Sex Differences in the Expression of Cardiac Remodeling and Inflammatory Cytokines in Patients with Obstructive Sleep Apnea and Atrial Fibrillation.

Although there is a link between obstructive sleep apnea (OSA) and atrial fibrillation (AF) and numerous investigations have examined the mechanism of AF development in OSA patients, which includes cardiac remodeling, inflammation, and gap junction-related conduction disorder, there is limited information regarding the differences between the sexes. This study analyzes the impact of sex differences on the expression of cardiac remodeling, inflammatory cytokines, and gap junctions in patients with OSA and AF. A total of 154 individuals diagnosed with sleep-related breathing disorders (SRBDs) were enrolled in the study and underwent polysomnography and echocardiography. Significant OSA was defined as an apnea-hypopnea index (AHI) of ≥15 per hour. Exosomes were purified from the plasma of all SRBD patients and incubated in HL-1 cells to investigate their effects on inflammatory cytokines and GJA1 expression. The differences in cardiac remodeling and expression of these biomarkers in both sexes were analyzed. Of the 154 enrolled patients, 110 patients were male and 44 patients were female. The LA sizes and E/e' ratios of male OSA patients with concomitant AF were greater than those of control participants and those without AF (all p < 0.05). Meanwhile, female OSA patients with AF had a lower left ventricular ejection fraction than those OSA patients without AF and control subjects (p < 0.05). Regarding the expression of inflammatory cytokines and GJA1, the mRNA expression levels of GJA1 were lower and those of IL-1ß were higher in those male OSA patients with AF than in those male OSA patients without AF and control subjects (p < 0.05). By contrast, mRNA expression levels of HIF-1α were higher in those female OSA patients with and without AF than in control subjects (p < 0.05). In conclusion, our study revealed sex-specific differences in the risk factors and biomarkers associated with AF development in patients with OSA.

Using a visual support package to facilitate independent leisure engagement and choice-making for individuals with moderate to severe autism in Taiwan.

LAY ABSTRACT: Self-determination encompasses various components, including decision-making and independence, making it a complex process. While the importance of self-determination for individuals with autism spectrum disorder has been explored in previous studies, there is limited research focusing on individuals with moderate to severe autism spectrum disorder. Evidence-based practices such as visual activity schedules and video modeling have shown effectiveness in promoting independence among individuals with autism spectrum disorder. To address the need for independence and choice-making among individuals with moderate to severe autism spectrum disorder, this study developed a visual support package incorporating visual activity schedules, video modeling, preference assessments, and prompt procedures. By investigating the intervention's effectiveness in three participants, this study contributes to the existing literature on the use of a visual activity schedule and video modeling in enhancing choice-making and independent leisure engagement. Following the intervention, all participants were able to select three leisure activities, develop their own visual schedules, and complete them. Notably, this study conducted preference assessments to determine participants' preferred leisure activities and did not provide additional reinforcement. Practical implications of this research include incorporating video prompting as needed and adjusting activity engagement time. Future research should explore the long-term effectiveness of the visual support package and its application in developing novel skills or vocational activities for individuals with moderate to severe autism spectrum disorder. This study fills a critical gap in the literature, providing important insights for practices and research in the field of autism spectrum disorder interventions.

A Degree-Dependent Polynomial-Based Reciprocally Convex Matrix Inequality and Its Application to Stability Analysis of Delayed Neural Networks.

In this article, several improved stability criteria for time-varying delayed neural networks (DNNs) are proposed. A degree-dependent polynomial-based reciprocally convex matrix inequality (RCMI) is proposed for obtaining less conservative stability criteria. Unlike previous RCMIs, the matrix inequality in this article produces a polynomial of any degree in the time-varying delay, which helps to reduce conservatism. In addition, to reduce the computational complexity caused by dealing with the negative definite of the high-degree terms, an improved lemma is presented. Applying the above matrix inequalities and improved negative definiteness condition helps to generate a more relaxed stability criterion for analyzing time-varying DNNs. Two examples are provided to illustrate this statement.

Exosomal hsa_circ_000200 as a potential biomarker and metastasis enhancer of gastric cancer via miR-4659a/b-3p/HBEGF axis.

BACKGROUND: Exosome, a component of liquid biopsy, loaded protein, DNA, RNA and lipid gradually emerges as biomarker in tumors. However, exosomal circRNAs as biomarker and function mechanism in gastric cancer (GC) are not well understood. METHODS: Differentially expressed circRNAs in GC and healthy people were screened by database. The identification of hsa_circ_000200 was verified by RNase R and sequencing, and the expression of hsa_circ_000200 was evaluated using qRT-PCR. The biological function of hsa_circ_000200 in GC was verified in vitro. Western blot, RIP, RNA fluorescence in situ hybridization, and double luciferase assay were utilized to explore the potential mechanism of hsa_circ_000200. RESULTS: Hsa_circ_000200 up-regulated in GC tissue, serum and serum exosomes. Hsa_circ_000200 in serum exosomes showed better diagnostic ability than that of tissues and serum. Combined with clinicopathological parameters, its level was related to invasion depth, TNM staging, and distal metastasis. Functionally, knockdown of hsa_circ_000200 inhibited GC cells proliferation, migration and invasion in vitro, while its overexpression played the opposite role. Importantly, exosomes with up-regulated hsa_circ_000200 promoted the proliferation and migration of co-cultured GC cells. Mechanistically, hsa_circ_000200 acted as a "ceRNA" for miR-4659a/b-3p to increase HBEGF and TGF-ß/Smad expression, then promoted the development of GC. CONCLUSIONS: Our findings suggest that hsa_circ_000200 promotes the progression of GC through hsa_circ_000200/miR-4659a/b-3p/HBEGF axis and affecting the expression of TGF-ß/Smad. Serum exosomal hsa_circ_000200 may serve as a potential biomarker for GC.

Exploring the Critical Driving Forces and Strategy Adoption Paths of Professional Competency Development for Various Emergency Physicians Based on the Hybrid MCDM Approach.

The implementation of competency-based medical education (CBME) focuses on learners' competency outcomes and performance during their training. Competencies should meet the local demands of the healthcare system and achieve the desired patient-centered outcomes. Continuous professional education for all physicians also emphasizes competency-based training to provide high-quality patient care. In the CBME assessment, trainees are evaluated on applying their knowledge and skills to unpredictable clinical situations. A priority of the training program is essential in building competency development. However, no research has focused on exploring strategies for physician competency development. In this study, we investigate the professional competency state, determine the driving force, and provide emergency physicians' competency development strategies. We use the Decision Making Trial and Evaluation Laboratory (DEMATEL) method to identify the professional competency state and investigate the relationship among the aspects and criteria. Furthermore, the study uses the PCA (principal component analysis) method to reduce the number of components and then identify the weights of the aspects and components using the ANP (analytic network process) approach. Therefore, we can establish the prioritization of competency development of emergency physicians (EPs) with the VIKOR (Vlse kriterijumska Optimizacija I Kompromisno Resenje) approach. Our research demonstrates the priority of competency development of EPs is PL (professional literacy), CS (care services), PK (personal knowledge), and PS (professional skills). The dominant aspect is PL, and the aspect being dominated is PS. The PL affects CS, PK, and PS. Then, the CS affects PK and PS. Ultimately, the PK affects the PS. In conclusion, the strategies to improve the professional competency development of EPs should begin with the improvement from the aspect of PL. After PL, the following aspects that should be improved are CS, PK, and PS. Therefore, this study can help establish competency development strategies for different stakeholders and redefine emergency physicians' competency to reach the desired CBME outcomes by improving advantages and disadvantages.

Establishing the Competency Development and Talent Cultivation Strategies for Physician-Patient Shared Decision-Making Competency Based on the IAA-NRM Approach.

Shared decision making (SDM) is a collaborative process involving patients and their healthcare workers negotiating to reach a shared decision about medical care. However, various physician stakeholders (attending physicians, medical residents, and doctors in post-graduate years) may have different viewpoints on SDM processes. The purpose of this study is to explore the core competence of physicians in performing SDM tasks and to investigate the significant competency development aspects/criteria by applying the literature research and expert interviews. We adopt the IAA (importance awareness analysis) technique for different stakeholders to evaluate the status of competency development aspects/criteria and to determine the NRM (network relation map) based on the DEMATEL (decision-making trial and evaluation laboratory) technique. The study combines the IAA and NRM methods and suggests using the IAA-NRM approach to evaluate the adoption strategies and common suitable paths for different levels of physicians. Our findings reveal that SDM perception and practice is the primary influencer of SDM competence development for all stakeholders. The current model can help hospital administrators and directors of medical education understand the diverse stakeholders' perspectives on the core competence of SDM tasks and determine common development plans. It provides strategic directions for SDM competency development and talent cultivation programs.

Determining the Development Strategy and Suited Adoption Paths for the Core Competence of Shared Decision-Making Tasks through the SAA-NRM Approach.

Shared decision making (SDM) is an interactive process that involves patients and their healthcare professionals reaching joint decisions about medical care through negotiation. As the initiators of medical decision-making in daily routine, physicians should be aware of and concerned about the SDM process. Thus, professional competency development for SDM has become increasingly critical for physicians' training. Therefore, this study investigates the professional competency and the important competency development aspects/criteria of SDM tasks through expert interviews and literature research. The study adopts the SAA (satisfaction-attention analysis) method to assess the status of competency development aspects/criteria and determine the NRM (network relation map) based on the DEMATEL (decision-making trial and evaluation laboratory) technique. The results demonstrate that the CE (concept and evaluation) aspect is the dominant aspect, and the CR (communication and relationship) aspect is the aspect being dominated. The CE aspect influences the aspects of SP (skill and practice), JM (joint information and decision making) and CR, and the SP aspect affects the aspects of JM and CR. Then, the JM aspect affects the CR aspect. The study also suggests suitable adoption paths of competency development for SDM tasks using the NRM approach. It provides recommendations and strategic directions for SDM competency development and sustainable training programs.

Type-Dependent Average Dwell Time Method and Its Application to Delayed Neural Networks With Large Delays.

This article investigates the stability of delayed neural networks with large delays. Unlike previous studies, the original large delay is separated into several parts. Then, the delayed neural network is viewed as the switched system with one stable and multiple unstable subsystems. To effectively guarantee the stability of the considered system, the type-dependent average dwell time (ADT) is proposed to handle switches between any two sequences. Besides, multiple Lyapunov functions (MLFs) are employed to establish stability conditions. Adding more delayed state vectors increases the allowable maximum delay bound (AMDB), reducing the conservatism of stability criteria. A general form of the global exponential stability condition is put forward. Finally, a numerical example illustrates the effectiveness, and superiority of our method over the existing one.

The Impact of Intermittent Hypoxemia on Left Atrial Remodeling in Patients with Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea syndrome (OSAS) is a significant risk factor for left atrial (LA) remodeling. Intermittent hypoxemia occurs during the sleep cycle in patients with OSAS and plays a crucial role in cardiovascular pathologies such as stroke, arrhythmia, and coronary artery disease. However, there is very little information about the role of intermittent hypoxemia in LA remodeling in patients with OSAS. In total, 154 patients with sleep-related breathing disorders (SRBD) were prospectively recruited for this study. All enrolled SRBD patients underwent polysomnography and echocardiography. Significant OSAS was defined as an oxygen desaturation index (ODI) of ≥10 per hour. Intermittent hypoxia/reoxygenation (IHR) stimulation was used to test the effect of hypoxia on the viability, reactive oxygen species, apoptosis, and inflammation-associated cytokine expression in the HL-1 cell line. To investigate the effect of patients' exosomes on HIF-1 and inflammation-associated cytokine expression, as well as the relationship between ODI and their expression, exosomes were purified from the plasma of 95 patients with SRBD and incubated in HL-1 cells. The LA size was larger in patients with significant OSAS than in those without. There was a significant association between ODI, lowest SpO2, mean SpO2, and LA size (all p < 0.05) but not between the apnea-hypopnea index and LA size. IHR condition caused increased LDH activity, reactive oxygen species (ROS) levels, and apoptosis in HL-1 cells and decreased cellular viability (all p < 0.05). The expression of HIF-1α, TNF-α, IL-6, and TGF-ß increased in the IHR condition compared with the control (all p < 0.05). The expression of HIF-1α, IL-1ß, and IL-6 increased in the HL-1 cells incubated with exosomes from those patients with significant OSAS than those without (all p < 0.05). There was a significantly positive correlation between ODI and the expression of HIF-1α, TNF-α, IL-1ß, IL-6, and TGF-ß; a significantly negative correlation between mean SpO2 and IL-6 and TGF-ß; and a significantly negative correlation between the lowest SpO2 and HIF-1α (all p < 0.05). In conclusion, intermittent hypoxemia was strongly associated with LA remodeling, which might be through increased ROS levels, LDH activity, apoptosis, and the expression of HIF-1α and inflammation-associated cytokines.

Comparison of Different Risk Scores for Prediction of In-Hospital Mortality in STEMI Patients Treated with PPCI.

Background: Several risk scores have been developed to predict and analyze in-hospital mortality and short- and long-term outcomes of ST-elevation myocardial infarction (STEMI) patients after primary percutaneous coronary intervention (PPCI); these can classify patients as having a high or low risk of death or complications. Objective: To compare the prognostic precision of four risk scores for predicting in-hospital mortality in patients with STEMI treated with PPCI. Methods: We performed a retrospective cohort analysis of patients with STEMI who underwent PPCI between 2012 and 2019 (N = 1346). GRACE (Global Registry of Acute Cardiac Events), CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications), Zwolle, and TIMI (Thrombolysis in Myocardial Infarction) risk scores were calculated for each patient according to different variables. We evaluated the predictive accuracy of these scores for in-hospital mortality using the C statistic, which was obtained using logistic regression and receiver operating characteristic curves. Results: The GRACE, CADILLAC, Zwolle, and TIMI risk scores all had good predictive precision for in-hospital mortality, with C statistics ranging from 0.842 to 0.923. The GRACE and CADILLAC risk scores were found to be superior. Conclusions: All GRACE, CADILLAC, Zwolle, and TIMI risk scores showed a high predictive value for in-hospital mortality due to all causes in patients with STEMI treated with PPCI. The GRACE and CADILLAC risk scores revealed a better accuracy for predicting in-hospital mortality than the Zwolle and TIMI risk scores.

Differential Risk of Dementia Between Patients With Atrial Flutter and Atrial Fibrillation: A National Cohort Study.

Objectives: Atrial fibrillation (AF) is linked to an increased risk of stroke and dementia. Atrial flutter (AFL) is also linked to an increased risk of stroke but at a different level of risk as compared to AF. Little is known about the difference in the risk of dementia between AF and AFL. This study aims to investigate whether the risk of dementia is different between AF and AFL. Methods: Patients with newly diagnosed AF and AFL during 2001-2013 were retrieved from Taiwan's National Health Insurance Research Database. Patients with incomplete demographic data, aged <20 years, history of valvular surgery, rheumatic heart disease, hyperthyroidism, and history of dementia were excluded. The incidence of new-onset dementia was set as the primary outcome and analyzed in patients with AF and AFL after propensity score matching (PSM). Results: A total of 232,425 and 7,569 patients with AF and AFL, respectively, were eligible for analysis. After 4:1 PSM, we included 30,276 and 7,569 patients with AF and AFL, respectively, for analysis. Additionally, patients with AF (n = 29,187) and AFL (n = 451) who received oral anticoagulants were enrolled for comparison. The risk of dementia was higher in patients with AF compared with patients with AFL (subdistribution hazard ratio (SHR) = 1.52, 95% CI 1.39-1.66; p < 0.0001) before PSM and remained higher in patients with AF (SHR = 1.14, 95% CI 1.04-1.25; p = 0.0064) after PSM. The risk of dementia was higher in patients with AF without previous history of stroke after PSM but the risk did not differ between patients with AF and AFL with previous history of stroke. Among patients who received oral anticoagulants, the cumulative incidences of dementia were significantly higher in patients with AF than in patients with AFL before and after PSM (all P < 0.05). Conclusions: This study found that, among patients without history of stroke, the risk of dementia was higher in patients with AF than in patients with AFL, and CHA2DS2-VASc score might be useful for risk stratification of dementia between patients with AF and AFL.

Macrophage Inflammatory Protein-1 Alpha, a Potential Biomarker for Predicting Left Atrial Remodeling in Patients With Atrial Fibrillation.

Objectives: Left atrial (LA) remodeling itself is an independent risk factor for ischemic stroke and mortality, with or without atrial fibrillation (AF). Macrophage inflammatory protein-1 alpha (MIP-1α) has been reported to be involved in the induction of autoimmune myocarditis and dilated cardiomyopathy. Little is known about whether MIP-1α can be used to predict LA remodeling, especially in patients with AF. Methods: We prospectively enrolled 78 patients who had received a cardiac implantable electronic device due to sick sinus syndrome in order to define AF accurately. AF was diagnosed clinically before enrollment, according to 12-lead electrocardiography (ECG) and 24-h Holter test in 54 (69%) patients. The serum cytokine levels and the mRNA expression levels of peripheral blood leukocytes were checked and echocardiographic study was performed on the same day within 1 week after the patients were enrolled into the study. The 12-lead ECG and 24-h Holter test were performed on the same day of the patients' enrollment, and the device interrogation was performed every 3 months after enrollment. The enrolled patients were clinically followed up for 1 year. Results: There was no difference in baseline characteristics, cytokine levels and mRNA expression between patients with and without AF. Larger LA volume was positively correlated with higher levels of MIP-1α (r = 0.461, p ≤ 0.001) and the atrial high-rate episodes (AHREs) burden (r = 0.593, p < 0.001), and negatively correlated with higher levels of transforming growth factor (TGF)-ß1 (r = -0.271, p = 0.047) and TGF-ß3 (r = -0.279, p = 0.041). The higher AHREs burden and MIP-1α level could predict LA volume independently. The mRNA expression of RORC was negatively associated with the MIP-1α level. Conclusions: This study showed that higher MIP-1α was significantly associated with LA remodeling and may have the potentials to predict LA remodeling in terms of a larger LA volume, and that circadian gene derangement might affect the expression of MIP-1α.

Corrigendum: Differential Risk of Dementia Between Patients With Atrial Flutter and Atrial Fibrillation: A National Cohort Study.

[This corrects the article DOI: 10.3389/fcvm.2021.787866.].

GJA1 Expression and Left Atrial Remodeling in the Incidence of Atrial Fibrillation in Patients with Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea syndrome (OSAS) is an important risk factor for atrial fibrillation (AF). GJA1 gene encoding connexin43, a major protein in cardiac gap junctions, plays a crucial role in the synchronized contraction of the heart and in cardiac arrhythmia. However, little is known regarding the role of GJA1 expression in the incidence of AF in patients with OSAS. All prospectively enrolled OSAS patients underwent polysomnography, electrocardiography, a 24-h Holter test, and echocardiography. Moderate-to-severe OSAS was defined as an apnea-hypopnea index (AHI) ≥ 15. Exosomes were purified from the plasma of all OSAS patients and incubated in HL-1 cells to investigate the effect of exosomes from patients with and without AF on GJA1 expression. A total of 129 patients were recruited for this study; 26 were excluded due to an AHI < 15. Of the 103 enrolled patients, 21 had AF, and 82 did not. Multivariate analysis showed diabetes mellitus, lower sleep efficiency, lower left ventricular ejection fraction, and larger left atrial (LA) size were independent predictors of AF occurrence in OSAS patients. The area under the receiver operating characteristic curve for LA with a size ≥38.5 mm for predicting AF occurrence in OSAS patients was 0.795 (95% confidence interval [0.666, 0.925]); p < 0.001). GJA1 expression in HL-1 cells incubated with exosomes from OSAS patients with AF was lower than that with exosomes from patients without AF after controlling for age and sex and was negatively correlated with the AHI and oxygen desaturation index (ODI), especially during the non-rapid eye movement period (NREM) of OSAS patients with AF (all p < 0.05). LA size was an independent predictor of AF occurrence in OSAS patients. The AHI and ODI in the NREM period of OSAS patients with AF were negatively correlated with GJA1 expression in HL-1 cells, which offers a hint that GJA1 may play a crucial role in the development of AF in patients with OSAS.

Sex Difference in the Risk of Dementia in Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is one of the risk factors for dementia. Female sex is an inconsistent risk factor for dementia after adjusting for age in the general population, and there lacks research on its impact in developing dementia in patients with AF. This paper aims to investigate whether female sex is a risk factor for dementia in AF patients. Data of patients with newly diagnosed AF between 2001-2013 were retrieved from Taiwan's National Health Insurance Research Database. Exclusion criteria were: patients with incomplete demographic data, age < 20 years, rheumatic heart disease, hyperthyroidism, past valvular heart surgery, and a history of dementia. Propensity score matching (PSM) between sexes was performed, including comorbidities, medications and index date stratified by age. The primary outcome was a new diagnosis of dementia at follow-up. A total of 117,517 men and 156,705 women were eligible for analysis. After 1:1 PSM, both 100,065 men and women (aged 72.5 ± 12.5 years) were included for analysis. Dementia risk varied with age in women compared with men. The difference was negligible for ≤55 years (sub distribution HR (SHR) = 0.89, 95% CI 0.73-1.07), but increased between 56-65 years (SHR = 1.13, 95% CI 1.02-1.25), 66-75 years (SHR = 1.14, 95% CI 1.09-1.20), 75-85 years (SHR = 1.11, 95% CI 1.07-1.15) and >85 years (SHR 1.10, 95% CI 1.04-1.16) for females. This study establishes that female sex increases the risk of developing dementia compared to male sex in AF patients aged >56 years. However, the impact of female sex on dementia in AF patients differs between dementia types.

Localization of right ventricular non-apical lead position: comparison of three-dimensional echocardiography, computed tomography, and fluoroscopic imaging.

OBJECTIVE: Right ventricular (RV) septal pacing is considered a better pacing procedure compared with traditional apical pacing. This study aimed to investigate agreement among computed tomography (CT), three-dimensional echocardiography (3D-echo), and fluoroscopy for evaluating the tip of the RV pacing lead in the non-apical position in patients with permanent pacemaker implantation. METHODS: Fifty-four patients were prospectively enrolled. Data on patients' characteristics and imaging findings were analyzed. The agreement rate in distinguishing the RV septal lead position among the three imaging modalities was determined. RESULTS: Thirty-three (61%) patients were men and the median age was 76 years. Overall, the agreement rate among the three imaging modalities was 87% (47/54; Kappa ratio: 0.734). The agreement of 3D-echo compared with thoracic CT (Kappa ratio: 0.893) was better than that for thoracic CT and fluoroscopy (Kappa ratio: 0.658). Agreement between fluoroscopy and 3D-echo was lowest (Kappa ratio: 0.632). CONCLUSIONS: Agreement in evaluating the position of the septal lead between thoracic CT and 3D-echo is better than that between other imaging modalities. Our findings indicate that 3D-echo imaging might be the best imaging tool for defining the tip of the RV non-apical lead position and be useful for guiding positioning of the RV lead.

Altered Expression of Circadian Clock Genes in Patients with Atrial Fibrillation Is Associated with Atrial High-Rate Episodes and Left Atrial Remodeling.

A prominent circadian variation is present in atrial fibrillation (AF) attacks that may be related to the expression of circadian clock genes. Little is known about the expression of circadian clock genes in AF. We prospectively enrolled 73 patients who had received pacemaker implantation, in order to define the burden of atrial high-rate episodes (AHREs) accurately. AF was diagnosed clinically in 43 (59%) patients (15 with persistent AF and 28 with paroxysmal AF). The expression levels of circadian clock genes of peripheral blood leukocytes were checked. There were more males and patients with a larger left atrial (LA) size and lower expression levels of BMAL1, CRY2, NR1D1, NR1D2, PER2, RORA, RORC, and TIM genes in persistent AF group than in other groups. There was a significant correlation between higher AHRE burden and larger LA size and between higher AHRE burden and decreased expression of circadian clock genes in patients with AF. LA volume and the expression of CRY1, NR1D1, and RORA are significantly associated with AHRE burden. However, the underlying mechanism needs to be elucidated in further studies.

Proposed A2C2S2-VASc score for predicting atrial fibrillation development in patients with atrial flutter.

AIMS: The clinical outcome and threshold of oral anticoagulation differs between patients with solitary atrial flutter (AFL) and those with AFL developing atrial fibrillation (AF) (AFL-DAF). We therefore investigated previously unevaluated predictors of AF development in patients with AFL, and also the predictive values of risk scores in predicting the occurrence of AF and ischaemic stroke. METHODS AND RESULTS: Participants were those diagnosed with AFL between 1 January 2001 and 31 December 2013. Patients were classified into solitary AFL and AFL-DAF groups during follow-up. Finally, 4101 patients with solitary AFL and 4101 patients with AFL-DAF were included after 1:1 propensity score matching with CHA2DS2-VASc scores and their components, AFL diagnosis year and other comorbidities. The group difference in the prevalence of ischaemic stroke/transient ischaemic attack (TIA) and congestive heart failure (CHF) was substantial, that of vascular disease was moderate, and that of diabetes and hypertension was negligible. Therefore, we reweighted the component of heart failure as 2 (the same with stroke/TIA) and vascular disease as 1 in the proposed A2C2S2-VASc score. The proposed A2C2S2-VASc and CHA2DS2-VASC scores showed patients with AFL who had higher delta scores and follow-up scores had higher risk of AF development. The delta score outperformed the follow-up score in both scoring systems in predicting ischaemic stroke. CONCLUSION: This study showed that new-onset CHF, stroke/TIA and vascular disease were predictors of AF development in patients with AFL. The dynamic score and changes in both CHA2DS2-VASC and the proposed A2C2S2-VASc score could predict the development of AF and ischaemic stroke.

A Strategy to Treat COVID-19 Disease With Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Preclinical Pharmacokinetic Study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing the coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, achievement of lung concentrations predicted to have in vivo antiviral efficacy might not be possible with the currently proposed oral dosing regimens. Further, high cumulative doses of HCQ raise concerns of systemic toxicity, including cardiotoxicity. Here, we describe a preclinical study to investigate the pharmacokinetics (PKs) of a novel formulation of liposomal HCQ administered by intratracheal (IT) instillation in Sprague-Dawley rats. Compared with unformulated HCQ administered intravenously, liposomal HCQ showed higher (~ 30-fold) lung exposure, longer (~ 2.5-fold) half-life in lungs, but lower blood exposure with ~ 20% of peak plasma concentration (Cmax ) and 74% of area under the curve from 0 to 72 hours (AUC0-72 ) and lower heart exposure with 23% of Cmax and 58% of AUC0-24 (normalized for dose). Similar results were observed relative to IT administration of unformulated HCQ. These PKs result in an animal model that demonstrated the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.

Stability Analysis of Continuous-Time Switched Neural Networks With Time-Varying Delay Based on Admissible Edge-Dependent Average Dwell Time.

This article investigates the stability of the switched neural networks (SNNs) with a time-varying delay. To effectively guarantee the stability of the considered system with unstable subsystems and reduce conservatism of the stability criteria, admissible edge-dependent average dwell time (AED-ADT) is first utilized to restrict switching signals for the continuous-time SNNs, and multiple Lyapunov-Kravosikii functionals (LKFs) combining relaxed integral inequalities are employed to develop two novel less-conservative stability conditions. Finally, the numeral examples clearly indicate that the proposed criteria can reduce conservatism and ensure the stability of continuous-time SNNs.