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Abstract To understand the genomic characteristics of Arctic plants, we generated 28–44 Gb of short-read sequencing data from 13 Arctic plants collected from the High Arctic Svalbard. We successfully estimated the genome sizes of eight species by using the k-mer-based method (180–894 Mb). Among these plants, the mountain sorrel (Oxyria digyna) and Greenland scurvy grass (Cochlearia groenlandica) had relatively small genome sizes and chromosome numbers. We obtained 45 × and 121 × high-fidelity long-read sequencing data. We assembled their reads into high-quality draft genomes (genome size: 561 and 250 Mb; contig N50 length: 36.9 and 14.8 Mb, respectively), and correspondingly annotated 43,105 and 29,675 genes using ~46 and ~85 million RNA sequencing reads. We identified 765,012 and 88,959 single-nucleotide variants, and 18,082 and 7,698 structural variants (variant size ≥ 50 bp). This study provided high-quality genome assemblies of O. digyna and C. groenlandica, which are valuable resources for the population and molecular genetic studies of these plants.

Abstract Background Clinical outcomes after catheter ablation (CA) or pacemaker (PM) implantation for the tachycardia–bradycardia syndrome (TBS) has not been evaluated adequately. We tried to compare the efficacy and safety outcomes of CA and PM implantation as an initial treatment option for TBS in paroxysmal atrial fibrillation (AF) patients. Methods Sixty-eight patients with paroxysmal AF and TBS (mean 63.7 years, 63.2% male) were randomized, and received CA (n = 35) or PM (n = 33) as initial treatments. The primary outcomes were unexpected emergency room visits or hospitalizations attributed to cardiovascular causes. Results In the intention-to-treatment analysis, the rates of primary outcomes were not significantly different between the two groups at the 2-year follow-up (19.8% vs. 25.9%; hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.25–2.20, P = 0.584), irrespective of whether the results were adjusted for age (HR 1.12, 95% CI 0.34–3.64, P = 0.852). The 2-year rate of recurrent AF was significantly lower in the CA group compared to the PM group (33.9% vs. 56.8%, P = 0.038). Four patients (11.4%) in the CA group finally received PMs after CA owing to recurrent syncope episodes. The rate of major or minor procedure related complications was not significantly different between the two groups. Conclusion CA had a similar efficacy and safety profile with that of PM and a higher sinus rhythm maintenance rate. CA could be considered as a preferable initial treatment option over PM implantation in patients with paroxysmal AF and TBS. Trial registration KCT0000155.

Abstract Background Detecting structural variations (SVs) at the population level using next-generation sequencing (NGS) requires substantial computational resources and processing time. Here, we compared the performances of 11 SV callers: Delly, Manta, GridSS, Wham, Sniffles, Lumpy, SvABA, Canvas, CNVnator, MELT, and INSurVeyor. These SV callers have been recently published and have been widely employed for processing massive whole-genome sequencing datasets. We evaluated the accuracy, sequence depth, running time, and memory usage of the SV callers. Results Notably, several callers exhibited better calling performance for deletions than for duplications, inversions, and insertions. Among the SV callers, Manta identified deletion SVs with better performance and efficient computing resources, and both Manta and MELT demonstrated relatively good precision regarding calling insertions. We confirmed that the copy number variation callers, Canvas and CNVnator, exhibited better performance in identifying long duplications as they employ the read-depth approach. Finally, we also verified the genotypes inferred from each SV caller using a phased long-read assembly dataset, and Manta showed the highest concordance in terms of the deletions and insertions. Conclusions Our findings provide a comprehensive understanding of the accuracy and computational efficiency of SV callers, thereby facilitating integrative analysis of SV profiles in diverse large-scale genomic datasets.

Background: The ideal long-term antithrombotic strategy for patients after successful catheter-based atrial fibrillation (AF) ablation is still uncertain. Presently, practices vary, and the advantages of oral anticoagulation (OAC) for the post-ablation population are not clearly established. To date, no randomized trials have addressed this therapeutic question. This study aimed to evaluate whether no OAC therapy is superior to apixaban in reducing the risk of stroke, systemic embolism, or major bleeding among patients without apparent recurrent atrial arrhythmias for at least 1 year after their AF ablation procedure. Methods: The ALONE-AF trial is a prospective, multicenter, open-label, randomized study with blinded outcome assessment. Patients with AF who have at least one non-gender stroke risk factor (as determined by the CHA2DS2-VASc score) and no documented recurrences of atrial arrhythmia for at least 12 months post-ablation will be randomly assigned to apixaban 5 mg b.i.d. or no OAC therapy. The primary endpoint is a composite outcome of stroke, systemic embolism, and major bleeding. Key secondary outcomes include clinically relevant non-major bleeding, all-cause mortality, myocardial infarction, transient ischemic attack, quality of life, and frailty analysis. Participants will be followed for a period of 2 years. The estimated total sample size is 840 subjects, with 420 subjects in each arm. Conclusion: The ALONE-AF trial aims to provide robust evidence for the optimal anticoagulation strategy for patients with stroke risk factors following successful AF ablation.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is characterized by hepatic steatosis and metabolic dysfunction and is often associated with obesity and insulin resistance. Recent research indicates a rapid escalation in MASLD cases, with projections suggesting a doubling in the United States by 2030. This review focuses on the central role of mitochondria in the pathogenesis of MASLD and explores potential therapeutic interventions. Mitochondria are dynamic organelles that orchestrate hepatic energy production and metabolism and are critically involved in MASLD. Dysfunctional mitochondria contribute to lipid accumulation, inflammation, and liver fibrosis. Genetic associations further underscore the relationship between mitochondrial dynamics and MASLD susceptibility. Although U.S. Food and Drug Administration-approved treatments for MASLD remain elusive, ongoing clinical trials have highlighted promising strategies that target mitochondrial dysfunction, including vitamin E, metformin, and glucagon-like peptide-1 receptor agonists. In preclinical studies, novel therapeutics, including nicotinamide adenine dinucleotide+ precursors, urolithin A, spermidine, and mitoquinone, have shown beneficial effects, such as improving mitochondrial quality control, reducing oxidative stress, and ameliorating hepatic steatosis and inflammation. In conclusion, mitochondrial dysfunction is central to MASLD pathogenesis. The innovative mitochondria-targeted approaches discussed in this review offer a promising avenue for reducing the burden of MASLD and improving global quality of life.

Abstract Suppressing the oxidation of active-Ir(III) in IrOx catalysts is highly desirable to realize an efficient and durable oxygen evolution reaction in water electrolysis. Although charge replenishment from supports can be effective in preventing the oxidation of IrOx catalysts, most supports have inherently limited charge transfer capability. Here, we demonstrate that an excess electron reservoir, which is a charged oxygen species, incorporated in antimony-doped tin oxide supports can effectively control the Ir oxidation states by boosting the charge donations to IrOx catalysts. Both computational and experimental analyses reveal that the promoted charge transfer driven by excess electron reservoir is the key parameter for stabilizing the active-Ir(III) in IrOx catalysts. When used in a polymer electrolyte membrane water electrolyzer, Ir catalyst on excess electron reservoir incorporated support exhibited 75 times higher mass activity than commercial nanoparticle-based catalysts and outstanding long-term stability for 250 h with a marginal degradation under a water-splitting current of 1 A cm−2. Moreover, Ir-specific power (74.8 kW g−1) indicates its remarkable potential for realizing gigawatt-scale H2 production for the first time.

Abstract Background The prognostic significance of resting heart rate and its therapeutic target in atrial fibrillation (AF) is uncertain. We sought to investigate the relationship between resting heart rate and cardiovascular outcomes in patients with non-paroxysmal AF (non-PAF). Methods In this propensity score-weighted, multi-center prospective cohort study, 3217 patients with non-PAF were analyzed. Patients were categorized according to the baseline resting heart rate and cardiovascular outcomes were accessed for a median follow-up of 30 months. The primary outcome was a composite of cardiovascular death, heart failure hospitalization, and myocardial infarction/critical limb ischemia. Results Freedom from primary outcome was longest among patients with resting heart rate 80–99 beats per minute (bpm) whereas shortest among those with ≤ 59 bpm (weighted log rank, p = 0.008). Compared with heart rate ≥ 100 bpm, resting heart rate 80–99 and 60–79 bpm was associated with reduced risk of primary outcome (weighted hazard ratio [WHR] 0.52, 95% confidence interval [CI] 0.32–0.84, p = 0.008 and WHR 0.58, 95% CI 0.37–0.92, p = 0.021 for heart rate 80–99 and 60–79 bpm, respectively). Using weighted restricted cubic spline curves, there was a U-shaped association between the resting heart rate and primary outcome with reduced risk of primary outcome in heart rate range of 68–99 bpm. This association was maintained regardless of atrioventricular node (AVN) blocker use or persistent/permanent AF (p for interaction 0.767 for AVN blocker use and 0.720 for AF type). Conclusion Resting heart rate was associated with cardiovascular outcomes in patients with non-PAF and those with resting heart rate between 68 and 99 bpm had lower risk of adverse cardiovascular events regardless of AVN blocker use or persistent/permanent AF.

Background There are limited data on the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation with significant tricuspid regurgitation (TR), which can lead to hepatic dysfunction and intestinal malabsorption. We aimed to compare the efficacy and safety of DOACs and warfarin for patients with atrial fibrillation with significant (moderate to severe) TR. Methods and Results A total of 1215 patients with significant TR and atrial fibrillation who were treated with warfarin (N=491) or DOACs (N=724) were retrospectively analyzed. The primary outcomes were ischemic stroke, systemic embolic events, and hospitalization for major bleeding. The secondary outcomes were intracranial hemorrhage, hospitalization for gastrointestinal bleeding, all‐cause mortality, and a composite outcome. The median follow‐up duration was 2.4 years. In the inverse probability treatment weighting–adjusted cohort, DOACs and warfarin had a similar risk for ischemic stroke and systemic embolic events (adjusted hazard ratio [aHR], 0.95 [95% CI, 0.67–1.36]; P=0.79) and major bleeding (aHR, 0.78 [95% CI, 0.57–1.06]; P=0.11). For the secondary outcomes, relative to warfarin, DOACs had a lower risk of intracranial hemorrhage and the composite outcome, and a comparable risk for gastrointestinal bleeding and all‐cause mortality. In the subgroup analysis, the effects of DOACs on ischemic stroke and systemic embolic events were comparable to the effects of warfarin, even in patients with inferior vena cava plethora (increased right atrial pressure) or severe TR. Conclusions In this study, relative to warfarin, DOACs demonstrated comparable efficacy for ischemic stroke and systemic embolic events and major bleeding, with a lower intracranial hemorrhage risk in patients with significant TR and atrial fibrillation, indicating their effectiveness and safety.

Abstract Background The clinical benefits and risks of anticoagulation therapy in patients with chronic kidney disease (CKD) are still inconclusive. We describe the outcomes of patients with atrial fibrillation (AF) after anticoagulation therapy according to differences in creatinine clearance (CrCl). We also aimed to determine the patients who could benefit from anticoagulation therapy. Methods This is a retrospective observational review of patients with AF who were managed at Asan Medical Center (Seoul, Korea) between January 1, 2006, and December 31, 2018. Patients were categorized into groups according to their baseline CrCl by Cockcroft–Gault equation and their outcomes were evaluated (CKD 1, ≥ 90 mL/min; CKD2, 60–89 mL/min; CKD3, 30–59 mL/min; CKD4, 15–29 mL/min; CKD 5,

Objective The “weekend effect” occurs when patients cared for during weekends versus weekdays experience worse outcomes. But reasons for this effect are unclear, especially amongst patients undergoing elective cervical spinal fusion (ECSF). Our aim was to analyze whether index weekend admission affects 30- and 90-day readmission rates post-ECSF. Methods All ECSF patients > 18 years were retrospectively identified from the 2016–2018 Healthcare Cost and Utilization Project Nationwide Readmissions Database (NRD), using unique patient linkage codes and International Classification of Diseases, Tenth Revision codes. Patient demographics, comorbidities, and outcomes were analyzed. Univariate logistic regression analyzed primary outcomes of 30- and 90-day readmission rates in weekday or weekend groups. Multivariate regression determined the impact of complications on readmission rates. Results Compared to the weekday group (n = 125,590), the weekend group (n = 1,026) held a higher percentage of Medicare/Medicaid insurance, incurred higher costs, had longer length of stay, and fewer routine home discharge (all p < 0.001). There was no difference in comorbidity burden between weekend versus weekday admissions, as measured by the Elixhauser Comorbidity Index (p = 0.527). Weekend admissions had higher 30-day (4.30% vs. 7.60%, p < 0.001) and 90-day (7.80% vs. 16.10%, p < 0.001) readmission rates, even after adjusting for sex, age, insurance status, and comorbidities. All-cause complication rates were higher for weekend admissions (8.62% vs. 12.7%, p < 0.001), specifically deep vein thrombosis, infection, neurological conditions, and pulmonary embolism. Conclusion Index weekend admission increases 30- and 90-day readmission rates after ECSF. In patients undergoing ECSF on weekends, postoperative care for patients at risk for specific complications will allow for improved outcomes and health care utilization.

Abstract Background Recent advances in long-read sequencing technologies have enabled accurate identification of all genetic variants in individuals or cells; this procedure is known as variant calling. However, benchmarking studies on variant calling using different long-read sequencing technologies are still lacking. Results We used two Caenorhabditis elegans strains to measure several variant calling metrics. These two strains shared true-positive genetic variants that were introduced during strain generation. In addition, both strains contained common and distinguishable variants induced by DNA damage, possibly leading to false-positive estimation. We obtained accurate and noisy long reads from both strains using high-fidelity (HiFi) and continuous long-read (CLR) sequencing platforms, and compared the variant calling performance of the two platforms. HiFi identified a 1.65-fold higher number of true-positive variants on average, with 60% fewer false-positive variants, than CLR did. We also compared read-based and assembly-based variant calling methods in combination with subsampling of various sequencing depths and demonstrated that variant calling after genome assembly was particularly effective for detection of large insertions, even with 10 × sequencing depth of accurate long-read sequencing data. Conclusions By directly comparing the two long-read sequencing technologies, we demonstrated that variant calling after genome assembly with 10 × or more depth of accurate long-read sequencing data allowed reliable detection of true-positive variants. Considering the high cost of HiFi sequencing, we herein propose appropriate methodologies for performing cost-effective and high-quality variant calling: 10 × assembly-based variant calling. The results of the present study may facilitate the development of methods for identifying all genetic variants at the population level.

Abstract Pulmonary vein isolation is an well-established treatment strategy for atrial fibrillation (AF), and it is especially effective for patients with paroxysmal AF. However, the success rate is limited for patients with persistent AF, because non-pulmonary vein triggers which increase AF recurrence are frequently found in these patients. The major non-pulmonary vein triggers are from the left atrial posterior wall, left atrial appendage, ligament of Marshall, coronary sinus, superior vena cava, and crista terminalis, but other atrial sites can also generate AF triggers. All these sites have been known to contain atrial myocytes with potential arrhythmogenic electrical activity. The prevalence and clinical characteristics of these non-pulmonary vein triggers are well studied; however, the clinical outcome of catheter ablation for persistent AF is still unclear. Here, we reviewed the current ablation strategies for persistent AF and the clinical implications of major non-pulmonary vein triggers.

Emerging cloud-native technologies, such as container runtime and container orchestrator, offer unprecedented agility in developing and running applications, especially when combined with microservice-style architecture. Several commercial Samsung Network products such as Samsung Element Management System (S-EMS), 5G Radio Access Network (RAN) & Core network elements are being redesigned to fit the microservice paradigm. The cloud environment allows enterprises to scale their applications on-demand with minimum cost; however, it is often difficult to use containers without sacrificing the many benefits offered by container technology. S-EMS manages 5G RAN & Core network elements (NEs) deployed nationwide, and systematically stores a huge volume of stateful data per second. Containers are characterized to have an ephemeral state, hence ‘stateful-ness’ aspect of S-EMS makes management more complex. The existing system in a container-based application does not support geo-redundancy where services/data are stateful/state dependent. In this paper, different challenges around geo-redundancy between different independent Kubernetes set up with active and standby modes between the sites where state-dependent data is stored in each site are described. To overcome these challenges, we propose the High Availability Control Method (HACM) - which enables the Kubernetes cluster to be active and standby, where state-dependent data and context-based operations are intrinsically supported by the underlying S-EMS container application. Our approach has been designed to maintain the geo-redundancy philosophy of cloud-native by associating the status of each site using high availability (HA), switching over services based on the health of applications, deciding state when there are conflicts in site state, and the option to auto fallback based on user preference and services are transferred between sites without user intervention with optimized storage that ensures consistency, persistence, reliability, and availability. Through evaluation, we show that HACM with S-EMS can facilitate geo-redundancy HA, while not posing a significant burden on the Cloud.

Knowledge about mitogenomes has been proven to be essential in human parasite diagnostics and understanding of their diversity. However, the lack of substantial data for comparative analysis is still a challenge in Trichuris trichiura research. To provide high quality mitogenomes, we utilized long-read sequencing technology of Oxford Nanopore Technologies (ONT) to better resolve repetitive regions and to construct de novo mitogenome assembly minimizing reference biases. In this study, we got three de novo assembled mitogenomes of T. trichiura isolated from Korean individuals. These circular complete mitogenomes of T. trichiura are 14,508 bp, 14,441 bp, and 14,440 bp in length. A total of 37 predicted genes were identified consisting of 13 protein-coding genes (PCGs), 22 transfer RNA (tRNAs) genes, two ribosomal RNA (rRNA) genes (rrnS and rrnL), and two non-coding regions. Interestingly, the assembled mitogenome has up to six times longer AT-rich regions than previous reference sequences, thus proving the advantage of long-read sequencing in resolving unreported non-coding regions. Furthermore, variant detection and phylogenetic analysis using concatenated protein coding genes, cox1, rrnL, and nd1 genes confirmed the distinct molecular identity of this newly assembled mitogenome while at the same time showing high genetic relationship with sequences from China or Tanzania. Our study provided a new set of reference mitogenome with better contiguity and resolved repetitive regions that could be used for meaningful phylogenetic analysis to further understand disease transmission and parasite biology.

Measurement(s) stroke lesion Technology Type(s) manual segmentation in ITK-SNAP Sample Characteristic - Organism Homo sapiens Sample Characteristic - Environment brain

Abstract Background The efficacy and safety of high-power, short-duration (HPSD) radiofrequency catheter ablation for atrial fibrillation (AF) have been demonstrated in several studies. We aimed to evaluate and compare the effects of the conventional method and the HPSD method for AF ablation on the sinus and AV node function in patients with paroxysmal AF. Methods The medical records of patients with paroxysmal AF who underwent pulmonary vein isolation (PVI) were retrieved from a prospectively collected AF ablation registry at a large-sized tertiary center. The HPSD group (n = 41) was distinguished from the conventional ablation group (n = 198) in terms of the power (50 W vs. 20–40 W) and duration (6–10 s vs. 20–30 s) of radiofrequency energy delivery during PVI. Peri-procedural changes in cardiac autonomy were assessed in terms of the changes in sinus cycle length (SCL), block cycle length (BCL), and effective refractory period (ERP) of the atrioventricular node (AVN). Results The SCL, BCL, and ERP of the AVN at baseline and post-ablation were not significantly different between the conventional ablation group and the HPSD group. Shortening of the SCL, BCL, and ERP of the AVN was observed immediately after AF ablation in both groups. One-year recurrence of AF/atrial flutter (35.1% vs. 20.3%; P = 0.011) and atrial flutter (13.8% vs. 4.7%; P = 0.015) were higher in the HPSD group than in the conventional ablation group. Conclusion Both the HPSD and the conventional ablation method resulted in post-ablation vagal modification as evidenced by the shortening of SCL, BCL, and ERP of the AVN. One-year recurrence of atrial flutter and AF/atrial flutter was higher in patients who underwent the HPSD method.

Treatment of osteoarthritis (OA) by administration of corticosteroids is a commonly used method in clinics using anti-inflammatory medicine. Oral administration or intra-articular injection of corticosteroids can reduce the pain and progress of cartilage degeneration, but they are usually insufficient to show local and long-term anti-inflammatory effects because of their fast clearance in the body. In this study, we suggest an injectable anti-OA drug depot system for sustained drug release that provides long-term effective therapeutic advantages. Amphiphilic poly(organophosphazene), which has temperature-dependent nanoparticle forming and sol-gel transition behaviors when dissolved in aqueous solution, was synthesized for triamcinolone acetonide (TCA) delivery. Because hydrophobic parts of the polymer can interact with hydrophobic parts of the TCA, the TCA was encapsulated into the self-assembled polymeric nanoparticles. The TCA-encapsulated polymeric nanoparticles (TePNs) were well dispersed in an aqueous solution below room temperature so that they can be easily injected as a sol state into an intra-articular region. However, the TePNs solution transforms immediately to a viscose 3D hydrogel like a synovial fluid in the intra-articular region via the conducted body temperature. An in vitro TCA release study showed sustained TCA release for six weeks. One-time injection of the TePN hydrogel system in an early stage of OA-induced rat model showed a great inhibition effect against further OA progression. The OA-induced knees completely recovered as a healthy cartilage without any abnormal symptoms.

We present a case of an adult with concurrent severe aortic coarctation, bilateral carotid artery stenosis, and anomalous right subclavian artery, posing the interventional dilemma of accepting potential cerebral hyperperfusion syndrome vs hypoperfusion ischemic injury. Transcatheter stenting of the aortic coarctation was successfully performed without any neurological deficits. (Level of Difficulty: Beginner.)

Abstract We sought to evaluate the clinical implication of LAE based on left atrial anterior–posterior (LA AP) dimension or LA volume index (LAVI) in Korean patients with atrial fibrillation (AF). We enrolled 8159 AF patients from the CODE-AF registry. The primary outcome was rate of stroke or systemic embolism (SSE). The prevalence of mild, moderate, and severe LAE by LA AP dimension was 30.6%, 18.5%, and 21.4%, and by LAVI (available in 5808 patients) was 15.7%, 12.5% and 37.8%, respectively. Compared with no or mild LAE, patients with significant LAE (moderate to severe LAE, n = 3258, 39.9%) were associated with a higher rate of SSE (2.5% vs. 1.4%, P = 0.001). Multivariable analysis suggested presence of significant LAE by LA AP dimension was associated with a higher risk of SSE in the overall population (HR 1.57, 95% CI: 1.14–2.17, P = 0.005) and in patients using anticoagulants (n = 5836, HR 1.79, 95% CI: 1.23–2.63, P = 0.002). Patients with significant LAE by LAVI were also at higher risk of SSE (HR 1.58, 95% CI: 1.09–2.29, P = 0.017). In conclusion, significant LAE by LA dimension or LAVI was present in 39.9% and 50.2% of AF patients, respectively, and was associated with a higher rate of SSE.

Abstract Background An association has been identified between mitral valve prolapse (MVP) and sudden cardiac arrest (SCA), and ventricular arrhythmias (VA). This study aimed to elucidate predictive factors for SCA or VA in MVP patients. Methods MVP patients who underwent cardiac magnetic resonance (CMR) were retrospectively included. Patients with other structural heart disease or causes of aborted SCA were excluded. Clinical characteristics (sex, age, body mass index, histories of diabetes, hypertension, and dyslipidemia) and electrocardiographic (PR interval, QRS duration, corrected QT interval, inverted T wave in the inferior leads, bundle branch block, and atrial fibrillation), echocardiographic [mitral regurgitation grade, prolapsing mitral leaflet, and right ventricular systolic pressure (RVSP)], and CMR [left atrial volume index, both ventricular ejection fractions, both ventricular end-diastolic and systolic volume indexes, prolapse distance, mitral annular disjunction, systolic curling motion, presence of late gadolinium enhancement (LGE), LGE volume and proportion] parameters were analyzed. Results Of the 85 patients [age, 54.0 (41.0–65.0) years; 46 men], seven experienced SCA or VA. Younger age and wide QRS complex were observed more often in the SCA/VA group than in the no-SCA/VA group. The SCA/VA group exhibited lower RVSP, more systolic curling motion and LGE, greater LGE volume, and higher LGE proportion. The presence of LGE [hazard ratio (HR), 19.8; 95% confidence interval (CI) 2.65–148.15; P = 0.004], LGE volume (HR 1.08; 95% CI 1.02–1.14; P = 0.006) and LGE proportion (HR 1.32; 95% CI 1.08–1.60; P = 0.006) were independently associated with higher risk of SCA or VA in MVP patients together with systolic curling motion in each model. Conclusions The presence of systolic curling motion, high LGE volume and proportion, and the presence of LGE on CMR were independent predictive factors for SCA or VA in MVP patients.

Condensins are molecular motors that compact DNA via linear translocation. In Caenorhabditis elegans, the X-chromosome harbors a specialized condensin that participates in dosage compensation (DC). Condensin DC is recruited to and spreads from a small number of recruitment elements on the X-chromosome (rex) and is required for the formation of topologically associating domains (TADs). We take advantage of autosomes that are largely devoid of condensin DC and TADs to address how rex sites and condensin DC give rise to the formation of TADs. When an autosome and X-chromosome are physically fused, despite the spreading of condensin DC into the autosome, no TAD was created. Insertion of a strong rex on the X-chromosome results in the TAD boundary formation regardless of sequence orientation. When the same rex is inserted on an autosome, despite condensin DC recruitment, there was no spreading or features of a TAD. On the other hand, when a ‘super rex’ composed of six rex sites or three separate rex sites are inserted on an autosome, recruitment and spreading of condensin DC led to the formation of TADs. Therefore, recruitment to and spreading from rex sites are necessary and sufficient for recapitulating loop-anchored TADs observed on the X-chromosome. Together our data suggest a model in which rex sites are both loading sites and bidirectional barriers for condensin DC, a one-sided loop-extruder with movable inactive anchor.

Summary: Advances in long-read DNA sequencing technologies have enabled researchers to obtain high-quality genomes and finely resolve structural variants (SVs) in many species, even from small laboratories. The hands-on protocol presented here will guide you through the process of analyzing three different types of publicly available Drosophila melanogaster datasets obtained using current long-read sequencing technologies. We hope that this protocol will help in guiding researchers who are new to the process of long-read sequencing analysis. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background: This study compares postoperative pain scores and functional outcomes between liposomal bupivacaine peri-articular injection (LB-PAI) vs a single-shot adductor canal block (ACB) using bupivacaine HCl in patients undergoing primary total knee arthroplasty (TKA). Methods: This is a randomized controlled trial of 56 patients who were treated with TKA for arthritis. Patients were randomized to receive an intraoperative LB-PAI (n = 27) or preoperative ACB using bupivacaine HCl (n = 29). Both groups were otherwise given our institutional standard multimodal pain protocol. Data on Visual Analog Scale (VAS) pain scores, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, knee range of motion, postoperative ambulation distance, hospital length of stay, and opioid use were collected. The total cost of each intervention was compared at the conclusion of the study. Results: Age, gender, or body mass index was similar between groups. Compared to the ACB group, the LB-PAI group trended to lower average VAS pain scores on postoperative days 0, 1, and 2 (average difference [95% confidence interval] = −0.5 [−0.7, 1.7], −1.0 [−0.1, 2.0], −0.2 [−0.8, 1.3]), and identical average VAS pain scores on postoperative days 4 and 7. These differences and all postoperative outcome measures were not statistically significant at any time point. A single 266-milligram vial of liposomal bupivacaine costs $351, and a single-shot ACB costs $893 at our institution. Conclusions: This randomized controlled trial shows similar postoperative pain control, functional outcomes, and opioid use between LB-PAI and a single-shot ACB in patients undergoing primary TKA. However, the single-shot ACB costs $542 more than the LB-PAI at our institution.

Objective While greater body mass index (BMI) is associated with increased risk of developing atrial fibrillation (AF), the impact of BMI on outcomes in newly diagnosed AF is unclear. We examine the influence of BMI on outcomes and whether this is modified by sex and evaluate the effect of non-vitamin K oral anticoagulants (NOACs) in patients with high BMI.Methods GARFIELD-AF is a prospective registry of 52 057 newly diagnosed AF patients. The study population comprised 40 482 participants: 703 underweight (BMI

Abstract Aims This study aimed to elucidate the risk for stroke and systemic embolism (SE) in patients with atrial fibrillation and heart failure (HF) according to HF type. Methods and results A total of 10 780 patients with atrial fibrillation were enrolled in a multicentre prospective registry and divided according to HF type: no‐HF, HF with preserved ejection fraction (EF) (HFpEF), HF with mid‐range EF (HFmrEF), and HF with reduced EF (HFrEF). Each group included 237 age‐matched and sex‐matched patients (age, 69.0 ± 10.3 years; men, 69.6%). The baseline characteristics, cumulative incidence, and hazard ratios for stroke/SE and major bleeding were compared across the groups. Patients with HF accounted for 10.3% of the total population; HFpEF, HFmrEF, and HFrEF represented 43.7%, 23.6%, and 32.7% of the patients with HF, respectively. The CHA2DS2‐VASc score was significantly higher in the HFpEF, HFmrEF, and HFrEF groups than in the no‐HF group. The annual stroke/SE incidence rates were 2.8%, 0.7%, 1.1%, and 0.9% in the HFpEF, HFmrEF, HFrEF, and no‐HF groups, respectively. The cumulative incidence of stroke/SE was significantly highest in the HFpEF group at 22.8 ± 10.0 months (P = 0.020). The stroke/SE risk was higher in the HFpEF group than in the HFmrEF and HFrEF groups (hazard ratio, 3.192; 95% confidence interval, 1.039–9.810; P = 0.043). E/e' value was an independent risk factor for stroke/SE. There were no significant differences in the incidence of major bleeding across the groups. Conclusions The stroke/SE risk was the highest in the HFpEF group and comparable between the HFmrEF and HFrEF groups.

Background: Prior studies have indicated the complex relationships of smartphone use and smartphone addiction with mental health and life satisfaction. The purpose of this study was to investigate the structural relationships among smartphone use, smartphone addiction, mental health problems (e.g., depression, anxiety, stress [DAS] and satisfaction with life [SWL]). Methods: Cross-sectional data were collected by convenience sampling via an online survey of undergraduate students at a Midwestern university in the United States. The sample size of601 collected from undergraduate students that owned a smartphone and completed responses to the variables was utilized in this study. We assessed the hypothesized variables, including smartphone use, smartphone addiction, and mental health outcomes variables on a Likert-type scale. Structural analysis was used to examine the relationships. Results: Results suggested that smartphone use had a significant negative association with DAS symptoms (β = -.31, t = -3.81, P < .001) and was positively associated with SWL (β =.25, t = 3.41, P < .001). However, smartphone use had a significant positive relationship with smartphone addiction (β = .48, t = 5.51, P < .001). Smartphone addiction was positively related to DAS (β = .44, t = 6.33, P < .001), but it was not related to SWL (β = -.08, t = -1.26, P > .05). Conclusion: This study enhances our understanding of the associations between smartphone use and the health and well-being of undergraduate students. Implications for supporting their psychological health are discussed.

Telomeres can be maintained by a telomerase-independent mechanism called an alternative lengthening of telomeres (ALT). Here the authors use mouse Terc (telomerase RNA) knockout embryonic cells and provide longitudinal analysis of ALT telomeres maintained with non-telomeric sequences.

Background/Aims Comparative occurrence of ischemic stroke for rhythm versus rate control strategy in patients with non-valvular atrial fibrillation (NVAF) is still inconclusive. The purpose of this study was to investigate whether the rhythm control strategy is associated with a lower risk of ischemic stroke compared to the rate control strategy in NVAF patients. Methods The CODE-AF registry prospectively enrolled 6,280 consecutive patients who were treated for NVAF at 10 tertiary referral centers in South Korea. Of these, 2,513 NVAF patients (age, 67 ± 10 years; male, 61.8%) were clinically followed up for over 1-year and divided into rate and rhythm control groups. Results Those treated with the rhythm control strategy were younger and had less proportions of underlying disease compared to those treated with the rate control strategy. After the propensity matching analysis, those treated with the rhythm control strategy had similar baseline characteristics including the CHA2DS2-VASC score compared to those treated with the rate control strategy. The rate of oral anticoagulation, all bleeding, and hospitalization were also similarly between the two groups. The incidence rate of ischemic stroke in the rhythm control group was significantly lower than in the rate control group (0.7 vs. 6.9 per 1,000 person-years, p = 0.011). Conclusions The rhythm control strategy demonstrated a beneficial effect to lower the risk of ischemic stroke during a 1-year follow-up compared to the rate control strategy.

BackgroundAtrial fibrillation (AF) is treated by heart rate (HR) control. However, the optimal HR target in AF patients with heart failure (HF) remains unclear. To evaluate the clinical implication of the resting HR in AF patients with HF accompanied by preserved, mid-range, or reduced ejection fraction (HFpEF, HFmrEF, or HFrEF, respectively).MethodsEchocardiographic data from June 2016 to April 2020 in a prospective, multicenter, observational registry from 11,104 patients were analyzed. The follow-up duration was 2.2 years. The main outcome was composite of death and hospitalization. We categorized patients according to the HF type and resting HR: ≤ 60 bpm, 61–80 bpm, 81–110 bpm, and >110 bpm.ResultsA total of 1,421 patients were enrolled in the study: 582 in the HFpEF group, 506 in the HFmrEF group, and 333 in the HFrEF group. The patients had a mean age of 69 ± 11 years and consisted of 872 (61.4%) men. Primary endpoint rates among HFpEF patients with 60 < HR ≤ 110 bpm were lower than those with HR ≤ 60 bpm (61–80 bpm group: hazard ratio, 0.66; 95% CI, 0.46–0.94; p = 0.021; 81–110 bpm group: hazard ratio, 0.60; 95% CI, 0.40–0.90; p = 0.013). Especially, HFpEF patients with HR 81–110 bpm had a lower incidence of hospitalization caused by HF aggravation than those with other HR strata (HR ≤ 80bpm strata or HR >110 bpm strata). In HFmrEF and HFrEF patients, the survival rates did not differ significantly among patients in the three groups with HR ≤ 110 bpm. Moreover, the event rates increased significantly in HFmrEF patients with HR >110 bpm (hazard ratio, 1.91; 95% CI, 1.16-3.14, p = 0.011).ConclusionIn patients with AF and HFpEF, the resting HR has U-shaped associations with the overall primary endpoint. A lower or higher resting HR is associated with increased cardiovascular outcomes, especially in patients with HFpEF and AF.

Performance measurement has become conventional in construction management. However, it is non-trivial to establish an effective system to capture, evaluate, and feedback the on-site data. Whilst 3D object–based technology prevails in the industry, project managers remain accustomed to text-based system. Unstructured data format requires a tremendous amount of time and effort when analyzing a project in detail. To overcome this issue, an extensive literature review in conjunction with industry feedback has been conducted. Based on this preliminary investigation, the authors have proposed an on-site performance measurement system that interlinks 3D object with a spreadsheet. The system enables project managers to recognize the performance and/or productivity of a project in real time and helps find timely remedies in updating the original plan. One of the key findings includes that the identified eight on-site productivity factors should be embedded into a 3D model in effectively measuring the performance for a particular project. The new system also provides a useful tool in managing the productivity of a project. The main contribution of this study is the proposition and verification of a novel methodology that effectively manages on-site performance information by relating 3D objects with productivity factors in building construction.

Abstract Background An automated tagging module (VISITAG™; Biosense Webster, Irvine, CA) allows objective demonstration of energy delivery. However, the effect of VISITAG™ on clinical outcomes remains unclear. This study evaluated (1) clinical outcome after AF ablation using VISITAG™ and (2) the prevalence of gaps in the ablation line. Methods This retrospective analysis included 157 consecutive patients (mean age, 56.7 years; 73.2% men) with paroxysmal atrial fibrillation who underwent successful PVI between 2013 and 2016. Outcomes after the index procedure were compared between those using the VISITAG™ module (VISITAG group, n = 62) and those not using it (control group, n = 95). The primary outcome was recurrence of AF or atrial tachycardia after a blanking period of 3 months. Results The VISITAG group showed significantly shorter overall procedure time (172.2 ± 37.6 min vs. 286.9 ± 66.7 min, P 15 s, 60% force over time, > 6 g contact force) showed higher recurrence-free survival rate compared with those with gaps (borderline statistical significance, 91.7% vs. 66.0%, P = 0.094). Conclusion Use of the VISITAG™ module significantly reduced procedure, ablation, and fluoroscopic times with a similar AF/AT recurrence rate compared with the conventional ablation. Clinical implications of minimizing gaps along the ablation line should be evaluated further in the future prospective studies.

Abstract Background The incidence of inappropriate shocks remains high at 30% in patients with implantable cardioverter-defibrillators (ICDs). This retrospective study sought to examine the efficacy of strategic programming (ICD programming with a long detection interval and high-rate cutoff) in reducing electrical storm, inappropriate shocks, and unexpected hospital visits in patients with ICDs with/without cardiac resynchronization therapy with defibrillator (CRT-Ds). Methods This was a single tertiary center retrospective study, evaluating the clinical outcomes, especially regarding inappropriate therapies in patients with ICDs or CRT-Ds. Enrolled patients underwent ICD or CRT-D implantations from January 2008 to May 2016. Clinical information was attained by a thorough chart review. Results We analyzed 155 defibrillator patients from January 2008 to May 2016 (124 patients had ICDs and 31 had CRT-Ds). Since we adopted this strategic programming as a default programming from 2015 implanted ICDs and CRT-Ds, we divided the patients into two groups: devices implanted before 2015 (group A, n = 94) versus implanted after 2015 (group B, n = 61). During a median of 1289 days of follow-up, electrical storms occurred in three patients (eight events) in group B versus 11 (28 events) in group A (P = 0.18); appropriate therapies were delivered in 27 patients (56 events) in group A versus 7 (15 events) in group B (P = 0.72); inappropriate therapies were delivered in 15 patients (21 events) in group A versus 1 with 1 episode in group B (P = 0.03); and 5 unexpected hospitalizations occurred in four patients in group B versus 36 in 24 patients in group A (P = 0.02). Conclusion The clinical application of strategic programming reduced inappropriate shocks and unexpected hospitalizations in ICD and CRT-D patients.

Objectives:In Korea, about 2,000 abandoned mine area has been polluted by harmful waste such as mine tailing, waste rock and acid mine drain without prevention facility. Mine waste contains high concentrations of various hazardous metallic and nonmetallic materials. Also, it can be a source of pollution for nearby soil, rivers, and ground water. Heavy metals may exist in ecosystems for a long time and may be taken by the residents through crops and drinking water. In this study, human risk assessment for heavy metal contamination was carried out. Methods:About the 564 soil samples were analyzed for heavy metal. The risk assessment of polluted soils was carried out in accordance with guideline of Korea Soil Environment Conservation Act. It was implied with hazard identification, exposure assessment, toxicity assessment, and risk characterization. Results and Discussion:The number of exceed sites for the worried level of soil concentration were 185 for As, 3 for Hg, 7 for Zn, 1 for Pb, 1 for Cu. Soil contact was the biggest impact on adults and children for carcinogenic risk followed by crop intake, soil intake, and soil inhalation. Non-carcinogenic risk for adults, were in order of crop intake > soil intake > soil contact > outdoor air inhalation (volatilization) > ground water intake and soil inhalation. For children, it was in the order of soil intake > crop intake > soil contact > outdoor air inhalation (volatilization) > ground water intake > soil inhalation. Conclusion:The carcinogenic purification target concentration for the site was determined to be 7.17 mg / kg level of arsenic, considering adult and child concentrations. However, carcinogenic purification target concentration by arsenic dermal absorption carcinogenic coefficients (SFabs) of USEPA method was 20.08 mg/kg, therefore requiring research for domestic risk assessment factor.

Abstract Purpose Dose reduction of non-vitamin K antagonist oral anticoagulants (NOACs) is indicated in patients with atrial fibrillation (AF) with renal impairment. This study investigated anticoagulation patterns and outcomes in patients with chronic kidney disease (CKD). Materials and methods In a prospective observational registry (CODE-AF), 3445 patients with non-valvular AF including 1129 with CKD (estimated glomerular filtration rate ≤ 60 mL min−1 1.73 m−2) were identified between June 1, 2016, and July 3, 2017. Results Compared with patients with no-CKD, patients with CKD more frequently had a high stroke risk (94.9% vs. 67.0%, p

Abstract Background Symptom burden is an important factor in determining the treatment of atrial fibrillation (AF). AF is frequently accompanied by heart failure (HF). This study investigated the characteristics of AF symptoms with concomitant HF. Methods A total of 4885 patients with AF were consecutively enrolled through a prospective observational registry (the Comparison Study of Drugs for Symptom Control and Complication Prevention of Atrial Fibrillation [CODE-AF] registry). Clinically diagnosed HF was divided into three categories (preserved, mid-range, and reduced ejection fraction [EF]). Symptom severity was assessed using the European Heart Rhythm Association (EHRA) classification. Results The presence of AF-related symptoms was comparable irrespective of concomitant HF. Patients with HF with reduced EF demonstrated severe (EHRA classes 3 and 4) and atypical symptoms. HF with preserved EF was also associated with atypical symptoms. Female sex and AF type were associated with the presence of symptoms in AF without HF, and non-maintenance of sinus rhythm and increased left atrial pressure (E/e′ ≥ 15) were factors related to the presence of symptoms in AF with HF. Conclusion AF with concomitant HF presented with more severe and atypical symptoms than AF without HF. Maintaining the sinus rhythm and reducing the E/e’ ratio are important factors for reducing symptoms in AF with concomitant HF.

Background/Aims Efforts to reduce stroke in patients with atrial fibrillation (AF) have focused on increasing physician adherence to oral anticoagulant (OAC) guidelines; however, the high early discontinuation rate of vitamin K antagonists (VKAs) is a limitation. Although non-VKA OACs (NOACs) are more convenient to administer than warfarin, their lack of monitoring may predispose patients to nonpersistence. We compared the persistence of NOAC and VKA treatment for AF in real-world practice. Methods In a prospective observational registry (COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation [CODE-AF] registry), 7,013 patients with nonvalvular AF (mean age 67.2 ± 10.9 years, women 36.4%) were consecutively enrolled between June 2016 and June 2017 from 10 tertiary hospitals in Korea. This study included 3,381 patients who started OAC 30 days before enrollment (maintenance group) and 572 patients who newly started OAC (new-starter group). The persistence rate of OAC was evaluated. Results In the maintenance group, persistence to OAC declined during 6 months, to 88.3% for VKA and 95.5% for NOAC (p < 0.0001). However, the persistence rate was not different among NOACs. In the new-starter group, persistence to OAC declined during 6 months, to 78.9% for VKA and 92.1% for NOAC (p < 0.0001). The persistence rate was lower for rivaroxaban (83.7%) than apixaban (94.6%) and edoxaban (94.1%, p < 0.001). In the new-starter group, diabetes, valve disease, and cancer were related to nonpersistence of OAC. Conclusions Nonpersistence was significantly lower with NOAC than VKA in both the maintenance and new-starter groups. In only the new-starter group, apixaban or edoxaban showed higher persistence rates than rivaroxaban.

Context: There is currently little research using short duration activities like a six-minute nature-based video with classical music to assist in improving tranquility levels of individuals with dementia. Previous studies have shown that the combined use of a nature-based video with music has improved the tranquility levels of individuals with dementia living in a dementia care unit. Objectives: The current study attempts to assess the efficacy of a six-minute nature-based slideshow video accompanied with classical music and its effect on the tranquility levels of individuals with dementia during an episode of sundown syndrome. Methods: A one-group pre-test/post-test quasi-experimental design with mixed-methods data collection was used for this exploratory study. Ten participants living in a dementia care unit, who were experiencing an episode of Sundowning had their tranquility levels collected along with comments before and after the research intervention. Findings: Descriptive statistics of both CNA and participant statistics indicated improved tranquility levels and comments appeared to be more positive after the research intervention. Discussion: Increased levels of tranquility, more positive participant behaviors, and improved attitudes after the nature-based video with music occurred. The research video with music appeared to assist in the mitigation of sundown syndrome symptoms. Limitations: A limited number of participants were studied before and after only one episode of Sundowning. Multiple occurrences of Sundowning and implementation of the research intervention may add more evidence-based findings. Implications: A simple short duration six-minute nature-based video with music intervention could be integrated into a care home worker’s daily routine for residents with dementia and who are Sundowning to assist in mitigating symptoms of sundown syndrome. This method could also be used by home health care workers and family caregivers.

Background: Rathke cleft cysts (RCCs) are known sellar/suprasellar lesions that can grow and become symptomatic. For most asymptomatic lesions, stability is a typical outcome of surveillance; however, random relapse or cyst size fluctuation may also be observed. The conventional treatment for growing cysts is transsphenoidal removal. Methods: A literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. For significance, all journals were screened. Only records of tissue diagnosed RCCs with changes in size were included. Age and sex at diagnosis, size of the lesion, symptoms (if any), pituitary dysfunction, follow-up period, and size reduction were included in the data items. Results: A total of 4 articles where selected after the second exclusion method. Three articles where case series and one was a case report. Eight total patients where histologically proven to have Rathke cleft cysts which fluctuated in size without intervention. Conclusion: This review shows that RCCs can decrease or fluctuate in size following a dynamic process that is not fully understood. In the absence of symptoms, a larger cyst or an absolute increase in a cyst size, which may traditionally provoke an early surgical intervention, should be assessed and managed carefully to avoid potentially unneeded surgical morbidity.

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Abstract Background Radiofrequency catheter ablation (RFCA) for accessory pathways (APs) at the site of prior valve surgery (VS) remains challenging. We aimed to clarify the factors associated with successful RFCA for such APs. Methods Upon reviewing a RFCA registry and previous case reports, we included nine patients who underwent RFCA of APs at the site of prior VS (total‐VS group; age, 34.0 [24.5‐45.0] years; men, 4/9) and 196 patients who underwent RFCA of APs with no history of VS (no‐VS group; age, 40.5 [23.0‐54.0] years; men, 114/196). Electrophysiological features, procedural details, and outcomes were examined. Results Accessory pathway exhibited decremental conduction in four of nine patients in the total‐VS group. The number of RFCA attempts was significantly higher in the total‐VS group than in the no‐VS group (10.0 [4.5‐14.5] vs 2.0 [1.0‐3.0]; P

Purpose: As the aging population is increasing, the incidence of age-related cataract is expected to increase globally. The surgical intervention, a treatment for cataract, still has complications and is limited to developed countries. In this study, we investigated whether the polyphenol-enriched fraction of Vaccinium uliginosum L. (FH) prevents cataract formation in Sprague-Dawley (SD) rat pups. Methods: Sixty rat pups were randomly divided into six groups: CTL, Se, FH40, FH80, FH120, and Cur80. The cataract was induced with subcutaneous injection of sodium selenite (18 μmol/kg bodyweight) on postnatal (P) day 10. All groups, except CTL, were injected with sodium selenite, and the FH40, FH80, and FH120 groups were given gastric intubation with FH40 mg/kg, 80 mg/kg, and 120 mg/kg on P9, P10, and P11. The Cur80 group was also given gastric intubation with curcumin 80 mg/kg on P9, P10, and P11. All rat pups were euthanized on P30. Results: Lens morphological analysis showed that FH dose-dependently inhibited cataract formation. In the Se group, soluble proteins were insolubilized, and the gene expression of the α-, β-, and γ-crystallins was downregulated. However, FH treatment statistically significantly inhibited insolubilization of soluble proteins and downregulation of the gene expression of the α-, β-, and γ-crystallins. In the Se group, the gene and protein levels of m-calpain were downregulated, which were attenuated with FH treatment. In addition, sodium selenite injection caused reduced antioxidant enzymes (superoxide dismutase (SOD) and glutathione peroxidase (GPx)), glutathione (GSH) depletion, and malondialdehyde (MDA) production in the lens. The administration of FH inhibited sodium selenite–induced oxidative stress in a dose-dependent manner. The mechanism of protection against oxidative stress by FH involves NF-E2-related factor (Nrf-2) and hemoxygenase-1 (HO-1). FH treatment inhibited decrease of Nrf-2 in the nucleus fraction and HO-1 in the cytosol fraction. Finally, the FH treatment protected poly (ADP)-ribose polymerase (PARP) from cleavage, determined with western blotting. Conclusions: FH showed a preventive effect against cataract formation by inhibiting m-calpain-mediated proteolysis and oxidative stress in the lens. These results suggest that FH could be a potential anticataract agent in age-related cataract.

A digital twin is a virtual model of a process, product, or service, which is one of the key technologies in the fourth industry. The pairing of the virtual and physical world allows analysis of data and monitoring of systems to head off problems before they occur. This paper presents a digital twin architecture and a system based on an interoperable data model. It explains how to build a digital twin for the integrated control monitoring using edge devices, data analytics, and realistic 3D visualization. The system allows continuous collaboration between field engineers for data gathering, designers for modeling 3D models, and layout engineers for layout changing by generating 3D digital twin models automatically. The system helps stakeholders focus on their respective roles to build digital twins. Examples applied to the Korean automotive parts makers are also introduced in this paper. The system can be easily used by small and medium-sized enterprises (SMEs) as well as large companies. Beyond simply watching the production site with CCTV, the production site can be intuitively managed based on the digital twin.

Background Postoperative atrial fibrillation (POAF) is common after cardiac surgery, but little is known about its incidence and natural course after noncardiac surgery. We evaluated the natural course and clinical impact of POAF and the long‐term impact of anticoagulation therapy in patients without a history of atrial fibrillation (AF) undergoing noncardiac surgery. Methods and Results We retrospectively analyzed the database of Asan Medical Center (Seoul, Korea) to identify patients who developed new‐onset POAF after undergoing noncardiac surgery between January 2006 and January 2016. The main outcomes were AF recurrence, thromboembolic event, and major bleeding during follow‐up. Of 322 688 patients who underwent noncardiac surgery, 315 patients (mean age, 66.4 years; 64.4% male) had new‐onset POAF with regular rhythm monitoring after discharge. AF recurred in 53 (16.8%) during 2 years of follow‐up. Hypertension (hazard ratio, 2.12; P=0.02), moderate‐to‐severe left atrial enlargement (hazard ratio, 2.33; P=0.007) were independently associated with recurrence. Patients with recurrent AF had higher risks of thromboembolic events (11.2% versus 0.8%; P

Background Severe conduction delay and inter/intra‐atrial dissociation may occur in patients who undergo an extensive catheter ablation or a maze procedure for atrial tachyarrhythmia. We report a series of patients with inter/intra‐atrial dissociation that mimicked complete atrioventricular block or ventricular tachycardia. Methods and Results We retrospectively reviewed the medical records of 7 patients who were referred for the evaluation of atrioventricular block (patients 1–6) or ventricular tachycardia (patient 7) that occurred after biatrial maze procedure and valvular surgery. During the electrophysiologic study, slow atrial or junctional escape rhythm dissociated from isolated atrial activity mimicked complete atrioventricular blocks. Intra‐atrial dissociation of the right atrium or left atrium was observed. Atrioventricular nodal conduction from the nondissociated atrium to the ventricle was preserved in all patients, while the conduction from the dissociated atrium was blocked. In patient 7, the pacing of the ventricle by tracking of atrial tachycardia from the nondissociated left atrium/coronary sinus mimicked ventricular tachycardia during pacemaker interrogation. A total of 5 patients received new permanent pacemaker implantations during the index hospitalization for the surgery (n=2) or as a deferred procedure (n=3) according to the treatment for sick sinus syndrome. Conclusions Pseudo‐atrioventricular block or pseudo‐ventricular tachycardia may occur because of inter/intra‐atrial dissociation after a maze procedure. The selection of patients for permanent pacemaker implantation should be determined based on the patient’s symptoms and the status of the escape pacemaker and not on the apparent atrioventricular block. Proper diagnosis is important to avoid unnecessary implantation of a pacemaker or a defibrillator.

When two therapeutic agents are combined in a single formulation, i.e., coformulated, the quality and safety of the individual agents must be preserved. Here we describe an approach to evaluate the quality attributes of two individual monoclonal antibodies (mAbs), designated mAb-A and mAb-B, in coformulation. The mAbs were fractionated from heat-stressed coformulated drug product (DP) by hydrophobic interaction chromatography. Each purified mAb fraction was then compared with mAb-A and mAb-B in their individual formulations from the same drug substance sources used to make the coformulated DP lot, which was subjected to the same stress conditions. Product variants were evaluated and compared by using several analytical tests, including high-performance size exclusion chromatography (HPSEC), reducing and nonreducing gel electrophoresis, ion-exchange chromatography, capillary isoelectric focusing, and peptide mapping with mass spectrometry. Intermolecular interactions in coformulated and photostressed DPs were studied by evaluating aggregates fractionated from coformulated DP by HPSEC. Aggregate fractions of coformulated DP contained dimers, but not coaggregates, of mAb-A or mAb-B. Moreover, extensive assays for higher-order structure and biological interactions confirmed that there was no interaction between the two mAb molecules in the coformulation. These results demonstrate that the two coformulated therapeutic mAbs had the same quality attributes as the individually formulated mAb-A and mAb-B, no new quality attributes were formed, and no physicochemical, intermolecular, or biological interactions occurred between the two components. The approach described here can be used to monitor the product quality of other coformulated antibodies.

The heterogeneity of glycosylation on therapeutic monoclonal antibodies (mAbs) may affect the safety and efficacy of these agents. In particular, glycans of nonhuman origin, such as galactose-alpha-1,3-galactose (gal-α-gal) and N-glycolylneuraminic acid (NGNA), in the Fc region of therapeutic mAbs produced from murine cell lines carry a risk of immunogenicity. Immunogenic glycan structures can have immune-mediated clearance, resulting in faster clearance from in vivo circulation than non-immunogenic structures. To demonstrate the impact of these Fc nonhuman glycans on in vivo clearance, we purified and analyzed the glycan profile of a monoclonal antibody (mAb1) from human serum samples collected from clinical study participants. We purified mAb1 in a three-step chromatographic separation process (protein A, immobilized anti-mAb1 antibody affinity, and weak cation exchange chromatography) and extracted and labeled its N-linked oligosaccharide structures with 2-aminobenzamide acid for analysis on ultrahigh-performance hydrophilic interaction liquid chromatography. A comparison of the glycan profile of mAb1 recovered from human serum on the same day and 4 weeks after dosing revealed no significant differences, indicating similar clearance of mAb1 with nonhuman gal-α-gal or NGNA glycan in the Fc region compared with the human glycans. The relative proportions of the glycans remained similar, and all patients who had already received multiple doses of mAb1 over the course of a year were negative for antidrug antibodies, suggesting that none of the glycans induced an immune response. Therefore, we concluded that mAb1 gal-α-gal and NGNA glycoforms represent a low risk of conferring immunogenicity.

To appraise the effects and involved mechanism of Dendropanax morbifera leaves extract (DLE) on diabetes and retinal degeneration, in this study, male C57BLKS/J-m+/db and five groups of db/db mice were treated with 0.5% CMC or metformin or three doses of DLE for 6 weeks. Administration of DLE stimulated AMP-activated protein kinase in the liver, skeletal muscle and adipose tissue, leading to the improvement of gene and protein expression related with insulin resistance and glucose homeostasis in db/db mice. Morphological changes and insulin depletion of pancreatic islets were also attenuated by treatment of DLE. Moreover, DLE treatment prevented the deterioration of retina by regulating not only the gene expression related with apoptosis and neovascularization, but also the level of activator protein-1 in retina. Therefore, DLE improves diabetic phenotype and retinal degeneration, suggesting that DLE could be a prospective agent for preventing diabetes and related eye complication.

Age-related macular degeneration is associated with the degeneration of photoreceptors and retinal pigmented epithelial (RPE) cells in the macular. We, previously, demonstrated the protective effect of hyperoside on RPE cell death. In this study, hyperoside inhibited A2E accumulation and UVA and blue light (BL) induced cell death in RPE cells. Hyperoside exhibited inhibitory effects on AP-1 and NF-kB activities, determined by luciferase assay. BL induced complement C3 activation and poly ADP-ribose polymerase (PARP) cleavage were inhibited by hyperoside treatment in A2E laden RPE cells. Furthermore, expression of AhR target genes (CYP1A1 and CYP1B1) were upregulated by hyperoside treatment. Finally, hyperoside prevented UVA and BL-induced photoreceptor degeneration in the Balb-c mice. The outer nuclear layer thickness, counts and retinal layer folds were ameliorated by hyperoside treatment. The results suggest that hyperoside could be a potential application to prevent the onset and development of AMD.