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Background Atrial fibrillation (AF) is prevalent in patients with type 2 diabetes mellitus (T2DM). Glycemic variability (GV) is associated with risk of micro- and macrovascular diseases. However, whether the GV can increase the risk of AF remains unknown. Methods The cohort study used a database from National Taiwan University Hospital, a tertiary medical center in Taiwan. Between 2014 and 2019, a total of 27,246 adult patients with T2DM were enrolled for analysis. Each individual was assessed to determine the coefficients of variability of fasting glucose (FGCV) and HbA1c variability score (HVS). The GV parameters were categorized into quartiles. Multivariate Cox regression models were employed to estimate the relationship between the GV parameters and the risk of AF, transient ischemic accident (TIA)/ischemic stroke and mortality in patients with T2DM. Results The incidence rates of AF and TIA/ischemic stroke were 21.31 and 13.71 per 1000 person-year respectively. The medium follow-up period was 70.7 months. In Cox regression model with full adjustment, the highest quartile of FGCV was not associated with increased risk of AF [Hazard ratio (HR): 1.12, 95% confidence interval (CI) 0.96–1.29, p = 0.148] or TIA/ischemic stroke (HR: 1.04, 95% CI 0.83–1.31, p = 0.736), but was associated with increased risk of total mortality (HR: 1.33, 95% CI 1.12–1.58, p Conclusions Our data demonstrate that high GV is independently associated with the development of new-onset AF in patients with T2DM. The benefit of maintaining stable glycemic levels to improve clinical outcomes warrants further studies.

Patients with heart failure and preserved ejection fraction (HFpEF) are known to have reduced systolic myocardial velocity (Sm) with impaired accommodation to exercise. We tested the impact of an aldosterone antagonist on Sm at rest and post-exercise. Forty-nine HFpEF patients (65 ± 11 years, 24 male) with HF signs/symptoms, mitral E/Ea (annular early diastolic velocity) &gt, 8, and left ventricular (LV) EF &gt, 50% were randomized to spironolactone (25 mg/day, 25 patients) or the Control. At baseline and 6 months, we analyzed Sm of basal LV segments at rest and after a 6 min treadmill exercise. At 6 months, post-exercise mean Sm in the spironolactone group became greater than that in the Control (9.2 ± 1.6 vs. 8.3 ± 1.0 cm/s, p = 0.021), mainly due to the increment of post-exercise % increase of lateral Sm (44 ± 30 vs. 30 ± 19% at baseline, p = 0.045). Further analyses showed the presence of systolic dyssynchrony (standard deviation of electromechanical delay of 6-basal LV segments &gt, 35 ms) was independently associated with a poorer response to spironolactone, defined as a post-exercise % increase of lateral Sm &lt, 50% (OR = 2.7, 95% CI = 1.8–4.2) and the increment of Ea &lt, 1.5 cm/s (OR = 1.5, 95% CI = 1.1–2.3). Spironolactone could improve exercise accommodation of regional systolic myocardial velocity for HFpEF patients. However, its benefits could be decreased in those with ventricular dyssynchrony. This suggested possible therapeutic impacts from underlying heterogeneity within HFpEF patients.

The recurrence rate of atrial fibrillation (AF) following catheter ablation is high. Successful non-recurrence prediction before ablation is financially and physically beneficial. Atrial fibrillation cycle length (AFCL) has been used for such predictions. The study explored a nonlinear and non-stationary signal analysis technique, ensemble empirical model decomposition (EEMD), to capture intrinsic AFCL pattern. Twenty-eight AF patients underwent regular catheter ablation protocols and follow-up treatments. Surface ECG were recorded before ablation procedures, and preprocessed with QRS-T cancellation method to extract intrinsic AF signals, which were then analyzed with EEMD to calculate AFCL adaptively. Conventional Fourier-based dominant frequency (DF) analysis was conducted for comparison. During 12 months follow-up, 17 patients maintained sinus rhythm while 11 patients had AF recurrence. Patients who maintained sinus rhythm had longer AFCL (152.2 (145.0, 157.6) ms) than those with AF recurrence (138.8 (135.0, 145.2) ms). Patients with AFCL >152.1 ms had no recurrence (Kaplan–Meier curve analysis, P=0.006, hazard ratio: 5.68). With AFCL as a predictor of AF non-recurrence at 12 months, the area under ROC curve is 0.80, while with DF analysis, the area is 0.66. EEMD-based intrinsic AFCL measured from surface ECG may serve as an effective non-invasive catheter ablation screening tool for AF non-recurrence.

Background Thoracic aortic aneurysm and dissection (TAAD) is a devastating but treatable disease if detected early. The clinical manifestations and genetic characteristics underlying TAAD patients in Taiwan, however, remain unclear. Methods We consecutively recruited patients referred for TAAD screening and/or management at a tertiary medical center in Taiwan. All patients received a comprehensive survey of the clinical manifestations and a genetic testing with a 29-gene next-generation sequencing (NGS) panel. Results Patients (n = 107) were referred for different reasons, and could be grouped into 4 categories: known aortic aneurysm or dissection (AoAD) (n = 57), Marfanoid features (n = 36), having family members of suspected AoAD (n = 11), and ectopic lens (n = 3). AoAD were confirmed in 73 (68.2%) of the entire cohort. Among all the clinical manifestations, skin striae distensae was the only physical sign that showed significant association with AoAD (p = 0.007 after adjusted). Disease-causing genes/variants were identified in 46 patients (43.0%); FBN1 was the most prevalent disease-causing gene, followed by TGFBR1, TGFBR2 and FBN2. A positive genetic testing was not only an independent predictor of AoAD (hazard ratio (HR) 3.468, 95% confidence interval (CI) [1.541–7.807], p = 0.003), but also had a higher chance of dissection among the patients with known dilated aorta (HR 4.552, 95% CI [1.578–13.135], p = 0.005). Conclusion The presence of skin striae distensae may serve as a clinical cue for physicians to search for AoAD in subjects who are at risk. The NGS panel test not only helps confirm the diagnosis, but also stratify the risk of dissection among patients with dilated aorta.

Background: Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications. Methods: We enrolled 335 unrelated BrS patients from 2000 to 2018 in the Taiwanese population. Microarray and exome sequencing were used for discovery phase whereas Sanger sequencing was used for the validation phase. HEK cells and zebrafish were used to characterize the function of the CNV variant. Findings: A copy number deletion of GSTM3 (chr1:109737011-109737301, hg38) containing the eighth exon and the transcription stop codon was observed in 23.9% of BrS patients versus 0.8% of 15,829 controls in Taiwan Biobank (P < 0.001), and 0% in gnomAD. Co-segregation analysis showed that the co-segregation rate was 20%. Patch clamp experiments showed that in an oxidative stress environment, GSTM3 down-regulation leads to a significant decrease of cardiac sodium channel current amplitude. Ventricular arrhythmia incidence was significantly greater in gstm3 knockout zebrafish at baseline and after flecainide, but was reduced after quinidine, consistent with clinical observations. BrS patients carrying the GSTM3 deletion had higher rates of sudden cardiac arrest and syncope compared to those without (OR: 3.18 (1.77–5.74), P

Introduction A novel amyloid β (Aβ) synthetic peptide vaccine (UB-311) has been evaluated in a first-in-human trial with patients of mild-to-moderate Alzheimer's disease. We describe translational research covering vaccine design, preclinical characterization, and phase-I clinical trial with supportive outcome that advances UB-311 into an ongoing phase-II trial. Methods UB-311 is constructed with two synthetic Aβ1–14–targeting peptides (B-cell epitope), each linked to different helper T-cell peptide epitopes (UBITh®) and formulated in a Th2-biased delivery system. The hAPP751 transgenic mouse model was used to perform the proof-of-concept study. Baboons and macaques were used for preclinical safety, tolerability, and immunogenicity evaluation. Patients with mild-to-moderate Alzheimer's disease (AD) were immunized by intramuscular route with 3 doses of UB-311 at weeks 0, 4, and 12, and monitored until week 48. Safety and immunogenicity were assessed per protocol, and preliminary efficacy was analyzed by Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), Mini–Mental State Examination (MMSE), and Alzheimer's Disease Cooperative Study–Clinician's Global Impression of Change (ADCS-CGIC). Results UB-311 covers a diverse genetic background and facilitates strong immune response with high responder rate. UB-311 reduced the levels of Aβ1–42 oligomers, protofibrils, and plaque load in hAPP751 transgenic mice. Safe and well-tolerated UB-311 generated considerable site-specific (Aβ1–10) antibodies across all animal species examined. In AD patients, UB-311 induced a 100% responder rate; injection site swelling and agitation were the most common adverse events (4/19 each). A slower rate of increase in ADAS-Cog from baseline to week 48 was observed in the subgroup of mild AD patients (MMSE ≥ 20) compared with the moderate AD subgroup, suggesting that UB-311 may have a potential of cognition improvement in patients with early stage of Alzheimer's dementia. Discussion The UBITh® platform can generate a high-precision molecular vaccine with high responder rate, strong on-target immunogenicity, and a potential of cognition improvement, which support UB-311 for active immunotherapy in early-to-mild AD patients currently enrolled in a phase-II trial (NCT02551809).

Visual Abstract, Highlights • In systolic heart failure, decreased renal perfusion due to impaired cardiac pumping activates the renal nerves, which send a signal to the brain to call for help. • The brain thus activates the neurohormonal system to increase organ perfusion, which may predispose the heart to ventricular arrhythmia. • Chemical renal denervation with phenol cuts the signal sent to the brain and thus decreases the susceptibility to ventricular arrhythmia in rats with systolic heart failure., Summary Several studies have shown the beneficial effect of renal denervation (RDN) in the treatment of ventricular arrhythmia, especially in the setting of heart failure (HF). However, the underlying mechanism of antiarrhythmic effect of RDN is unknown. Arrhythmogenic cardiac alternans, particularly spatially discordant repolarization alternans, characterized by simultaneous prolongation and shortening of action potential duration (APD) in different myocardial regions, is central to the genesis of ventricular fibrillation in HF. Whether RDN decreases the susceptibility to arrhythmogenic cardiac alternans in HF has never been addressed before. The authors used a rat model of post-myocardial infarction HF and dual voltage-calcium optical mapping to investigate whether RDN could attenuate arrhythmogenic cardiac alternans that predisposes to ventricular arrhythmias, as well as the hemodynamic effect of RDN in HF. The HF rats had increased body weights, dilated hearts, and lower blood pressure. The HF rats also had longer ventricular APDs and a delay in the decay of the calcium transient, typical electrophysiological features of human HF. Susceptibility to calcium transient alternans, APD alternans, and spatially discordant APD alternans was increased in the HF hearts. RDN significantly attenuated a delay in the decay of the calcium transient, calcium transient and APD alternans, and importantly, the discordant APD alternans, and thereby decreased the incidence of induced ventricular arrhythmia in HF. RDN did not further decrease blood pressure in HF rats. In conclusion, RDN improves calcium cycling and prevents spatially discordant APD alternans and ventricular arrhythmia in HF. RDN does not aggravate hemodynamics in HF.

Objectives Whether the spironolactone treatment remains effective for the prevention of atrial fibrillation (AF) in dialysis patients is unclear. Methods We used a database from the Registry for Catastrophic Illness from the National Health Research Institute. All dialysis patients aged 18 or older without history of AF before ESRD were incorporated. A total of 113,191 dialysis patients were enrolled in the study. The median follow-up time was 4.17years. We collected information on prescribed drug dosage, number of days of treatment and the total number of pills dispensed from the outpatient pharmacy prescription database. All individuals in the study cohort with the first occurrence of AF were included as cases. Results In spironolactone group, the incidence of developing new AF was significantly lower than that in the control group both before (0.8% vs. 3.3%, P=0.019) and after PS matching (1.2% vs. 3.0%, P=0.019). Before PS matching, Cox's proportional hazard regression analyses showed that spironolactone was associated with 60% reduction of new AF (HR=0.372 [0.200–0.692], P=0.002) and the protective effect is dose-responsive in accumulated dose, treatment duration and mean daily dose. After PS matching, the overall AF prevention effect remained significant (HR=0.400 [0.179–0.895], P=0.026) while the dose–response relationship became borderline significant. Subgroup analyses showed that the protective effect was more evident in some specific subgroup patients. Conclusion Our study showed that spironolactone therapy was associated with lower risk of developing AF in a dose-responsive manner in patients with dialysis. Further randomized study is needed to confirm this observation.

AIMS This was a randomized controlled study performed to compare 8 mm-tip catheter cryoablation (CRYO) with radiofrequency ablation (RFA) in treating atrioventricular nodal re-entrant tachycardia (AVNRT). METHODS AND RESULTS A total of 158 patients (103 women, mean age 48.9 ± 14.1) with symptomatic AVNRT (140 typical; 18 atypical) were randomized to undergo CRYO with an 8 mm-tip catheter (n = 80) or RFA (n = 78). The primary endpoint was a composite of acute procedural failure, inadvertent permanent atrioventricular block (AVB) and recurrence at 12 months. No significant difference was observed between CRYO and RFA groups in primary endpoint (7.5 vs. 11.5%; P = 0.764), 12-month recurrence rate (3.8 vs. 1.3%; P = 0.358), inadvertent permanent AVB (0 vs. 1.3%; P = 0.307), and acute procedural failure (3.7 vs. 9%; P = 0.128). In patients with acute procedure failure, success was achieved in 5 of 7 patients (71.4%) in RFA group and 2 of 3 patients (66.7%) in CRYO group on cross-over. There was no significant difference in procedural duration between CRYO and RFA groups (72.4 ± 41.6 vs. 63.7 ± 29.8 min; P = 0.13), but fluoroscopic duration in CRYO group was significantly shorter (3.4 ± 6.3 vs. 6.7 ± 7.4 min; P = 0.005). Patient pain score (2.7 ± 2.7 vs. 4.6 ± 2.7; P

Background/Purpose Brugada syndrome (BrS) is a hereditable sudden cardiac death (SCD). Mutations in the SCN5A gene (the most common BrS-causing gene) are responsible for 20–25% of this disease in Caucasian populations. However, the prevalence of SCN5A mutations in patients with BrS in the Chinese Han population in Taiwan remains unknown. Therefore, in this study, we investigated the prevalence of the SCN5A mutation in the largest BrS cohort in Taiwan. Methods We consecutively enrolled 47 unrelated patients with BrS from medical centers and hospitals in Taiwan between 2000 and 2010. Mutations within all the 27 translated exons, and exon–intron boundaries of the SCN5A -encoded cardiac sodium channel were screened in all patients with BrS using direct sequencing. A total of 500 unrelated healthy volunteers with a normal electrocardiogram were genotyped as a control group. Results SCN5A genetic variants were identified in 14 of the 47 patients with BrS and four of the 14 patients with BrS had missense mutations (1651 G>A, 1776 C>G, 3578 G>A). The prevalence rate of SCN5A mutations was approximately 8% (4/47), which was significantly lower than that reported in Caucasian populations (20–25%; p = 0.0007). The average age of these 14 BrS patients with SCN5A variants at diagnosis (12 men and 2 women) was 40 ± 13 years. Four patients experienced SCD, and six presented with seizure or syncope. Only three patients (3/14, 21.4%) had a family history of SCD. Conclusion The prevalence of SCN5A mutations in the Chinese Han population in Taiwan may be lower than that reported in the Caucasian populations. In addition, most patients with BrS did not have a family history of SCD.

Background— The transmural distribution of apamin-sensitive small conductance Ca 2+ -activated K + (SK) current ( I KAS ) in failing human ventricles remains unclear. Methods and Results— We optically mapped left ventricular wedge preparations from 12 failing native hearts and 2 rejected cardiac allografts explanted during transplant surgery. We determined transmural action potential duration (APD) before and after 100 nmol/L apamin administration in all wedges and after sequential administration of apamin, chromanol, and E4031 in 4 wedges. Apamin prolonged APD from 363 ms (95% confidence interval [CI], 341–385) to 409 (95% CI, 385–434; P P =0.001) in 12 native failing hearts at 1000 ms pacing cycle length (PCL). The percent APD prolongation is negatively correlated with baseline APD and positively correlated with PCL. Only 1 wedge had M-cell islands. The percentages of APD prolongation in the last 4 hearts at 2000 ms PCL after apamin, chromanol, and E4031 were 9.1% (95% CI, 3.9–14.2), 17.3% (95% CI, 3.1–31.5), and 35.9% (95% CI, 15.7–56.1), respectively. Immunohistochemical staining of subtype 2 of SK protein showed increased expression in intercalated discs of myocytes. Conclusions— SK current is important in the transmural repolarization in failing human ventricles. The magnitude of I KAS is positively correlated with the PCL, but negatively correlated with APD when PCL is fixed. There is abundant subtype 2 of SK protein in the intercalated discs of myocytes.

Objectives: We tested the acute effects of resynchronization in heart failure patients with a normal (>50%) left ventricular (LV) ejection fraction (HFNEF) and mechanical dyssynchrony. Methods: Twenty-four HFNEF patients (72 ± 6 years, 5 male) with mechanical dyssynchrony (standard deviation of electromechanical time delay among 12 LV segments >35 ms) were studied with temporary pacing catheters in the right atrium, LV, and right ventricle (RV), and high-fidelity catheters for pressure recording. Using selected atrioventricular (AV) intervals of 60, 90, 120, 150, and 180 ms to optimize transmitral flow during simultaneous biventricular pacing, the RV-LV (VV) interval was then evaluated at RV30, RV15, 0, LV15, LV30, and LV45 (RV or LV indicates which ventricle was paced first, the number indicates by how many ms). Results: During simultaneous pacing, longer AV intervals were associated with improved LV pressure-derivative minimums and increased aortic pressures (p < 0.05 vs. normal sinus rhythm). In the VV interval from RV30 to LV45, there was a graded increase in the aortic velocity time integral and a decrease in dyssynchrony during simultaneous or LV-first pacing (p < 0.05 vs. normal sinus rhythm). Conclusions: For HFNEF patients with mechanical dyssynchrony, acute simultaneous biventricular or LV-first pacing with longer AV intervals reduced mechanical dyssynchrony and improved diastolic and systolic hemodynamics.

Background The association between diastolic abnormality and postexercise contractile decompensation is uncertain in heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF). Hypothesis The higher mitral E/annular early diastolic velocity (E/e′) is relevant to postexercise regional myocardial contractile maladaptation. Methods Seventy HF patients with LVEF 65 ms (OR: 64, 95% CI: = 6–651, P < 0.001) in HF patients with reduced LVEF in multivariate analysis. Conclusions The higher mitral E/e′-related postexercise maladaptation of myocardial contractile motion and synchronicity suggests the involvement of systolic abnormality in exercise pathophysiology in HF patients with reduced LVEF.

We investigated the measurement of soluble ST2 (sST2) in stable heart failure (HF) with a normal ejection fraction (HFNEF) in hypertensive patients.Echocardiography and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and sST2 concentrations were evaluated in 107 hypertensive patients (65 ± 12 years, 57 male) with ejection fraction (EF)50%. Among them, 68 patients with stable HF in functional class II and III were the HFNEF group. We found that the area under the receiver operating characteristic curve (AUC) for sST2 was 0.80 (95% CI 0.70-0.89; P.001), relatively better than that for NT-proBNP (AUC 0.70, 95% CI 0.58-0.79; P = .003) to detect HFNEF. However, the NT-proBNP concentration, rather than sST2, was higher in HFNEF patients with functional class III (562 ± 891 vs 185 ± 242 pg/mL in functional class II; P = .009), and correlated better with mitral E/e' (annular early diastolic velocity) (r = 0.327; P = .008) than sST2 concentrations in HFNEF patients. Multivariate analysis showed that sST213.5 ng/mL was independently associated with HFNEF in hypertensive patients (odds ratio 11.7, 95% CI = 2.9-47.4; P = .001).sST2 measurement provides diagnostic aid of stable HFNEF for hypertensive patients. Addition of NT-proBNP to sST2 could give further information regarding HF functional class and diastolic abnormality.

Recently zebrafish has become a powerful vertebrate model system for cardiac arrhythmia and another advantage is that the heart could be rapidly excised for in-vitro electrophysiological recording.We made direct in-vitro recordings of adult zebrafish heart ECG using the microelectrode and tested the effects of various drugs on zebrafish heart ECG.The QT interval change in the ECG was verified by optically mapped action potential duration (APD). The mean in-vitro heart rate (HR) of the adult zebrafish was 118 ± 22 beats/min. The mean QT interval was 312 ± 36 ms and mean HR corrected QT interval (QTc) 439 ± 39 ms. The mean optically mapped APD was 308 ± 30 ms, which was close to the QT interval in ECG (p=0.815). We found that sympathomimetic drug isoproterenol increased HR, whereas L-type calcium channel blocker verapamil decreased HR. Sodium channel blocker quinidine and L-type calcium channel activator BayK8644 prolonged QTc interval in a dose-dependent manner (515 ± 24 ms and 519 ± 27 ms, respectively, both p0.01). The APD was also prolonged accordingly. Both rapidly and slowly activating delayed rectifier potassium channel (IKr and IKs) blockers E4031 and chromanol 293B, respectively, also prolonged QTc interval in a dose-dependent manner (523 ± 25 ms and 529 ± 27 ms, respectively, both p0.01). Quinidine, E4031 and chromanol 293B also decreased HR.Direct in-vitro recording of adult zebrafish heart is an efficient platform for test of drugs which exert electrophysiological effects on cardiomyocytes, and perturbation of ionic channels that are responsible for human long QT syndrome also modulates QT interval in adult zebrafish heart.

Wing scales of male Euploea mulciber (E. mulciber) and Troides aeacus (T. aeacus) butterflies were investigated from interest in photonic crystal by scanning electron microscopy and optical reflectance measurement. On the basis of the structural observation, the colouration in different areas in their wings was discussed. It was particularly deduced that a violet-green iridescence characteristic of E. mulciber's forewing is caused only in a wavelength range from ∼380 to ∼510nm by multiple interference from a highly tilted, triple-layered cuticle arrangement on the brown scales. It was also found that T. aeacus does not produce a blue-green sheen such as observed by Troides magellanus because its scales have no multiple cuticle layers but microrib layers unable to produce any backscattering diffraction.

Considering full resolution and without 3D glasses, time-multiplexed type is the better choice for 3D display, such as directional sequential backlight system. However, the current directional sequential backlight system can only produce a single-user 3D display provided 3D image for single observer. Thus, the multi-user 3D film was proposed to add in front of the directional sequential backlight system and make the display become a multiuser (each observer watches the same image) 3D display provided full-resolution 3D images for three observers.

Marfan syndrome (MFS) is a rare disease that has a devastating outcome when cardiovascular complications occur. MFS diagnostic criteria have been revised several times since the causative mutation was detected. The most specific diagnostic phenotype is cardiovascular manifestation, which also signals the need for close follow-up; MFS patients may ultimately develop lethal complications during their third or fourth decade of life. An echocardiographer must be familiar with the cardiovascular presentation of the MFS patient and be aware of specific measures to be followed if MFS is suspected. Patients should be examined carefully for other disease symptoms to differentiate MFS from alternative diagnoses.

Background/Purpose This study examined the psychometric properties and clinical validity of the EORTC QLQ-PR25, a questionnaire for assessing the quality of life of patients with prostate cancer. Methods The Taiwan Chinese version of the prostate cancer module (EORTC QLQ-PR25) and the core questionnaires (EORTC QLQ-C30) were administered to 81 patients with prostate cancer after they had been treated with surgery or hormone therapy or both. The QLQ-PR25 module assesses urinary symptoms, bowel symptoms, hormonal treatment-related symptoms, sexual activity and sexual functioning. Results The questionnaires were well accepted by the patients and very few of the items had missing data. Only the urinary symptom scale showed satisfactory internal consistency. Scales were able to differentiate clinical groups of patients with corresponding symptoms, but the differences were smaller than that of major functioning scales in the core questionnaire. Conclusion The Taiwan Chinese version of the EORTC QLQ-PR25 is acceptable in patients with prostate cancer in Taiwan, able to differentiate corresponding symptoms, but the scale structure needs further improvement.

With atomic-layer-deposition grown zinc oxide as the electron selective layer, we developed plastic substrate compatible processing for organic photovoltaic devices and demonstrated flexible inverted organic solar cells on poly(ethylene naphthalate) with a power conversion efficiency of 4.18%.

Low temperature processing of sol-gel spin coated ferroelectric Pb(Zr0.52Ti0.48)TiO3 (PZT) thin film and sputtered (La 0.7 Sr 0.3 )MnO 3 (LSMO) buffer layer on Cr/SiO2/Si and SUS430 substrates using a continuous wave CO2 laser annealing technique was studied in the present work. The laser annealed PZT films coated on LSMO/Cr/SiO2/Si substrates shows an enhancement in the remanent polarization from 6.22 to 11.94 μC/cm2 as the PZT irradiated with a laser fluence of 267 to 334 W/cm2. The Cr electrodes were oxidized easily which deteriorate the electrical properties of specimens, even upon using CO2 laser annealing. On the other hand, the LSMO films (0.2 μm) sputtered on SUS430 substrate and spin coated PZT thin films (0.2 μm) were laser annealed sequentially, showed remanent polarization from 18.07 to 24.01 μC/cm2. CO2 laser annealing not only improves ferroelectric properties and electric leakage currents of PZT films, but also diminishes the inter-diffusion of elements in electrode and ferroelectrics. More...

Permanent pacing is the treatment for chronotropically incompetent hearts. However, the right ventricular (RV) apical pacing-induced asynchrony, even maintaining the atrioventricular (AV) sequential activation, has depressed left ventricular contractility. Whether RV septal pacing would less compromise the electromechanical performance of the left ventricle and the chronotropic effect on myocardial contractility, is unknown.We prospectively studied 42 patients without structural heart diseases and with symptomatic bradycardia. There were 10 patients receiving atrial pacing (AAI) pacemakers, 18 patients having AV sequential pacing at RV apex (DDDapx) and 14 patients being AV sequentially paced at septum (DDDspt). Echocardiography was performed before and within 72 h after the pacemaker implantation. The ventricular mechanical performance and asynchrony was compared in conditions of programmed rates of 60, 80 and 100/min.Myocardial performance index was significantly better in DDDspt than in DDDapx patients (p=0.003). With faster programmed rate, the QRS/RR increased (p0.05) in DDDapx patients with more inter- and intraventricular asynchrony, implicating the disadvantage of prolonged depolarization time. The DDDspt group demonstrated comparable parameters of diastolic function to AAI patients and preserved mechanical performance during accelerated pacing.RV septal pacing showed the advantages of shorter depolarization time, less ventricular contractile asynchrony, better mechanical performance and preserved chronotropic response on myocardial contractility in comparison with apical pacing.

Parallel process units are often encountered in chemical process systems for different considerations, e.g., parallel reactors from reactor network synthesis, parallel columns for heat integration. One notable example is the feed split configuration of heatintegrated distillation columns. In this work, the control of parallel processes is illustrated with the heat-integrated distillation column example. Results show that more consistent control performance can be achieved using the proposed control structure for both feed composition and feed flow disturbances. More importantly, the improvement is obtained using simpler instrumentation and much less engineering effort.

Background Little evidence is available regarding the impact of genetic polymorphisms on the risk of stroke in patients with atrial fibrillation (AF). Angiotensin II plays a pathophysiologic role in prothrombotic atrial endocardial remodeling. Objective The purpose of this study was to investigate the effect of polymorphisms of renin–angiotensin system genes on the incidence of stroke in a prospective cohort of patients with AF. Methods A total of 712 AF patients were longitudinally followed-up for 10.3 ± 2.7 years. Eight polymorphisms of renin–angiotensin system genes were genotyped. Results Patients carrying the G-6 allele in the promoter of the angiotensinogen gene, which was associated with higher promoter activity, were more likely to develop stroke than were noncarriers (hazard ratio 2.54, 95% confidence interval [1.26–5.12], P = .009 after adjustment for CHADS 2 score). G-6A polymorphism provides information additional to CHADS 2 on stroke risk prediction ( C -statistic 0.672 vs 0.724, P = .039). In haplotype analysis, angiotensinogen gene promoter haplotypes containing –217G/–6G, which was associated with the highest promoter activity, were associated with an increased risk of stroke ( P = .004). G-217/G-6 haplotype carriers were even more likely to develop stroke than were noncarriers (hazard ratio 2.78, 95% confidence interval 1.37–5.64, P = .003 after multivariable adjustment). In pharmacogenetic analysis, the increased risk of stroke in subjects carrying G-6 was eliminated by concomitant treatment with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker ( P = .012 for interaction). Conclusion In addition to the CHADS 2 score, angiotensinogen gene polymorphisms may be considered an additional genetic predictor of stroke in patients with AF. Genotyping of the angiotensinogen gene is helpful to determine which AF patients may benefit from treatment with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker.

Being the chamber receiving systemic venous return, the right atrium is a structure of morphological mosaic, comprising the smooth vestibule, the septum, the trabeculated appendage and junctional crista terminalis, the Eustachian ridge, the fanning pectinate muscle, and the tendon of Todaro. The mosaic milieu by itself predisposes to the formation of reentrant atrial tachyarrhythmias. Meanwhile, the right atrium is also common with secondary isthmus structures resulting from surgical iatrogenic scars or stretch-related spontaneous scars. Inside the heterogenous scars, between adjacent scars, and between natural structural barriers and the scars, there are also facilitated opportunities of creating clinical microreentrant (focal) and macroreentrant atrial tachyarrhythmias.

Plasma gelsolin (pGSN) produced by muscle is an abundant protein of extracellular fluids capable of severing actin filaments and eliminating actin from the circulation. Additionally, pGSN modulates the cellular effects of some bioactive lipids. In this study we test the hypothesis that hormonal and metabolic adaptations to exercise are associated with changes in gelsolin concentration in blood. Plasma samples were collected from twenty healthy males recruited from untrained (UT, n=10) and endurance trained (ET, n=10) groups that performed 30-60 minutes of exercise on a cycloergometer at a workload corresponding to 70% of VO2max. Gelsolin concentration was determined by quantitative Western blot analysis with an anti-human gelsolin antibody. The gelsolin concentration in UT and ET subjects before starting exercise ranged from 104 to 330 and 163 to 337 µg · ml(-1) respectively. After 30 minutes of exercise we observed a significant decrease of plasma gelsolin in the UT group (p0.05) while the gelsolin concentration in the ET group rose on average from 244 to 271 µg · ml(-1). However, this increase did not reach statistical significance. Endurance training might increase the ability of muscle tissue to express plasma gelsolin as part of an adaptive mechanism.

Contact-hole patterning is even more challenging than line/space patterning because of the lower image contrast and smaller process window. To enable single exposure solution of 40-45nm half pitch contact-hole at this nearly resolvable limit of current 1.35NA ArF immersion lithography, negative tone development (NTD) process, source mask co-optimization (SMO) methodology and free-form source were explored in this study. The optimization of free form source and mask for NTD process was firstly carried out via Brion Tachyon SMOTM software. The wafer-level performance was then compared for different mask layout solutions and different mask types. A manufacture worthy process window was achieved for 40nm technology node Flash memory product through the combination of free-from source, SMO and NTD technologies. In the performance comparison for mask types, 6% HTPSM performed wider DoF and exposure latitude for all three pitch designs. But OMOG mask is superior to 6% HTPSM on mask and wafer CD uniformity. To further improve the overlapping process window, preserving the SMO layout solution as possible for the sparse environments and minimizing the SRAF writing errors were proposed as the two most critical tuning knobs.

Background Reducing low-density lipoprotein cholesterol (LDL-C) is associated with reduced risk for major coronary events. Despite statin efficacy, a considerable proportion of statin-treated hypercholesterolemic patients fail to reach therapeutic LDL-C targets as defined by guidelines. This study compared the efficacy of ezetimibe added to ongoing statins with doubling the dose of ongoing statin in a population of Taiwanese patients with hypercholesterolemia. Methods This was a randomized, open-label, parallel-group comparison study of ezetimibe 10 mg added to ongoing statin compared with doubling the dose of ongoing statin. Adult Taiwanese hypercholesterolemic patients not at optimal LDL-C levels with previous statin treatment were randomized (N = 83) to ongoing statin + ezetimibe (simvastatin, atorvastatin or pravastatin + ezetimibe at doses of 20/10, 10/10 or 20/10 mg) or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg or pravastatin 40 mg) for 8 weeks. Percent change in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides, and specified safety parameters were assessed at 4 and 8 weeks. Results At 8 weeks, patients treated with statin + ezetimibe experienced significantly greater reductions compared with doubling the statin dose in LDL-C (26.2% vs 17.9%, p = 0.0026) and total cholesterol (20.8% vs 12.2%, p = 0.0003). Percentage of patients achieving treatment goal was greater for statin + ezetimibe (58.6%) vs doubling statin (41.2%), but the difference was not statistically significant (p = 0.1675). The safety and tolerability profiles were similar between treatments. Conclusion Ezetimibe added to ongoing statin therapy resulted in significantly greater lipid-lowering compared with doubling the dose of statin in Taiwanese patients with hypercholesterolemia. Studies to assess clinical outcome benefit are ongoing. Trial registration Registered at ClinicalTrials.gov: NCT00652327

In patterning the via-hole, uneven hole-size and missing-hole defects were identified through after etch inspection (AEI), and these defects were characterized as yield killer since it led to electrical open. Through the after development inspection (ADI) and AEI comparison, the uneven hole-size and missing-hole defects are attributed to the postdeveloped satellite spots. The distribution of satellite spots always show a strong photo field map that is discovered to correlate with the local pattern density in mask scribe lane. Apart from the possible modifications on pattern density in the scribe lane by retooling the photo mask, this paper describes the work done in reducing the satellite defect. Several development experiments including multiple wafer agitation cycles of dynamic puddle, multiple cycles of scanning rinse, pre-wet before development, wafer rotation speed in rinse, wafer rotation speed in drying and advanced defect reduction (ADR) function of track were carried out. The multiple cycles of scanning rinse coupling with the optimal wafer rotation speed of rinse effectively suppresses the count of satellite spots. Pre spin dry in advance of the deionized water (DIW) rinse to minimize the pH shock is also effective to reduce the defect count. Multiple cycles of development puddle and scanning rinse have a synergy effect to lower defectivity up to complete suppression of satellite defect. To minimize the throughput loss induced by the long development time, ADR is proposed as better candidate for fully eliminating the satellite defect.

Objectives The purpose of this study was to investigate the effect of stretch (the major risk factor for atrial fibrillation [AF]) on spatial and temporal alternations of action potential duration (APD-ALT) and calcium transient in cultured atrial myocyte monolayer. Background How rapid firings or premature beats trigger AF is not completely understood. Discordant repolarization alternans, characterized by simultaneous prolongation and shortening of APD in different myocardial regions, is central to the genesis of ventricular fibrillation. We hypothesized that repolarization alternans also is central to the initiation of multiple re-entry circuits and AF. Methods Confluent HL-1 atrial myocyte monolayer with spontaneous depolarization was cultured in silicone membrane and subjected to mechanical stretch. Rapid field pacing was used to induce alternans. A high-resolution dual optical mapping system was used to record action potentials and calcium transients. Results High-rate pacing induced APD-ALT and calcium transient in atrial myocyte monolayer. Mechanical stretch significantly decreased the thresholds for APD-ALT and calcium transient. Mechanical stretch decreased the expression of sarcoplasmic reticulum adenosine triphosphatase 2, and thus slower calcium reuptake kinetics, which was responsible for the susceptibility to alternans. Mechanical stretch did not alter the APD restitution kinetics. Mechanical stretch also enhanced spatially discordant alternans. Overexpression of sarcoplasmic reticulum adenosine triphosphatase 2 reversed all the effects of stretch on susceptibility to alternans. In intact atrium, mechanical stretch also enhanced discordant alternans. Conclusions Mechanical stretch increased the susceptibility to alternans in atrial myocytes, which may explain the susceptibility to AF in conditions of atrial stretch, such as mitral valvular heart disease, heart failure, and hypertension.

Atrial fibrillation (AF) is a risk factor for ischemic stroke. Stroke-prevention strategies based on risk schemes have been developed but most of the data are from western people. Our goal is to investigate the risk factors of ischemic stroke in Taiwanese with AF in a nation-wide database.A universal national health insurance (NHI) program has been implemented in Taiwan since 1995. We used system sampling database from 1997 to 2008 with a total of 1,000,000 subjects. By using ambulatory and inpatient claim data, we included subjects with AF and were above 20 years old. We excluded those who had ever taken warfarin or aspirin or had valvular heart diseases.A total of 7920 patients (3633 women, 4287 men) were included in the final analyses. Cox regression analysis showed that the risk factors for ischemic stroke were age (OR=1.338 for age 65-74 years vs. age 20-64 years, P=0.014; OR=1.652 for age over 75 years vs. age 20-64 years, P0.001), hypertension (HTN) (OR=2.656, P0.001), diabetes mellitus (DM) (OR=1.341, P=0.005), heart failure (OR=1.611, P0.001), previous ischemic stroke or transient ischemic accident (TIA) (OR=2.752, P0.001) and peripheral arterial disease (PAD) (OR=1.814, P=0.006). The gender, coronary artery disease, history of myocardial infarction and chronic renal insufficiency were not associated with ischemic stroke. The rate of ischemic stroke was much lower in current cohort as compared with that in whites. Frequent used risk schemes including CHADS₂ and CHA₂DS₂-VASC had comparable but only limited ability to predict ischemic stroke in subjects with AF.Compare with western people, hypertension plays a more important role in ischemic stroke in Taiwanese with AF and the incidence is lower. A substantial number of ischemic strokes cannot be accurately predicted by current risk schemes.

Inclined Al2O3column array was fabricated by using hollow nanosphere template. Birefringence and photonic crystals behavior can be observed in the orderly inclined column array. Compared to substrate without patterns, photonic crystals property was enhanced.

ObjectivesThis study was designed to evaluate the status of steroidogenesis proteins and de novo synthesis of aldosterone in the atrium, and relationships of these factors to atrial fibrillation (AF).BackgroundThe role of mineralocorticoid in the pathogenesis of AF is unknown.MethodsWe studied atrial expression of steroidogenesis proteins and aldosterone level in patients with and without AF, and in HL-1 atrial myocytes. We also investigated the electrophysiologic effects and signal transduction of aldosterone on atrial myocytes.ResultsWe found basal expressions of mineralocorticoid receptors (MRs), glucocorticoid receptors, and 11-beta-hydroxysteroid dehydrogenase type 2 (11bHSD2) but not 11-beta-hydroxylase (CYP11B1) or aldosterone synthase (CYP11B2) in human atria and HL-1 myocytes. There was no significant difference of mean atrial aldosterone level between patients with AF and those with normal sinus rhythm. However, patients with AF had a significantly higher atrial MR expression compared with those with normal sinus rhythm (1.73 ± 0.24-fold, p < 0.001). Using mouse HL-1 atrial myocytes as a cellular AF model, we found that rapid depolarization increased MR expression (1.97 ± 0.72-fold, p = 0.008) through a calcium-dependent mechanism, thus augmenting the genomic effect of aldosterone signaling as evaluated by MR reporter. Aldosterone increased intracellular oxidative stress through a nongenomic pathway, which was attenuated by nicotinamide adenine dinucleotide phosphate oxidase inhibitor diphenyleneiodonium, but not by MR-blockade spironolactone. Aldosterone increased expression of the alpha-1G and -1H subunits of the T-type calcium channel and thus increased the T-type calcium current (–13.6 ± 2.9 pA/pF vs. –4.5 ± 1.6 pA/pF, p < 0.01) and the intracellular calcium load through a genomic pathway, which were attenuated by spironolactone, but not by diphenyleneiodonium.ConclusionsExpression of MR increased in AF, thus augmenting the genomic effects of aldosterone. Aldosterone induced atrial ionic remodeling and calcium overload through a genomic pathway, which was attenuated by spironolactone. These results suggest that aldosterone may play a role in AF electrical remodeling and provide insight into the treatment of AF with MR blockade.

A quadrature voltage controlled oscillator (QVCO) with nested cross-coupled topology is presented. With this topology, the circuit operates at very low voltage, and achieves low phase noise with low power consumption. The nested cross-coupled topology employs two nMOS cross-couple pairs. The one with pMOS active loads and coupling transistors plays the major role. The other one, by enhancing the negative resistance, improves performances of QVCO. The prototype is implemented using TSMC 0.18-?m 1P6M Mixed Signal/RF process technology. With 0.8 V power supply, the phase noise of the QVCO is -118.3 dBc/Hz at 1 MHz offset frequency from the carrier frequency of 5.73 GHz. The figure of merit (FoM) is -185.3, total power consumption is 6.44 mW, tuning range is 280 MHz and I/Q are balanced.

Background/Purpose Desmosome gene mutations have been reported in patients with arrhythmogenic right ventricular dysplasia (ARVD). However, there are hardly any genetic studies in Asians. We studied the clinical characteristics, cardiac manifestations and desmosome gene mutations in ARVD patients in Taiwan. Methods Medical records of five ARVD patients were reviewed and genomic DNA was obtained from peripheral blood samples. Mutation screening in desmoplakin (DSP), plakophilin-2, desmoglein-2 (DSG2) and desmocollin-2 genes was performed using polymerase chain reaction and DNA sequencing techniques. Results Among the five patients, three presented with palpitations followed by loss of consciousness, and the other two had palpitations or chest tightness without loss of consciousness. Electrocardiogram (ECG), magnetic resonance imaging and signal averaged ECG results were similar to those reported in Western countries. Mutations in the desmosome genes were identified in four of the five patients (three with a DSG2 mutation and one with a DSP mutation). Five gene mutations were noted in four patients and all mutations were novel (one patient had a DSG2 double mutation). The mutation types were missense in four and splicing mutation in one. Conclusion Patients with ARVD in Taiwan had similar clinical and cardiac manifestations as reported in the Western literature. More than half of the patients had desmosome gene mutations.

α-Dystroglycanopathy (α-DGP) is a group of muscular dystrophy characterized by abnormal glycosylation of α-dystroglycan (α-DG), including Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease, Walker-Warburg syndrome and congenital muscular dystrophy type 1D (MDC1D), etc. LARGE, the causative gene for MDC1D, encodes a glycosyltransferase to form [-3Xyl-α1,3GlcAβ1-] polymer in the terminal end of the post-phosphoryl moiety, which is essential for α-DG function. It has been proposed that LARGE possesses the great potential to rescue glycosylation defects in α-DGPs regardless of causative genes. However, the in vivo therapeutic benefit of using LARGE activity is controversial. To explore the conditions needed for successful LARGE gene therapy, here we used Large-deficient and fukutin-deficient mouse models for MDC1D and FCMD, respectively. Myofibre-selective LARGE expression via systemic adeno-associated viral gene transfer ameliorated dystrophic pathology of Large-deficient mice even when intervention occurred after disease manifestation. However, the same strategy failed to ameliorate the dystrophic phenotype of fukutin-conditional knockout mice. Furthermore, forced expression of Large in fukutin-deficient embryonic stem cells also failed to recover α-DG glycosylation, however coexpression with fukutin strongly enhanced α-DG glycosylation. Together, our data demonstrated that fukutin is required for LARGE-dependent rescue of α-DG glycosylation and thus suggesting new directions for LARGE-utilizing therapy targeted to myofibres.

Background Recent findings indicate that small-conductance Ca 2+ -activated K + (SK) channels are abundantly present in atrial tissues and are upregulated in the diseased ventricles. Almost all studies used apamin, which is a specific SK channel blocker in neurons that does not block any other neural type of ion channels. However, the specificity of apamin in blocking SK currents in cardiac tissues remains unclear because apamin has been reported to block fetal L-type Ca 2+ current in embryonic chick heart. The purpose of the present study was to test the hypothesis that apamin does not block any major cardiac type ion currents. Methods We studied human embryonic kidney (HEK293) cells that either stably expressed human voltage-gated Na + currents or were transiently transfected to express major human cardiac type K + and Ca 2+ currents. Whole-cell patch-clamp techniques were used to determine ionic current densities before and after apamin administration. Results Ca 2+ currents ( CACNA1C+CACNAB2B ) in 4 cells (–17 ± 4.9 pA/pF) were not affected by apamin (500 nM) (–17 ± 5.9 pA/pF, P = NS) but were reduced by nifedipine (2 µM) to –5 ± 4.0 pA/pF ( P = .008). Na + currents (SCN5A) in 9 cells (–231 ± 96 pA/pF) were not affected by apamin (500 nM) (–232 ± 107 pA/pF, P = NS) but were reduced by flecainide (100 µM) in a use-dependent manner to 71 ± 51 pA/pF ( P = Ks (KCNQ1+KCNE1) (25 ± 9 pA/pF) was not blocked by apamin (500 nM) (n = 8, 22 ± 9 pA/pF, P = NS) but was blocked by chromanol 293B (50 µM) to 5 ± 2 pA/pF (n = 4, P = .01). I Kr (KCNH2+KCNE2) (27 ± 8 pA/pF) was not blocked by apamin (500 nM) (n = 6, 26 ± 6 pA/pF, P = NS) but was blocked by E4031 (100 nM) to 13 ± 4 pA/pF (n = 6, P K1 (KCNJ2) (–45 ± 14 pA/pF) was not blocked by apamin (500 nM) (n = 7, –46 ± 17 pA/pF, P = NS) but was blocked by CsCl (5 mM) to –16 ± 5 pA/pF (n = 7, P = .004). I to (KCND3) (526 ± 115 pA/pF) was not blocked by apamin (500 nM) (n = 2, 516 ± 110 pA/pF, P = NS) but was blocked by 4-aminopyridine (10 mM) to 235 pA/pF (n = 1). Conclusions Apamin does not block human Na + current, L-type Ca 2+ current, or other major K + currents in HEK293 cells. These findings indicate that apamin is a specific SK current blocker in human cardiac tissues.

We fabricated an orderly inclined Al2O3 column array using a hollow microsphere template. The microstructure and optical properties were investigated with scanning electron micrography and a UV/VIS spectrometer, respectively. Microsphere shell templates were formed using atomic layer deposition to prevent the melting of polystyrene microspheres during the following high-temperature deposition process. An inclined Al2O3 column array with a 30° tilt angle was grown by oblique deposition on a substrate with a 75.5° tilt angle with respect to the substrate normal. Birefringence and photonic crystalline behavior can be observed in the orderly inclined column array. The difference in the refractive indices between the p and s polarizations of the orderly inclined Al2O3 column array was about 0.1. The photonic properties of the crystal were enhanced compared to those of substrates without patterns.