How to handle the delayed or the missed dose of edoxaban in patients with non-valvular atrial fibrillation: model-informed remedial strategy

Aim: Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for long-term stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOACs is unsatisfactory and decreases over time. The aim of this study was to explore appropriated remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through the Monte Carlo simulation. Methods: Six proposed regimens were compared with the recommendations in the European Heart Rhythm Association (EHRA) guide regarding the trough total deviation time considering both edoxaban plasma concentration and inactive factor Xa activity. Monte Carlo simulations were performed using RxODE based on the published population pharmacokinetics/pharmacodynamics model. Results: The proposed remedial strategies were different from EHRA recommendations and were related to delay duration. The missed dose can be taken immediately if the delay time is within 11 h. When the delay period is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred compared to that recommended in the EHRA guide. Our proposed strategies resulted in a shorter total deviation time than EHRA guide. Conclusion: PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which could help maximize its therapeutic effect.

Optimized delay of the second COVID-19 vaccine dose reduces ICU admissions

Slower than anticipated, COVID-19 vaccine production and distribution have impaired efforts to curtail the current pandemic. The standard administration schedule for most COVID-19 vaccines currently approved is two doses administered 3 to 4 wk apart. To increase the number of individuals with partial protection, some governments are considering delaying the second vaccine dose. However, the delay duration must take into account crucial factors, such as the degree of protection conferred by a single dose, the anticipated vaccine supply pipeline, and the potential emergence of more virulent COVID-19 variants. To help guide decision-making, we propose here an optimization model based on extended susceptible, exposed, infectious, and removed (SEIR) dynamics that determines the optimal delay duration between the first and second COVID-19 vaccine doses. The model assumes lenient social distancing and uses intensive care unit (ICU) admission as a key metric while selecting the optimal duration between doses vs. the standard 4-wk delay. While epistemic uncertainties apply to the interpretation of simulation outputs, we found that the delay is dependent on the vaccine mechanism of action and first-dose efficacy. For infection-blocking vaccines with first-dose efficacy ≥50%, the model predicts that the second dose can be delayed by ≥8 wk (half of the maximal delay), whereas for symptom-alleviating vaccines, the same delay is recommended only if the first-dose efficacy is ≥70%. Our model predicts that a 12-wk second-dose delay of an infection-blocking vaccine with a first-dose efficacy ≥70% could reduce ICU admissions by 400 people per million over 200 d.

Single caudate neurons encode temporally discounted value for formulating motivation for action

The term ‘temporal discounting’ describes both choice preferences and motivation for delayed rewards. Here we show that neuronal activity in the dorsal part of the primate caudate head (dCDh) signals the temporally discounted value needed to compute the motivation for delayed rewards. Macaque monkeys performed an instrumental task, in which visual cues indicated the forthcoming size and delay duration before reward. Single dCDh neurons represented the temporally discounted value without reflecting changes in the animal’s physiological state. Bilateral pharmacological or chemogenetic inactivation of dCDh markedly distorted the normal task performance based on the integration of reward size and delay, but did not affect the task performance for different reward sizes without delay. These results suggest that dCDh is involved in encoding the integrated multidimensional information critical for motivation.

Apparent preferences for cognitive effort fade when multiple forms of effort and delay are interleaved in a foraging environment

Cognitive and physical effort are typically regarded as costly, but demands for effort also seemingly boost the value of prospects under certain conditions. One contextual factor that might influence the perceived value of effort is the mix of different demand types a decision maker encounters in a given environment. Here, we embedded both cognitive and physical effort in a "prey selection" foraging task, which required decision makers not only to evaluate the magnitude and delay of a focal prospective reward but also to estimate the general opportunity cost of time. In two experiments, participants encountered prospective rewards that required equivalent intervals of cognitive effort, physical effort, or unfilled delay. Monetary offers varied per trial, and the two experiments differed in whether the type of effort or delay cost was the same on every trial (between-participant manipulation, n=21 per condition), or varied across trials (within-participant manipulation, n=48). When each participant faced only one type of cost, cognitive effort persistently produced the highest acceptance rate compared to trials with an equivalent period of either physical effort or unfilled delay. We theorized that if cognitive effort were intrinsically rewarding, we would observe the same pattern of preferences when participants foraged for varying cost types in addition to rewards. Contrary to this prediction, in the within-participant experiment, an initially higher acceptance rate for cognitive effort trials disappeared over time amid an overall decline in acceptance rates as participants gained experience with all three conditions. Our results indicate that cognitive demands may reduce the discounting effect of delays, but not because decision makers assign intrinsic value to cognitive effort. Rather, the results suggest that a cognitive effort requirement might influence contextual factors such as subjective delay duration estimates, which can be recalibrated if multiple forms of demand are interleaved.

Electrocardiographic Screening of Arrhythmogenic Cardiomyopathy in Genotype-Positive and Phenotype-Negative Relatives

Background: Arrhythmogenic cardiomyopathy is a hereditary cause of ventricular arrhythmias and sudden death. Identifying the healthy genetic carriers who will develop the disease remains a challenge. A novel approach to the analysis of the digital electrocardiograms of mutation carriers through signal processing may identify early electrocardiographic abnormalities.Methods: A retrospective case–control study included a population of healthy genetics carriers and their wild-type relatives. Genotype-positive/phenotype-negative individuals bore mutations associated with the development of arrhythmogenic cardiomyopathy. The relatives included had a non-pathological 12-lead electrocardiogram, echocardiogram, and a cardiac magnetic resonance. Automatic digital electrocardiographic analyses comprised QRS and terminal activation delay duration, the number of QRS fragmentations, ST slope, and T-wave voltage.Results: Digital 12-lead electrocardiograms from 41 genotype-positive/ phenotype-negative (29 simple carriers and 12 double mutation carriers) and 73 wild-type relatives were analyzed. No differences in the QRS length, the number of QRS fragmentations, and the voltage of the T-wave were observed. After adjusting for potential confounders, double carriers showed an average ST-slope flatter than those of the simple carriers and wild type [5.18° (0.73–8.01), 7.15° (5.14–11.05), and 11.46° (3.94–17.49), respectively, p = 0.005]. There was a significant negative correlation between the ST slope and the age in genotype-positive/phenotype-negative relatives (r = 0.376, p = 0.021) not observed in their wild-type counterparts (r = 0.074, p = 0.570).Conclusions: A flattened ST segment may be an early sign of electrical remodeling that precedes T-wave inversion in healthy genetic carriers. A thorough analysis of the digital electrocardiographic signal may help identify and measure early electrical abnormalities.

The Effect of Delay Duration on Delay Discounting across Adulthood

Literature has been mixed about the relationship between age and delay discounting, or the willingness to wait for delayed rewards. We posit that some of this heterogeneity may be attributable to inconsistent delay durations across studies. Here we investigate how delay duration influences discounting across adulthood by systematically varying the duration of the delay between the smaller, sooner and the larger, later option. 288 healthy participants (Age range: 25-84 years) completed an online delay-discounting task that probed 12 different time delays across 3 discount rates. Discounting was analyzed in two statistical models that treated delay duration as either a categorical or a continuous predictor. Longer delays were generally associated with decreased discounting. However, this was dependent on both age of the participant and delay duration. Both models revealed that, at short to moderate time delays, older adults discounted less than younger adults. However, at very long delays (10 years), older adults discounted more than younger adults. The future time horizons of the participants significantly did not significantly impacted discounting. Results suggest older adults may discount more than younger adults only for extremely long delays (i.e: ~10 years). If this result is replicable, future research could investigate why this reversal in discounting exists and where the inflection point lies.

On Periodic Solutions of a Time-Delayed, Discontinuous System with a Hyperbola Switching Control Law

In this paper, the existence of periodic motions of a discontinuous delayed system with a hyperbolic switching boundary is investigated. From the delay-related [Formula: see text]-function, the crossing, sliding and grazing conditions of a flow to the switching boundary are first developed. For this time-delayed discontinuous dynamical system, there are 17 classes of generic mappings in phase plane and 66 types of local mappings in a delay duration. The generic mappings are determined by subsystems in three domains and two switching boundaries. Periodic motions in such a delay discontinuous system are constructed and predicted analytically from specific mapping structures. Three examples are given for the illustration of periodic motions with or without sliding motion on the switching boundary. This paper shows how to develop switchability conditions of motions at the switching boundary in the time-delayed discontinuous systems and how to construct the specific periodic solutions for the time-delayed discontinuous systems. This study can help us understand complex dynamics in time-delayed discontinuous dynamical systems, and one can use such analysis to control the time-delayed discontinuous dynamical systems.

Single caudate neurons encode temporally discounted value for formulating motivation for action

Temporal discounting captures both choice preferences and motivation for delayed rewards. While temporally discounted value for choice is represented in brain areas including the dorsolateral prefrontal cortex (DLPFC) and the striatum, the neural process of motivation for delayed rewards remains unidentified. Here we show that neuronal activity of the dorsal part of the primate caudate head (dCDh) — a striatal region receiving projection from the DLPFC — signals temporally discounted value essential for computing motivation for delayed rewards. Macaque monkeys performed an instrumental task, in which a visual cue indicated the forthcoming size and delay duration before reward. Single dCDh neurons represented the temporally discounted value without reflecting changes in the animal’s physiological state. Bilateral pharmacological or chemogenetic inactivation of dCDh specifically distorted a normal motivational performance based on the integration of reward size and delay. These results suggest a major contribution of dCDh to encoding a temporally discounted value, the integrated multidimensional information critical for formulating the motivation for action.

Exploring the Relationships between the Topological Characteristics of Subway Networks and Service Disruption Impact

Although numerous studies have considered the topological characteristics and the impact of disruptions in subway systems, their results have not been verified by empirical data. To address this limitation, we used a data set containing 392 detailed records of disruptions to subway services in Beijing from 2011 to 2017. The Spearman rank correlation coefficient analysis results indicate that the delay duration exhibits no significant relationship with the topological characteristics, whereas the reverse is true for the relationship between the number of affected trains and the topological characteristics. The results also demonstrate that subway network expansion will not result in a paradox between convenience and vulnerability from an actual data perspective. Moreover, contrary to previous research results, no significant relationship was found to exist between service interruption impact and the transit and key bridge stations. However, a high degree of clustering, characterized by redundant tracks between neighbours, tends to provide protection against service disruption for stations. In terms of the spatial variation, the influence of the disruption is greater when the station is further from the centre of the line. These results can support sustainable design in subway network planning.