Functionalized tetrahedral DNA frameworks for the capture of circulating tumor cells.

Identification and characterization of circulating tumor cells (CTCs) from blood samples of patients with cancer can help monitor parameters such as disease stage, disease progression and therapeutic efficiency. However, the sensitivity and specificity of current multivalent approaches used for CTC capture is limited by the lack of control over the ligands' position. In this Protocol Update, we describe DNA-tetrahedral frameworks anchored with aptamers that can be configured with user-defined spatial arrangements and stoichiometries. The modified tetrahedral DNA frameworks, termed 'n-simplexes', can be used as probes to specifically target receptor-ligand interactions on the cell membrane. Here, we describe the synthesis and use of n-simplexes that target the epithelial cell adhesion molecule expressed on the surface of CTCs. The characterization of the n-simplexes includes measuring the binding affinity to the membrane receptors as a result of the spatial arrangement and stoichiometry of the aptamers. We further detail the capture of CTCs from patient blood samples. The procedure for the preparation and characterization of n-simplexes requires 11.5 h, CTC capture from clinical samples and data processing requires ~5 h per six samples and the downstream analysis of captured cells typically requires 5.5 h. The protocol is suitable for users with basic expertise in molecular biology and handling of clinical samples.

Direct Bilirubin, but not Indirect Bilirubin, is Associated with Short-term Adverse Events in HFpEF.

OBJECTIVE: Abnormal live function tests have been identified as independent risk factors for ominous prognosis in patients with heart failure. However, most of the previous studies have failed to determine the contribution of direct bilirubin (DBIL) and indirect bilirubin (IBIL) separately. Hence, we aimed to explore whether DBIL or IBIL is correlated with the prognosis of heart failure with preserved ejection fraction (HFpEF).

Methods: A total of 19837 patients were hospitalized for HFpEF between January 2012 and January 2022 in Fuqing City Hospital affiliated with Fujian Medical University. The primary endpoint was in-hospital all-cause mortality. Secondary endpoints included in-hospital cardiovascular mortality and 30-day re-admission for heart failure.

Results: Univariable analysis indicated that patients with elevated DBIL or IBIL were exposed to a higher risk of mortality and re-admission. However, in multivariable models, both ln-transformed DBIL and TBIL, but not IBIL, were independent risk factors for in-hospital all-cause mortality [hazard ratio (HR)=1.796, 95% confidential interval (CI)=1.477-2.183, P＜0.001; HR=1.854, 95% CI=1.461-2.352, P＜0.001; HR=1.161, 95% CI=0.959-1.407, P=0.126] and in-hospital cardiovascular mortality (HR=1.831, 95% CI=1.345-2.492, P＜0.001; HR=1.899, 95% CI=1.300-2.773, P=0.001; HR=1.145, 95% CI=0.841-1.561, P=0.389). Only DBIL remained independently associated with 30-day readmission for heart failure (HR=1.361, 95% CI=1.036-1.787, P=0.027). Adding ln-transformed DBIL to model 1 increased its discriminatory capacity (C-statistic: 0.851 to 0.869, respectively), whereas adding ln-transformed IBIL yielded little increment (C-statistic: 0.851 to 0.852, respectively).

Conclusion: DBIL, but not IBIL, was associated with short-term ominous prognosis in patients with HFpEF. Hence, DBIL may be the superior predictor for prognosis in HFpEF.

Local Electric Potential-Driven Nanofluidic Ion Transport for Ultrasensitive Biochemical Sensing.

Nanofluidic biosensors have been widely used for detection of analytes based on the change of system resistance before and after target-probe interactions. However, their sensitivity is limited when system resistance barely changes toward low-concentration targets. Here, we proposed a strategy to address this issue by means of target-induced change of local membrane potential under relatively unchanged system resistance. The local membrane potential originated from the directional diffusion of photogenerated carriers across nanofluidic biosensors and gated photoinduced ionic current signal before and after target-probe interactions. The sensitivity of such biosensors for the detection of biomolecules such as circulating tumor DNA (ctDNA) and lysozyme exceeds that of applying a traditional strategy by more than 3 orders of magnitude under unchanged system resistance. Such biosensors can specifically detect the small molecule biomarker in the blood sample between prostate cancer patients and healthy humans. The key advantages of such nanofluidic biosensors are therefore complementary to traditional nanofluidic biosensors, with potential applications in a point-of-care analytical tool.

Solid-State Nanopore/Nanochannel Sensors with Enhanced Selectivity through Pore-in Modification.

Nanopore sensing technology, as an emerging analytical method, has the advantages of simple operation, fast output, and label-free and has been widely used in fields such as protein analysis, gene sequencing, and biomarker detection. Inspired by biological ion channels, scientists have prepared various artificial solid-state nanopores/nanochannels. Biological ion channels have extremely high ion transport selectivity, while solid-state nanopores/nanochannels have poor selectivity. The selectivity of solid-state nanopores and nanochannels can be enhanced by modifying channel charge, varying pore size, incorporating specific chemical functionality, and adjusting operating (or solution) conditions. This Perspective highlights pore-in modification strategies for enhancing the selectivity of solid-state nanopore/nanochannel sensors by summarizing the articles published in the last 10 years. The future development prospects and challenges of pore-in modification in solid-state nanopore and nanochannel sensors are discussed. This Perspective helps readers better understand nanopore sensing technology, especially the importance of detection selectivity. We believe that solid-state nanopore/nanochannel sensors will soon enter our homes after various challenges.

The impact of CYP3A5*3 on oral quetiapine: A population pharmacokinetic model in Chinese bipolar disorder patients.

BACKGROUND: There is great interindividual difference in the plasma concentration of quetiapine, and optimizing quetiapine therapy to achieve a balance between efficacy and safety is still a challenge. In our study, a population pharmacokinetic (PPK) model considering genetic information was developed with the expectation of comprehensively explaining this observation in Chinese patients with bipolar disorder. METHODS: Patients who were dispensed quetiapine and underwent the therapeutic drug monitoring (TDM) were included. The genotypes of CYP3A5*3, CYP2D6*10, and ABCB1 C3435T/G2677T were analyzed. Finally, a multivariable linear regression model was applied to describe the PPK of quetiapine considering the covariates weight, height and genotype information. RESULTS: A total of 175 TDM points from 107 patients were adopted for PPK model development. Resultantly, the CL/F of quetiapine in CYP3A5 expressers was 81.1 CL/h, whereas it was 43.6 CL/h in CYP3A5 nonexpressers. The interindividual variability in CL/F was 47.7 %. However, neither the ABCB1 nor CYP2D6 genotype was significantly associated with the predictor of quetiapine clearance in our study. LIMITATIONS: Only trough concentrations were collected, and the span between different points was relatively wide, impeding the application of the typical nonlinear compartment model for PPK analysis. In addition, this was a single-center study which limited the sample of wild-type CYP3A5 carriers. CONCLUSIONS: The currently established PPK model of quetiapine considering the contribution of the CYP3A5 genotype could efficiently predict the population and individual pharmacokinetic parameters of Chinese bipolar disorder patients, which could better guide the personalized therapy with quetiapine, thus to achieve the best clinical response.

Continuities and discontinuities in the cultural evolution of global consciousness.

Global consciousness (GC), encompassing cosmopolitan orientation, global orientations (i.e. openness to multicultural experiences) and identification with all humanity, is a relatively stable individual difference that is strongly associated with pro-environmental attitudes and behaviours, less ingroup favouritism and prejudice, and greater pandemic prevention safety behaviours. Little is known about how it is socialized in everyday life. Using stratified samples from six societies, socializing institution factors correlating positively with GC were education, white collar work (and its higher income) and religiosity. However, GC also decreased with increasing age, contradicting a 'wisdom of elders' transmission of social learning, and not replicating typical findings that general prosociality increases with age. Longitudinal findings were that empathy-building, network-enhancing elements like getting married or welcoming a new infant, increased GC the most across a three-month interval. Instrumental gains like receiving a promotion (or getting a better job) also showed positive effects. Less intuitively, death of a close-other enhanced rather than reduced GC. Perhaps this was achieved through the ritualized management of meaning where a sense of the smallness of self is associated with growth of empathy for the human condition, as a more discontinuous or opportunistic form of culture-based learning. This article is part of the theme issue 'Evolution and sustainability: gathering the strands for an Anthropocene synthesis'.

Behavioral evidence for global consciousness transcending national parochialism.

While national parochialism is commonplace, individual differences explain more variance in it than cross-national differences. Global consciousness (GC), a multi-dimensional concept that includes identification with all humanity, cosmopolitan orientation, and global orientation, transcends national parochialism. Across six societies (N = 11,163), most notably the USA and China, individuals high in GC were more generous allocating funds to the other in a dictator game, cooperated more in a one-shot prisoner's dilemma, and differentiated less between the ingroup and outgroup on these actions. They gave more to the world and kept less for the self in a multi-level public goods dilemma. GC profiles showed 80% test-retest stability over 8 months. Implications of GC for cultural evolution in the face of trans-border problems are discussed.

Solid-State Nanopore Sensors with Enhanced Sensitivity through Nucleic Acid Amplification.

Solid-state nanopores have wide applications in DNA sequencing, energy conversion and storage, seawater desalination, sensors, and reactors due to their high stability, controllable geometry, and a variety of pore-forming materials. Solid-state nanopore sensors can be used for qualitative and quantitative analyses of ions, small molecules, proteins, and nucleic acids. The combination of nucleic acid amplification and solid-state nanopores to achieve trace detection of analytes is gradually attracting attention. This review outlines nucleic acid amplification strategies for enhancing the sensitivity of solid-state nanopore sensors by summarizing the articles published in the past 10 years. The future development prospects and challenges of nucleic acid amplification in solid-state nanopore sensors are discussed. This review helps readers better understand the field of solid-state nanopore sensors. We believe that solid-state nanopore sensors will break through the bottleneck of traditional detection and become a powerful single-molecule detection platform.

A fuel-initiated DNA molecular machine for microRNA detection in serum via poly-adenine-mediated spherical nucleic acids.

MicroRNAs (miRNAs) have been identified as promising disease diagnostic biomarkers. However, it is challenging to sensitively detect miRNAs, especially in complex biological environments, due to their low abundance and small size. Herein, we have developed a DNA-fueled molecular machine for sensitive detection of miRNA-22 (miR-22) in undiluted serum by combining poly-adenine-mediated spherical nucleic acids (polyA-SNAs) with a toehold mediated strand displacement reaction (TMSDR). The polyA-SNAs are constructed by the assembly of diblock DNA probes on a AuNP surface through the high binding affinity of polyA to AuNPs. The surface density of the diblock DNA probe can be controlled by tuning the length of the polyA block, and the orientation of the diblock DNA probe can adopt an upright conformation, which is beneficial to target hybridization and TMSDRs. TMSDR is an enzyme-free target recycling amplification approach. Taking advantage of polyA-mediated SNAs and TMSDR, the operation of the molecular machine based on two successive TMSDRs on polyA20-SNAs is rapid and efficient, which can significantly amplify the fluorescence response for detection of miR-22 in an undiluted complex matrix. The developed sensor can detect as low as 10 pM of target miRNA/DNA in undiluted fetal bovine serum within 30 min. The synergetic effect of polyA-mediated SNAs and TMSDR presents a potential alternative tool for the detection of biomarkers in real biological samples.

Construction and bioanalytical applications of poly-adenine-mediated gold nanoparticle-based spherical nucleic acids.

Owing to the versatile photophysical and chemical properties, spherical nucleic acids (SNAs) have been widely used in biosensing. However, traditional SNAs are formed by self-assembly of thiolated DNA on the surface of a gold nanoparticle (AuNP), where it is challenging to precisely control the orientation and surface density of DNA. As a new SNA, a polyadenine (polyA)-mediated SNA using the high binding affinity of consecutive adenines to AuNPs shows controllable surface density and configuration of DNA, which can be used to improve the performance of a biosensor. Herein, we first introduce the properties of polyA-mediated SNAs and fundamental principles regarding the polyA-AuNP interaction. Then, we provide an overview of current representative synthesis methods of polyA-mediated SNAs and their advantages and disadvantages. After that, we summarize the application of polyA-mediated SNAs in biosensing based on fluorescence and colorimetric methods, followed by discussion and an outlook of future challenges in this field.

Effect of Food on the Pharmacokinetics of Tenofovir Amibufenamide: A Phase I, Randomized, Open-Label, Two-Period Crossover Trial in Healthy Adult Subjects.

Purpose: Tenofovir amibufenamide (TMF) is a novel nucleotide reverse transcriptase inhibitor. The aim of this study was to investigate the effect of food on the single-dose pharmacokinetic properties of TMF. Patients and Methods: In this open-label, randomized, crossover study, after an overnight fast, eligible subjects received a single 25 mg dose of TMF tablet, either under fasted conditions or following consumption of a high-fat, high-calorie meal, followed by a two-week washout period. Blood samples were collected until 144 h after administration. TMF and its metabolite, tenofovir (TFV), were analyzed using validated liquid chromatography-tandem mass spectrometry methods. The geometric mean ratio (GMR) and the corresponding 90% confidence interval (CI) values of AUC0-t, AUC0-∞, and Cmax were acquired for analysis. The absence of an effect of food was indicated if the 90% CI values were within the predefined equivalence limits of 80%-125%. Safety and tolerability were also assessed. Results: For TMF, adjusted GMR (90% CI) values for the fed versus fasted states were 150.28% (125.36%-180.16%), 158.24% (130.42%-192.00%), and 57.65% (45.68%-72.76%) for AUC0-t, AUC0-∞, and Cmax, respectively. For TFV, the GMR (90% CI) of Cmax was 82.00% (74.30%-90.49%) after administration under fed conditions, slightly outside the bioequivalence boundary of 80%-125%, while the corresponding values for AUC0-t and AUC0-∞ were within range. The absorption of TMF was delayed by food, with median Tmax values of 0.33 and 1.00 h in fasted and fed conditions, respectively. The adverse events observed in subjects were all mild. Conclusion: Our results demonstrated that TMF tablets were well-tolerated in healthy volunteers. When TMF tablets were taken with food, Tmax was delayed and exposures of TMF and TFV were higher than under fasted conditions. The modest changes observed are not considered clinically relevant, so TMF can be taken with or without food.

RUNX-3-expressing CAR T cells targeting glypican-3 in patients with heavily pretreated advanced hepatocellular carcinoma: a phase I trial.

Background: Glypican-3 (GPC3) is a well-characterized hepatocellular carcinoma (HCC)-associated antigen and a promising target for HCC treatment. CT017 CAR T cells were engineered to co-express CAR-GPC3 and runt-related transcription factor 3 (RUNX3), which triggers CD8+ T-cell infiltration into the cancer microenvironment. Methods: This single-center, single-arm, open-label, phase I clinical study enrolled heavily pretreated patients with GPC3-positive HCC between August 2019 and December 2020 (NCT03980288). Patients were treated with CT017 CAR T cells at a dose of 250 × 106 cells. The primary objective was to assess the safety and tolerability of this first-in-human product. Findings: Six patients received 7 infusions (one patient received 2 infusions) at the 250 × 106 cells dose. Three patients received CT017 monotherapy, and three patients received CT017-tyrosine kinase inhibitor (TKI) combination therapy at the first infusion. One patient received CT017-TKI combination therapy at the second infusion after CT017 monotherapy. All patients experienced cytokine release syndrome (CRS), with 50% (3/6) at Grade 2, 50% (3/6) at Grade 3, and all events resolved after treatment. No immune effector cell-associated neurotoxicity syndrome was observed. Dose escalation was not performed due to the investigator's decision regarding safety. Of six evaluable patients, one achieved partial response and two had stable disease for a 16.7% objective response rate, 50% disease control rate, 3.5-month median progression-free survival, 3.2-month median duration of disease control, and 7.9-month median overall survival (OS) with 7.87-month median follow-up. The longest OS was 18.2 months after CT017 infusion. Interpretation: Current preliminary phase I data showed a manageable safety profile and promising antitumor activities of CT017 for patients with advanced HCC. These results need to be confirmed in a robust clinical trial. Funding: This study was funded by CARsgen Therapeutics Co., Ltd.

Stochastic Sensing of Dynamic Interactions and Chemical Reactions with Nanopores/Nanochannels.

Nanopore sensing technology is an emerging analysis method with the advantages of simple operation, high sensitivity, fast output and being label free, and it is widely used in protein analysis, gene sequencing, biomarker detection, and other fields. The confined space of the nanopore provides a place for dynamic interactions and chemical reactions between substances. The use of nanopore sensing technology to track these processes in real time is helpful to understand the interaction/reaction mechanism at the single-molecule level. According to nanopore materials, we summarize the development of biological nanopores and solid-state nanopores/nanochannels in the stochastic sensing of dynamic interactions and chemical reactions. The goal of this paper is to stimulate the interest of researchers and promote the development of this field.

Bioequivalence study of domperidone dry suspension in healthy Chinese subjects under fasted and fed conditions: An open-label, randomized, single-dose, crossover trial.

BACKGROUND: Domperidone has long been used as a prokinetic agent in the treatment of epigastric distress symptoms. This study aimed to provide adequate evidence for registration approval of a new generic dry suspension formulation of domperidone by comparing the safety and pharmacokinetic profiles between the test and branded reference formulation in the context of fasted and fed condition. MATERIALS AND METHODS: This was designed as a randomized, open-label, single-dose, two-period, two-treatment crossover study. 32 and 28 eligible healthy subjects were enrolled in the fasted and fed study, respectively. Each subject was randomly assigned to receive either the test or reference formulation in the first period, followed by a 1-week washout period and dosing of the alternate formulation in the second period. A series of blood samples were collected at scheduled timepoints within 48 hours after administration during each treatment period. Plasma concentrations of domperidone were determined by validated HPLC-MS/MS. Pharmacokinetic parameters, including Cmax, tmax, AUC0-t, AUC0-∞, and T1/2, were acquired based on the concentration vs. time profiles by non-compartmental analysis using WinNonlin software. Then the geometric mean ratios (GMR) of Cmax, AUC0-t, and AUC0-∞ between the two formulations and corresponding 90% confidence intervals (CIs) were calculated for bioequivalence determination. Safety was assessed as routine. RESULTS: The two formulations showed similar pharmacokinetic profiles. Under fasted condition, the GMR and corresponding 90% CIs of AUC0-t, AUC0-∞, and Cmax were 101.48% (96.79 - 106.38%), 101.17% (96.66 - 105.90%), and 104.61% (96.73 - 113.14%), respectively. Under fed condition, the GMR and corresponding 90% CIs were 105.46% (99.19 - 112.12%), 104.21% (98.19 - 110.61%), and 112.78% (103.64 - 122.73%), respectively, for AUC0-t, AUC0-∞, and Cmax. All values fell within the accepted bioequivalence range of 80 - 125%. Both the test and the reference products were well tolerated without any serious or unexpected adverse reactions. CONCLUSION: Pharmacokinetic bioequivalence was established between the two dry suspension formulations of domperidone in healthy Chinese subjects. Both products were safe and well tolerated.

Social-Emotional Development of Children in Asia: A Systematic Review.

There has been growing interest in the social-emotional development of children. However, the social-emotional development of children in Asia remains a knowledge gap. This systematic review identifies and summarizes existing studies on children's social-emotional development in Asia. We conducted a systematic review using the Guidelines for Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). We reviewed 45 studies that met the inclusion criteria, and they were from 12 Asian countries, primarily the East Asia region (China and Hong Kong). Most of the studies were cross-sectional in design (n = 28, 62.2%). Six themes emerged, including (a) social-emotional development (overall) (n = 24, 53.3%); (b) social competence (n = 7, 15.6%); (c) emotional development (n = 5, 11.1%); (d) social-emotional learning (n = 3, 6.7%); (e) problem behavior (n = 3, 6.7%); (f) self-regulation (n = 2, 4.4%); and (g) both social-emotional learning and problem behavior (n = 1, 2.2%). The findings highlighted the paucity of studies, the need for examining more diverse variables in a similar population, and the low quality of intervention studies in social-emotional research in Asia. Research gaps indicate the need for more social-emotional and ethnocultural studies in other Asian regions. Parent and teacher knowledge of children's social-emotional functioning should be examined more closely in future research.

Programming the dynamic range of nanobiosensors with engineering poly-adenine-mediated spherical nucleic acid.

Spherical nucleic acid (SNA) conjugates consisting of gold cores functionalized with a densely packed DNA shells are of great significance in the field of medical detection and intracellular imaging. Especially, poly adenine (polyA)-mediated SNAs can improve the controllability and reproducibility of DNA assembly on the nanointerface, showing the tunable hybridization ability. However, due to the physics of single-site binding, the biosensor based on SNA usually exhibits a dynamic range spanning a fixed 81-fold change in target concentration, which limits its application in disease monitoring. To address this problem, we report a tri-block DNA-based approach to assemble SNA for nucleic acid detection based on structure-switching mechanism with programmable dynamic range. The tri-block DNA is a FAM-labeled stem-loop structure, which contains three blocks: polyA block as an anchoring block for tunable surface density, stem block with different GC base pair content for varying the structure stability, and the fixed loop block for target recognition. We find that varying the polyA block, the reaction temperature, and the GC base pair, SNA shows different target binding affinity and detection limit but with normally 81-fold dynamic range. We can extend the dynamic range to 1000-fold by using the combination of two SNAs with different affinity, and narrow the dynamic range to 5-fold by sequestration mechanism. Furthermore, the tunable SNA enables sensitive detection of mRNA in cells. Given its tunable dynamic range, such nanobiosensor based on SNA offers new possibility for various biomedical and clinical applications.

Inner Wall and Outer Surface Distinguished Solid-State Nanopores for Sensing.

Solid-state nanopores, inspired by biological nanopores, have the advantages of good mechanical properties, stability, and easy modification. They have attracted wide attention in the fields of sequencing, sensing, molecular sieving, nanofluidic devices, nanoelectrochemistry, and energy conversion. Because of the ion/molecule transport characteristic of the pore, the research on solid-state nanopores mainly focuses on the functional modification of its inner wall. In recent years, the outer surface of nanopores has also attracted the attention of researchers, and the functional elements on the outer surface have the functions of anti-interference and ionic signal enhancement. In this perspective, we review research progress of inner wall and outer surface distinguished solid-state nanopores, highlight their processing and advantages, summarize their functions and applications in sensing, and give insight into further research.

Polydopamine-Induced Modification on the Highly Charged Surface of Asymmetric Nanofluidics: A Strategy for Adjustable Ion Current Rectification Properties.

Surface charge effects in nanoconfines is one of the fundamentals in the ion current rectification (ICR) of nanofluidics, which provides entropic driving force by asymmetric surface charges and causes ion enrichment/depletion by the electrostatic interaction of fixed surface charges. However, the surface charge effect causes a significant electrostatic repulsion in nanoconfines, restricting additional like charge or elaborate chemistry on the highly charged confined surface, which limits ICR manipulation. Here, we use polydopamine (PDA), a nearly universal adhesive, that adheres to the highly positive-charged poly(ethyleneimine) (PEI) gel network in a nanochannel array. PDA enhances the ICR effect from a low rectification ratio of 9.5 to 92.6 by increasing the surface charge and hydrophobicity of the PEI gel network and, meanwhile, shrinking its gap spacing. Theoretical and experimental results demonstrate the determinants of the fixed surface charge in the enrichment/depletion region on ICR properties, which is adjustable by PDA-induced change in a nanoconfined environment. Chemically active PDA brings Au nanoparticles by chloroauric reduction for further hydrophobization and the modification of negative-charged DNA complexes in nanochannels, whereby ICR effects can be manipulated in versatile means. The results describe an adjustable and versatile strategy for adjusting the ICR behaviors of nanofluidics by manipulating local surface charge effects using PDA.

The effect of strategy game types on inhibition.

Past studies have shown evidence of transfer of learning in action video games, less so in other types, e.g. strategy games. Further, the transfer of learning from games to inhibitory control has yet to be examined from the perspectives of time constraint and logic contradiction. We examined the effect of strategy games (puzzle, turn-based strategy 'TBS', and real-time strategy 'RTS') on inhibition (response inhibition and distractor inhibition) and cerebral hemispheric activation over 4 weeks. We predicted that compared to RTS, puzzle and TBS games would (1) improve response and distractor inhibition, and (2) increase cerebral hemispheric activation demonstrating increased inhibitory control. A total of 67 non-habitual video game players (Mage = 21.63 years old, SD = 2.12) played one of three games: puzzle (n = 19), TBS (n = 24) or RTS (n = 24) for 4 weeks on their smartphones. Participants completed three inhibition tasks, working memory (WM), and had their tympanic membrane temperature (TMT) taken from each ear before and after playing the games. Results showed that only the puzzle game group showed an improved response inhibition while controlling for WM. There were no significant changes in the distractor inhibition tasks. We also found that there was an increase in left TMT while playing RTS, suggesting the presence of increased impulsivity in RTS. Our findings suggest that puzzle games involving logical contradiction could improve response inhibition, showing potential as a tool for inhibition training.

Effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with hypertrophic cardiomyopathy with non-valvular atrial fibrillation.

Hypertrophic cardiomyopathy (HCM) patients with nonvalvular atrial fibrillation (AF) have an increased risk of suffering thromboembolic events. Vitamin K antagonists (VKA) are recommended as therapy but there is still limited data regarding the efficacy of prescribing non-vitamin K antagonist oral anticoagulants (NOACs). This retrospective study investigates the effectiveness and safety of NOAC administration in patients with HCM and AF. A total of 124 patients with HCM and AF on an oral anticoagulant therapy were recruited between January 2015 and December 2019; these patients were followed up until March 31, 2020. Kaplan-Meier analysis was used to compare the clinical outcomes in patients treated with NOACs versus warfarin. The Cox model was used to estimate the risk of clinically relevant bleeding. Our study included 124 patients, of which 48 (38.7%) received warfarin and 76 (61.3%) received NOACs. Survival analysis showed the patients undergoing NOACs had a lower risk of clinically relevant bleeding (log-rank P = 0.039) over a period of 53.6 months. The median time in therapeutic range (TTR) score was 50% (interquartile range: 40.43 to 57.08%). A total of nine patients (18.75%) had a good TTR with a median score of 66.35% (interquartile range: 64.58 to 77.75%). The incidence of death by all causes, cardiovascular death and thromboembolism were similar between NOAC and warfarin-treated patients (log-rank P = 0.239, log-rank P = 0.386, and log-rank P = 0.257, respectively). Patients treated with NOACs showed a significant reduction in the risk of clinical (P = 0.011) and gastrointestinal bleeding (P = 0.032). Cox multiple regression analysis showed age (HR 1.13, 95% CI 1.03-1.24; P = 0.013) and warfarin therapy (HR 7.37, 95% CI 1.63-33.36; P = 0.010) were independent predictors of clinically relevant bleeding. Compared to warfarin, NOACs were associated with a lower incidence of clinically relevant bleeding in HCM patients with AF, as demonstrated by the similar incidence of death by all causes, cardiovascular death and thromboembolic events.