Three-dimensional mapping and superior approach for catheter ablation in patients without inferior vena cava access.

Catheter ablation for tachyarrhythmia via superior approach has been used in patients without possible inferior vena cava access such as in cases of venous occlusion or complex anomaly. Difficulty in catheter manipulation, instability, number of required vascular access, and radiation exposure of operator had been described in the procedure. Application of three-dimensional (3-D) mapping system in catheter ablation via superior approach could navigate the guiding catheter and provide more precise ablation. We reported four cases receiving catheter ablation due to atrioventricular nodal reentry tachycardia, atrial fibrillation, and right ventricular arrhythmia via superior approach facilitated by 3-D mapping system with fewer vascular access and catheters.

Impact of proximity of left atrium to descending aorta on left inferior pulmonary vein triggers or drivers of atrial fibrillation: A risk score model.

BACKGROUND: Prior studies have investigated cardiac anatomy and clinical parameters as predictors for pulmonary vein and non-pulmonary vein triggers. OBJECTIVE: We aimed to assess the link between the descending aorta to left inferior pulmonary vein (Dao-LIPV) distance and the occurrence of triggers and drivers in atrial fibrillation (AF) ablation procedures. METHODS: Drug-refractory AF patients who underwent first-time index catheter ablation from January 2010 to December 2019 were retrospectively assembled. The Dao-LIPV distance was measured from preablation pulmonary vein computed tomography. Patients were assigned to groups on the basis of the presence of LIPV triggers or drivers. Multivariate logistic regression was used to identify risk factors. RESULTS: A total of 886 consecutive patients with drug-refractory AF were studied, and 63 (7.1%) patients were identified to have LIPV triggers or drivers. The Dao-LIPV distance had a better predictive performance (area under the curve, 0.70) compared with persistent AF (area under the curve, 0.57). Multivariate logistic regression analysis showed that Dao-LIPV distance ≤2.5 mm (odds ratio, 3.96; 95% CI, 2.15-7.29; P < .001) and persistent AF (odds ratio, 1.73; 95% CI, 1.02-2.94]; P = .044) were independent predictors for the presence of LIPV triggers or drivers. A risk score model was established to predict the probability of LIPV triggers or drivers with persistent AF (10.2%), Dao-LIPV distance ≤2.5 mm (11.4%), and both (15.0%). CONCLUSION: The proximity of the Dao-LIPV was correlated to the presence of LIPV triggers or drivers. We developed a risk score model indicating that persistent AF and Dao-LIPV distances ≤2.5 mm significantly increase the risk of LIPV triggers or drivers, aiding electrophysiologists in preparing for and performing catheter ablation more effectively.

Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment.

A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1H-pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33, exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8+ T-cells, and helper CD4+ T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 (BPR5K230) with excellent oral bioavailability (F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.

Persistent Mesodermal Differentiation Capability of Bone Marrow MSCs Isolated from Aging Patients with Low-Energy Traumatic Hip Fracture and Osteoporosis: A Clinical Evidence.

A low-energy hit, such as a slight fall from a bed, results in a bone fracture, especially in the hip, which is a life-threatening risk for the older adult and a heavy burden for the social economy. Patients with low-energy traumatic bone fractures usually suffer a higher level of bony catabolism accompanied by osteoporosis. Bone marrow-derived stem cells (BMSCs) are critical in osteogenesis, leading to metabolic homeostasis in the healthy bony microenvironment. However, whether the BMSCs derived from the patients who suffered osteoporosis and low-energy traumatic hip fractures preserve a sustained mesodermal differentiation capability, especially in osteogenesis, is yet to be explored in a clinical setting. Therefore, we aimed to collect BMSCs from clinical hip fracture patients with osteoporosis, followed by osteogenic differentiation comparison with BMSCs from healthy young donors. The CD markers identification, cytokines examination, and adipogenic differentiation were also evaluated. The data reveal that BMSCs collected from elderly osteoporotic patients secreted approximately 122.8 pg/mL interleukin 6 (IL-6) and 180.6 pg/mL vascular endothelial growth factor (VEGF), but no PDGF-BB, IL-1b, TGF-b1, IGF-1, or TNF-α secretion. The CD markers and osteogenic and adipogenic differentiation capability in BMSCs from these elderly osteoporotic patients and healthy young donors are equivalent and compliant with the standards defined by the International Society of Cell Therapy (ISCT). Collectively, our data suggest that the elderly osteoporotic patients-derived BMSCs hold equivalent differentiation and proliferation capability and intact surface markers identical to BMSCs collected from healthy youth and are available for clinical cell therapy.

Investigating cartilage-related diseases by polarization-resolved second harmonic generation (P-SHG) imaging.

Establishing quantitative parameters for differentiating between healthy and diseased cartilage tissues by examining collagen fibril degradation patterns facilitates the understanding of tissue characteristics during disease progression. These findings could also complement existing clinical methods used to diagnose cartilage-related diseases. In this study, cartilage samples from normal, osteoarthritis (OA), and rheumatoid arthritis (RA) tissues were prepared and analyzed using polarization-resolved second harmonic generation (P-SHG) imaging and quantitative image texture analysis. The enhanced molecular contrast obtained from this approach is expected to aid in distinguishing between healthy and diseased cartilage tissues. P-SHG image analysis revealed distinct parameters in the cartilage samples, reflecting variations in collagen fibril arrangement and organization across different pathological states. Normal tissues exhibited distinct χ33/χ31 values compared with those of OA and RA, indicating collagen type transition and cartilage erosion with chondrocyte swelling, respectively. Compared with those of normal tissues, OA samples demonstrated a higher degree of linear polarization, suggesting increased tissue birefringence due to the deposition of type-I collagen in the extracellular matrix. The distribution of the planar orientation of collagen fibrils revealed a more directional orientation in the OA samples, associated with increased type-I collagen, while the RA samples exhibited a heterogeneous molecular orientation. This study revealed that the imaging technique, the quantitative analysis of the images, and the derived parameters presented in this study could be used as a reference for disease diagnostics, providing a clear understanding of collagen fibril degradation in cartilage.

Signal-averaged electrocardiography as a noninvasive tool for evaluating the ventricular substrate in patients with nonischemic cardiomyopathy: reassessment of an old tool.

Introduction: Signal-averaged electrocardiography (SAECG) provides diagnostic and prognostic information regarding cardiac diseases. However, its value in other nonischemic cardiomyopathies (NICMs) remains unclear. This study aimed to investigate the role of SAECG in patients with NICM. Methods and results: This retrospective study included consecutive patients with NICM who underwent SAECG, biventricular substrate mapping, and ablation for ventricular arrhythmia (VA). Patients with baseline ventricular conduction disturbances were excluded. Patients who fulfilled at least one SAECG criterion were categorized into Group 1, and the other patients were categorized into Group 2. Baseline and ventricular substrate characteristics were compared between the two groups. The study included 58 patients (39 men, mean age 50.4 ± 15.5 years), with 34 and 24 patients in Groups 1 and 2, respectively. Epicardial mapping was performed in eight (23.5%) and six patients (25.0%) in Groups 1 and 2 (p = 0.897), respectively. Patients in Group 1 had a more extensive right ventricular (RV) low-voltage zone (LVZ) and scar area than those in Group 2. Group 1 had a larger epicardial LVZ than Group 2. Epicardial late potentials were more frequent in Group 1 than in Group 2. There were more arrhythmogenic foci within the RV outflow tract in Group 1 than in Group 2. There was no significant difference in long-term VA recurrence. Conclusion: In our NICM population, a positive SAECG was associated with a larger RV endocardial scar, epicardial scar/late potentials, and a higher incidence of arrhythmogenic foci in the RV outflow tract.

Use of artificial intelligence and I-Score for prediction of recurrence before catheter ablation of atrial fibrillation.

BACKGROUND: Based solely on pre-ablation characteristics, previous risk scores have demonstrated variable predictive performance. This study aimed to predict the recurrence of AF after catheter ablation by using artificial intelligence (AI)-enabled pre-ablation computed tomography (PVCT) images and pre-ablation clinical data. METHODS: A total of 638 drug-refractory paroxysmal atrial fibrillation (AF) patients undergone ablation were recruited. For model training, we used left atria (LA) acquired from pre-ablation PVCT slices (126,288 images). A total of 29 clinical variables were collected before ablation, including baseline characteristics, medical histories, laboratory results, transthoracic echocardiographic parameters, and 3D reconstructed LA volumes. The I-Score was applied to select variables for model training. For the prediction of one-year AF recurrence, PVCT deep-learning and clinical variable machine-learning models were developed. We then applied machine learning to ensemble the PVCT and clinical variable models. RESULTS: The PVCT model achieved an AUC of 0.63 in the test set. Various combinations of clinical variables selected by I-Score can yield an AUC of 0.72, which is significantly better than all variables or features selected by nonparametric statistics (AUCs of 0.66 to 0.69). The ensemble model (PVCT images and clinical variables) significantly improved predictive performance up to an AUC of 0.76 (sensitivity of 86.7% and specificity of 51.0%). CONCLUSIONS: Before ablation, AI-enabled PVCT combined with I-Score features was applicable in predicting recurrence in paroxysmal AF patients. Based on all possible predictors, the I-Score is capable of identifying the most influential combination.

Feasibility of Auto-Quantified Epicardial Adipose Tissue in Predicting Atrial Fibrillation Recurrence After Catheter Ablation.

BACKGROUND: The aim of this study was to build an auto-segmented artificial intelligence model of the atria and epicardial adipose tissue (EAT) on computed tomography (CT) images, and examine the prognostic significance of auto-quantified left atrium (LA) and EAT volumes for AF. METHODS AND RESULTS: This retrospective study included 334 patients with AF who were referred for catheter ablation (CA) between 2015 and 2017. Atria and EAT volumes were auto-quantified using a pre-trained 3-dimensional (3D) U-Net model from pre-ablation CT images. After adjusting for factors associated with AF, Cox regression analysis was used to examine predictors of AF recurrence. The mean (±SD) age of patients was 56±11 years; 251 (75%) were men, and 79 (24%) had non-paroxysmal AF. Over 2 years of follow-up, 139 (42%) patients experienced recurrence. Diabetes, non-paroxysmal AF, non-pulmonary vein triggers, mitral line ablation, and larger LA, right atrium, and EAT volume indices were linked to increased hazards of AF recurrence. After multivariate adjustment, non-paroxysmal AF (hazard ratio [HR] 0.6; 95% confidence interval [CI] 0.4-0.8; P=0.003) and larger LA-EAT volume index (HR 1.1; 95% CI 1.0-1.2; P=0.009) remained independent predictors of AF recurrence. CONCLUSIONS: LA-EAT volume measured using the auto-quantified 3D U-Net model is feasible for predicting AF recurrence after CA, regardless of AF type.

Deep learning-based workflow for automatic extraction of atria and epicardial adipose tissue on cardiac computed tomography in atrial fibrillation.

BACKGROUND: Preoperative estimation of the volume of the left atrium (LA) and epicardial adipose tissue (EAT) on computed tomography (CT) images is associated with an increased risk of atrial fibrillation (AF) recurrence. We aimed to design a deep learning-based workflow to provide reliable automatic segmentation of the atria, pericardium, and EAT for future applications in the management of AF. METHODS: This study enrolled 157 patients with AF who underwent first-time catheter ablation between January 2015 and December 2017 at Taipei Veterans General Hospital. Three-dimensional (3D) U-Net models of the LA, right atrium (RA), and pericardium were used to develop a pipeline for total, LA-EAT, and RA-EAT automatic segmentation. We defined fat within the pericardium as tissue with attenuation between -190 and -30 HU and quantified the total EAT. Regions between the dilated endocardial boundaries and endocardial walls of the LA or RA within the pericardium were used to detect voxels attributed to fat, thus estimating LA-EAT and RA-EAT. RESULTS: The LA, RA, and pericardium segmentation models achieved Dice coefficients of 0.960 ± 0.010, 0.945 ± 0.013, and 0.967 ± 0.006, respectively. The 3D segmentation models correlated well with the ground truth for the LA, RA, and pericardium ( r = 0.99 and p < 0.001 for all). The Dice coefficients of our proposed method for EAT, LA-EAT, and RA-EAT were 0.870 ± 0.027, 0.846 ± 0.057, and 0.841 ± 0.071, respectively. CONCLUSION: Our proposed workflow for automatic LA, RA, and EAT segmentation using 3D U-Nets on CT images is reliable in patients with AF.

Catheter ablation in patients with atrial fibrillation and dilated cardiomyopathy.

Introduction: Catheter ablation is an effective and safe strategy for treating atrial fibrillation patients. Nevertheless, studies on the long-term outcomes of catheter ablation in patients with dilated cardiomyopathy are limited. This study aimed to assess the electrophysiological characteristics of atrial fibrillation patients with dilated cardiomyopathy and compare the long-term clinical outcomes between patients undergoing catheter ablation and medical therapy. Method: Patient baseline characteristics and electrophysiological parameters were examined to identify the predictors of atrial fibrillation recurrence following catheter ablation. The clinical outcomes of catheter ablation and medical therapy were compared using the propensity score matched method. Results: A total of 343 patients were enrolled, with 46 in the catheter ablation group and 297 in the medical therapy group. Among the catheter ablation group, 58.7% (n = 27) had persistent atrial fibrillation. The recurrence rate of atrial arrhythmia was 30.4% (n = 14) after an average follow-up duration of 7.7 years following catheter ablation. The only predictive factor for atrial fibrillation recurrence after catheter ablation was the left atrial diameter. When compared to medical therapy, catheter ablation demonstrated significantly better outcomes in terms of overall survival, freedom from heart failure hospitalization, improvement in left ventricular ejection fraction, and a greater reduction in left ventricular diameter and left atrial diameter after propensity score matching. Conclusions: Therefore, catheter ablation proves to be effective in providing long-term control of atrial fibrillation in patients with dilated cardiomyopathy. In addition to standard heart failure care, catheter ablation significantly enhanced both morbidity and mortality outcomes and reversed structural remodeling when compared to heart failure medication alone.

Lower contact force predicts right pulmonary vein carina breakthrough after ablation index-guided pulmonary vein isolation using high-power short-duration.

INTRODUCTION: Carina breakthrough (CB) at the right pulmonary vein (RPV) can occur after circumferential pulmonary vein isolation (PVI) due to epicardial bridging or transient tissue edema. High-power short-duration (HPSD) ablation may increase the incidence of RPV CB. Currently, the surrogate of ablation parameters to predict RPV CB is not well established. This study investigated predictors of RPV CB in patients undergoing ablation index (AI)-guided PVI with HPSD. METHODS: The study included 62 patients with symptomatic atrial fibrillation (AF) who underwent AI-guided PVI using HPSD. Patients were categorized into two groups based on the presence or absence of RPV CB. Lesions adjacent to the RPV carina were assessed, and CB was confirmed through residual voltage, low voltage along the ablation lesions, and activation wavefront propagation. RESULTS: Out of the 62 patients, 21 (33.87%) experienced RPV CB (Group 1), while 41 (66.13%) achieved first-pass RPV isolation (Group 2). Despite similar AI and HPSD, patients with RPV CB had lower contact force (CF) at lesions adjacent to the RPV carina. Receiver operating characteristic (ROC) curve analysis identified CF < 10.5 g as a predictor of RPV CB, with 75.7% sensitivity and 56.2% specificity (area under the curve: 0.714). CONCLUSION: In patients undergoing AI-guided PVI with HPSD, lower CF adjacent to the carina was associated with a higher risk of RPV CB. These findings suggest that maintaining higher CF during ablation in this region may reduce the occurrence of RPV CB.

Skin sympathetic nerve activity in different ablation settings for atrial fibrillation.

BACKGROUND: Modifying the autonomic system after catheter ablation may prevent the recurrence of atrial fibrillation (AF). Evaluation of skin sympathetic nerve activity (SKNA) is a noninvasive method for the assessment of sympathetic activity. However, there are few studies on the effects of different energy settings on SKNA. OBJECTIVE: To investigate the changes in SKNA in different energy settings and their relationship to AF ablation outcomes. METHODS: Seventy-two patients with paroxysmal and persistent AF were enrolled. Forty-three patients received AF ablation with the conventional (ConV) energy setting (low power for long duration), and 29 patients using a high-power, short-duration (HPSD) strategy. The SKNA was acquired from the right arm 1 day before and after the radiofrequency ablation. We analyzed the SKNA and ablation outcomes in the different energy settings. RESULTS: Both groups had a similar baseline average SKNA (aSKNA). We found that the median aSKNA increased significantly from 446.82 µV to 805.93 µV (p = 0.003) in the ConV group but not in the HPSD group. In the ConV group, patients without AF recurrence had higher aSKNA values. However, the 1-year AF recurrence rate remained similar between both groups (35 % vs. 28 %, p = 0.52). CONCLUSION: The post-ablation aSKNA levels increased significantly in the ConV group but did not change significantly in the HPSD group, which may reflect different neuromodulatory effects. However, the one-year AF recurrence rates were similar for both groups. These results demonstrate that the HPSD strategy has durable lesion creation but less lesion depth, which may reduce collateral damage.

Clinical significance of substrate characteristics and ablation outcomes in patients with atrial fibrillation and significant functional mitral regurgitation.

Background: Atrial fibrillation (AF) and mitral regurgitation (MR) have a complex interplay. Catheter ablation (CA) of AF may be a potential method to improve the severity of MR in AF patients. Methods: Patients with symptomatic AF and moderate to severe MR who underwent catheter ablation from 2011 to 2021 were retrospectively included in the study. Patients' baseline characteristics and electrophysiological features were examined. These patients were classified as group 1 with improved MR and group 2 with refractory MR after CA. Results: Fifty patients (age 60.2 ± 11.6 years, 29 males) were included in the study (32 in group 1 and 18 in group 2). Group 1 patients had a lower CHA2DS2-VASc score (1.7 ± 1.5 vs. 2.7 ± 1.5, P = 0.005) and had a lower incidence of hypertension (28.1% vs. 66.7%, P = 0.007) and diabetes mellitus (3.1% vs. 22.2%, P = 0.031) as compared to group 2 patients. Electroanatomic three-dimensional (3D) mapping showed that group 1 patients demonstrated less scars on the posterior bottom of the left atrium compared to group 2 patients (12.5% vs. 66.7%, P < 0.001). AF recurrence was not different between the two groups. After multivariate logistic regression analysis, a posterior bottom scar in the left atrium independently predicted refractory MR despite successful AF ablation. Conclusion: Most patients with AF and MR showed improvement of MR after AF ablation. A scar involving the posterior bottom of the left atrium is associated with poor recovery of MR.

Catheter Ablation With Morphologic Repetitiveness Mapping for Persistent Atrial Fibrillation.

Importance: Catheter ablation for persistent atrial fibrillation (AF) has shown limited success. Objective: To determine whether AF drivers could be accurately identified by periodicity and similarity (PRISM) mapping ablation results for persistent AF when added to pulmonary vein isolation (PVI). Design, Setting, and Participants: This prospective randomized clinical trial was performed between June 1, 2019, and December 31, 2020, and included patients with persistent AF enrolled in 3 centers across Asia. Data were analyzed on October 1, 2022. Intervention: Patients were assigned to the PRISM-guided approach (group 1) or the conventional approach (group 2) at a 1:1 ratio. Main Outcomes and Measures: The primary outcome was freedom from AF or other atrial arrhythmia for longer than 30 seconds at 6 and 12 months. Results: A total of 170 patients (mean [SD] age, 62.0 [12.3] years; 136 men [80.0%]) were enrolled (85 patients in group 1 and 85 patients in group 2). More group 1 patients achieved freedom from AF at 12 months compared with group 2 patients (60 [70.6%] vs 40 [47.1%]). Multivariate analysis indicated that the PRISM-guided approach was associated with freedom from the recurrence of atrial arrhythmia (hazard ratio, 0.53 [95% CI, 0.33-0.85]). Conclusions and Relevance: The waveform similarity and recurrence pattern derived from high-density mapping might provide an improved guiding approach for ablation of persistent AF. Compared with the conventional procedure, this novel specific substrate ablation strategy reduced the frequency of recurrent AF and increased the likelihood of maintenance of sinus rhythm. Trial Registration: ClinicalTrials.gov Identifier: NCT05333952.

Factors predicting the progression from paroxysmal to persistent atrial fibrillation despite an index catheter ablation.

INTRODUCTION: Despite undergoing an index ablation, some patients progress from paroxysmal atrial fibrillation (PAF) to persistent AF (PersAF), and the mechanism behind this is unclear. The aim of this study was to investigate the predictors of progression to PersAF after catheter ablation in patients with PAF. METHODS: This study included 400 PAF patients who underwent an index ablation between 2015 and 2019. The patients were classified into three groups based on their outcomes: Group 1 (PAF to sinus rhythm, n = 226), Group 2 (PAF to PAF, n = 146), and Group 3 (PAF to PersAF, n = 28). Baseline and procedural characteristics were collected, and predictors for AF recurrence and progression were evaluated. RESULTS: The mean age of the patients was 58.4 ± 11.1 years, with 272 males. After 3 years of follow-up, 7% of the PAF cases recurred and progressed to PersAF despite undergoing an index catheter ablation. In the multivariable analysis, a larger left atrial (LA) diameter and the presence of non-pulmonary vein (PV) triggers during the index procedure independently predicted recurrence. Moreover, a larger LA diameter, the presence of non-PV triggers, and a history of thyroid disease independently predicted AF progression. CONCLUSION: The progression from PAF to PersAF after catheter ablation is associated with a larger LA diameter, history of thyroid disease, and the presence of non-PV triggers. Meticulous preprocedural evaluation, patient selection, and comprehensive provocation tests during catheter ablation are recommended.

Comparison of Long-Term Clinical Outcomes Between Segmental and Circumferential Pulmonary Vein Isolation in Patients Undergoing Repeat Atrial Fibrillation Ablation.

BACKGROUND: Circumferential pulmonary vein isolation (CPVI) has supplanted segmental PVI (SPVI) as standard procedure for atrial fibrillation (AF). However, there is limited evidence examining the efficacy of these strategies in redo ablations. In this study, we investigated the difference in recurrence rates between SPVI and CPVI in redo ablations for PV reconnection.Methods and Results: This study retrospectively enrolled 543 patients who had undergone AF ablation between 2015 and 2017. Among them, 167 patients (30.8%, including 128 male patients and 100 patients with paroxysmal AF) underwent redo ablation for recurrent AF. Excluding 26 patients without PV reconnection, 141 patients [90 patients of SPVI (Group 1) and 51 patients of CPVI (Group 2)] were included. The AF-free survival rates were 53.3% and 56.9% in Group 1 and Group 2, respectively (P=0.700). The atrial flutter (AFL)-free survival rates were 90% and 100% in Group 1 and Group 2, respectively (P=0.036). The ablation time was similar between groups, and there no major complications were observed. CONCLUSIONS: For redo AF ablation procedures, SPVI and CPVI showed similar outcomes, except for a higher AFL recurrence rate for SPVI after long-term follow-up (>2 years). This may be due to a higher probability of residual PV gaps causing reentrant AFL.

Shared decision making for anticoagulation reduces anxiety and improves adherence in patients with atrial fibrillation.

BACKGROUND: Treatment with oral anticoagulants (OACs) could prevent stroke in atrial fibrillation (AF), but side effects developed due to OACs may cause patients anxiety during decision making. This study aimed to investigate whether shared decision making (SDM) reduces anxiety and improves adherence to stroke prevention measures in patients with AF. METHODS: A one-group pretest-posttest design using a questionnaire survey was applied at the outpatient cardiology clinic between July 2019 until September 2020. A Patient Decision Aid (PDA) tool was used for the completion of the questionnaire survey after health education and counseling. Ten questions were included for patients' recognition of SDM, and a 5-point scoring method was used, where "very much" was scored as 5 points, and "totally not" was scored as 1 point. RESULTS: Fifty-two patients with AF were enrolled. In terms of patients' recognition of SDM, points of more than 4.17 out of 5 were noted, indicating recognition above the level of "very much." The patients' anxiety scores before SDM were 3.56 (1.2), with a decrease of 0.64 points (p < 0.001) to 2.92 (1.3) after SDM. After SDM, the number of patients who decided to take OAC increased from 76.9% to 88.5%, and the 15.4% answering "unclear" decreased to 1.9% (p = 0.006). The patients' anxiety levels after SDM were associated with gender (p = 0.025). CONCLUSIONS: The approach using SDM enhanced our understanding of the pros and cons of OAC treatment and, in patients with AF, decreased anxiety about therapeutic decisions and increased willingness to accept treatment options.

Discovery of tetrasubstituted thiophenes as Cisd2 activators: A potential novel therapeutic option in nonalcoholic fatty liver disease.

Down-regulation of Cisd2 in the liver has been implicated in the development of nonalcoholic fatty liver disease (NAFLD) and increasing the level of Cisd2 is therefore a potential therapeutic approach to this group of diseases. Herein, we describe the design, synthesis, and biological evaluation of a series of Cisd2 activators, all thiophene analogs, based on a hit obtained using two-stage screening and prepared via either the Gewald reaction or by intramolecular aldol-type condensation of an N,S-acetal. Metabolic stability studies of the resulting potent Cisd2 activators suggest that thiophenes 4q and 6 are suitable for in vivo studies. The results from studies on 4q-treated and 6-treated Cisd2hKO-het mice, which carry a heterozygous hepatocyte-specific Cisd2 knockout, confirm that (1) there is a correlation between Cisd2 levels and NAFLD and (2) these compounds have the ability to prevent, without detectable toxicity, the development and progression of NAFLD.

Administration of mRNA-Nanomedicine-Augmented Calvarial Defect Healing via Endochondral Ossification.

Large-area craniofacial defects remain a challenge for orthopaedists, hastening the need to develop a facile and safe tissue engineering strategy; osteoconductive material and a combination of optimal growth factors and microenvironment should be considered. Faced with the unmet need, we propose that abundant cytokines and chemokines can be secreted from the bone defect, provoking the infiltration of endogenous stem cells to assist bone regeneration. We can provide a potent mRNA medicine cocktail to promptly initiate the formation of bone templates, osteogenesis, and subsequent bone matrix deposition via endochondral ossification, which may retard rapid fibroblast infiltration and prevent the formation of atrophic non-union. We explored the mutual interaction of BMP2 and TGFß3 mRNA, both potent chondrogenic factors, on inducing endochondral ossification; examined the influence of in vitro the transcribed polyA tail length on mRNA stability; prepared mRNA nanomedicine using a PEGylated polyaspartamide block copolymer loaded in a gelatin sponge and grafted in a critical-sized calvarial defect; and evaluated bone regeneration using histological and µCT examination. The BMP2 and TGFß3 composite mRNA nanomedicine resulted in over 10-fold new bone volume (BV) regeneration in 8 weeks than the BMP2 mRNA nanomedicine administration alone, demonstrating that the TGFß3 mRNA nanomedicine synergistically enhances the bone's formation capability, which is induced by BMP2 mRNA nanomedicine. Our data demonstrated that mRNA-medicine-mediated endochondral ossification provides an alternative cell-free tissue engineering methodology for guiding craniofacial defect healing.