Intravascular Imaging-Guided Optimization of Complex Percutaneous Coronary Intervention by Sex: A Subgroup Analysis of the RENOVATE-COMPLEX-PCI Trial.

Importance: There have been heterogeneous results related to sex differences in prognosis after percutaneous coronary artery intervention (PCI) for complex coronary artery lesions. Objective: To evaluate potential differences in outcomes with intravascular imaging-guided PCI of complex coronary artery lesions between women and men. Design, Setting, and Participants: This prespecified substudy evaluates the interaction of sex in the investigator-initiated, open-label, multicenter RENOVATE-COMPLEX-PCI randomized clinical trial, which demonstrated the superiority of intravascular imaging-guided PCI compared with angiography-guided PCI in patients with complex coronary artery lesions. The trial was conducted at 20 sites in Korea. Patients with complex coronary artery lesions undergoing PCI were enrolled between May 2018 and May 2021, and the median (IQR) follow-up period was 2.1 (1.4-3.0) years. Data were analyzed from December 2022 to December 2023. Interventions: After diagnostic coronary angiography, eligible patients were randomly assigned in a 2:1 ratio to receive intravascular imaging-guided PCI or angiography-guided PCI. The choice and timing of the intravascular imaging device were left to the operators' discretion. Main Outcomes and Measures: The primary end point was target vessel failure, defined as a composite of cardiac death, target vessel-related myocardial infarction, or clinically driven target vessel revascularization. Secondary end points included individual components of the primary end point. Results: Of 1639 included patients, 339 (20.7%) were women, and the mean (SD) age was 65.6 (10.2) years. There was no difference in the risk of the primary end point between women and men (9.4% vs 8.3%; adjusted hazard ratio [HR], 1.39; 95% CI, 0.89-2.18; P = .15). Intravascular imaging-guided PCI tended to have lower incidence of the primary end point than angiography-guided PCI in both women (5.2% vs 14.5%; adjusted HR, 0.34; 95% CI, 0.15-0.78; P = .01) and men (8.3% vs 11.7%; adjusted HR, 0.72; 95% CI, 0.49-1.05; P = .09) without significant interaction (P for interaction = .86). Conclusions and Relevance: In patients undergoing complex PCI, compared with angiographic guidance, intravascular imaging guidance was associated with similar reduction in the risk of target vessel failure among women and men. The treatment benefit of intravascular imaging-guided PCI showed no significant interaction between treatment strategy and sex. Trial Registration: ClinicalTrials.gov Identifier: NCT03381872.

Standardization of the Korean Version of the Acceptance and Action Questionnaire for Obsessions and Compulsions in University Students and Patients With Obsessive-Compulsive Disorder.

OBJECTIVE: The Acceptance and Action Questionnaire for Obsessions and Compulsions (AAQ-OC) is a version of the Acceptance and Action Questionnaire (AAQ) that specifically measures unwanted intrusive thoughts and responses (e.g., experiential avoidance) to them. This study aimed to investigate the reliability and validity of the Korean version of the AAQ-OC in clinical and nonclinical Korean samples. METHODS: In this study, 561 university students and 121 patients with obsessive-compulsive disorder (OCD) completed the AAQ-OC and several other psychological scales. Descriptive, correlation, and exploratory and confirmatory factor analyses as well as group comparisons were conducted. RESULTS: The results of the exploratory and confirmatory factor analyses indicated a two-factor structure that best fits the data in the university sample: Factors 1 and 2 matched the original Valued Action and Willingness subscales, respectively. The reliability analyses revealed that the AAQ-OC and its factors had excellent internal consistencies. As regards the concurrent validity, the AAQ-OC and its factors had a positive correlation with the AAQ-II and Cognitive Fusion Questionnaire. Compared with the university students, the OCD patients had higher AAQ-OC scores, and their obsessive-compulsive symptoms, particularly the two symptom dimensions of responsibility for harm and mistakes and unacceptable thoughts, were significantly associated with the AAQ-OC and two subscales. CONCLUSION: The findings of this study confirm the reliability and validity of the Korean version of the AAQ-OC.

Brief guide to RNA sequencing analysis for nonexperts in bioinformatics.

Transcriptome analysis is widely used for current biological research, but remains challenging for many experimental scientists. Here, we present a brief but broad guideline for transcriptome analysis, focusing on RNA sequencing, by providing the list of publicly available datasets, tools, and R packages for practical transcriptome analysis. This work will be useful for biologists to perform key transcriptomic analysis with minimum expertise in bioinformatics.

Three new phthalide derivatives from culture broth of Dentipellis fragilis and their cytotoxic activities.

Three new phthalide derivatives (1‒3) together with two known compounds, erinaceolactone B (4) and hericerin III (5), were isolated from the culture broth of Dentipellis fragilis. The chemical structures of 1‒5 were determined by analyses of their 1D-, 2D-NMR, and MS. The absolute configuration of 1 was determined by CD analysis. The isolated compounds were assessed for their cytotoxic activities against A549, DU145, HCT116, and HT1080 cancer cell lines. Compounds 1‒5 showed strong cytotoxic activities against DU145, with IC50 values ranging from 14.3 to 16.1 µM. Additionally, all compounds showed moderate or weak cytotoxic activities against all cell lines except for compounds 4 and 1 which showed no cytotoxic activities against A549 and HCT116 cancer cell lines, respectively. Against HT1080 cancer cell line, only compound 2 displayed moderate cytotoxic activity.

Combinatorial transcriptomic and genetic dissection of insulin/IGF-1 signaling-regulated longevity in Caenorhabditis elegans.

Classical genetic analysis is invaluable for understanding the genetic interactions underlying specific phenotypes, but requires laborious and subjective experiments to characterize polygenic and quantitative traits. Contrarily, transcriptomic analysis enables the simultaneous and objective identification of multiple genes whose expression changes are associated with specific phenotypes. Here, we conducted transcriptomic analysis of genes crucial for longevity using datasets with daf-2/insulin/IGF-1 receptor mutant Caenorhabditis elegans. Our analysis unraveled multiple epistatic relationships at the transcriptomic level, in addition to verifying genetically established interactions. Our combinatorial analysis also revealed transcriptomic changes associated with longevity conferred by daf-2 mutations. In particular, we demonstrated that the extent of lifespan changes caused by various mutant alleles of the longevity transcription factor daf-16/FOXO matched their effects on transcriptomic changes in daf-2 mutants. We identified specific aging-regulating signaling pathways and subsets of structural and functional RNA elements altered by different genes in daf-2 mutants. Lastly, we elucidated the functional cooperation between several longevity regulators, based on the combination of transcriptomic and molecular genetic analysis. These data suggest that different biological processes coordinately exert their effects on longevity in biological networks. Together our work demonstrates the utility of transcriptomic dissection analysis for identifying important genetic interactions for physiological processes, including aging and longevity.

Bakuchicin alleviates ovalbumin-induced allergic asthma by regulating M2 macrophage polarization.

OBJECTIVE: Asthma is an airway inflammatory disease caused by activation of numerous immune cells including macrophages. Bakuchicin (BKC) is known to exhibit anti-inflammatory effects and type 2 T helper (Th2) regulation, but has not been investigated for airway inflammation. This study aimed to evaluate the effects of BKC on airway inflammation and demonstrate the mechanisms of macrophage polarization. METHODS: The anti-inflammatory effects were determined using lipopolysaccharide (LPS)-stimulated macrophages. The ovalbumin (OVA)-induced asthma mouse model was used to evaluate the effects of BKC on airway inflammation and Th2 responses. Moreover, the effect of BKC on macrophage polarization was confirmed in bone marrow-derived macrophages (BMDMs) differentiation. RESULTS: BKC suppressed nitric oxide production and expression of pro-inflammatory cytokines by inhibiting signaling pathway in LPS-stimulated macrophages. In an OVA-induced asthma model, BKC treatment alleviated histological changes and mast cell infiltration and reduced the levels of eosinophil peroxidase, ß-hexosaminidase, and immunoglobulin levels. In addition, BKC alleviated Th2 responses and M2 macrophage populations in bronchoalveolar fluid. In BMDMs, BKC suppressed IL-4-induced M2 macrophage polarization and the expression of M2 markers such as arginase-1 and Fizz-1 through inhibiting sirtuin 2 levels. CONCLUSION: BKC could be a drug candidate for the treatment of allergic asthma.

CRISPR-based identification of N-terminal acetylation in synucleinopathies.

A recent study by Kumar et al. identified several biological pathways that regulate the levels of endogenous alpha-synuclein (α-synuclein). They specifically highlighted the N-terminal acetylation (NTA) pathway as an important factor in maintaining the stability of endogenous α-synuclein, suggesting targeting the NTA pathway as a potential therapeutic approach.

Cost-Effectiveness of Intravascular Imaging-Guided Complex PCI: Prespecified Analysis of RENOVATE-COMPLEX-PCI Trial.

BACKGROUND: Although clinical benefits of intravascular imaging-guided percutaneous coronary intervention (PCI) in patients with complex coronary artery lesions have been observed in previous trials, the cost-effectiveness of this strategy is uncertain. METHODS: RENOVATE-COMPLEX-PCI (Randomized Controlled Trial of Intravascular Imaging Guidance vs Angiography-Guidance on Clinical Outcomes After Complex Percutaneous Coronary Intervention) was conducted in Korea between May 2018 and May 2021. This prespecified cost-effectiveness substudy was conducted using Markov model that simulated 3 states: (1) post-PCI, (2) spontaneous myocardial infarction, and (3) death. A simulated cohort was derived from the intention-to-treat population, and input parameters were extracted from either the trial data or previous publications. Cost-effectiveness was evaluated using time horizon of 3 years (within trial) and lifetime. The primary outcome was incremental cost-effectiveness ratio (ICER), an indicator of incremental cost on additional quality-adjusted life years (QALYs) gained, in intravascular imaging-guided PCI compared with angiography-guided PCI. The current analysis was performed using the Korean health care sector perspective with reporting the results in US dollar (1200 Korean Won, ₩=1 dollar, $). Willingness to pay threshold was $35 000 per QALY gained. RESULTS: A total of 1639 patients were included in the trial. During 3-year follow-up, medical costs ($8661 versus $7236; incremental cost, $1426) and QALY (2.34 versus 2.31; incremental QALY, 0.025) were both higher in intravascular imaging-guided PCI than angiography-guided PCI, resulting incremental cost-effectiveness ratio of $57 040 per QALY gained within trial data. Conversely, lifetime simulation showed total cumulative medical cost was reversed between the 2 groups ($40 455 versus $49 519; incremental cost, -$9063) with consistently higher QALY (8.24 versus 7.89; incremental QALY, 0.910) in intravascular imaging-guided PCI than angiography-guided PCI, resulting in a dominant incremental cost-effectiveness ratio. Consistently, 70% of probabilistic iterations showed cost-effectiveness of intravascular imaging-guided PCI in probabilistic sensitivity analysis. CONCLUSIONS: The current cost-effectiveness analysis suggests that imaging-guided PCI is more cost-effective than angiography-guided PCI by reducing medical cost and increasing quality-of-life in complex coronary artery lesions in long-term follow-up. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03381872.

Multitemporal analysis of land subsidence induced by open-pit mining activity using improved combined scatterer interferometry with deep learning algorithm optimization.

Mine operational safety is an important aspect of maintaining the operational continuity of a mining area. In this study, we used the InSAR time series to analyze land surface changes using the ICOPS (improved combined scatterers with optimized point scatters) method. This ICOPS method combines persistent scatterers (PS) with distributed scatterers (DS) to increase surface deformation analysis's spatial coverage and quality. One of the improvements of this study is the use of machine learning in postprocessing, based on convolutional neural networks, to increase the reliability of results. This study used data from the Sentinel-1 SAR C-band satellite during the 2016-2022 observation period at the Musan mine, North Korea. In the InSAR surface deformation time analysis, the maximum average rate of land subsidence was approximately > 15.00 cm per year, with total surface deformation of 170 cm and 70 cm for the eastern dumping area and the western dumping area, respectively. Analyzing the mechanism of land surface changes also involved evaluating the geological conditions in the Musan mining area. Our research findings show that combining machine learning and statistical methods has great potential to enhance the understanding of mine surface deformation.

Meta-analysis of the transcriptome identifies aberrant RNA processing as common feature of aging in multiple species.

Aging is accompanied by the gradual deregulation of the transcriptome. However, whether age-dependent changes in the transcriptome are evolutionarily conserved or diverged remains largely unexplored. Here, we performed a meta-analysis examining the age-dependent changes in the transcriptome using publicly available datasets of 11 representative metazoans, ranging from Caenorhabditis elegans to humans. To identify the transcriptomic changes associated with aging, we analyzed various aspects of the transcriptome, including genome composition, RNA processing, and functional consequences. The use of introns and novel splice sites tended to increase with age, particularly in the brain. In addition, our analysis suggests that the age-dependent accumulation of premature termination codon-containing transcripts is a common feature of aging across multiple animal species. Using C. elegans as a test model, we showed that several splicing factors that are evolutionarily conserved and age-dependently downregulated were required to maintain a normal lifespan. Thus, aberrant RNA processing appears to be associated with aging and a short lifespan in various species.

Development of a deep learning model to distinguish the cause of optic disc atrophy using retinal fundus photography.

The differential diagnosis for optic atrophy can be challenging and requires expensive, time-consuming ancillary testing to determine the cause. While Leber's hereditary optic neuropathy (LHON) and optic neuritis (ON) are both clinically significant causes for optic atrophy, both relatively rare in the general population, contributing to limitations in obtaining large imaging datasets. This study therefore aims to develop a deep learning (DL) model based on small datasets that could distinguish the cause of optic disc atrophy using only fundus photography. We retrospectively reviewed fundus photographs of 120 normal eyes, 30 eyes (15 patients) with genetically-confirmed LHON, and 30 eyes (26 patients) with ON. Images were split into a training dataset and a test dataset and used for model training with ResNet-18. To visualize the critical regions in retinal photographs that are highly associated with disease prediction, Gradient-Weighted Class Activation Map (Grad-CAM) was used to generate image-level attention heat maps and to enhance the interpretability of the DL system. In the 3-class classification of normal, LHON, and ON, the area under the receiver operating characteristic curve (AUROC) was 1.0 for normal, 0.988 for LHON, and 0.990 for ON, clearly differentiating each class from the others with an overall total accuracy of 0.93. Specifically, when distinguishing between normal and disease cases, the precision, recall, and F1 scores were perfect at 1.0. Furthermore, in the differentiation of LHON from other conditions, ON from others, and between LHON and ON, we consistently observed precision, recall, and F1 scores of 0.8. The model performance was maintained until only 10% of the pixel values of the image, identified as important by Grad-CAM, were preserved and the rest were masked, followed by retraining and evaluation.

Current evidence for prognostic benefit of intravascular imaging-guided percutaneous coronary intervention in chronic total occlusion intervention.

Although percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) has been increasing in recent years, CTO PCI is still one of the most challenging procedures with relatively higher rates of procedural complications and adverse clinical events after PCI. Due to the innate limitations of invasive coronary angiography, intravascular imaging (IVI) has been used as an adjunctive tool to complement PCI, especially in complex coronary artery disease. Considering the complexity of CTO lesions, the role of IVI is particularly important in CTO intervention. IVI has been a useful adjunctive tool in every step of CTO PCI including assisted wire crossing, confirmation of wire location within CTO segment, and stent optimization. The meticulous use of IVI has been one of the greatest contributors to recent progress of CTO PCI. Nevertheless, studies evaluating the role of IVI during CTO PCI are limited. The current review provides a comprehensive overview of the mechanistic advantages of IVI in CTO PCI, summarizes previous studies and trials, and presents future perspective of IVI in CTO PCI.

Association Between ECG Abnormalities and Mortality in a Low-Risk Population.

BACKGROUND: The ECG is a simple, noninvasive screening method for cardiovascular disease and arrhythmia. The impact of ECG abnormality on mortality is not certain in low-risk populations. To address this, we evaluated the association between ECG abnormality and mortality. METHODS AND RESULTS: We retrospectively assessed baseline ECG and all-cause mortality and cardiovascular mortality in 660 383 patients presenting for medical check-ups. Baseline ECG abnormalities were classified according to the Minnesota Code. Among the total 660 383 participants, 23 609 (3.6%) had major and 110 038 (16.7%) had minor ECG abnormalities. All-cause mortality occurred in 7751 patients (1.1%) and cardiovascular mortality in 1180 (0.18%) over a median follow-up period of 8.8 years. Major ECG abnormalities were associated with all-cause mortality (hazard ratio [HR], 1.11 [95%, 1.03-1.2]) and cardiovascular mortality (HR, 1.92 [95% CI, 1.63-2.27]) compared with no ECG abnormalities. All-cause mortality was associated with right atrial enlargement (HR, 2.11 [95% CI, 1.1-4.07]), left atrial enlargement (HR, 1.76 [95% CI, 1.1-2.84]), sinus tachycardia (HR, 1.52 [95% CI, 1.15-2.01]), complete atrioventricular block (HR, 2.1 [95% CI, 1.05-4.2]), atrial fibrillation (HR, 1.52 [95% CI, 1.26-1.84]), and left ventricular hypertrophy (HR, 1.15 [95% CI, 1.02-1.3]). Cardiovascular mortality was associated with left atrial enlargement (HR, 4.52 [95% CI, 2.15-9.5]), atrial fibrillation (HR, 3.22 [95% CI, 2.33-4.46]), left ventricular hypertrophy (HR, 1.72 [95% CI, 1.35-2.19]), major Q-wave abnormality (HR, 1.6 [95% CI, 1.08-2.39]), and major ST-T abnormality (HR, 1.76 [95% CI, 1.01-3.04]). CONCLUSIONS: ECG abnormalities, including left atrial enlargement, left ventricular hypertrophy, atrial fibrillation, and major Q-wave and ST-T abnormalities, were associated with cardiovascular mortality in a low-risk population.

Consensus Statements on the Definition, Classification, and Diagnostic Tests for Tinnitus: A Delphi Study Conducted by the Korean Tinnitus Study Group.

BACKGROUND: Tinnitus is a bothersome condition associated with various symptoms. However, the mechanisms of tinnitus are still uncertain, and a standardized assessment of the diagnostic criteria for tinnitus is required. We aimed to reach a consensus on diagnosing tinnitus with professional experts by conducting a Delphi study with systematic review of the literature. METHODS: Twenty-six experts in managing tinnitus in Korea were recruited, and a two-round modified Delphi study was performed online. The experts evaluated the level of agreement of potential criteria for tinnitus using a scale of 1-9. After the survey, a consensus meeting was held to establish agreement on the results obtained from the Delphi process. Consensus was defined when over 70% of the participants scored 7-9 (agreement) and fewer than 15% scored 1-3 (disagreement). To analyze the responses of the Delphi survey, the content validity ratio and Kendall's coefficient of concordance were evaluated. RESULTS: Consensus was reached for 22 of the 38 statements. For the definition of tinnitus, 10 out of 17 statements reached consensus, with three statements achieving complete agreement including; 1) Tinnitus is a conscious perception of an auditory sensation in the absence of a corresponding external stimulus, 2) Tinnitus can affect one's quality of life, and 3) Tinnitus can be associated with hearing disorders including sensorineural hearing loss, vestibular schwannoma, Meniere's disease, otosclerosis, and others. For the classification of tinnitus, 11 out of 18 statements reached consensus. The participants highly agreed with statements such as; 1) Vascular origin is expected in pulse-synchronous tinnitus, and 2) Tinnitus can be divided into acute or chronic tinnitus. Among three statements on the diagnostic tests for tinnitus only Statement 3, "There are no reliable biomarkers for sensory or emotional factors of tinnitus." reached consensus. All participants agreed to perform pure-tone audiometry and tinnitus questionnaires, including the Tinnitus Handicap Inventory and Tinnitus Questionnaire. CONCLUSION: We used a modified Delphi method to establish a consensus-based definition, a classification, and diagnostic tests for tinnitus. The expert panel reached agreement for several statements, with a high level of consensus. This may provide practical information for clinicians in managing tinnitus.

Early Postoperative Benefits in Receptive and Expressive Language Development After Cochlear Implantation Under 9 Months of Age in Comparison to Implantation at Later Ages.

OBJECTIVES: The recent expansion of eligibility for cochlear implantation (CI) by the U.S. Food and Drug Administration (FDA) to include infants as young as 9 months has reignited debates concerning the clinically appropriate cut-off age for pediatric CI. Our study compared the early postoperative trajectories of receptive and expressive language development in children who received CI before 9 months of age with those who received it between 9 and 12 months. This study involved a unique pediatric cohort with documented etiology, where the timing of CI was based on objective criteria and efforts were made to minimize the influence of parental socioeconomic status. METHODS: A retrospective review of 98 pediatric implantees recruited at a tertiary referral center was conducted. The timing of CI was based on auditory and language criteria focused on the extent of delay corresponding to the bottom 1st percentile of language development among age-matched controls, with patients categorized into very early (CI at <9 months), early (CI at 9-12 months) and delayed (CI at 12-18 months) CI groups. Postoperative receptive/expressive language development was assessed using the Sequenced Language Scale for Infants receptive and expressive standardized scores and percentiles. RESULTS: Only the very early CI group showed significant improvements in receptive language starting at 3 months post-CI, aligning with normal-hearing peers by 9 months and maintaining this level until age 2 years. During this period (<2 years), all improvements were more pronounced in receptive language than in expressive language. CONCLUSION: CI before 9 months of age significantly improved receptive language development compared to later CI, with improvements sustained at least up to the age of 2. This study supports the consideration of earlier CI, beyond pediatric Food and Drug Administration labeling criteria (>9 months), in children with profound deafness who have a clear deafness etiology and language development delays (<1st percentile).

OASIS portable: User-friendly offline suite for secure survival analysis.

Online application for survival analysis (OASIS) and its update, OASIS 2, have been widely used for survival analysis in biological and medical sciences. Here, we provide a portable version of OASIS, an all-in-one offline suite, to facilitate secure survival analysis without uploading the data to online servers. OASIS portable provides a virtualized and isolated instance of the OASIS 2 webserver, operating on the users' personal computers, and enables user-friendly survival analysis without internet connection and security issues.

Decoding the Parkinson's Symphony: PARIS, Maestro of Transcriptional Regulation and Metal Coordination for Dopamine Release.

Parkin interacting substrate (PARIS) is a pivotal transcriptional regulator in the brain that orchestrates the activity of various enzymes through its intricate interactions with biomolecules, including nucleic acids. Notably, the binding of PARIS to insulin response sequences (IRSs) triggers a cascade of events that results in the functional loss in the substantia nigra, which impairs dopamine release and, subsequently, exacerbates the relentless neurodegeneration. Here, we report the details of the interactions of PARIS with IRSs via classical zinc finger (ZF) domains in PARIS, namely, PARIS(ZF2-4). Our biophysical studies with purified PARIS(ZF2-4) elucidated the binding partner of PARIS, which generates specific interactions with the IRS1 (5'-TATTTTT, Kd = 38.9 ± 2.4 nM) that is positioned in the promoter region of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). Mutational and metal-substitution studies demonstrated that Zn(II)-PARIS(ZF2-4) could recognize its binding partner selectively. Overall, our work provides submolecular details regarding PARIS and shows that it is a transcriptional factor that regulates dopamine release. Thus, PARIS could be a crucial target for therapeutic applications.