All-Cause Death and Major Adverse Events in Atrial Fibrillation with Frailty: Observations from the Korea National Health Insurance Service Data.

Background: Atrial fibrillation (AF) is an indicator of frailty in old patients. This study aimed to investigate the effect of frailty on the use of oral anticoagulants (OAC) and clinical outcomes in a nationwide cohort of patients with new-onset AF. Methods: This study included 451,368 participants without AF from the Korea National Health Insurance Service-Health Screening cohort between 2002 and 2009. The Hospital Frailty Risk Score was retrospectively calculated for each patient using all available International Classification of Disease 10th revision diagnostic codes. According to the aggregate score, patients were divided into two groups: the participants without frailty ( < 5 points) and the participants with frailty ( ≥ 5 points). The primary outcome was death from any cause, and the secondary outcomes were cardiovascular death, ischemic stroke, major bleeding, and heart failure admission. Results: With up to 7.2 ± 1.5 years of follow-up, 11,953 participants (median age, 67 [interquartile range, 59.5-74.5] years; 7200 [60.2%] males) developed new-onset AF. Among the patients with AF, 3224 (26.9%) had frailty. Frailty was significantly associated with old age, female sex, polypharmacy, and other comorbidities. In patients with AF, frailty was negatively associated with OAC prescription after new-onset AF (p < 0.001). Compared to patients without frailty, patients with frailty had a significantly higher incidence and risk of all-cause death (hazard ratio [HR] 2.88, 95% confidence interval [CI] 2.65-3.14), cardiovascular death (HR 2.42, 95% CI 2.10-2.80), ischemic stroke (HR 2.25, 95% CI 2.02-2.51), major bleeding (HR 2.44, 95% CI 2.17-2.73), and heart failure admission (HR 1.29, 95% CI 1.09-1.52). In subgroup analysis, when compared to the non-OAC group, the risks associated with frailty were significantly lower in the OAC group for all-cause death, cardiovascular death, ischemic stroke, and heart failure admission. Conclusions: Frailty was negatively associated with the use of OAC and was a predictor of poor prognosis owing to the association of frailty with death, thromboembolic events, bleeding, and heart failure admission. However, OAC use was associated with lower risks related to frailty for all-cause death and major adverse cardiovascular events in patients with AF.

Predictors of stroke or systemic embolism in patients with non-valvular atrial fibrillation with CHA2 DS2 -VASc score of 0.

BACKGROUND: Anticoagulant therapy has been important for stroke prevention in patients with atrial fibrillation (AF). However, it was not recommended due to its relatively higher risk of bleeding than its lower risk of stroke in patients with a CHA2 DS2 -VASc score of 0. HYPOTHESIS: This study aimed to evaluate the predictors of stroke in AF patients with very low risk of stroke. METHODS: Between 1990 and 2020, 542 patients with non-valvular AF (NVAF) with a CHA2 DS2 -VASc score of 0 followed up for at least 6 months were enrolled. Patients with only being woman as a risk factor were included as a CHA2 DS2 -VASc score of 0 in this study. The primary outcome was stroke or systemic embolism. RESULTS: The primary outcome rate was 0.78%/year. In Cox hazard model, age of ≥50 years at diagnosis (hazard ratio [HR] 6.710, 95% confidence interval [CI] 1.811-24.860, p = .004), LVEDD of ≥46 mm (HR 4.513, 95% CI 1.038-19.626, p = .045), and non-paroxysmal AF (HR 5.575, 95% CI 1.621-19.175, p = .006) were identified as independent predictors of stroke or systemic embolism. Patients with all three independent predictors had a higher risk of stroke or systemic embolism (4.21%/year), whereas those without did not have a stroke or systemic embolism. CONCLUSION: The annual stroke or systemic embolism rate in NVAF patients with CHA2 DS2 -VASc score of 0 was 0.78%/year, and age at AF diagnosis, LVEDD, and non-paroxysmal AF were independent predictors of stroke or systemic embolism in patients considered to have a very low risk of stroke.

Diagnostic Value of a Wearable Continuous Electrocardiogram Monitoring Device (AT-Patch) for New-Onset Atrial Fibrillation in High-Risk Patients: Prospective Cohort Study.

BACKGROUND: While conventional electrocardiogram monitoring devices are useful for detecting atrial fibrillation, they have considerable drawbacks, including a short monitoring duration and invasive device implantation. The use of patch-type devices circumvents these drawbacks and has shown comparable diagnostic capability for the early detection of atrial fibrillation. OBJECTIVE: We aimed to determine whether a patch-type device (AT-Patch) applied to patients with a high risk of new-onset atrial fibrillation defined by the congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, sex scale (CHA2DS2-VASc) score had increased detection rates. METHODS: In this nonrandomized multicenter prospective cohort study, we enrolled 320 adults aged ≥19 years who had never experienced atrial fibrillation and whose CHA2DS2-VASc score was ≥2. The AT-Patch was attached to each individual for 11 days, and the data were analyzed for arrhythmic events by 2 independent cardiologists. RESULTS: Atrial fibrillation was detected by the AT-Patch in 3.4% (11/320) of patients, as diagnosed by both cardiologists. Interestingly, when participants with or without atrial fibrillation were compared, a previous history of heart failure was significantly more common in the atrial fibrillation group (n=4/11, 36.4% vs n=16/309, 5.2%, respectively; P=.003). When a CHA2DS2-VASc score ≥4 was combined with previous heart failure, the detection rate was significantly increased to 24.4%. Comparison of the recorded electrocardiogram data revealed that supraventricular and ventricular ectopic rhythms were significantly more frequent in the new-onset atrial fibrillation group compared with nonatrial fibrillation group (3.4% vs 0.4%; P=.001 and 5.2% vs 1.2%; P<.001), respectively. CONCLUSIONS: This study detected a moderate number of new-onset atrial fibrillations in high-risk patients using the AT-Patch device. Further studies will aim to investigate the value of early detection of atrial fibrillation, particularly in patients with heart failure as a means of reducing adverse clinical outcomes of atrial fibrillation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04857268; https://classic.clinicaltrials.gov/ct2/show/NCT04857268.

Impact of Positron Emission Tomography Viability Imaging: Guided Revascularizations on Clinical Outcomes in Patients With Myocardial Scar on Single-Photon Emission Computed Tomography Scans.

BACKGROUND: Positron emission tomography (PET) viability scan is used to determine whether patients with a myocardial scar on single-photon emission computed tomography (SPECT) may need revascularization. However, the clinical utility of revascularization decision-making guided by PET viability imaging has not been proven yet. The purpose of this study was to investigate the impact of PET to determine revascularization on clinical outcomes. METHODS: Between September 2012 and May 2021, 53 patients (37 males; mean age = 64 ± 11 years) with a myocardial scar on MIBI SPECT who underwent PET viability test were analyzed in this study. The primary outcome was a temporal change in echocardiographic findings. The secondary outcome was all-cause mortality. RESULTS: Viable myocardium was presented by PET imaging in 29 (54.7%) patients. Revascularization was performed in 26 (49.1%) patients, including 18 (34.0%) with percutaneous coronary intervention (PCI) and 8 (15.1%) with coronary artery bypass grafting. There were significant improvements in echocardiographic findings in the revascularization group and the viable myocardium group. All-cause mortality was significantly lower in the revascularization group than in the medical therapy-alone group (19.2% vs. 44.4%, log-rank P = 0.002) irrespective of viable (21.4% vs. 46.7%, log-rank P = 0.025) or non-viable myocardium (16.7% vs. 41.7%, log-rank P = 0.046). All-cause mortality was significantly lower in the PCI group than in the medical therapy-alone group (11.1% vs. 44.4%, log-rank P < 0.001). CONCLUSION: Revascularization improved left ventricular systolic function and survival of patients with a myocardial scar on SPECT scans, irrespective of myocardial viability on PET scans.

NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer's models.

BACE1 is the rate-limiting enzyme for amyloid-ß peptides (Aß) generation, a key event in the pathogenesis of Alzheimer's disease (AD). By an unknown mechanism, levels of BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1 expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/NFE2L2) represses the expression of BACE1 and BACE1-AS through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of BACE1 and BACE1-AS expression is independent of redox regulation. NRF2 activation decreases production of BACE1 and BACE1-AS transcripts and Aß production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and Aß production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.

COVID-19 Vaccination-Induced Ventricular Fibrillation in an Afebrile Patient With Brugada Syndrome.

A 43-year-old man presented with cardiac arrest 2 days after the second coronavirus disease 2019 (COVID-19) vaccination with an mRNA vaccine. Electrocardiograms showed ventricular fibrillation and type 1 Brugada pattern ST segment elevation. The patient reported having no symptoms, including febrile sensation. There were no known underlying cardiac diseases to explain such electrocardiographic abnormalities. ST segment elevation completely disappeared in two weeks. Although there were no genetic mutations or personal or family history typical of Brugada syndrome, flecainide administration induced type 1 Brugada pattern ST segment elevation. This case suggests that COVID-19 vaccination may induce cardiac ion channel dysfunction and cause life threatening ventricular arrhythmias in specific patients with Brugada syndrome.

Comparison of Factors Associated With Direct Versus Transferred-in Admission to Government-Designated Regional Centers Between Acute Ischemic Stroke and Myocardial Infarction in Korea.

BACKGROUND: There has been no comparison of the determinants of admission route between acute ischemic stroke (AIS) and acute myocardial infarction (AMI). We examined whether factors associated with direct versus transferred-in admission to regional cardiocerebrovascular centers (RCVCs) differed between AIS and AMI. METHODS: Using a nationwide RCVC registry, we identified consecutive patients presenting with AMI and AIS between July 2016 and December 2018. We explored factors associated with direct admission to RCVCs in patients with AIS and AMI and examined whether those associations differed between AIS and AMI, including interaction terms between each factor and disease type in multivariable models. To explore the influence of emergency medical service (EMS) paramedics on hospital selection, stratified analyses according to use of EMS were also performed. RESULTS: Among the 17,897 and 8,927 AIS and AMI patients, 66.6% and 48.2% were directly admitted to RCVCs, respectively. Multivariable analysis showed that previous coronary heart disease, prehospital awareness, higher education level, and EMS use increased the odds of direct admission to RCVCs, but the odds ratio (OR) was different between AIS and AMI (for the first 3 factors, AMI > AIS; for EMS use, AMI < AIS). EMS use was the single most important factor for both AIS and AMI (OR, 4.72 vs. 3.90). Hypertension and hyperlipidemia increased, while living alone decreased the odds of direct admission only in AMI; additionally, age (65-74 years), previous stroke, and presentation during non-working hours increased the odds only in AIS. EMS use weakened the associations between direct admission and most factors in both AIS and AMI. CONCLUSIONS: Various patient factors were differentially associated with direct admission to RCVCs between AIS and AMI. Public education for symptom awareness and use of EMS is essential in optimizing the transportation and hospitalization of patients with AMI and AIS.

Cardiac intramural arteriovenous malformations presented as ventricular tachycardia and fibrillation storm.

We report a case of cardiac intramural arteriovenous malformations (AVMs) misdiagnosed as hypertrophic cardiomyopathy and presented as life-threatening ventricular arrhythmia storm that was successfully controlled by cardiac sympathetic denervation. A 46-year-old male patient with an implantable cardioverter-defibrillator was admitted for recurrent ventricular tachycardia requiring repeated shock refractory to antiarrhythmic drugs. Although the patient was previously diagnosed with hypertrophic cardiomyopathy, multimodality imaging studies showed large left ventricular intramural AVMs, potentially representing arrhythmogenic substrates. Life-threatening ventricular arrhythmia storm, which could not be controlled by radiofrequency catheter ablation and therapeutic hypothermia. However, cardiac sympathetic denervation surgery successfully controlled the ventricular arrhythmia storm.

Prognostic effect of increased left ventricular wall thickness in severe aortic stenosis.

BACKGROUND: It is unclear whether increased left ventricular (LV) thickness is associated with worse clinical outcomes in severe aortic stenosis (AS). The aim of this study was to determine the effect of increased LV wall thickness (LVWT) on major clinical outcomes in patients with severe AS. METHODS AND RESULTS: This study included 290 severe AS patients (mean age 69.4 ± 11.0 years; 136 females) between January 2008 and December 2018. For outcome assessment, the endpoint was defined as death from all causes, cardiovascular death, and the aortic valve replacement (AVR) surgery rate. During follow-up (48.7 ± 39.0 months), 157 patients had AVR, 43 patients died, and 28 patients died from cardiovascular causes. Patients with increased LVWT underwent AVR surgery much more than those without LVWT (60.0% vs. 39.0%, p < 0.001). Furthermore, in patients with increased LVWT, the all-cause and cardiovascular death rates were significantly lower in the AVR group than in the non-AVR group (8.8% vs. 27.3%, p < 0.001, 4.8%, vs. 21.0%, p < 0.001). Multivariate analysis revealed that increased LVWT, age, dyspnea, and AVR surgery were significantly correlated with cardiovascular death. CONCLUSIONS: In patients with severe AS, increased LVWT was associated with a higher AVR surgery rate and an increased rate of cardiovascular death independent of other well-known prognostic variates. Thus, these findings suggest that increased LVWT might be used as a potential prognostic factor in severe AS patients.

Yield Stress Enhancement of a Ternary Colloidal Suspension via the Addition of Minute Amounts of Sodium Alginate to the Interparticle Capillary Bridges.

Capillary suspensions are ternary solid-liquid-liquid systems produced via the addition of a small amount of secondary fluid to the bulk fluid that contained the dispersed solid particles. The secondary fluid could exert strong capillary forces between the particles and dramatically change the rheological properties of the suspension. So far, research has focused on capillary suspensions that consist of additive-free fluids, whereas capillary suspensions with additives, particularly those of large molecular weight that are highly relevant for industrial purposes, have been relatively less studied. In this study, we performed a systematic analysis of the properties of capillary suspensions that consist of paraffin oil (bulk phase), water (secondary phase), and α-Al2O3 microparticles (particle phase), in which the aqueous secondary phase contained an important eco-friendly polymeric binder, sodium alginate (SA). It was determined that the yield stress of the suspension increased significantly with the increase in the SA content in the aqueous secondary phase, which was attributed to the synergistic effect of the capillary force and hydrogen bonding force that may be related to the increase in the number of capillary bridges. The amounts of SA used to induce a significant change in the yield stress in this study were very small (<0.02% of the total sample volume). The addition of Ca2+ ions to the SA-containing secondary phase further increased the yield stress with possible gelation of the SA chains-in the presence of excess Ca2+ ions, however, the yield stress decreased because of the microscopic phase separation that occurred in the aqueous secondary phase. The microstructures of the sintered porous materials that were produced by using capillary suspensions as precursors were qualitatively well correlated to the rheological behavior of the precursor suspensions, suggesting a new method for the subtle control of the microstructures of porous materials using the addition of minute amounts of polymeric additives.

Stereotactic Cardiac Radiation to Control Ventricular Tachycardia and Fibrillation Storm in a Patient with Apical Hypertrophic Cardiomyopathy at Burnout Stage: Case Report.

Stereotactic cardiac radiation for ablation (radioablation) of life-threatening ventricular arrhythmia was recently introduced into clinical practice. A 76-year-old male patient with apical hypertrophic cardiomyopathy at burnout stage, who received defibrillator implantation for the secondary prevention of sudden arrhythmic death, was admitted for repeated defibrillator therapy. Radiofrequency catheter ablation was unsuccessful due to the induction of ventricular fibrillation (VF) and hemodynamically unstable sustained monomorphic ventricular tachycardia (VT). However, intracardiac activation mapping for the induced VT revealed the earliest ventricular activation at the apical aneurysm. Radioablation was performed to control VT and VF storm refractory to antiarrhythmic drug therapy. A total of 24 Gray was radiated, divided into three fractions around the apical aneurysm. The onset of electrical modulation was instantaneous and the antiarrhythmic effect was maintained for at least 6 months without significant radiation toxicities. This case suggests that radioablation may be considered as a rescue therapy for VT and VF storm refractory to other treatment modalities.

Clinical Impact of Implantable Cardioverter-Defibrillator Therapy and Mortality Prediction Model for Effective Primary Prevention in Korean Patients.

BACKGROUND: Studies on the efficacy of implantable cardioverter-defibrillator (ICD) therapy for primary prevention in Asian patients are relatively lacking compared to those for secondary prevention. Also, it is important to stratify which patients will benefit from ICD therapy for primary prevention. METHODS: Of 483 consecutive patients who received new implantation of ICD in 9 centers in Korea, 305 patients with reduced left ventricular systolic function and/or documented ventricular fibrillation/tachycardia were enrolled and divided into primary (n = 167) and secondary prevention groups (n = 138). RESULTS: During mean follow-up duration of 2.6 ± 1.6 years, appropriate ICD therapy occurred in 78 patients (25.6%), and appropriate ICD shock and anti-tachycardia pacing occurred in 15.1% and 15.1% of patients, respectively. Appropriate ICD shock rate was not different between the two groups (primary 12% vs. secondary 18.8%, P = 0.118). However, appropriate ICD therapy rate including shock and anti-tachycardia pacing was significantly higher (primary 18% vs. secondary 34.8%, P = 0.001) in the secondary prevention group. Type of prevention and etiology, appropriate and inappropriate ICD shock did not affect all-cause death. High levels of N-terminal pro-B-type natriuretic peptide, New York Heart Association functional class, low levels of estimated glomerular filtration ratio, and body mass index were associated with death before appropriate ICD shock in the primary prevention group. When patients were categorized in 5 risk score groups according to the sum of values defined by each cut-off level, significant differences in death rate before appropriate ICD shock were observed among risk 0 (0%), 1 (3.6%), 2 (3%), 3 (26.5%), and 4 (40%) (P < 0.001). CONCLUSION: In this multicenter regional registry, the frequency of appropriate ICD therapy is not low in the primary prevention group. In addition, combination of poor prognostic factors of heart failure is useful in risk stratification of patients who are not benefiting from ICD therapy for primary prevention.

Left ventricular geometric patterns in patients with type A aortic dissection.

BACKGROUND: Aortic dilatation is a major risk factor for aortic dissection. The aim of the present study was to assess the relationship between left ventricular (LV) geometry and maximal ascending aorta (MAA). METHODS: We reviewed data from patients who were diagnosed with acute type A aortic dissection and who underwent surgical management from December 2002 to March 2016 at Dong-A University Hospital. Among 151 patients with non-Marfan aortic dissection in the study, 50 who had echocardiography preoperatively were investigated and MAA diameter was analyzed by LV geometric patterns. RESULTS: Patients' mean age was 59.6 ± 13.5 years and 38.0% were male. The mean MAA diameter was 52.9 ± 8.5 mm. MAA diameter was significantly correlated with LV mass index (r = 0.62, P < 0.001). On analysis by LV geometry, MAA diameter showed a significant difference between the 4 groups (P = 0.02), and the eccentric and concentric hypertrophy groups showed significantly larger MAA diameter than the other two groups. CONCLUSION: MAA diameter was associated with LV mass index and was significantly different between LV geometry types. In this study, not only concentric hypertrophy but also eccentric LV hypertrophy was related to larger MAA in type A aortic dissection patients.

Asymmetric aortic valve is related to development of eccentric aortic regurgitation in patients with tricuspid aortic valve.

BACKGROUND: It is unclear whether asymmetry itself plays a role in developing eccentric aortic regurgitation (AR) in patients with tricuspid aortic valve (TAV). The aim of this study was to determine whether an asymmetric aortic valve structure may have association with the development of eccentric AR in patients with TAV. METHODS: Of the 164 410 patients who underwent echocardiography between January 2006 and January 2018 at Dong-A University Hospital, 306 (mean age 69.9 ± 12.6 years; 62% men) eccentric AR were identified. After excluding patients with bicuspid and prolapsed AV, 104 patients who had eccentric AR with TAV were enrolled for the study. Comprehensive echocardiographic AV cusp measurements were compared to those of 104 age- and gender-matched control patients with central AR. RESULTS: In the eccentric and central AR groups, 66 (63.5%) and 48 patients (46.2%) had asymmetric AV, respectively. Mean cusp height was significantly larger in the eccentric AR group than in the central AR group (1.8 ± 0.3 cm vs 1.7 ± 0.2 cm, P = 0002). Furthermore, the mean cusp area and average asymmetry index of the cusp area were also significantly larger in the eccentric AR group than in the central AR group (2.6 ± 0.8 cm2 vs 2.3 ± 0.6 cm2 , P = 0.001, and 7.1 ± 4.5% vs 4.9 ± 2.5%, P < 0.001, respectively). CONCLUSION: AV asymmetry indices of eccentric AR were significantly larger than those of patients with central AR. These data suggest that the presence of asymmetric AV might have association with the development of eccentric AR in patients with TAV.

Supraventricular tachyarrhythmias in patients with a persistent left superior vena cava.

Aims: A persistent left superior vena cava (PLSVC) is the most common thoracic venous anomaly. This venous anomaly can impact the evaluation and treatment of supraventricular tachyarrhythmia (SVA). The aim of this study was to assess the proportion and characteristics of PLSVC in adult SVA patients. Methods and results: From July 2002 to July 2012, clinical and procedural data from databases of 10 cardiac electrophysiology laboratories in the Yeungnam region of the Republic of Korea were reviewed. Of 6662 adult SVA patients who underwent an EP study or catheter ablation of SVA during the 10-year study period, 18 patients had PLSVC (mean age 47.6 ± 14.8 years, 10 men). The proportion of PLSVC in adult SVA patients was 0.27% (18/6662). SVA type and procedural outcomes of radiofrequency (RF) catheter ablation in these patients were investigated and the results were as follows: successful slow pathway modification in six of seven patients with atrioventricular nodal reentrant tachycardia (AVNRT), successful ablation of accessory pathway in three of four patients with atrioventricular reentrant tachycardia, and successful ablation of atrial tachycardia (cavotricuspid isthmus-dependent in two, septal macroreentry in one, focal from the PLSVC in one) in three of four patients. In one patient with junctional tachycardia, catheter ablation failed. In two patients with atrial fibrillation, catheter ablation was successful. Conclusion: Among adult SVA patients who underwent an EP study or RF catheter ablation during the 10-year study period, 0.27% had PLSVC. The most common type of SVA was AVNRT. The success rate of catheter ablation was 82% in SVA patients with PLSVC. There were no procedure-related complications.

Changes in mitral annular velocities after cardioversion of atrial fibrillation.

AIMS: The early diastolic mitral annular velocity (e') and mitral E/e' criteria for clinically evaluating diastolic dysfunction in patients with atrial fibrillation (AF) are almost the same as in patients with sinus rhythm. In this study, we aimed to investigate whether e' is useful to assess diastolic function in AF patients. METHODS: Thirty patients who underwent successful electric cardioversion (EC) due to persistent AF and who maintained sinus rhythm for 1 month after EC were enrolled in this study. Transthoracic echocardiography was performed on all patients before and 1 month after EC. Standard diastolic parameters, the global longitudinal strain (GLS), and left ventricular (LV) twist were measured. RESULTS: Conventional Doppler parameters measured before EC were not significantly different from 1 month after EC. However, the lateral and septal e' were significantly decreased 1 month after EC (from 12.8 ± 2.5 to 9.8 ± 2.3 cm/s and from 9.5 ± 1.9 to 7.1 ± 1.5 cm/s, respectively, P < 0.001). Likewise, the lateral and septal E/e' were also significantly increased 1 month after EC (P < 0.001). The GLS was significantly improved from -15.9 ± 2.2% to -19.4 ± 2.4% after EC (P < 0.001), as was the LV twist (from 5.8 ± 1.7° to 9.1 ± 2.4°, P < 0.001). CONCLUSION: We demonstrated that e' was significantly higher in AF compared with during sinus rhythm in the same patients. Thus, in AF patients, diastolic dysfunction should be suspected even when e' values are normal.

Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells.

UNLABELLED: Liver fibrosis is a common outcome of chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. No US Food and Drug Administration-approved targeted antifibrotic therapy exists. Activated hepatic stellate cells (aHSCs) are the major cell types responsible for liver fibrosis; therefore, eradication of aHSCs, while preserving quiescent HSCs and other normal cells, is a logical strategy to stop and/or reverse liver fibrogenesis/fibrosis. However, there are no effective approaches to specifically deplete aHSCs during fibrosis without systemic toxicity. aHSCs are associated with elevated expression of death receptors and become sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. Treatment with recombinant TRAIL could be a potential strategy to ameliorate liver fibrosis; however, the therapeutic application of recombinant TRAIL is halted due to its very short half-life. To overcome this problem, we previously generated PEGylated TRAIL (TRAILPEG ) that has a much longer half-life in rodents than native-type TRAIL. In this study, we demonstrate that intravenous TRAILPEG has a markedly extended half-life over native-type TRAIL in nonhuman primates and has no toxicity in primary human hepatocytes. Intravenous injection of TRAILPEG directly induces apoptosis of aHSCs in vivo and ameliorates carbon tetrachloride-induced fibrosis/cirrhosis in rats by simultaneously down-regulating multiple key fibrotic markers that are associated with aHSCs. CONCLUSION: TRAIL-based therapies could serve as new therapeutics for liver fibrosis/cirrhosis and possibly other fibrotic diseases. (Hepatology 2016;64:209-223).

Synaptic transistor with a reversible and analog conductance modulation using a Pt/HfOx/n-IGZO memcapacitor.

A synaptic transistor emulating the biological synaptic motion is demonstrated using the memcapacitance characteristics in a Pt/HfOx/n-indium-gallium-zinc-oxide (IGZO) memcapacitor. First, the metal-oxide-semiconductor (MOS) capacitor with Pt/HfOx/n-IGZO structure exhibits analog, polarity-dependent, and reversible memcapacitance in capacitance-voltage (C-V), capacitance-time (C-t), and voltage-pulse measurements. When a positive voltage is applied repeatedly to the Pt electrode, the accumulation capacitance increases gradually and sequentially. The depletion capacitance also increases consequently. The capacitances are restored by repeatedly applying a negative voltage, confirming the reversible memcapacitance. The analog and reversible memcapacitance emulates the potentiation and depression synaptic motions. The synaptic thin-film transistor (TFT) with this memcapacitor also shows the synaptic motion with gradually increasing drain current by repeatedly applying the positive gate and drain voltages and reversibly decreasing one by applying the negative voltages, representing synaptic weight modulation. The reversible and analog conductance change in the transistor at both the voltage sweep and pulse operations is obtained through the memcapacitance and threshold voltage shift at the same time. These results demonstrate the synaptic transistor operations with a MOS memcapacitor gate stack consisting of Pt/HfOx/n-IGZO.

Artificial synaptic characteristics with strong analog memristive switching in a Pt/CeO2/Pt structure.

Artificial synaptic potentiation and depression characteristics were demonstrated with Pt/CeO2/Pt devices exhibiting polarity-dependent analog memristive switching. The strong and sequential resistance change with its maximum to minimum ratio >105, imperatively essential for stable operation, as repeating voltage application, emulated the potentiation and depression motion of a synapse with variable synaptic weight. The synaptic weight change could be controlled by the amplitude, width, and number of repeated voltage pulses. The voltage polarity-dependent and asymmetric current-voltage characteristics and consequential resistance change are thought to be due to local inhomogeneity of electrical and physical states of CeO2 such as charging at interface states, valence changes of Ce cations, and so on. These results revealed that the CeO2 layer could be a promising material for analog memristive switching elements with strong resistance change, as an artificial synapse in neuromorphic systems.

Biodegradable DNA Nanoparticles that Provide Widespread Gene Delivery in the Brain.

Successful gene therapy of neurological disorders is predicated on achieving widespread and uniform transgene expression throughout the affected disease area in the brain. However, conventional gene vectors preferentially travel through low-resistance perivascular spaces and/or are confined to the administration site even with the aid of a pressure-driven flow provided by convection-enhanced delivery. Biodegradable DNA nanoparticles offer a safe gene delivery platform devoid of adverse effects associated with virus-based or synthetic nonbiodegradable systems. Using a state-of-the-art biodegradable polymer, poly(ß-amino ester), colloidally stable sub-100 nm DNA nanoparticles are engineered with a nonadhesive polyethylene glycol corona that are able to avoid the adhesive and steric hindrances imposed by the extracellular matrix. Following convection enhanced delivery, these brain-penetrating nanoparticles are able to homogeneously distribute throughout the rodent striatum and mediate widespread and high-level transgene expression. These nanoparticles provide a biodegradable DNA nanoparticle platform enabling uniform transgene expression patterns in vivo and hold promise for the treatment of neurological diseases.