephrine modulation affected exploration via outcome sensitivity. Together, these findings suggested that the mechanisms that govern the transition between exploration and exploitation are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration.

Sex Differences Among Patients Receiving Edoxaban vs Vitamin K Antagonist for Atrial Fibrillation After TAVR.

Background: In the ENVISAGE-TAVI AF (Edoxaban vs Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation-Atrial Fibrillation) trial, edoxaban was noninferior to vitamin K antagonists (VKA) for a composite outcome of ischemic and bleeding complications but increased major bleeding in patients with atrial fibrillation after successful transcatheter aortic valve replacement. Women are at higher risk of bleeding and stroke than men after transcatheter aortic valve replacement. It is unclear whether the effect of edoxaban on these complications varies in relation to sex. Objectives: This study was to assess the effect of edoxaban vs VKA according to sex in the ENVISAGE-TAVI AF trial. Methods: The primary outcomes were net adverse cardiovascular events (NACE) and major bleeding, assessed considering the effective time on study medication (safety analysis). Results: Out of 1,377 patients, 658 (47.8%) were women. Risks for ischemic and major bleeding outcomes were similar between women and men. Edoxaban compared to VKA was associated with a similar risk of NACE in women (HR: 1.16; 95% CI: 0.81-1.65) and men (HR: 1.08; 95% CI: 0.76-1.53; P for interaction = 0.820) and a higher risk of major bleeding in both sexes (P for interaction = 0.170). The risk increase of major bleeding was attenuated in women (HR: 1.11; 95% CI: 0.69-1.79) as compared to men (HR: 1.75; 95% CI: 1.07-2.85). There were no treatment-related differences for ischemic complications in both sexes. Conclusions: Edoxaban compared to VKA was associated with a similar risk of NACE and higher risk of major bleeding in both sexes. The increase in bleeding complications with edoxaban was attenuated in women.

Bayesian Forecasting of Bounded Poisson Distributed Time Series.

This research models and forecasts bounded ordinal time series data that can appear in various contexts, such as air quality index (AQI) levels, economic situations, and credit ratings. This class of time series data is characterized by being bounded and exhibiting a concentration of large probabilities on a few categories, such as states 0 and 1. We propose using Bayesian methods for modeling and forecasting in zero-one-inflated bounded Poisson autoregressive (ZOBPAR) models, which are specifically designed to capture the dynamic changes in such ordinal time series data. We innovatively extend models to incorporate exogenous variables, marking a new direction in Bayesian inferences and forecasting. Simulation studies demonstrate that the proposed methods accurately estimate all unknown parameters, and the posterior means of parameter estimates are robustly close to the actual values as the sample size increases. In the empirical study we investigate three datasets of daily AQI levels from three stations in Taiwan and consider five competing models for the real examples. The results exhibit that the proposed method reasonably predicts the AQI levels in the testing period, especially for the Miaoli station.