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Background: Cardiovascular complications after Pfizer–BioNTech COVID-19 (BNT) vaccination are a concern, especially in adolescents. We analyzed the risk factors for myocarditis after BNT vaccination. Methods: We used a special evaluation protocol for all patients aged 12–18 years who presented to our emergency department with cardiovascular symptoms after BNT vaccination. Results: A total of 195 patients (109 boys and 86 girls) were enrolled. Eleven (5.6%) patients presented with arrhythmia (arrhythmia group), 14 (7.2%) had a diagnosis of pericarditis/myocarditis (the peri/myocarditis group), and the remaining 170 were controls (no cardiac involvement). Chest pain (77.6%) was the most common symptom. The median time from vaccination to symptom onset was 3 days. In the peri/myocarditis group (13 myocarditis and 1 pericarditis), the median time to the peak troponin T level was 5 days after vaccination. Abnormal electrocardiographic changes, including ST-T changes and conduction blocks, were more commonly detected in the peri/myocarditis group (85.7% vs. 12.4% in the control group, p

Background: Normal ECG standards in newborns, infants, children and adolescents have been collected and published by many authors. Only those by Davignon et al., Rijinbeek et al. and our two studies covered all ages from birth to adolescence. The standards reflecting the growth and development of the heart in infants, children and adolescents remained to be studied and explored. Methods: We selected from our ECG database, after discussions and consultation, 15 key ECG parameters and analyzed for their age- and sex-specific mean, standard deviation and 2nd to 98th percentiles and their percentile charts were constructed. Results: The ranges and distributions of the normal ECG standards, means and 2nd to 98th percentiles of 15 key parameters were established. Conclusion: A complete set of normal ECG standards of 15 key parameters from birth to adolescents is available for clinicians and researchers.

Background: A widely used method of treating left-sided arrhythmia substrates in children is retrograde transaortic ablation under fluoroscopic guidance. However, the feasibility, safety, and efficacy of this approach under zero fluoroscopy (ZF) guidance, especially the mid-term safety of anatomy and function of aortic valves, have yet to be proven. Methods: All consecutive patients who received ablation of left-sided arrhythmias between January 2012 and June 2020 and below 20 years-old were enrolled. The study group submitted to 55 ZF-guided procedures using cardiac mapping system (EnSite Precision), whereas 49 procedures were performed under fluoroscopic guidance in the control group. Echocardiographic studies took place before and 6-months after ablative procedures. Results: One-hundred-and-two patients (male, 66; female, 36) underwent a total of 104 ablative procedures. Mean procedural durations were 83.9 ± 44.4 min in the study group and 64.8 ± 29.1 min in the control group, respectively (p = .01; the 95% confidence interval, −33.57 to −4.63). Corresponding fluoroscopic times were .5 ± 2.2 min and 24.7 ± 13.9 min (p

Abstract Moiré lattice in artificially stacked monolayers of two-dimensional (2D) materials effectively modulates the electronic structures of materials, which is widely highlighted. Formation of the electronic Moiré superlattice promises the prospect of uniformity among different moiré cells across the lattice, enabling a new platform for novel properties, such as unconventional superconductivity, and scalable quantum emitters. Recently, epitaxial growth of the monolayer transition metal dichalcogenide (TMD) is achieved on the sapphire substrate by chemical vapor deposition (CVD) to realize scalable growth of highly-oriented monolayers. However, fabrication of the scalable Moiré lattice remains challenging due to the lack of essential manipulation of the well-aligned monolayers for clean interface quality and precise twisting angle control. Here, scalable and highly-oriented monolayers of TMD are realized on the sapphire substrates by using the customized CVD process. Controlled growth of the epitaxial monolayers is achieved by promoting the rotation of the nuclei-like domains in the initial growth stage, enabling aligned domains for further grain growth in the steady-state stage. A full coverage and distribution of the highly-oriented domains are verified by second-harmonic generation (SHG) microscopy. By developing the method for clean monolayer manipulation, hetero-stacked bilayer (epi-WS2/epi-MoS2) is fabricated with the specific angular alignment of the two major oriented monolayers at the edge direction of 0°/ ± 60°. On account of the optimization for scalable Moiré lattice with a high-quality interface, the observation of interlayer exciton at low temperature illustrates the feasibility of scalable Moiré superlattice based on the oriented monolayers.

Background/Purpose: Fontan operation is the standard surgical procedure for achieving long-term survival in single-ventricular complex congenital heart diseases (SV-CHD). We aim to identify the perioperative outcomes and impact of heterotaxy syndrome (HS) after Fontan operation in a tertiary pediatric cardiology center. Methods: Medical records were reviewed for all patients who received Fontan operation and who were born between 1997 and 2017 in our institution. Preoperative, operative, and postoperative risk factors for perioperative mortality and morbidity were analyzed. Results: Totally, 154 patients were enrolled (103 SV-CHD and 51 HS), and the male to female ratio was 92:62. The mean age of Fontan operation was 5.1 years, and extracardiac conduit comprised the majority (90.9%) of Fontan operation. Overall perioperative event-free survival to discharge was 91.6% (84.3% in HS and 95.1% in other SV-CHD, P = 0.032). For secondary outcomes, length of intensive care stay and duration of pleural effusion drainage were not significantly different between patients with HS and other SV-CHD, but postoperative arrhythmia was more common in HS group (31.4% vs. 12.6%, P = 0.005). In multivariable regression analysis, preoperative risk factors including operation year before 2007 and high PAP and postoperative factors of elevated postoperative CVP were associated with worse outcomes. HS was not a predictor of worse outcome after adjusting for preoperative PAP and operation era. Conclusion: Surgical outcome has improved much in current era. Perioperative outcome is poorer in patients with HS than other SV-CHD, but HS is not a predictor of perioperative mortality after adjusting for hemodynamic factors.

Background/purpose: Prognostic factors remain unclear in patients undergoing transcatheter implantation of Venus P-valve for their severe pulmonary regurgitation associated with native right ventricular (RV) outflow tract. Method: Between January 2017 and October 2018, we prospectively collected data of patient characteristics, cardiac magnetic resonance imaging, cardiopulmonary exercise testing, and levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) before and 6–12 months after valve graft implantation. Results: Fifteen patients (male: 8, median age: 24.8 years) were enrolled. The procedure success rate was 100%. The median follow-up was 16.3 months without any dysfunction of the valve graft. The cohort demonstrated a significant improvement in cardiac index (from 3.3 to 3.9 L/min/m2) and increase of percentage of New York Heart Association functional class I (P

Objective: Lower serum low-density lipoprotein cholesterol (LDL-C) levels are associated with increased intracerebral hemorrhage (ICH) risk. However, reverse causality and residual confounding has not attracted public attention. Therefore, we assessed whether people with LDL-C have increased risk of mortality adjusting for potential confounders using two large Taiwan cohorts.Methods: The Mei-Jhao (MJ) cohort has 414,372 adults participating in a medical screening program with 378 ICH deaths within 15 years of follow-up (1994–2008). Cox proportional hazards regressions estimated hazard death ratios according to LDL-C levels. We identified 4,606 ICH patients from the Taiwan Stroke Registry (TSR) and analyzed the impact of LDL-C on 3-month mortality.Results: Low cholesterol (LDL-C

Background/purpose: Outlet-type VSD is frequently associated with aortic valve prolapse that surgery is frequently required. The literature regarding outcomes of transcatheter closure of outlet-type VSDs is scant. This study was conducted to know the safety and efficacy of transcatheter closure of outlet-type ventricular septal defects (VSDs) with Amplatzer Duct Occluder II (ADO II). Methods: Medical records of patients underwent attempted transcatheter closure of outlet-type VSD with ADO II between October 2013 and August 2019 were retrospectively reviewed. Results: Among 49 patients, transcatheter closure was successful in 45 (91.8%; 33 males and 12 females; mean [± standard deviation] age and body weight: 15.8 (±17.7) years and 36.6 (±23.3) kg, respectively). The median VSD diameter was 4.0 mm (range: 1.2–6.0 mm). Device closure failed in four because the sheath could not be advanced through a prograde or retrograde route in one patient, occluder embolization in the two patients, and failed right ventricular disc anchoring in one patient. After a mean follow-up of 22.7 months (range: 0.3–51.1 months), only nine (20.0%) patients had increased severity in aortic regurgitation (AR) on the echocardiography. Preprocedural AR decreased in severity or even disappeared in 11 (24.4%) patients. No heart block or device failure occurred during follow-up. A trivial-to-small residual shunt was detected in 19 patients (42.2%) in the most recent echocardiography. Conclusion: Transcatheter closure of outlet-type VSDs with ADO II is feasible. Although no significant aggravation of AR was observed in the short-to-mid-term follow-up, long-term follow-up is mandatory.

Background The epidemiology of pulmonary hypertension (PH) in patients with adult congenital heart disease in Western countries is already known. We investigate clinical characteristics of PH in adult congenital heart disease with emphasis on complex congenital heart disease (CHD) from an Asian cohort in Taiwan. Methods and Results All adult patients (aged >18 years) diagnosed with CHD between January 2007 and July 2018 qualified for the study. PH was determined by cardiac catheterization data or echocardiography reports. In accord with the World Symposia on Pulmonary Hypertension, CHD was further categorized as simple, severe, or complex CHD (including pulmonary atresia‐ventricular septal defect and single‐ventricle anomalies). There were 4301 patients (55.6% women), 15.7% with severe and 3.9% with complex CHD. The cumulative incidence of PH was 4.4% (95% CI, 3.8–5.0). Our multivariable regression model indicated 4.2‐fold mortality increase (95% CI, 3.0–5.9) in the presence of PH, with age, female sex, and severe or complex CHD linked to higher incidence of PH. Only 49% of patients received PH‐specific therapy. Five‐ and 10‐year survival rates of patients with PH (n=190) were 72.3% (95% CI, 65.1%–78.4%) and 58.8% (95% CI, 50.1%–66.5%), respectively. Survival rates in those with Eisenmenger syndrome, PH after defect correction, and complex CHD were similar. Low oxygen saturation and high uric acid levels were associated with increased mortality. Conclusions In this sizable Asian adult CHD cohort, the cumulative incidence of PH was aligned with that of Western countries. Mortality proved higher in patients with PH versus without PH. Although complex CHD carried greater risk of PH compared with other adult CHD subsets, survival rate was similar.

Objective: To define the impact of associated abnormalities on the efficacy of the novel subtropical guidelines for palivizumab prophylaxis on respiratory syncytial virus (RSV)-related hospitalizations in patients with hemodynamically significant congenital heart disease (hsCHD).Method: This prospective study enrolled every patient seen at a tertiary care center for hsCHD, who was born between 2014 and 2018 and received at least 1 dose of palivizumab, according to the subtropical guidelines. The patients were followed until the age of 2 years.Results: A total of 772 patients (49% male) were enrolled. Cyanotic CHD was seen in 46% of patients, of whom 23% had associated abnormalities. Lung/airway abnormalities (14%) were the most common followed by the genetic syndromes associated with CHD (7.3%). Among the 772 patients, RSV-related hospitalizations occurred in 3.2 and 2.2% children aged ≤ 12 and 13–24 months, respectively. Most of the RSV infections occurred in patients no longer satisfying the criteria for palivizumab prophylaxis. The patients with associated abnormalities but not the type of CHD, patient age, and patient sex were risk factors for RSV-related hospitalizations. The rates of RSV-related hospitalizations, admission to the intensive care unit, and endotracheal intubation were higher for patients with associated anomalies than for other patients before 24 months of age (10.2 vs. 4.0%, 67 vs. 33%, and 39 vs. 4.2%, p = 0.004, 0.06, 0.013, respectively).Conclusion: Children with abnormalities, especially genetic syndromes and lung/airway problems associated with CHD, are at high risk for RSV-related hospitalization. Our current subtropical guidelines for palivizumab prophylaxis in patients with hsCHD, should be revised to include the results of this study.

Background: Dilated cardiomyopathy (DCM) is the most common childhood cardiomyopathy. The epidemiological profiles and prognosticators of clinical outcomes in Asian populations are not well elucidated.Methods: Data of 104 children aged 3 years and severe mitral regurgitation at initial diagnosis were independent risk factors for death or transplantation (hazard ratios = 2.93 and 3.31, respectively; for both, P

Exciton energy transfer in monolayer transition metal dichalcogenides is limited to short distances. Here, Shi et al. fabricate a planar metal-oxide-semiconductor structure and show that exciton energy transfer can be extended to tens of microns, mediated by an exciton-surface-plasmon-polariton–exciton conversion mechanism.

Abstract Background Kawasaki disease (KD) is an acute systemic vasculitis that occurs in children and may lead to cardiovascular morbidity and mortality. Progressive coronary dilatation for at least 2 months is associated with worse late coronary outcomes in patients with KD having medium or giant aneurysms. However, the risk factors and occurrence of progressive coronary dilatation in patients with KD but without medium or giant aneurysms have been insufficiently explored. Methods We retrospectively enrolled 169 patients with KD from a tertiary medical center in Taiwan during 2009–2013. Medical records of all patients were reviewed. Echocardiography was performed during the acute KD phase and at 3–4 weeks, 6–8 weeks, 6 months, and 12 months after KD onset. Progressive coronary dilatation was defined as the progressive enlargement of coronary arteries on three consecutive echocardiograms. Logistic regression analysis was conducted to evaluate the potential risk factors for coronary aneurysms and progressive coronary dilatation. Results Of a total of 169 patients with KD, 31 (18.3%) had maximal coronary Z-scores of ≥ + 2.5 during the acute KD phase, 16 (9.5%; male/female: 9/7) had coronary aneurysms at 1 month after KD onset, and 5 (3.0%) satisfied the definition of progressive coronary dilatation. Multivariate logistic regression analysis revealed that an initial maximal coronary Z-score of ≥ + 2.5 [odds ratio (OR): 5.24, 95% confidence interval (CI): 1.31–21.3, P = 0.020] and hypoalbuminemia (OR: 4.83, 95% CI: 1.11–20.9, P = 0.035) were independent risk factors for coronary aneurysms and were significantly associated with progressive coronary dilatation. However, the association between intravenous immunoglobulin unresponsiveness and the development of coronary aneurysms at 1 month after KD onset didn’t reach the level of significance (P = 0.058). Conclusions In the present study, 3% (5/169) of patients with KD had progressive coronary dilatation, which was associated with persistent coronary aneurysms at 1 year after KD onset. Initial coronary dilatation and hypoalbuminemia were independently associated with the occurrence of progressive coronary dilatation. Therefore, such patients may require intensive cardiac monitoring and adjuvant therapies apart from immunoglobulin therapies.

Purpose – The main purpose of this study is to find ways on how to promote bike tourism globally, and use Taiwan as a model to explore this aspect. Design – The development of the study structure involved brainstorming and the assistance of an expert panel. The study framework is composed of 7 aspects with 8-12 subitems each. Methodology – The opinions of experts were gathered through a questionnaire survey. Afterwards, the CLPEM (Control Limits Performance Evaluation Method) was adopted to determine the means to promote bike tourism. Findings – The results show how the government and operators could prioritize service enhancements and improvements such as "bike rental at one station with drop off at another designated location, nanny vans to accommodate bike tourists, bike tourist information center, training for bike tour guides who can provide practical and historical knowledge for tourists, creative bike touring routes depending on the rider’s abilities, local friendly hospitality for riders, and comprehensive travel insurance policies". Originality of the research – This study has constructed a framework to promote bike tourism.

The aim of this study is to characterize antibiotic-nonsusceptible Salmonella isolates in Taiwan. Methods: A total of 76 Salmonella isolates showing lower susceptibility to cephalosporins or quinolones were identified from 1416 clinical isolates from 1999 to 2008. Minimal inhibitory concentrations for selected antimicrobial agents were tested by the agar dilution method. Antibiotic resistance-related genes were determined by polymerase chain reaction (PCR) combined with sequencing. Southern blotting, conjugation tests, and transformation tests were used to characterize plasmid-mediated quinolone resistance (PMQR) determinants. Results: The observed nonsusceptible phenotypes of 76 isolates were against cefoxitin (57.9%), cefotaxime (43.4%), ceftazidime (40.8%), ceftriaxone (42.1%), cefepime (5.3%), ciprofloxacin (80.3%), and levofloxacin (81.6%). Among 44 cephalosporin-resistant isolates, TEM-1, CMY-2, CMY-14, CTX-M-3-like and CTX-M-15-like determinants were present in 31 (70.5%), 32 (72.7%), 1 (2.3%), 1 (2.3%), and 1 (2.3%) of isolates, respectively. PCR screening for PMQR genes of 62 quinolone-nonsusceptible isolates revealed the presence of qnrS, qnrD, aac(6′)-Ib-cr, and oqxAB in 3 (4.8%), 2 (3.2%), 1 (1.6%), and 10 (16.1%) isolates, respectively. Among 36 isolates showing high resistance to quinolones, S83F/D87N and S83F/D87G amino acid substitutions of GyrA were found in 29 (80.6%) and 6 (16.7%) isolates, respectively. Moreover, among quinolone highly resistant isolates, eight (22.2%) of isolates showed over-expression of the PAβN-sensitive efflux pump. Transformants and transconjugants harboring qnrD- or oqxAB-plasmids showed decreased susceptibility to quinolones. Conclusion: GyrA mutations are the major mechanisms associated with quinolone-resistant Salmonella isolates in Taiwan. Overproduction of efflux pump genes and the presence of qnr and oqxAB play additional roles in reduced susceptibility to quinolones.

Background: Kawasaki disease (KD) is one of the most common vasculitis in childhood. Intravenous γ-immunoglobulin (IVIG) is recommended to be administrated within 10 days after fever onset. However, some patients didn't have IVIG therapies because of atypical disease presentations or spontaneous defervescence. We aimed to evaluate the coronary outcomes of the KD patients who didn't receive IVIG and had defervescence within 10 days.Methods: We retrospectively reviewed the KD patients in NTUCH between 2008 and 2015. The patients with a diagnosis of KD and had a febrile length between 5 and 10 days were enrolled. Days of fever, clinical symptoms, laboratory data at the acute stage, and series of coronary artery measurements within a minimum of 3 months after disease onset were recorded. Risk factors associated with coronary lesions 1 month after KD onset were also analyzed.Results: Two hundred ninety-three eligible KD patients were enrolled (Male: 55.1%, mean age of onset: 1.8 years old). Thirty-seven patients had spontaneous defervescence without IVIG treatment. The incidence of coronary aneurysms at the 4th week after disease onset was higher in spontaneously defervesced KD patients than those treated with IVIG (18.9% vs. 5.1%, p = 0.002). Interestingly, of the 238 KD patients without coronary lesions at their acute phase, percentages of emerging coronary aneurysms became significantly higher if they didn't have IVIG therapies due to spontaneous defervescence (4/31), compared with those who received IVIG (3/208). Further analysis showed the development of coronary lesions at 1 month after disease onset was associated with younger age ( 17,000/cumm, p = 0.031).Conclusions: 18.9% of KD patients with spontaneous defervescence had coronary aneurysms. Even without initial coronary lesions, such patients were still riskier to develop coronary aneurysms, compared with KD patients who received IVIG therapies. Such findings address the importance of refining the strategy for use of IVIG in the spontaneously defervesced KD patients within 10 days after fever onset, at least in those with age younger than 1 year and those with leukocytosis.

Abstract Background Pathogenic infections can significantly impact the health of livestock. Traditionally, antibiotic growth promoters (AGPs) have been used in feed to enhance growth performance and disease control. However, concerns regarding antibiotic resistance have led to the exploration of traditional herbal medicine as a natural alternative, guided by the principle of medicine-food homology. The Taguchi method was employed to optimize the culture formula for cordycepin production, an active component of Cordyceps militaris (C. militaris). The influences of C. militaris supplementing solid-state fermentation (CMSSF) in feed on the growth performance and immune responses of grower pigs were evaluated in the present study. Results The C. militaris ethanol extract (CME) displayed potent free radical scavenging activity against 2, 2-Diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) after undergoing fermentation. Additionally, the antibacterial testing revealed that CME effectively inhibits the growth of common pig pathogens such as Glaesserella parasuis, Pasteurella multocida, Staphylococcus hyicus, and Streptococcus suis. In lipopolysaccharide (LPS)-treated intestinal porcine enterocyte cell line (IPEC-J2), CME significantly suppressed the production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6. In addition, higher antioxidative activity was detected as indicated by elevated concentration of superoxide dismutase (SOD) in pig serum. The levels of immunoglobulin M (IgM), IgA, and IgG antibodies, as well as classical swine fever virus (CSFV) antibodies (S/P ratio) in serum were all increased. Growth performance of pigs fed with dietary CMSSF supplementation was improved in comparison with the control. Conclusions Results demonstrated that CMSSF has the potential to be used as a natural growth promoter to enhance immunity, antioxidation, as well as overall health and growth performance of grower pigs.

As the most common primary glomerular disease in the world, IgA nephropathy (IgAN) is one of the major causes of end-stage renal disease (ESRD). With the in-depth studies of IgAN, researchers have gradually clarified the important roles of galactose-deficient IgA1 (Gd-IgA1) production, gut microbiome dysbacteriosis, genetic susceptibility and immune system abnormalities in the pathogenesis of IgAN. Therefore this review summarized the latest researches based upon the four-hit hypothesis of IgAN, dysbacteriosis, genetics and immunological mechanism and provides comprehensive perspectives for understanding the multidimensional factors of this disease.

Kawasaki disease (KD) is the most common pediatric vasculitis. The study aimed to identify the risk factors of intravenous immunoglobulin (IVIG) unresponsiveness from the initial clinical parameters of the Taiwanese KD patients. Methods: We enrolled 248 KD (development dataset: 181, validation: 67) patients who received IVIG within 10 days after fever onset. IVIG unresponsiveness was defined by persistent fever beyond 24 hours after IVIG or recrudescent fever with KD symptoms. Results: From the development dataset (181 patients), IVIG unresponsiveness was noted in 22 patients (12.1%). The preIVIG levels of albumin, percentage of neutrophils, and positive lymphadenopathy were identified with highest risk for IVIG unresponsiveness. These three variables were used to construct a three-variable logistic regression model, which yielded an area under the receiver–operating-characteristics curve of 0.87. These three variables were further used to generate a composite scoring model (Formosa score) which yielded a sensitivity of 90.9% and specificity of 81.3% for a cut-off point of three or more. Validation in an independent cohort (67 KD patients) yielded sensitivity and specificity of 71.4% and 81.0%, respectively. Conclusion: We have established a simple three-variable Formosa score for KD patients to identify early those at risk of IVIG unresponsiveness for timely aggressive immunomodulation initially.

This paper aims to explore the narrative expression skill of design students through manipulating image structure. Moreover, narrative expression is the skill of interpreting design with narrative. The study is a classroom experiment conducted naturally, and the experimental data is obtained and analysed by quantitative analysis. We found differences in students' narrative tendencies and richness in overall narrative expression. The teaching and training of design narrative can effectively help students familiarise themselves with the design process and personal skill integration and encourage students to pay attention to the design of elements and content. This will improve students' design competencies under skills different from technology. The paper concludes that students must improve and integrate design competencies through practical methods under other narrative tendencies. Furthermore, the lecturer can explore and adjust design teaching through design narrative training to strengthen or balance students' design performance competency.

Diodes with an erbium and nitrogen codoped magnesium zinc oxide (MgZnO:Er,N) active layer were fabricated by spray pyrolysis on Si substrate with aqueous solutions including magnesium nitrate, zinc acetate, erbium acetate, ammonium acetate, and indium nitrate precursors. Diodes with different nitrogen content in their precursor were prepared and their properties were investigated. With scanning electron microscopy, film surface with mixed hexagonal flakes and tiny blocks was characterized for all samples. Certain morphologies varied for samples with different N contents. In the photoluminescence analyses, the intensity of the oxygen-related defects peak increased with the increasing of nitrogen content. The diodes were fabricated with an Au and In deposition on the top and backside. The diode current−voltage as well as capacitance−voltage characteristics were examined. An ununiformed n-type concentration distribution with high concentration near the interface in the MgZnO:Er,N layer was characterized for all samples. Diodes with high nitrogen content exhibit reduced breakdown voltage and higher interface concentration characteristics. Under reversed bias conditions with an injection current of 50 mA, a light spectrum with two distinct green emissions around wavelengths 532 and 553 nm was observed. A small spectrum variation was characterized for diodes prepared from different nitrogen content. The diode luminescence characteristics were examined and the diode prepared from N/Zn=1 in the precursor showed an optimal injection current-to-luminescence property. The current and luminescence properties of the diode were characterized and discussed.

Although cell survival post-transplantation is very low, emerging evidence using stem cell therapy for myocardial repair points toward a primary role of paracrine signaling mechanisms as the basis for improved cardiac function, decreased fibrosis, and increased angiogenesis. Recent studies have demonstrated that extracellular vesicles (EVs) such as exosomes secreted by stem cells stimulate angiogenesis, provide cytoprotection, and modulate apoptosis. However, the angiogenic potential of EVs secreted from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), a terminally differentiated cell type, has not been elucidated yet. Therefore, the main objective of this study is to isolate, characterize, and evaluate the in vitro angiogenic potential of EVs collected from hiPSC-CM conditioned media. The hiPSC-CM were cultured for 2 weeks and EVs were isolated from cell culture medium. Isolated EVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis, and immunoblotting. Furthermore, the angiogenic potential of these EVs was evaluated by tube formation, wound-healing, and cell-proliferation assays in bovine aortic endothelial cells (BAEC). In addition, gene expression levels of growth factors was evaluated in hiPSC-derived endothelial cells (hiPSC-EC) treated with hiPSC-CM-derived EV (CM-EVs) to assess their role in promoting angiogenesis. TEM imaging of CM-EVs showed a presence of a double-membrane bound structure, which is a characteristic of EV. Nanoparticle tracking analysis further confirmed the size and shape of the secreted particles to be consistent with EVs. Furthermore, EV-specific markers (CD63 and HSP70) were enriched in these particles as illustrated by immunoblotting. Most importantly, BAEC treated with 100 μg/ml of CM-EVs showed significant increases in tube formation, wound closure, and cell proliferation as compared to control (no-EVs). Finally, treatment of hiPSC-EC with CM-EVs induced increased expression of pro-angiogenic growth factors by the endothelial cells. Overall, our results demonstrated that EVs isolated from hiPSC-CM enhance angiogenesis in endothelial cells. This acellular/cell-free approach constitutes a potential translational therapeutic to induce angiogenesis in patients with myocardial infarction.

Mitogen-activated protein kinases (MAPKs) signaling cascades regulate several cellular functions, including differentiation, proliferation, survival, and apoptosis. The duration and magnitude of phosphorylation of these MAPKs are decisive determinants of their physiological functions. Dual-specificity phosphatases exert kinetic control over these signaling cascades. Previously, we demonstrated that DUSP4−/− hearts sustain a larger infarct and have poor functional recovery, when isolated hearts were subjected to ischemia/reperfusion. Uncontrolled p38 activation and upregulation of Nox4 expression are the main effectors for this functional alteration. Here, dual-specificity phosphatase 4 (DUSP4) overexpression in endothelial cells was used to investigate the role of DUSP4 on the modulation of reactive oxygen species (ROS) generation and vascular function, when cells were subjected to hypoxia/reoxygenation (H/R) insult. Immunostaining with cleaved caspase-3 revealed that DUSP4 overexpression prevents caspase-3 activation and apoptosis after H/R. The beneficial effects occur via modulating p38 activity, increased NO bioavailability, and reduced oxidative stress. More importantly, DUSP4 overexpression upregulates eNOS protein expression (1.62 ± 0.33 versus 0.65 ± 0.16) during H/R-induced stress. NO is a critical small molecule involved in regulating vascular tone, vascular growth, platelet aggregation, and modulation of inflammation. The level of NO generation determined using DAF-2 fluorescence demonstrated that DUSP4 overexpression augments NO production and thus improves vascular function. The level of superoxide generated from cells after being subjected to H/R was determined using dihydroethidium-HPLC method. The results suggested that DUSP4 overexpression in cells decreases H/R-induced superoxide generation (1.56 ± 0.14 versus 1.19 ± 0.05) and thus reduces oxidant stress. This also correlates with the reduction in the total protein S-glutathionylation, an indicator of protein oxidation. These results further support our hypothesis that DUSP4 is an antioxidant gene and a key phosphatase in modulating MAPKs, especially p38, during oxidative stress, which regulates ROS generation and eNOS expression and thus protects against oxidant-induced injury or apoptosis. Overall, DUSP4 may serve as an excellent molecular target for the treatment of ischemic heart disease.

Stem cell transplantation therapy is a promising adjunct for regenerating damaged heart tissue; however, only modest improvements in cardiac function have been observed due to poor survival of transplanted cells in the ischemic heart. Therefore, there remains an unmet need for therapies that can aid in attenuating cardiac damage. Recent studies have demonstrated that exosomes released by stem cells could serve as a potential cell-free therapeutic for cardiac repair. These exosomes/nanoshuttles, once thought to be merely a method of waste disposal, have been shown to play a crucial role in physiological functions including short- and long-distance intercellular communication. In this review, we have summarized studies demonstrating the potential role of exosomes in improving cardiac function, attenuating cardiac fibrosis, stimulating angiogenesis, and modulating miRNA expression. Furthermore, exosomes carry an important cargo of miRNAs and proteins that could play an important role as a diagnostic marker for cardiovascular disease post-myocardial infarction. Although there is promising evidence from preclinical studies that exosomes released by stem cells could serve as a potential cell-free therapeutic for myocardial repair, there are several challenges that need to be addressed before exosomes could be fully utilized as off-the-shelf therapeutics for cardiac repair.

Gene editing provides a promising alternative approach that may achieve long-term FVIII expression for hemophilia A (HemA) treatment. In this study, we investigated in vivo correction of a mutant factor VIII (FVIII) gene in HemA mice. We first developed MC3-based LNPs for efficient mRNA delivery into liver sinusoidal endothelial cells (LSECs), the major site of FVIII biosynthesis. To target a five base pair deletion in FVIII exon 1 in a specific HemA mouse strain, we injected LNPs encapsulating Cas9 mRNA and specifically designed sgRNAs intravenously for in vivo gene editing of the mutant FVIII. Indel variants generated at the mutant site contained mostly a single base-pair deletion, resulting in frameshift correction of FVIII gene. Sustained endogenous FVIII activity up to 6% was achieved over 26 weeks in treated HemA mice. Sequencing data indicated an average gene editing rate of 15.3% in LSECs. Our study suggests that optimized MC3 LNP formulations, combined with CRISPR-Cas9 technology, can effectively correct the mutant FVIII gene in LSECs and restore FVIII activity for therapeutic treatment of HemA.

Background: Cardiac power output (CPO) predicts outcomes in advanced heart failure (HF) and cardiogenic shock, but its role in early HF stages is unclear. This study assessed the prognostic value of CPO in coronary artery disease patients with asymptomatic left ventricular systolic dysfunction (ALVSD) at stage B HF. Methods: We conducted a retrospective analysis of coronary artery disease patients who underwent coronary and pulmonary artery catheterization between 2006 and 2016. Stage B HF with ALVSD was defined as left ventricular ejection fraction

IntroductionBoth cellular and humoral responses are important for vaccine protection, but recommendations on immunosuppressants in dermatology are largely based on pre-pandemic experiences. This study aimed to investigate the impacts of immunosuppressants on humoral and cellular immunogenicity to COVID-19 vaccinations in pemphigus patients.MethodsSARS-CoV-2-naïve pemphigus patients and age-, and sex-matched healthy controls were recruited from multiple tertiary medical centers during 2021-2023. Anti-spike protein-related T-cell responses, antibody titers, and high-parameter cell analysis of the peripheral blood were utilized to investigate the inhibitory effects of immunosuppressants, including rituximab and azathioprine.ResultsA total of 32 patients and 120 healthy controls were enrolled. COVID-19 vaccinations spaced at least six months after the last rituximab infusion did not cause a significant difference in anti-viral T-cell or antibody responses between rituximab-naïve and rituximab-treated patients. All pemphigus patients demonstrated improved antibody responses after the third vaccination and none of them suffered from severe COVID-19 illness. Intriguingly, we found that daily dosages of 100 mg or more of azathioprine were linked to significantly decreased anti-viral T-cell responses induced by the vaccination (mean of fold change [SD]; higher azathioprine dosage = 0.70 [0.61] folds vs. lower azathioprine dosage = 2.11 [1.03] folds; p = 0.044).ConclusionExcept for a subset of patients with unrecovered B-cell deficiency, rituximab infusion with proper scheduling of vaccination preserved better anti-viral T-cell responses and did not lead to hindered antibody responses in pemphigus patients. All pemphigus patients benefited from receiving the third booster regardless of B-cell status.

Total anomalous pulmonary venous connection (TAPVC) is a rare congenital heart disease in which the connection between the pulmonary vein (PV) and left atrium needs to be surgically created. This study investigated the spectrum and outcome of a Taiwanese cohort. Methods: Isolated TAPVC cases were identified from our institutional database between 1995 and 2009. We reviewed the medical chart and conducted telephone interviews with those lost to follow-up. Results: There were 78 patients (52% male). The anomalous drainage sites were mainly supracardiac type (42.3%) and cardiac type (39.8%). Before operation, PV stenosis was found in 100% of infracardiac type, and in 69.7% of supracardiac type. Among the 75 patients undergoing operation, the surgical mortality was 9% (7/75). Perioperative arrhythmias (mainly of atrial origin) occurred in 35% of the patients. Of the 68 patients who survived the first operation, 28 (41%) developed pulmonary vein restenosis. Half of them progressed to severe PV stenosis, which required reintervention or resulted in mortality. Preoperative PV stenosis was the most significant predictor for postoperative PV restenosis and PV re-intervention. For the cohort, the 1-year and 5-year survivals were 78.9% and 74.2%, respectively, and the predictor for survival was again preoperative PV stenosis. Conclusion: The surgical mortality of isolated TAPVC is now low. Preoperative PV stenosis not only increased the risk of late PV restenosis and its reintervention, but also the overall mortality. The spectrum of PV drainage, per se, was not associated with worse outcome. PV restenosis remained the most important issue after correction of TAPVC.

The optimal management of interrupted aortic arch (IAA) with ventricular septal defect is controversial. The aim of this study was to evaluate our 12 years of experience of surgical outcomes of one-stage and rapid two-stage total corrections of IAA with ventricular septal defect and to delineate the management of postoperative complications. Methods: We reviewed the medical charts of all patients from 1996 to 2007. Neonates with inherent complex anatomy were excluded. There were 26 patients in our series, with 11 type A and 15 type B IAA. Nineteen patients received one-stage repair and seven patients received rapid two-stage total correction. Rapid two-stage total correction was defined as two operations performed within 1 week. Results: The 1-month postoperative survival rate was 81% (21/26), with 79% (15/19) in the one-stage group, and 86% (6/7) in the rapid two-stage group. The rapid two-stage group had a shorter cardiopulmonary bypass time (160.1 ± 58.4 vs. 216.8 ± 73.7 minutes, p = 0.054) and aortic cross clamp (AXC) time (65.6 ± 24.4 vs. 91.8 ± 22.4 minutes, p = 0.022) than the one-stage group. Postoperative left ventricular outflow tract obstruction (LVOTO) and aortic arch restenosis were common in survivors, with frequencies of 48% (10/21) and 71% (15/21) respectively. Within the postoperative arch stenosis subgroup, nine out of 15 patients received balloon angioplasties, which proved effective after only one treatment. The overall late survival rate was 73% (19/26), with 68% (13/19) in the one-stage group, and 86% (6/7) in the rapid two-stage group. Conclusion: The outcome of rapid two-stage repair is comparable to that of one-stage repair. Rapid two-stage repair has the advantages of significantly shorter cardiopulmonary bypass duration and AXC time, and avoids deep hypothermic circulatory arrest. LVOTO remains an unresolved issue, and postoperative aortic arch restenosis can be dilated effectively by percutaneous balloon angioplasty.

The brain is sensitive to the dose of MeCP2 such that small fluctuations in protein quantity lead to neuropsychiatric disease. Despite the importance of MeCP2 levels to brain function, little is known about its regulation. In this study, we report eleven individuals with neuropsychiatric disease and copy-number variations spanning NUDT21, which encodes a subunit of pre-mRNA cleavage factor Im. Investigations of MECP2 mRNA and protein abundance in patient-derived lymphoblastoid cells from one NUDT21 deletion and three duplication cases show that NUDT21 regulates MeCP2 protein quantity. Elevated NUDT21 increases usage of the distal polyadenylation site in the MECP2 3′ UTR, resulting in an enrichment of inefficiently translated long mRNA isoforms. Furthermore, normalization of NUDT21 via siRNA-mediated knockdown in duplication patient lymphoblasts restores MeCP2 to normal levels. Ultimately, we identify NUDT21 as a novel candidate for intellectual disability and neuropsychiatric disease, and elucidate a mechanism of pathogenesis by MeCP2 dysregulation via altered alternative polyadenylation.

Aortopulmonary window (APW) is a rare congenital heart disease and surgical correction is advised as early as possible. However, few studies have focused on infants. This study sought to define the clinical features and outcomes in patients who underwent surgical repair of APW in early infancy. Methods: Between 1983 and 2004, there were 14 patients (0.15%) with APW out of 9414 patients with congenital heart disease. Ten underwent surgical repair of APW when they were younger than 4 months of age and constituted the study population. Results: There were four patients with type I APW, three with type II and three with type III. Concomitant cardiovascular anomalies were present in all patients, mainly aortic arch anomalies (80%, including right aortic arch, interrupted aortic arch [IAA] and severe coarctation of the aorta [CoA]). Patients were further grouped according to the presence (n =5) or absence (n = 5) of IAA or severe CoA. All patients underwent surgical repair of APW with various techniques, including direct ligation, division and patch or flap closure. There was one early postoperative death. None of the survivors died during a median follow-up of 34 months (range, 8-116 months). Patients with IAA or severe CoA had longer intubation time, intensive care unit stay and hospital stay. Early reintervention was required only in patients with IAA or severe CoA (n =3, 60%). Among them, two had significant residuals and both had type III APW. Conclusion: Long-term outcomes are generally good in patients with APW who have undergone surgical correction in early infancy. However, associated IAA or severe CoA may predict a prolonged hospital course and an increased risk of early reintervention. In patients with type III APW requiring early reintervention, significant hemodynamic residuals may be common even after reintervention.

BACKGROUND: Patients with transfusion-dependent beta-thalassemia major (TM) are at risk for myocardial iron overload and cardiac complications. Spatial repolarization heterogeneity is known to be elevated in patients with certain cardiac diseases, but little is known in TM patients. The purpose of this study was to evaluate spatial repolarization heterogeneity in patients with TM, and to investigate the relationships between spatial repolarization heterogeneity, cardiac iron load, and adverse cardiac events. METHODS AND RESULTS: Fifty patients with TM and 55 control subjects received 64-channel magnetocardiography (MCG) to determine spatial repolarization heterogeneity, which was evaluated by a smoothness index of QTc (SI-QTc), a standard deviation of QTc (SD-QTc), and a QTc dispersion. Left ventricular function and myocardial T2* values were assessed by cardiac magnetic resonance. Patients with TM had significantly greater SI-QTc, SD-QTc, and QTc dispersion compared to the control subjects (all p values