Purpose: The aim of this study was to assess the effects of tyrosine kinase inhibitors (TKIs) following metastasectomy in patients with metastatic renal cell carcinoma (mRCC). Materials and Methods: A systematic search of multiple electronic databases was conducted. The inclusion criteria encompassed randomized clinical trials evaluating the use of TKIs after metastasectomy in mRCC patients. Study outcomes were relapse-free survival (RFS)/disease-free survival (DFS), overall survival (OS), and adverse events of TKIs. Results: Two studies with 197 randomized participants that compared TKIs following metastasectomy versus metastasectomy alone were identified. According to these studies, TKIs following metastasectomy may result in little to no difference in RFS/DFS (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.65–1.57; I2=29%; low-certainty evidence). TKIs after metastasectomy may slightly increase OS, but the CI crossed the line of no effect (HR, 0.80; 95% CI, 0.06–9.87; I2=86%; low-certainty evidence). TKIs after metastasectomy likely resulted in a large increase in adverse events (risk ratio, 2.76; 95% CI: 1.65–4.62; I2=not applicable; moderatecertainty evidence). Conclusions TKIs following metastasectomy did not improve RFS/DFS, but slightly improved OS. It is likely that TKIs following metastasectomy increase adverse events compared to surgery only. The certainty of evidence ranged from moderate (signaling confidence that the reported effect size is likely close to the true effect) to low (indicating that the true effect may be substantially different from the effect estimate). The findings of this study should help to inform future guidelines and clinical decision-making at the point of care.

Background: Cardiac resynchronization therapy (CRT) is an effective treatment option for patients with heart failure (HF) and left ventricular (LV) dyssynchrony. However, the problem of some patients not responding to CRT remains unresolved. This study aimed to propose a novel in silico method for CRT simulation. Methods: Three-dimensional heart geometry was constructed from computed tomography images. The finite ele‑ ment method was used to elucidate the electric wave propagation in the heart. The electric excitation and mechani‑ cal contraction were coupled with vascular hemodynamics by the lumped parameter model. The model parameters for three-dimensional (3D) heart and vascular mechanics were estimated by matching computed variables with measured physiological parameters. CRT effects were simulated in a patient with HF and left bundle branch block (LBBB). LV end-diastolic (LVEDV) and end-systolic volumes (LVESV), LV ejection fraction (LVEF), and CRT responsiveness measured from the in silico simulation model were compared with those from clinical observation. A CRT responder was defined as absolute increase in LVEF ≥ 5% or relative increase in LVEF ≥ 15%. Results: A 68-year-old female with nonischemic HF and LBBB was retrospectively included. The in silico CRT simu‑ lation modeling revealed that changes in LVEDV, LVESV, and LVEF by CRT were from 174 to 173 mL, 116 to 104 mL, and 33 to 40%, respectively. Absolute and relative ΔLVEF were 7% and 18%, respectively, signifying a CRT responder.In clinical observation, echocardiography showed that changes in LVEDV, LVESV, and LVEF by CRT were from 162 to 119 mL, 114 to 69 mL, and 29 to 42%, respectively. Absolute and relative ΔLVESV were 13% and 31%, respectively, also signifying a CRT responder. CRT responsiveness from the in silico CRT simulation model was concordant with that in the clinical observation. Conclusion This in silico CRT simulation method is a feasible technique to screen for CRT non-responders in patients with HF and LBBB.

Background: As the number of large-scale studies involving multiple organizations producing data has steadily increased, an integrated system for a common interoperable format is needed. In response to the coronavirus disease 2019 (COVID-19) pandemic, a number of global efforts are underway to develop vaccines and therapeutics. We are therefore observing an explosion in the proliferation of COVID-19 data, and interoperability is highly requested in multiple institutions participating simultaneously in COVID-19 pandemic research. Results: In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface. The main aim of the implemented system is to integrate, standardize, and organize data collected from laboratories in multiple institutes for COVID-19 non-clinical efficacy testings. Six animal biosafety level 3 institutions proved the feasibility of our system. Substantial benefits were shown by maximizing collaborative high-quality non-clinical research. Conclusions This LIMS platform can be used for future outbreaks, leading to accelerated medical product development through the systematic management of extensive data from non-clinical animal studies.

Background/Aims: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. Methods: The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. Results: The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. Conclusions The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.

BACKGROUND AND OBJECTIVES: Nationwide social inequalities of oral anticoagulation (OAC) usage after the introduction of non-vitamin K antagonist oral anticoagulants (NOACs) have not been well identified in patients with atrial fibrillation (AF). This study assessed overall rate and social inequalities of OAC usage after the introduction of NOAC in Korea.METHODS: Between January 2002 and December 2016, we identified 888,540 patients with AF in the Korea National Health Insurance system database. The change of OAC rate in different medical systems after the introduction of NOAC were evaluated.RESULTS: In all population, overall OAC use increased from 13.2% to 23.4% (p for trend <0.001), and NOAC use increased from 0% to 14.6% (p for trend <0.001). Compared with pre-reimbursement (0.48%), the annual increase of OAC use was significantly higher after partial (1.16%, p<0.001), and full reimbursement of OAC (3.72%, p<0.001). Full reimbursement of NOAC (adjusted odds ratio, 2.10; 95% confidence interval, 2.04–2.15) was independently associated with higher OAC use. However, the difference of overall OAC usage between tertiary referral hospitals and nursing or public health centers increased from 17.9% in 2010 to 36.8% in 2016. Moreover, usage rate of NOAC was significantly different among different medical systems from 37.2% at the tertiary referral hospital and 5.5% at nursing or public health centers.CONCLUSIONS: Introduction of NOACs in routine practice for stroke prevention in AF was associated with improved rates of overall OAC use. However, significant practice-level variations in OAC and NOAC use remain producing social inequalities of OAC despite full reimbursement.
Anticoagulants ; Atrial Fibrillation ; Humans ; Insurance ; Korea ; National Health Programs ; Nursing ; Odds Ratio ; Public Health ; Socioeconomic Factors ; Stroke ; Tertiary Care Centers

BACKGROUND AND OBJECTIVES: The objective of this study was to evaluate the long-term clinical outcomes and the incidence of permanent pacemaker implantation after catheter ablation in patients with of atrial fibrillation (AF) and sinus node dysfunction (SND).METHODS: Among 3,068 total consecutive patients who underwent AF catheter ablation (AFCA), this study included 222 (9.5%; men 53.2%, 63.7±9.2 years of age, 81.5% paroxysmal AF) with underlying SND and a regular rhythm follow-up. We analyzed the rhythm outcomes, changes in the mean heart rate or heart rate variability, and permanent pacemaker implantation rate.RESULTS: During 47.5±28.8 months of follow-up, 25 (11.3%) patients received pacemaker implantations due to symptomatic SND. More than half (56.0%, 14/25) underwent a pacemaker implantation within 3 months of the AFCA, and the annual pacemaker implantation rate was 2.0% afterwards. Both the early (68.0% vs. 31.0%, p<0.001) and clinical AF recurrence (68.0% vs. 32.5%, p=0.001) rates and continuous antiarrhythmic drug use after 3 months (44.0% vs. 24.4%, p=0.036) were significantly higher in patients requiring pacemaker implantations than those that did not. An anterior linear ablation (odds ratio [OR], 9.37 [3.03–28.9]; p<0.001) and the E/Em (OR, 1.15 [1.02–1.28]; p=0.018) were independently associated with permanent pacemaker implantations after AFCA in patients with AF and SND.CONCLUSIONS: After AFCA in patients with AF and SND, 1 of 9 patients needed a pacemaker implantation and half needed implantations within 3 months. The AF recurrence rate was significantly higher in those who required pacemaker implantations after the AFCA.
Atrial Fibrillation ; Catheter Ablation ; Catheters ; Follow-Up Studies ; Heart Rate ; Humans ; Incidence ; Male ; Pacemaker, Artificial ; Recurrence ; Sick Sinus Syndrome ; Sinoatrial Node

BACKGROUND AND OBJECTIVES: The objective of this study was to evaluate the long-term clinical outcomes and the incidence of permanent pacemaker implantation after catheter ablation in patients with of atrial fibrillation (AF) and sinus node dysfunction (SND). METHODS: Among 3,068 total consecutive patients who underwent AF catheter ablation (AFCA), this study included 222 (9.5%; men 53.2%, 63.7±9.2 years of age, 81.5% paroxysmal AF) with underlying SND and a regular rhythm follow-up. We analyzed the rhythm outcomes, changes in the mean heart rate or heart rate variability, and permanent pacemaker implantation rate. RESULTS: During 47.5±28.8 months of follow-up, 25 (11.3%) patients received pacemaker implantations due to symptomatic SND. More than half (56.0%, 14/25) underwent a pacemaker implantation within 3 months of the AFCA, and the annual pacemaker implantation rate was 2.0% afterwards. Both the early (68.0% vs. 31.0%, p<0.001) and clinical AF recurrence (68.0% vs. 32.5%, p=0.001) rates and continuous antiarrhythmic drug use after 3 months (44.0% vs. 24.4%, p=0.036) were significantly higher in patients requiring pacemaker implantations than those that did not. An anterior linear ablation (odds ratio [OR], 9.37 [3.03–28.9]; p<0.001) and the E/Em (OR, 1.15 [1.02–1.28]; p=0.018) were independently associated with permanent pacemaker implantations after AFCA in patients with AF and SND. CONCLUSIONS After AFCA in patients with AF and SND, 1 of 9 patients needed a pacemaker implantation and half needed implantations within 3 months. The AF recurrence rate was significantly higher in those who required pacemaker implantations after the AFCA.

BACKGROUND AND OBJECTIVES: Nationwide social inequalities of oral anticoagulation (OAC) usage after the introduction of non-vitamin K antagonist oral anticoagulants (NOACs) have not been well identified in patients with atrial fibrillation (AF). This study assessed overall rate and social inequalities of OAC usage after the introduction of NOAC in Korea. METHODS: Between January 2002 and December 2016, we identified 888,540 patients with AF in the Korea National Health Insurance system database. The change of OAC rate in different medical systems after the introduction of NOAC were evaluated. RESULTS: In all population, overall OAC use increased from 13.2% to 23.4% (p for trend <0.001), and NOAC use increased from 0% to 14.6% (p for trend <0.001). Compared with pre-reimbursement (0.48%), the annual increase of OAC use was significantly higher after partial (1.16%, p<0.001), and full reimbursement of OAC (3.72%, p<0.001). Full reimbursement of NOAC (adjusted odds ratio, 2.10; 95% confidence interval, 2.04–2.15) was independently associated with higher OAC use. However, the difference of overall OAC usage between tertiary referral hospitals and nursing or public health centers increased from 17.9% in 2010 to 36.8% in 2016. Moreover, usage rate of NOAC was significantly different among different medical systems from 37.2% at the tertiary referral hospital and 5.5% at nursing or public health centers. CONCLUSIONS Introduction of NOACs in routine practice for stroke prevention in AF was associated with improved rates of overall OAC use. However, significant practice-level variations in OAC and NOAC use remain producing social inequalities of OAC despite full reimbursement.

Background and objectives: A prolonged QTc interval is associated with an increased risk of a stroke or atrial fibrillation (AF). However, its direct causal relationship with AF associated a stroke has not been proven yet. To examine whether QTc interval is causally linked with risk of stroke in AF patients, we used the Mendelian randomization analysis. Subjects and methods: Among 2742 patients (73.6% male; 58.2 ± 11.0 years old; 69.5% with paroxysmal AF) who underwent AF catheter ablation, we analyzed 1766 patients who had preablation sinus rhythm electrocardiograms off antiarrhythmic drugs after excluding amiodarone users. Among them, 1213 subjects had genome-wide association study dataset analyzable for the Mendelian randomization. We explored the mechanistic relationships between QTc interval (ms) and the risk of a stroke by analyzing the Mendelian randomization (1213 subjects) after reviewing 35 genetic polymorphisms associated with the QTc in 31 European descent studies. Results: Among the patients in the higher quartile with a higher QTc, CHA2DS2-VASc score (p < 0.001), and age (p  < 0.001), the proportions of a prior stroke (p  < 0.001), females, heart failure, and persistent AF were significantly higher than in those in the lower quartile. The QTc was independently associated with the CHA2DS2-VASc score (β, 4.63E−5; 95% confidence interval, 3.57E−6–8.90E−5; p  = 0.034) and ischemic strokes (odds ratio, 1.01; 95% confidence interval, 1.00–1.01; p  = 0.027). However, there was no direct causal relationship between the QTc and CHA2DS2-VASc score or a prior stroke in either the one-sample or two-sample Mendelian randomizations. Conclusion The QTc was independently associated with the CHA2DS2-VASc score and strokes among the patients with AF who underwent catheter ablation, despite no genetically direct causal relationship.

Background: Although myocardial thickness is an important variable for therapeutic catheter ablation of cardiac arrhythmias, quantification of wall thickness has been overlooked. We developed a software (AMBER) that measures 3D-myocardial thickness using a cardiac computed tomogram (CT) image, verified its accuracy, and tested its clinical feasibility. Methods: We generated 3D-thickness maps by calculating wall thickness (WT) from the CT images of 120 patients’ hearts and a 3D-phantom model (PhM). The initial vector field of the Laplace equation was oriented to calculate WT with the field lines derived from the 3D mesh. We demonstrate the robustness of the Laplace WT algorithm by comparing with the real thickness of 3D-PhM, echocardiographically measured left ventricular (LV) WT, and regional left atrial (LA) WT reported from previous studies. We conducted a pilot case of catheter ablation for atrial fibrillation (AF) utilizing real-time LAWT map-guided radiofrequency (RF) energy titration. Results: AMBER 3D-WT had excellent correlations with the real thickness of the PhM (R = 0.968, p < 0.001) and echocardiographically measured LVWT in 10 patients (R = 0.656, p = 0.007). AMBER 3D-LAWT (n = 120) showed a relatively good match with 12 previously reported regional LAWT. We successfully conducted pilot AF ablation utilizing AMBER 3D-LAWT map-guided real-time RF energy titration. Conclusion We developed and verified an AMBER 3D-cardiac thickness map measured by cardiac CT images for LAWT and LVWT, and tested its feasibility for RF energy titration during clinical catheter ablation.