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BackgroundCatheter ablation (CA) is a treatment strategy for atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM). We investigated the electrophysiological characteristics of recurrence in a tertiary referral center and compared long-term clinical outcomes after CA therapy with patients who did not undergo CA.MethodsPatients with HCM and AF who underwent CA (group 1, n = 60) or pharmacological treatment (group 2, n = 298) between 2006 and 2021 were enrolled in this study. The baseline characteristics and electrophysiological characteristics of group 1 patients were examined to elucidate the reason for the recurrence of AF after CA therapy. The clinical results of the patients in Group 1 and Group 2 were compared using a propensity score (PS)-matched method.ResultsThe most common cause of recurrence was pulmonary vein reconnection (86.5%), followed by non-pulmonary vein triggers (40.5%), cavotricuspid isthmus flutter (29.7%), and atypical flutter (24.3%). Thyroid disease (HR, 14.713; P

The Guangdong-Hong Kong-Macao Greater Bay Area (GBA) is built across three different governance contexts; these three cities have different socio-political structures, legal systems, and cultural identities. From the perspective of media geography, this article proposes a framework with four dimensions and three categories, to explore how cross-border media communication affects the formation and accumulation of social capital, and thus influences regional coordination under the political structure of "one country, two systems" in the region. To fully understand the different characteristics of each development stage, the research further divides the synergic development process into five phases: economic bonding, policy-economic bonding, policy-economic bridging, policy-social linking, and policy-economic-social bridging. The study found that even though media interactions between Guangdong, Hong Kong, and Macao have intensified in frequency, social capital at the "socio-cultural" level is relatively weak. Owing to the lack of a widely accepted regional media platform that fits into the communication habits of people in all GBA cities, it is difficult to build an effective monitoring mechanism and feedback system that enables a detection and response to people's opinions on the ground. Consequently, disagreements and conflicts have led to high social costs for some cross-border infrastructure projects. By exploring the mechanisms of media interaction and social capital formation within the regional coordination process, this paper concludes with three strategies to achieve effective multilevel connection and coordination between GBA cities, especially in social and cultural aspects. 1) Governments in each city should work together to build up a regional platform and broaden media channels for the circulation of shared information, which fits various local situations and media usage habits. 2) There is a need for the GBA to establish an effective public opinion monitoring and feedback system on a regional scale, which penetrates people's daily lives, and is accessible to the wider public. Updating prompt information based on people's needs, views, and expectations helps strengthen the entire regional cooperation system and resilient governance structure. 3) Linking propagation is important for the stabilization of social development. Overall, there is a need for the GBA to build a more flexible multilevel dialogue mechanism that facilitates vertical communication to enhance non-institutional and effective bottom-level collaboration.

A comprehensive catalog of 1,589 Saturn magnetosheath traversals by Cassini between 2004 and 2012 was used to perform a statistical study of mirror mode (MM) waves and assess their role in influencing magnetic reconnection at the magnetopause (MP). MM waves have been observed in many planetary magnetospheres and magnetosheaths, comets and the solar wind. Understanding the conditions under which they grow and dominate can reveal their role in influencing plasma dynamics. Using a thresholding method on both magnetic field and plasma data, MM wave candidates can be identified. The magnetic field characteristics and occurrence distributions of these waves against different locations and conditions were found. MM waves were found from 4 to 19 hr local time (partly due to data coverage), and distances of 0–12 RS ${\mathrm{R}}_{\mathrm{S}}$ from the magnetopause (MP). The occurrence of MM dips was more frequent near the MP and magnetosheath flanks, analogous to the Jovian system. MM dips exhibited a minimum field strength saturation ∼ ${\sim} $ 0.5 nT, with the largest dip inferred to be in mirror‐stable plasma. Notably, larger amplitude MM dips were typically found nearer the MP boundary which increases Δβ ${\Delta }\beta $ across the boundary thus increasing the magnetic shear necessary for the onset of MP reconnection. Thus, MM waves may be important in plasma dynamics near Saturn's magnetopause. Plain Language Summary: Mirror mode waves (MM waves) are fluctuations in plasma density and magnetic fields that move with the bulk flow. They are commonly observed by spacecraft around planetary magnetospheres and other space environments. Their growth occurs when the plasma temperature perpendicular‐to‐magnetic‐field is greater than some threshold of the temperature parallel‐to‐magnetic‐field direction. After reaching saturation, some MM structures can remain stable for a long time. These waves can transfer energy between particles and electromagnetic fields, and could also influence more energetic events like magnetic reconnection. This study investigates the nature and role of mirror mode waves in Saturn's magnetosheath and surroundings. Key Points: Mirror mode (MM) dips at Saturn occur more frequently near the magnetopause (MP) and magnetosheath flanks, akin to the Jovian systemMM dips saturated at a field strength ∼ ${\sim} $0.5 nT. 83% of dips were in mirror stable region, whilst 46% peaks were in mirror unstable regionLarge MM dips enhance Δβ across the MP boundary, limiting the range of magnetic shear to near anti‐parallel for MP reconnection to occur [ABSTRACT FROM AUTHOR]

The WHAMP (Rönnmark, 1982, https://inis.iaea.org/search/search.aspx?orig%5fq=RN:14744092) and LEOPARD (Astfalk & Jenko, 2017, https://doi.org/10.1002/2016ja023522) dispersion relation solvers were used to evaluate the growth rate and scale size for mirror mode (MM) and ion cyclotron (IC) instabilities under plasma conditions resembling Saturn's magnetosheath in order to compare observations to predictions from linear kinetic theory. Instabilities and waves are prevalent in planetary magnetosheaths. Understanding the origin and conditions under which different instabilities grow and dominate can help shed light on the role each instability plays in influencing the plasma dynamics of the region. For anisotropic plasmas modeled with bi‐Maxwellian particle distribution, the dispersion, growth rate, and scale size of MM and IC were studied as functions of proton temperature anisotropy, proton plasma beta, and oxygen ion abundance. The dispersion solvers showed that the IC mode dominated over MM under typical conditions in Saturn's magnetosheath, but that MM could dominate for high enough O+ ${O}^{+}$ abundance >40%ne $\left(> 40\%\ {\mathrm{n}}_{\mathrm{e}}\right)$. These water ion‐rich plasma conditions are occasionally found in Saturn's magnetosheath (Sergis et al., 2013, https://doi.org/10.1002/jgra.50164). The maximum linear growth rates γm/Ωp $\left({\gamma }_{m}/{{\Omega }}_{p}\right)$ for MM ranged from 0.02 to 0.2, larger than expected from observations. The scale size at maximum growth rate ranged from 4 to 12 ρp ${\rho }_{\mathrm{p}}$, smaller than expected from observations. These inconsistencies could potentially be attributed to diffusion and non‐linear growth processes. Plain Language Summary: Plasma instabilities have well‐defined relationships between the wavevector and the frequency captured in the dispersion relation. Linear kinetic theory provides a basis for interpreting instability growth rates and scale sizes in simulations and observations with small plasma fluctuations. However, it cannot describe the fate of the instability such as the maximum amplitude, nor its interactions with other modes. The ion cyclotron (IC) and mirror mode (MM) instabilities lead to fluctuations of different frequencies and spatial scales. Their growth occurs when the plasma exhibits temperature perpendicular‐to‐magnetic‐field greater than some threshold of the temperature parallel‐to‐magnetic‐field direction known as temperature anisotropy. Each instability has a role to play in influencing the plasma dynamics of the region. This study investigates the growth and scale size of IC and MM instabilities in conditions resembling Saturn's magnetosheath. Key Points: Dispersion solvers indicate ion cyclotron (IC) mode dominates over mirror mode (MM) at Saturn, but MM prevails with high O+ abundanceThe predicted MM linear growth rates at Saturn were 0.02–0.2, exceeding the inferred maximum rate of 0.008 from observationsThe scale size of MM at maximum linear growth rate was 4–12 ρp, smaller than the inferred size of 18–38 ρp from observations [ABSTRACT FROM AUTHOR]

Background/Objectives: While previous evidence has shown that using free weights for resistance training is a more practical approach to enhancing strength, there is a relatively low prevalence of free-weight resistance training among adolescent kayak/canoe athletes. Therefore, this study aims to assess the impact of free-weight resistance training on body composition and various performance factors among adolescent canoe/kayak athletes. Methods: Twenty-seven young sprint kayakers and canoeists (14 ± 1 years; 164 ± 7 cm; 56 ± 8 kg) completed this study. Following baseline assessments, athletes were randomly divided into two training groups: the free-weight resistance training group (FW) or the control group (C). The FW group underwent free-weight resistance training sessions twice weekly for 24 weeks. The C group maintained their regular bodyweight training sessions during the same timeframe. All participants performed both the pre- and post-training assessments for the following dependent variables: body composition, upper-body power, upper-body isometric muscle strength, isometric mid-thigh pull, core strength, countermovement jump, balance, anaerobic ability, and aerobic performance. Results: After 24 weeks of training, the free-weight resistance training group exhibited a significant increase in body weight (from 56 ± 5 kg to 58 ± 4 kg, p < 0.05) and improvements in the number of straight leg raise repetitions (from 23 ± 6 to 26 ± 4, p < 0.05) compared to the control group. However, the two groups observed no significant differences between upper-body isometric muscle strength, power, balance, and anaerobic/aerobic performance. Conclusions: A 24-week training duration might be insufficient for novice participants in resistance training. Future research should consider incorporating an adaptation period or a learning phase for movements before training, thereby enhancing the efficacy of free-weight resistance training in increasing strength. [ABSTRACT FROM AUTHOR]

Addressing the critical need for swift and precise nutritional profiling in healthcare and in food industry, this study pioneers the integration of vision‐language models (VLMs) with chemical analysis techniques. A cutting‐edge VLM is unveiled, utilizing the expansive UMDFood‐90k database, to significantly improve the speed and accuracy of nutrient estimation processes. Demonstrating a macro‐AUCROC of 0.921 for lipid quantification, the model exhibits less than 10% variance compared to traditional chemical analyses for over 82% of the analyzed food items. This innovative approach not only accelerates nutritional screening by 36.9% when tested amongst students but also sets a new benchmark in the precision of nutritional data compilation. This research marks a substantial leap forward in food science, employing a blend of advanced computational models and chemical validation to offer a rapid, high‐throughput solution for nutritional analysis. [ABSTRACT FROM AUTHOR]

Retailers in competitive markets must determine the optimal order quantity of the product while ensuring that the product keeps a stable performance of profitability. The achievable capacity index (ACI) has a streamlined form to measure the profitability of a newsboy-type product with normally distributed demand. In situations wherein the parameters of the normal distribution are unknown, it is also possible to estimate accurate ACI values using statistical approaches based on historical demand; however, the results tend to vary with the statistical approaches employed (e.g., frequentist or Bayesian). Furthermore, point estimates of ACI lead to overestimates of profitability due to sampling error. This study used frequentist and Bayesian approaches to derive the lower confidence bounds of ACI with the aim of obtaining conservative estimates of profitability. The comparison of the levels of conservatism and confidence between the two approaches was also explored. Our results could be used as a guide for the selection of approaches by which to estimate profitability. [ABSTRACT FROM AUTHOR]

Canopy resistance is a key parameter in the Penman–Monteith (P–M) equation for calculating evapotranspiration (ET). In this study, we compared a machine learning algorithm–support vector machine (SVM) and an analytical solution (Todorovic, 1999) for estimating canopy resistances. Then, these estimated canopy resistances were applied to the P–M equation for estimating ET; as a benchmark, a constant (fixed) canopy resistance was also adopted for ET estimations. ET data were measured using the eddy-covariance method above three sites: a grassland (south Ireland), Cypress forest (north Taiwan), and Cryptomeria forest (central Taiwan) were used to test the accuracy of the above two methods. The observed canopy resistance was derived from rearranging the P–M equation. From the measurements, the average canopy resistances for the grassland, Cypress forest, and Cryptomeria forest were 163, 346, and 321 (s/m), respectively. Our results show that both methods tend to reproduce canopy resistances within a certain range of intervals. In general, the SVM model performs better, and the analytical solution systematically underestimates the canopy resistances and leads to an overestimation of evapotranspiration. It is found that the analytical solution is only suitable for low canopy resistance (less than 100 s/m) conditions.

With advances in learning technologies, new pedagogical models are being developed to improve students' learning performance. One notable model is the flipped classroom, which has attracted the attention of many researchers, particularly in K-12 education. However, research on effective approaches for managing the flipped classroom model to improve mathematics learning is lacking. This study explored approaches to manage the flipped classroom in a Chinese context and designed an approach to improve the mathematical learning performance of middle school students. In a flipped classroom teaching and learning, students took notes while watching videos at home and then teacher utilized the notes for in-class discussion. A total of 88 sixth-grade students in a secondary school in mainland China participated in this study. An experiment was conducted to evaluate the effectiveness of the proposed approach by situating the experimental and control groups in flipped and traditional classrooms, respectively. The results show that the proposed flipped classroom approach significantly improves the students' mathematical learning performance. The proposed approach is more beneficial to students at the middle mathematics level comparing to those at high or low levels. Furthermore, some suggestions are provided for teachers to manage flipped classroom more effectively.

This study presents a voltage restoration control (VRC) based on battery energy storage system (BESS), which can be used for both supporting power source and voltage compensation. Voltage restoration is an important task for the power control of microgrid during utility disturbances. One of the disturbances is caused by short circuit on power line of the microgrid, which may lead to voltage sag and even blackout of the microgrid system. To tackle this problem, the recurrent wavelet petri fuzzy neural network (RWPFNN) controller is proposed in this study for the VRC of BESS to provide fast control response to mitigate the transient impact. Moreover, to examine the compliance with the requirements of low voltage ride through (LVRT) of the photovoltaic (PV) plant and investigate the performance of the proposed VRC, the microgrid built in Cimei Island in Penghu Archipelago, Taiwan, is investigated. Furthermore, the PV system, the wind turbine generator (WTG) system and the BESS are connected to the same point of common coupling (PCC) with separated step-up transformers in the microgrid. In addition, the diesel generators provide the main power sources and form the isolated microgrid system. Through the hardware in the loop (HIL) mechanism, which is built using OPAL-RT real-time simulator, with two floating-point digital signal processors (DSPs), the effectiveness of proposed intelligent controllers can be verified and demonstrated.

Abstract The SARS‐CoV‐2 Delta (B.1.617.2) variant is capable of infecting vaccinated persons. An open question remains as to whether deficiencies in specific vaccine‐elicited immune responses result in susceptibility to vaccine breakthrough infection. We investigated 55 vaccine breakthrough infection cases (mostly Delta) in Singapore, comparing them against 86 vaccinated close contacts who did not contract infection. Vaccine breakthrough cases showed lower memory B cell frequencies against SARS‐CoV‐2 receptor‐binding domain (RBD). Compared to plasma antibodies, antibodies secreted by memory B cells retained a higher fraction of neutralizing properties against the Delta variant. Inflammatory cytokines including IL‐1β and TNF were lower in vaccine breakthrough infections than primary infection of similar disease severity, underscoring the usefulness of vaccination in preventing inflammation. This report highlights the importance of memory B cells against vaccine breakthrough and suggests that lower memory B cell levels may be a correlate of risk for Delta vaccine breakthrough infection.

Cardiovascular diseases remain the leading cause of death throughout the world. Accumulation of lipoprotein-associated lipids and their interaction with macrophages are early steps in the development of atherosclerotic lesions. For decades, it has been known that aggregates of lipoproteins in the subendothelial space are found in early plaques, and these aggregates are tightly associated with extracellular matrix fibers. Additionally, most of the cholesterol in these subendothelial aggregates is unesterified, in contrast to the core of low-density lipoproteins (LDL), in which cholesteryl esters predominate. This suggests that the hydrolysis of cholesteryl esters occurs extracellularly. At the cellular level, macrophages in early plaques engage with the LDL and ingest large amounts of cholesterol, which is esterified and stored in lipid droplets. When excessive lipid droplets have accumulated, endoplasmic reticulum stress responses are activated, leading to cell death. The cholesterol-laden dead cells must be cleared by other macrophages. For many years, it was unclear how unesterified (free) cholesterol could be formed extracellularly in early lesions. Papers in the past decade have shown that macrophages form tightly sealed extracellular attachments to aggregates of LDL. These sealed regions become acidified, and lysosomal contents are secreted into these compartments. Lysosomal acid lipase hydrolyzes the cholesteryl esters, and the free cholesterol is transported into the macrophages. High concentrations of cholesterol can also lead to formation of crystals of cholesterol hydrate, and these crystals have been observed in atherosclerotic blood vessels. Characterization of this process may lead to novel therapies for the prevention and treatment of atherosclerosis.

Dengue non-structural protein (NS1) is an important diagnostic marker during the acute phase of infection. Because NS1 is partially conserved across the flaviviruses, a highly specific DENV NS-1 diagnostic test is needed to differentiate dengue infection from Zika virus (ZIKV) infection. In this study, we characterized three newly isolated antibodies against NS1 (A2, D6 and D8) from a dengue-infected patient and a previously published human anti-NS1 antibody (Den3). All four antibodies recognized multimeric forms of NS1 from different serotypes. A2 bound to NS1 from DENV-1, -2, and -3, D6 bound to NS1 from DENV-1, -2, and -4, and D8 and Den3 interacted with NS1 from all four dengue serotypes. Using a competition ELISA, we found that A2 and D6 bound to overlapping epitopes on NS1 whereas D8 recognized an epitope distinct from A2 and D6. In addition, we developed a capture ELISA that specifically detected NS1 from dengue viruses, but not ZIKV, using Den3 as the capture antibody and D8 as the detecting antibody. This assay detected NS1 from all the tested dengue virus strains and dengue-infected patients. In conclusion, we established a dengue-specific capture ELISA using human antibodies against NS1. This assay has the potential to be developed as a point-of-care diagnostic tool.

Prion diseases are a group of rare neurodegenerative diseases caused by the structural conversion of cellular prion into Scrapie prion resulting aggregated fibrils. Therapy of prion diseases has been developed for several decades, especially drug designs based on the structure of prion monomers. Unfortunately, none of the designed anti-prion drugs function well clinically. To fight against prion fibrils, a drug design based on the precise structure of mammalian prion fibrils is highly required. Fortunately, based on the advantage of newly advanced cryo-electron microscopy (cryo-EM) in the deconvolution of large complexes, three prion fibril structures were resolved in the last 2 years. Based on the cryo-EM solved prion fibril structures, we are able to find some molecules fighting against prion fibrils. Quercetin, one flavonoid molecule in the polyphenol group, has been found to disaggregate the prion fibrils in vitro. In this study, we performed the molecular docking and molecular dynamics simulation on quercetin-like molecules possessing pharmacological properties to evaluate the anti-prion ability of tested molecules. As a result, four quercetin-like molecules interact with prion fibril and decrease the β-strand content by converting some β-strands into loop and helical structures to disintegrate the existing fibril structure. The results of this study are significant in the treatment of prion diseases, and the approaches used in this study are applicable to other amyloid diseases.

Summary: Background: Brugada syndrome (BrS) is a severe inherited arrhythmia syndrome that can be unmasked by fever. Methods: A multicentre clinical analysis was performed in 261 patients diagnosed with fever-induced BrS, including 198 (75.9%) and 27 (10.3%) patients who received next-generation genetic sequencing and epicardial arrhythmogenic substrate (AS) mapping, respectively. Findings: In fever-induced BrS patients, pathogenic or likely pathogenic (P/LP) SCN5A variant carriers developed fever-induced BrS at a younger age, and more often in females and those of Caucasian descent. They exhibited significant electrophysical abnormalities, including a larger epicardial AS area, and more prolonged abnormal epicardial electrograms. During a median follow-up of 50.5 months (quartiles 32.5–81.5 months) after the diagnosis, major cardiac events (MCE) occurred in 27 (14.4%) patients. Patients with P/LP SCN5A variants had a higher ratio of MCE compared with the rest. Additionally, history of syncope, QRS duration, and Tpe interval could also predict an increased risk for future MCE according to univariate analysis. Multivariate analysis indicated that only P/LP SCN5A variants were independent significant predictors of MCE. Computational structural modelling showed that most variants are destabilizing, suggesting that Nav1.5 structure destabilization caused by SCN5A missense variants may contribute to fever-induced BrS. Interpretation: In our cohort, P/LP SCN5A variant carriers with fever-induced BrS are more prevalent among patients of Caucasian descent, females, and younger patients. These patients exhibit aggressive electrophysiological abnormalities and worse outcome, which warrants closer monitoring and more urgent management of fever. Funding: None.

The swell of experimental imaging technologies to noninvasively measure immune checkpoint protein expression presents the opportunity for rigorous comparative studies toward identifying a gold standard. 89Zr-atezolizumab is currently in man, and early data show tumor targeting but also abundant uptake in several normal tissues. Therefore, we conducted a reverse translational study both to understand if tumor to normal tissue ratios for 89Zr-atezolizumab could be improved and to make direct comparisons to 89Zr-C4, a radiotracer that we showed can detect a large dynamic range of tumor-associated PD-L1 expression. PET/CT and biodistribution studies in tumor bearing immunocompetent and nu/nu mice revealed that high specific activity 89Zr-atezolizumab (∼2 μCi/μg) binds to PD-L1 on tumors but also results in very high uptake in many normal mouse tissues, as expected. Unexpectedly, 89Zr-atezolizumab uptake was generally higher in normal mouse tissues compared to 89Zr-C4 and lower in H1975, a tumor model with modest PD-L1 expression. Also unexpectedly, reducing the specific activity at least 15-fold suppressed 89Zr-atezo uptake in normal mouse tissues but increased tumor uptake to levels observed with high specific activity 89Zr-C4. In summary, these data reveal that low specific activity 89Zr-atezo may be necessary for accurately measuring PD-L1 in the tumor microenvironment, assuming a threshold can be identified that preferentially suppresses binding in normal tissues without reducing binding to tumors with abundant expression. Alternatively, high specific activity approaches like 89Zr-C4 PET may be simpler to implement clinically to measure the broad dynamic range of PD-L1 expression known to manifest among tumors.

ObjectiveBody mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population.SubjectsUsing eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models.ResultsWe replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P

High sensitivity imaging tools could provide a more holistic view of target antigen expression to improve the identification of patients who might benefit from cancer immunotherapy. We developed for immunoPET a novel recombinant human IgG1 (termed C4) that potently binds an extracellular epitope on human and mouse PD-L1 and radiolabeled the antibody with zirconium-89. Small animal PET/CT studies showed that 89Zr-C4 detected antigen levels on a patient derived xenograft (PDX) established from a non-small-cell lung cancer (NSCLC) patient before an 8-month response to anti-PD-1 and anti-CTLA4 therapy. Importantly, the concentration of antigen is beneath the detection limit of previously developed anti-PD-L1 radiotracers, including radiolabeled atezolizumab. We also show that 89Zr-C4 can specifically detect antigen in human NSCLC and prostate cancer models endogenously expressing a broad range of PD-L1. 89Zr-C4 detects mouse PD-L1 expression changes in immunocompetent mice, suggesting that endogenous PD-1/2 will not confound human imaging. Lastly, we found that 89Zr-C4 could detect acute changes in tumor expression of PD-L1 due to standard of care chemotherapies. In summary, we present evidence that low levels of PD-L1 in clinically relevant cancer models can be imaged with immunoPET using a novel recombinant human antibody.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy caused by defective desmosomal proteins. The typical histopathological finding of ARVC is characterized by progressive fibrofatty infiltration of the right ventricle due to the dysfunction of cellular adhesion molecules, thus, developing arrhythmogenic substrates responsible for the clinical manifestation of ventricular tachycardia/fibrillation (VT/VF). Current guidelines recommend implantable cardiac defibrillator (ICD) implantation to prevent sudden cardiac death (SCD) in ARVC, especially for those experiencing VT/VF or aborted SCD, while antiarrhythmic drugs, despite their modest effectiveness and several undesirable adverse effects, are frequently used for those experiencing episodes of ICD interventions. Given the advances in mapping and ablation technologies, catheter ablation has been implemented to eliminate drug-refractory VT in ARVC. A better understanding of the pathogenesis, underlying arrhythmogenic substrates, and putative VT isthmus in ARVC contributes to a significant improvement in ablation outcomes through comprehensive endocardial and epicardial approaches. Regardless of ablation strategies, there is a diversity of arrhythmogenic substrates in ARVC, which could partly explain the nonuniform ablation outcome and long-term recurrences and reflect the role of potential factors in the modification of disease progression and triggering of arrhythmic events.

The emergence of escape variants of SARS-CoV-2 carrying mutations in the spike protein poses a challenge for therapeutic antibodies. Here, we show that through the comprehensive engineering of the variable region of the neutralizing monoclonal antibody 5A6, the engineered antibody, 5A6CCS1, is able to neutralize SARS-CoV-2 variants that escaped neutralization by the original 5A6 antibody. In addition to the improved affinity against variants, 5A6CCS1 was also optimized to achieve high solubility and low viscosity, enabling a high concentration formulation for subcutaneous injection. In cynomolgus monkeys, 5A6CCS1 showed a long plasma half-life and good subcutaneous bioavailability through engineering of the variable and constant region. These data demonstrate that 5A6CCS1 is a promising antibody for development against SARS-CoV-2 and highlight the importance of antibody engineering as a potential method to counteract escape variants.