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Xu Jiang,1 Sungyeun Bae,1 Deok Yong Yoon,2 Shin Jung Park,3 Jaeseong Oh,1 Joo-Youn Cho,1,4 Kyung-Sang Yu1,4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA; 3Department of Pharmaceutical Research Laboratory, Chong Kun Dang Research Institute, Chong Kun Dang Pharmaceutical Corporation, Yongin, Republic of Korea; 4Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of KoreaCorrespondence: Kyung-Sang Yu, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101, Dae-hak ro, Jong-ro gu, Seoul, 03080, Republic of Korea, Tel/Fax +82-2072-1666, Email ksyu@snu.ac.krPurpose: Empagliflozin is a sodium-glucose cotransporter 2 inhibitor that is commonly used for the treatment of type 2 diabetes mellitus. As cocrystal formulation can improve the chemical properties of drugs, CKD-370 was newly developed as a cocrystal formulation of empagliflozin with solvate L-proline. This study aimed to compare the pharmacokinetics, safety, and tolerability of these two empagliflozin formulations in healthy Korean subjects.Methods: A randomized, open-label, two-sequence, two-period crossover study was conducted on healthy Korean participants. The subjects received a single oral 25 mg dose of either test (CKD-370) or reference treatment (Jardiance®) tablet at each period. Plasma empagliflozin concentrations were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic (PK) parameters were analyzed using non-compartmental methods. The primary PK parameters included the maximum concentration (Cmax) and the area under the concentration-time curve from 0 to last (AUClast). The safety of both formulations was monitored and evaluated.Results: A total of 28 healthy Korean adult subjects were randomized, and 27 subjects were included in the PK analysis. The mean ± standard deviation values of the primary PK parameters, Cmax and AUClast after administration of the test treatment, were 442.02 ± 103.37 μg/L and 3131.08 ± 529.30 μg·h/L, respectively, and those after administration of the reference treatment were 436.29 ± 118.74 μg/L and 3006.88 ± 514.21 μg·h/L, respectively. The geometric mean ratio and its 90% confidence interval of test to reference treatment for Cmax and AUClast were 1.0221 (0.9527– 1.0967) and 1.0411 (1.0153– 1.0677), respectively, which were within the commonly accepted bioequivalence criteria of 0.80 to 1.25. Both treatments were well-tolerated.Conclusion: The two formulations of empagliflozin showed similar PK characteristics and were generally well tolerated in healthy subjects.Keywords: T2DM, cocrystal, L-proline, biosimilar, CKD-370

Deok Yong Yoon,1 Sang-In Park,2 Jin-A Jung,3 Yong-Il Kim,3 In-Jin Jang,1 Jae-Yong Chung4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Hanmi Pharm. Co., Ltd., Seoul, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of KoreaCorrespondence: Jae-Yong ChungDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, 82, Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of KoreaTel +82-31-787-3955Fax +82-31-787-4045Email jychung@snubh.orgBackground: A fixed-dose combination (FDC) tablet formulation of amlodipine/losartan/rosuvastatin 5/100/20 mg was developed to improve medication compliance in patients with both hypertension and dyslipidemia. The comparative pharmacokinetic study was performed to compare the profile of an FDC tablet formulation of amlodipine/losartan/rosuvastatin with that of concomitant administration of a currently marketed FDC tablet of amlodipine/losartan with a rosuvastatin tablet.Subjects and Methods: A randomized, open-label, single oral dose, two-way crossover study was conducted in 60 healthy subjects. Subjects were orally administered the FDC tablet of amlodipine/losartan/rosuvastatin and a loose combination (LC) of two tablets comprising an FDC of amlodipine/losartan and rosuvastatin. Blood samples were collected for up to 144 h post dose for pharmacokinetic evaluations. Plasma concentrations of amlodipine, losartan, EXP3174 (an active metabolite of losartan), and rosuvastatin were measured by using liquid chromatography-tandem mass spectrometry. The geometric mean ratio (GMR) and its 90% confidence interval (90% CI) in the FDC treatment to LC treatment for the area under the concentration-time curve from zero to the last quantifiable time point (AUClast) and the maximum plasma concentration (Cmax) were calculated. Safety was monitored throughout the study.Results: The GMR (90% CI) values of AUClast and Cmax were 0.9946 (0.9663– 1.0238) and 0.9690 (0.9379– 1.0011) for amlodipine, 0.9855 (0.9422– 1.0308) and 0.9178 (0.8349– 1.0089) for losartan, 0.9814 (0.9501– 1.0136) and 0.9756 (0.9313– 1.0219) for EXP3174, and 0.9448 (0.8995– 0.9923) and 0.9609 (0.8799– 1.0494) for rosuvastatin, respectively. No clinically significant changes were observed in any of the safety parameters, including clinical laboratory tests, vital signs, electrocardiograms, and physical examinations, between the FDC treatment and the LC treatment.Conclusion: We confirmed the pharmacokinetic equivalence of the FDC and LC treatments. This triple combination FDC formulation could be a clinically useful replacement for LC therapy.Keywords: fixed-dose combination, loose combination, bioequivalence, pharmacokinetics, hypertension, dyslipidemia

Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, poses an emerging threat as it can lead to colorectal cancer, thrombosis, and other chronic conditions. The present study demonstrated the protective effects of peanut sprout extracts (PSEs) prepared from day 2 to day 7 of germination against lipopolysaccharide (LPS)-induced epithelial barrier breakdown. Although the peanut sprout length increased in a time-dependent manner from day 1 to day 7, the extraction yields remained relatively consistent from day 2 to day 7. With regard to antioxidant activities, the PSE from day 6 of germination exhibited the highest oxidative radical scavenging activity and total phenolic content. Similarly, it showed remarkable anti-permeability effects in LPS-stimulated Caco-2 cells and suppressed the degradation and dissociation of junctional markers (e.g., ZO-1 and E-cadherin) at cell-cell junctions. Collectively, these data demonstrate that PSE from day 6 of germination can be used as a functional food resource to reduce inflammatory barrier dysfunction., Competing Interests: AUTHOR DISCLOSURE STATEMENT The authors declare no conflict of interest., (© 2024 The Korean Society of Food Science and Nutrition.)

Aims: This study aims to evaluate the exposure-efficacy relationship of nilotinib and longitudinal BCR::ABL1 levels in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase (CML-CP) and those who are imatinib-resistant or intolerant using a semimechanistic disease model., Methods: The analysis included 489 CML-CP patients from 3 nilotinib trials (NCT00109707; NCT00471497; NCT01043874) with duration of follow-up ranging from 2 to 9 years. The semimechanistic disease model of CML-CP consisted of quiescent leukaemic stem cells, proliferating drug-susceptible and -resistant bone marrow cells. Drug effect on the elimination of susceptible cells was characterized by a maximum response model based on the individual daily area under the concentration-time curve over the last 24 h simulated using their empirical Bayes estimates from a population pharmacokinetic model. The influence of line of therapy was evaluated on model parameters and its impact was investigated through simulations of the major molecular response (MMR) rate, defined as the proportion of the simulated profiles that achieved BCR::ABL1 level of ≤0.1% at 48 and 96 weeks of treatment., Results: The final disease model was based on a truncated 3-year data that characterized the biphasic pattern of BCR::ABL1 transcript profiles. Line of therapy was a significant covariate of the drug kill effect, susceptible and resistant cells. Simulations of BCR::ABL1 time course predicted MMR rates at 48 weeks and 96 weeks for both nilotinib 300 and 400 mg twice-daily of 66-71 and 77-82% in first-line, and 34-39 and 46-54% in second-line, respectively. Results are consistent with observed MMR rates in the respective trials., Conclusion: The ability to distinguish molecular response between lines of therapy is demonstrated using model-based analysis. These nilotinib information enable the extrapolation of novel tyrosine kinase inhibitors (e.g., asciminib) response to other lines of therapy in patients with CML-CP., (© 2024 British Pharmacological Society.)

Aim: To determine the ultrasonographic (US) features that could help to distinguish between parathyroid masses abutting the thyroid gland and thyroid masses extending into the parathyroid area., Materials and Methods: Two blinded readers retrospectively evaluated the US images of 76 histopathologically confirmed parathyroid masses abutting the thyroid gland and 34 thyroid masses extending into the parathyroid area. Maximal diameter, transverse diameter/anterior-posterior diameter (T/AP) ratio, longitudinal diameter/AP diameter (L/AP) ratio, margin, shape, echogenicity, echotexture, and echogenic interface were evaluated and compared between the two groups., Results: Echogenic interface (p<0.001) and L/AP ratio (p<0.001) were statistically significant US features that differentiated parathyroid and thyroid masses. Other US features did not show any significant differences between the two groups. Interobserver agreement was excellent for all US features. Sensitivity/specificity of the presence of echogenic interface and L/AP ratio >2.0 were 85.5%/100% and 43.2%/82.4% in distinguishing parathyroid from thyroid masses, respectively., Conclusion: The presence of an echogenic interface and L/AP ratio >2.0 were useful US features for differentiating parathyroid masses abutting the thyroid gland from thyroid masses extending into theparathyroid area.

Background: Current guidelines recommend the perioperative continuation of aspirin in patients with coronary drug-eluting stents (DES) undergoing noncardiac surgery. However, supporting evidence is limited., Objectives: This study aimed to compare continuing aspirin monotherapy vs temporarily holding all antiplatelet therapy before noncardiac surgery in patients with previous DES implantation., Methods: We randomly assigned patients who had received a DES >1 year previously and were undergoing elective noncardiac surgery either to continue aspirin or to discontinue all antiplatelet agents 5 days before noncardiac surgery. Antiplatelet therapy was recommended to be resumed no later than 48 hours after surgery, unless contraindicated. The primary outcome was a composite of death from any cause, myocardial infarction, stent thrombosis, or stroke between 5 days before and 30 days after noncardiac surgery., Results: A total of 1,010 patients underwent randomization. Among 926 patients in the modified intention-to-treat population (462 patients in aspirin monotherapy group and 464 patients in the no-antiplatelet therapy group), the primary composite outcome occurred in 3 patients (0.6%) in the aspirin monotherapy group and 4 patients (0.9%) in the no antiplatelet group (difference, -0.2 percentage points; 95% CI: -1.3 to 0.9; P > 0.99). There was no stent thrombosis in either group. The incidence of major bleeding did not differ significantly between groups (6.5% vs 5.2%; P = 0.39), whereas minor bleeding was significantly more frequent in the aspirin group (14.9% vs 10.1%; P = 0.027)., Conclusions: Among patients undergoing low-to-intermediate risk noncardiac surgery >1 year after stent implantation primarily with a DES, in the setting of lower-than-expected event rates, we failed to identify a significant difference between perioperative aspirin monotherapy and no antiplatelet therapy with respect to ischemic outcomes or major bleeding. (Perioperative Antiplatelet Therapy in Patients With Drug-eluting Stent Undergoing Noncardiac Surgery [ASSURE-DES]; NCT02797548)., Competing Interests: Funding Support and Author Disclosures This research was supported by the CardioVascular Research Foundation (Seoul, Korea) (grant number: AMCCV2016-10), a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HC19C0022), and Medtronic. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite consistent recommendations from clinical guidelines, data from randomized trials on a long-term antithrombotic treatment strategy for patients with atrial fibrillation and stable coronary artery disease are still lacking., Methods: We conducted a multicenter, open-label, adjudicator-masked, randomized trial comparing edoxaban monotherapy with dual antithrombotic therapy (edoxaban plus a single antiplatelet agent) in patients with atrial fibrillation and stable coronary artery disease (defined as coronary artery disease previously treated with revascularization or managed medically). The risk of stroke was assessed on the basis of the CHA 2 DS 2 -VASc score (scores range from 0 to 9, with higher scores indicating a greater risk of stroke). The primary outcome was a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, and major bleeding or clinically relevant nonmajor bleeding at 12 months. Secondary outcomes included a composite of major ischemic events and the safety outcome of major bleeding or clinically relevant nonmajor bleeding., Results: We assigned 524 patients to the edoxaban monotherapy group and 516 patients to the dual antithrombotic therapy group at 18 sites in South Korea. The mean age of the patients was 72.1 years, 22.9% were women, and the mean CHA 2 DS 2 -VASc score was 4.3. At 12 months, a primary-outcome event had occurred in 34 patients (Kaplan-Meier estimate, 6.8%) assigned to edoxaban monotherapy and in 79 patients (16.2%) assigned to dual antithrombotic therapy (hazard ratio, 0.44; 95% confidence interval [CI], 0.30 to 0.65; P<0.001). The cumulative incidence of major ischemic events at 12 months appeared to be similar in the trial groups. Major bleeding or clinically relevant nonmajor bleeding occurred in 23 patients (Kaplan-Meier estimate, 4.7%) in the edoxaban monotherapy group and in 70 patients (14.2%) in the dual antithrombotic therapy group (hazard ratio, 0.34; 95% CI, 0.22 to 0.53)., Conclusions: In patients with atrial fibrillation and stable coronary artery disease, edoxaban monotherapy led to a lower risk of a composite of death from any cause, myocardial infarction, stroke, systemic embolism, unplanned urgent revascularization, or major bleeding or clinically relevant nonmajor bleeding at 12 months than dual antithrombotic therapy. (Funded by the CardioVascular Research Foundation and others; EPIC-CAD ClinicalTrials.gov number, NCT03718559.)., (Copyright © 2024 Massachusetts Medical Society.)

Aims: This study evaluates how changes in intestinal bile acid composition, induced by cholestyramine, a bile acid sequestrant, affect metformin's pharmacodynamics (PD)., Methods: An open-label, 2-period 1-sequence crossover study was conducted with healthy male adults. Each period consisted of both before and after metformin treatments. Cholestyramine was administered during the second period to change the bile acid pool. For, PD assessment, an oral glucose tolerance test was conducted at each treatment in both periods. Metformin was administered 3 times during each period, and cholestyramine was administered 3 times per day for 7 days during the second period. Maximum serum glucose concentration, area under the glucose concentration curve and homeostatic model assessment of insulin resistance were calculated. Baseline-corrected PD parameters were derived by subtracting pre-metformin values from post-metformin values. Lipid and panels and bile acid profiles in stool were measured. Adverse events were monitored throughout the study., Results: Fourteen subjects completed the study. The mean values of 3 PD parameters were all decreased after metformin administration in both periods. Cholestyramine administration led to a further decrease in baseline-corrected PD parameters, significantly reducing the area under the glucose concentration curve by 44.7%. Diarrhoea, the most common adverse event, was reported in 10 subjects during the metformin alone treatment and in 1 subject during the cholestyramine combined treatment (P < .01)., Conclusion: Cholestyramine affected the glucose-lowering effect of metformin by the possible change in the bile acid pool in the gut, and metformin-associated diarrhoea was improved by cholestyramine., (© 2024 British Pharmacological Society.)

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T 2 ) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T 2 . Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T 2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T 2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T 2 . Sigmoid I max and E max models best captured the profiles of 6MWD and MRI-T 2 over age. Steroid use, baseline 6MWD, and baseline MRI-T 2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T 2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T 2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T 2 , supporting the use of MRI-T 2 . The developed models will guide drug developers in using the MRI-T 2 to most efficient use in DMD clinical trials., Competing Interests: Declarations. Conflict of interests: The authors declared no competing interests for this work., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: A change from the supine to prone position causes hemodynamic alterations. We aimed to evaluate the effect of fluid preloading in the supine position, the subsequent hemodynamic changes in the prone position and postoperative outcomes., Patients and Methods: This prospective, assessor-blind, randomized controlled trial was conducted between March and June 2023. Adults scheduled for elective orthopaedic lumbar surgery under general anaesthesia were enrolled. In total, 80 participants were randomly assigned to fluid maintenance (M) or loading (L) groups. Both groups were administered intravenous fluid at a rate of 2 ml/kg/h until surgical incision; Group L was loaded with an additional 5 ml/kg intravenous fluid for 10 min after anaesthesia induction. The primary outcome was incidence of hypotension before surgical incision. Secondary outcomes included differences in the mean blood pressure (mBP), heart rate, pleth variability index (PVi), stroke volume variation (SVV), pulse pressure variation (PPV), stroke volume index and cardiac index before surgical incision between the two groups. Additionally, postoperative complications until postoperative day 2 and postoperative hospital length of stay were investigated., Results: Hypotension was prevalent in Group M before surgical incision and could be predicted by a baseline PVi >16. The mBP was significantly higher in Group L immediately after fluid loading. The PVi, SVV and PPV were lower in Group L after fluid loading, with continued differences at 2-3 time points for SVV and PPV. Other outcomes did not differ between the two groups., Conclusion: Fluid loading after inducing general anaesthesia could reduce the occurrence of hypotension until surgical incision in patients scheduled for surgery in the prone position. Additionally, hypotension could be predicted in patients with a baseline PVi >16. Therefore, intravenous fluid loading is strongly recommended in patients with high baseline PVi to prevent hypotension after anaesthesia induction and in the prone position., Trial Number: KCT0008294 (date of registration: 16 March 2023).

Duchenne muscular dystrophy (DMD), a rare pediatric disease, presents numerous challenges when designing clinical trials, mainly due to the scarcity of available trial participants and the heterogeneity of disease progression. A quantitative clinical trial simulator (CTS) has been developed based on previously published five disease progression models describing each of the longitudinal changes in the velocity at which individuals can complete specified timed functional tests, frequently used as clinical trial efficacy endpoints (supine-stand, 4-stair climb, and 10 m walk/run test or 30-foot walk/run test), as well as each of the longitudinal changes in forced vital capacity and North Star Ambulatory Assessment total score. The model-based CTS allows researchers to optimize the selection of numerous trial parameters for designing trials for the five functional measures commonly used as endpoints in DMD clinical trials. This case report serves as a demonstration of the tool's functionality while providing an easy-to-follow guide for users to reference when preparing simulations of their own design. Two case studies, using input selection based on previous DMD clinical trials, provide realistic examples of how the tool can help optimize clinical trial design without the risk of decreasing statistical significance. This optimization allows researchers to mitigate the risk of designing trials that may be longer, larger, or more inclusive/exclusive than necessary., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The incidence of melanoma, a highly aggressive skin cancer, continues to increase worldwide, particularly among populations with lighter skin tones. The diagnostic challenge of melanoma lies in the absence of a distinctive clinical presentation, as its characteristics vary based on anatomical location, growth type, and histopathology. The melanoma-associated antigen (MAGE) gene family is differentially expressed in various human cancers, including melanoma. In this study, we explored the association between human MAGEA2 (hMAGEA2) expression and melanoma. Using a human melanoma tissue array, we confirmed that hMAGEA2 expression was higher in melanoma and metastatic melanoma than in normal tissues. Additionally, we used SK-MEL-5 and SK-MEL-28 cell lines to investigate the cellular and molecular mechanisms underlying melanoma progression and invasiveness. In SK-MEL-5 and SK-MEL-28 cells, hMAGEA2 overexpression accelerated cell proliferation. Conversely, the knockdown of hMAEGA2 reduced cell proliferation, colony formation, and migration significantly and induced arrest at the G2/M phase of the cell cycle. With respect to the molecular mechanism, the knockdown of hMAGEA2 decreased the phosphorylation of Akt, JNK, and p38 MAPK. Additionally, hMAGEA2 knockdown reduced tumor formation significantly at the in vivo level. Collectively, the robust correlation between hMAGEA2 and melanoma metastasis supports the potential utility of hMAGEA2 as both a diagnostic marker and novel therapeutic target for patients with melanoma metastasis.

The impact of complete revascularization (CR), achieved through the recanalization of coronary chronic total occlusions (CTOs), on long-term patient outcomes remains uncertain. To evaluate this in patients who achieved CR after CTO-PCI with those who did not due to deferred CTO-PCI, the Asan Medical Center Registry was reviewed to identify coronary artery disease (CAD) patients with CTOs treated between January 2003 and December 2018. Patients were included with single-vessel disease with CTO and with multivessel disease who had undergone revascularization for non-CTO lesions. These subjects were divided into those who achieved CR with CTO-PCI and those who did not due to deferred CTO-PCI. Their outcomes were compared following 1:1 propensity score matching. Of the 2746 enrolled CAD patients with CTOs, 1837 achieved CR with CTO-PCI and 909 did not. Propensity score matching yielded 653 patient pairs. The CR-achieving group had a significantly lower 10-year risk of the primary composite outcome of death, myocardial infarction, stroke, or repeat revascularization (hazard ratio [HR]: 0.57; 95 % confidence interval [CI]: 0.46-0.72; P < 0.001), as well as significantly lower risks of death (HR: 0.66; 95 % CI: 0.51-0.87; P = 0.003) and repeat revascularization (HR: 0.67; 95 % CI: 0.48-0.95; P = 0.023). CR was beneficial in all subgroups, including patients with major cardiovascular risk factors such as older age, hypertension, diabetes, and advanced CAD. Compared with incomplete revascularization, CR may significantly reduce the 10-year incidence of major adverse cardiac events in patients with CTO., Competing Interests: This study was supported by a grant (2024IE0006) from the 10.13039/501100005006Asan Institute for Life Sciences, Asan Medical Center. The funding source had no involvement in the design of the study, the collection, analysis, and interpretation of data, the writing of the manuscript, or the decision to submit the paper for publication. The authors have no conflicts of interest to declare., (© 2024 The Authors.)

Background: This study aimed to investigate the hemodynamic and anatomic factors associated with sinus thrombosis following transcatheter aortic valve replacement (TAVR), integrating in vivo patient data analysis and in vitro experiments., Methods and Results: Postprocedural, 4-dimensional, multiphase computed tomography data from 211 patients enrolled in the ADAPT-TAVR (Anticoagulation Versus Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement) study were analyzed. The prevalence of native sinus thrombosis was examined in relation to valve type, implant depth, and anatomic features. In vitro experiments used particle image velocimetry to observe changes in sinus flow based on the transcatheter heart valves (23-mm SAPIEN3, Edwards Lifesciences; and 29-mm CoreValve, Medtronic) height and coronary artery flow. Native sinus thrombosis was more common in self-expanding valves (39.1% versus 14.9%, P =0.004). In per-cusp analysis of in vivo patient data, adjusted transcatheter heart valve implant depth (odds ratio, 1.2 [95% CI, 1.1-1.3]; P <0.001), noncoronary sinus of Valsalva (odds ratio, 4.0 [95% CI, 2.0-7.8]; P <0.001), sinus inflow diameter (odds ratio, 0.8 [95% CI, 0.6-0.9]; P =0.008), and implanted valve size (odds ratio, 0.8 [95% CI, 0.7-1.0]; P =0.025) were significant factors associated with native sinus thrombosis. In the in vitro experiments, CoreValve showed noticeable flow stasis compared with SAPIEN3. High-positioned SAPIEN3 was linked to reduced velocity within the native sinus of Valsalva. Coronary artery flow led to higher sinus velocity and improved particle washout, reducing sinus thrombosis risk., Conclusions: This study provides insights into the relationship between transcatheter heart valve deployment and native sinus thrombosis, emphasizing the role of anatomic factors in relation to the risk of sinus thrombosis.

Despite the use of conventional dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI), the risk of adverse events remains high among patients with increased thrombotic risk. Until recently, the optimal antiplatelet strategy to balance the ischaemic and bleeding risks in patients who are undergoing complex high-risk PCI has been unclear. The TAILored Versus COnventional AntithRombotic StratEgy IntenDed for Complex HIgh-Risk PCI (TAILORED-CHIP) trial is an investigator-initiated, multicentre, prospective randomised trial to evaluate the efficacy and safety of a time-dependent tailored antiplatelet therapy with an early (<6 months post-PCI) escalation (low-dose ticagrelor at 60 mg twice daily plus aspirin) and a late (>6 months post-PCI) de-escalation (clopidogrel monotherapy) in patients undergoing complex high-risk PCI as compared with standard DAPT (clopidogrel plus aspirin for 12 months). Eligible patients had to have at least one high-risk anatomical or procedural feature or clinical characteristic associated with an increased risk of ischaemic or thrombotic events. The primary endpoint was the net clinical outcome, a composite of death from any cause, myocardial infarction, stroke, stent thrombosis, urgent revascularisation, or clinically relevant bleeding (Bleeding Academic Research Consortium type 2, 3, or 5) at 12 months after randomisation. (ClinicalTrials.gov: NCT03465644).

The left main coronary artery (LMCA) supplies over 70% of the myocardium, and significant LMCA disease is associated with high morbidity and mortality. With remarkable advances in percutaneous coronary intervention (PCI), including stent technology, antithrombotic agents, and evolving procedural techniques, PCI has become an important treatment option in clinical practice guidelines for the revascularization of LMCA disease. In contemporary clinical practice, a heart-team approach to shared decision-making, considering clinical/anatomic factors along with patient preferences, is emphasized for patients with significant LMCA disease requiring myocardial revascularization. Furthermore, recent progress in PCI procedures combined with intravascular imaging or functional guidance has resulted in significant improvements in PCI outcomes, especially for complex lesions, including LMCA disease. Nevertheless, owing to inherent anatomic complexities and frequent multivessel involvement, several unmet issues remain regarding the determination of the appropriate treatment approach for significant LMCA disease, for which further clinical research is required. This contemporary review article provides a comprehensive overview of left main PCI based on current guidelines and underlying trial data, addresses important unresolved diagnostic and therapeutic issues, and identifies future perspectives likely to advance progress in this field., Competing Interests: Dr Kang reports receiving speaker fees from Abbott Vascular, Daiichi-Sankyo, Viatris, Boryoung, and Daewoong Pharm. S.-J. Park reports receiving research grants or speaker fees from Abbott Vascular, Medtronic, Daiichi-Sankyo, ChongKunDang Pharm, Daewoong Pharm, and Edwards. D.-W. Park reports receiving research grants or speaker fees from Abbott Vascular, Medtronic, Daiichi-Sankyo, Edwards Lifesciences, ChongKunDang Pharm, and Daewoong Pharm. The other authors report no conflicts.

Keratinocytes are susceptible to airborne particulate matter (PM) exposure, resulting in human skin barrier dysfunction. Therefore, it is important to find useful reagents to resolve skin damages caused by PM. Here, we explored the protective effect of 7S MaR1, a specialized pro-resolving mediator derived from docosahexaenoic acid, on skin inflammation and the oxidative stress induced by PM with a diameter 10 μm or less (PM10) in human keratinocyte HaCaT cells. Interestingly, PM10-induced ROS generation was modulated by 7S MaR1 via the recovery of ROS scavenger genes. 7S MaR1 reduced PM10-induced IL-6 expression via modulating the p38/ERK/NF-κB signaling pathways. These results demonstrate that PM 10 induces inflammatory cytokines, which can lead to skin diseases. In addition, 7S MaR1 can resolve inflammation caused by PM 10 -induced oxidative stress and inflammatory cytokines. [BMB Reports 2024; 57(11): 490-496].

Production of functional biocompounds from microalgae has garnered interest from different industrial sectors; however, their overall productivity must be substantially improved for commercialization. Herein, long-term acclimation of Scenedesmus deserticola was conducted using glucose as an organic carbon source to enhance its heterotrophic capabilities and the production potential of loliolide. A year-long acclimation on agar plates led to the selection of S. deserticola HS4, which exhibited at least 2-fold increase in loliolide production potential; S. deserticola HS4 was subjected to further screening of its cultivation conditions and fed-batch cultivation was subsequently performed in liter-scale reactors. While S. deserticola HS4 exhibited shifts in cellular morphology and biochemical composition, the results suggested a substantial increase in its loliolide productivity regardless of trophic modes. Collectively, these results highlight the potential of long-term acclimation as an effective strategy for improving microalgal crops to align with industrial production practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study investigated caregivers' job image, abilities, and educational needs, which are rapidly increasing owing to an aging society., Design: A self-administered written survey was conducted at 12 general hospitals in Korea from February 1, 2022 to March 15, 2023., Sample: A total of 451 caregivers participated in the survey as subjects of analysis, and 560 nurses participated as external observers., Measurements: The caregivers' self-assessment results regarding job performance, educational needs, and retraining needs were compared with those of external observers., Results: Caregivers evaluated themselves significantly higher in all areas of job performance compared to the evaluations of external observers. In particular, the caregivers' self-evaluation of their abilities in "Recording and Reporting," "Basic Resuscitation," "Safety and Infection Control," and "Understanding Major Illnesses" was different from the evaluation of nurses. Both the caregivers and external observers agreed on the need for caregiver retraining, with 1-2 hours of supplementary training every 12 months being the most preferred amount of retraining., Conclusions: There was a significant difference between caregivers' self-evaluations of their capabilities and the external observers' evaluations. Therefore, systematic professional caregiver retraining is necessary., (© 2024 The Author(s). Public Health Nursing published by Wiley Periodicals LLC.)

Background: Recently developed artificial intelligence-based coronary angiography (AI-QCA, fully automated) provides real-time, objective, and reproducible quantitative analysis of coronary angiography without requiring additional time or labor., Objectives: This study aimed to evaluate the efficacy of AI-QCA-assisted percutaneous coronary intervention (PCI) compared to optical coherence tomography (OCT)-guided PCI in terms of post-PCI results., Methods: This trial enrolled 400 patients with significant coronary artery disease undergoing PCI from 13 participating centers in South Korea. Patients were randomized in a 1:1 ratio to either AI-QCA-assisted or OCT-guided PCI. The primary endpoint was the post-PCI minimal stent area (MSA) assessed by OCT. The noninferiority of AI-QCA-assisted PCI to OCT-guided PCI regarding the post-PCI MSA was tested with a noninferiority margin of 0.8 mm 2 ., Results: A total of 395 patients (199 in the AI-QCA group and 196 in the OCT group) were included in the primary endpoint analysis. The post-PCI MSA was 6.3 ± 2.2 mm 2 in the AI-QCA group and 6.2 ± 2.2 mm 2 in the OCT group (difference, -0.16; 95% CI: -0.59 to 0.28; P for noninferiority < 0.001). Other OCT-defined endpoints, such as stent underexpansion (50.8% [101/199] vs 54.6% [107/196]; P = 0.48), dissection (15.6% [31/199] vs 12.8% [25/196]; P = 0.42), and untreated reference segment disease (15.1% [30/199] vs 13.3% [26/196]; P = 0.61), were not significantly different between groups, except for a higher incidence of stent malapposition in the AI-QCA group (13.6% [27/199] vs 5.6 [11/196]; P = 0.007)., Conclusions: This study demonstrated the noninferiority of AI-QCA-assisted PCI to OCT-guided PCI in achieving MSA with comparable OCT-defined endpoints. (Fully Automated Quantitative Coronary Angiography Versus Optical Coherence Tomography Guidance for Coronary Stent Implantation [FLASH]; NCT05388357)., Competing Interests: Funding Support and Author Disclosures This work was supported by the Korea Medical Device Development Fund grant funded by the Korean government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health and Welfare, and the Ministry of Food and Drug Safety) (Project Number: 1711179379, RS-2022-00141289) and Medipixel, Inc. Dr Kang has received consulting fees from Medipixel, Inc; and owns stock options of Medipixel, Inc. Dr Kweon has received consulting fees and research grant support from Medipixel, Inc. Dr Y-H Kim has received consulting fees from Medipixel, Inc. Dr Ahn has received consulting fees from Medipixel, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Interleukin-32γ (IL-32γ) has diverse functions in various malignancies. In this study, we investigated the role of IL-32γ in autophagy induction in liver cancer cells and delineated the underlying mechanisms. We found that the increased IL-32γ expression inhibited the growth, cell cycle progression, and migration of HepG2 and Hep3B cell lines; it also decreased the expression of related proteins. Furthermore, the IL-32γ overexpression induced autophagy, as indicated by the number of puncta, the expression of LC3, and the expression of autophagy-related markers. The expression levels of LAMP1, a protein essential for autophagosome formation, and colocalization with LC3 also increased. Big data analysis revealed that the expression of MET, a well-known target of autophagy, and the expression of mTOR and mTOR-related proteins were decreased by the IL-32γ overexpression. The combination treatment of MET inhibitor, cabozantinib (2 µM), and IL-32γ overexpression further increased the number of puncta, the colocalization of LC3 and LAMP1, and the expression of autophagy-related proteins. In vivo, liver tumor growth was suppressed in the IL-32γ-overexpressing mouse model, and autophagy induction was confirmed by the increased expression of LC3 and LAMP1 and the decreased expression of autophagy pathway markers (MET and mTOR). Autophagy was also decreased in the liver tumor sample of human patients. ROC curve and spearman analysis revealed that the expression levels of LC3 and IL-32γ were significantly correlated in human tumor serum and tissues. Therefore, IL-32γ overexpression induced autophagy in liver tumors through the suppression of MET and mTOR pathways critical for tumor growth inhibition.

Background: There is a dearth of research on the factors linked with adverse events (AEs) associated with nirmatrelvir/ritonavir (NMVr) and molnupiravir (MOL), particularly in the elderly. Therefore, this study aimed to investigate self-reported AEs and identify factors associated with the occurrence of AEs following NMVr or MOL treatment among survey participants aged 60 years or older in South Korea., Methods: This nationwide survey was conducted through in-person interviews using structured questionnaires, from July 24 to August 31, 2023. Eligible participants included individuals aged 60 years or older who had been diagnosed with coronavirus disease 2019 (COVID-19) and received NMVr or MOL. The study outcomes included self-reported demographic, lifestyle, and health characteristics associated with the occurrence of AEs. Multivariate logistic regression analysis was used to estimate the adjusted odds ratio (aOR) and 95% confidence interval (CI) of each characteristic in participants with and without AEs., Results: Of the 520 participants, 123 (23.7%) experienced at least one AE with oral COVID-19 treatment: 21.0% (96/458) for NMVr and 43.5% (27/62) for MOL. None of the participants reported any serious AEs. Increased odds of AE occurrence were observed in participants treated with MOL compared to those treated with NMVr (aOR, 3.05; 95% CI, 1.67-5.57), a history of two or more compared to one COVID-19 diagnosis (1.93; 1.03-3.62), and self-reported health status as "Unhealthy" compared to "Healthy" (2.65; 1.31-5.36)., Conclusion: No AEs required further evaluation to change treatment strategies in elderly patients on NMVr or MOL. Several factors, including the use of MOL, history of COVID-19, and reported health status, were associated with an increased incidence of AEs. Both treatments may still be useful choices for patients with non-severe COVID-19 aged 60 years or older. However, close monitoring of unidentified potential harm and further investigation of the factors associated with the occurrence of AEs are needed., Competing Interests: Ju-Young Shin received grants from the Korea Institute of Drug Safety and Risk Management. Other authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Percutaneous coronary intervention (PCI) has been most commonly guided by coronary angiography. However, to overcome the inherent limitations of conventional coronary angiography, there has been an increasing interest in the adjunctive tools of intracoronary imaging for PCI guidance. Recently, optical coherence tomography (OCT) has garnered substantial attention as a valid intravascular imaging modality for guiding PCI. However, despite the unparalleled high-resolution imaging capability of OCT, which offers detailed anatomical information on coronary lesion morphology and PCI optimisation, its broad application in routine PCI practice remains limited. Several factors may have curtailed the widespread adoption of OCT-guided PCI in daily practice, including the transitional challenge from intravascular ultrasound (IVUS), the experienced skill required for image acquisition and interpretation, the lack of a uniform algorithm for OCT-guided PCI optimisation, and the limited clinical evidence. Herein, we provide an in-depth review of OCT-guided PCI, involving the technical aspects, optimal strategies for OCT-guided PCI, and the wide application of OCT-guided PCI in various anatomical subsets. Special attention is given to the latest clinical evidence from recent randomised clinical trials with respect to OCT-guided PCI.

Competing Interests: The authors have no financial conflicts of interest.

The production of transgenic animals using non-viral methods has raised questions regarding their long-term health and genomic stability. In this study, we evaluated these aspects in transgenic cattle over ten years, using transposon-mediated gene transfer. Our longitudinal analysis included a comprehensive health assessment and whole-genome DNA resequencing. We found no significant alterations in physiological parameters or health complications in transposon-mediated transgenic cattle that exceeded 10 years of age. Genomic analysis revealed that the rates of somatic mutations and copy number variations in transgenic cattle were comparable to those in non-transgenic cattle. Furthermore, structural variants were infrequent, suggesting that transposon-mediated gene insertion did not compromise genomic integrity. These findings highlight the viability of transposon systems for generating transgenic livestock, potentially expanding their applications in agriculture and biotechnology. This study contributes significantly to our understanding of the long-term implications of transgenesis in large animals and supports the safety and stability of this method., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: A "Smart Cancer Care" platform that integrates patient-reported outcomes (PROs) with management has been established in Korea. This study focused on improving health behaviors and connecting patients to welfare services by introducing and assessing the feasibility of "Smart Cancer Care 2.0," an enhanced version designed for monitoring complications post-cancer treatment., Materials and Methods: Smart Cancer Care 2.0 was developed by conducting a literature review and consulting with expert panels to identify symptoms or variables requiring monitoring and management guidelines based on the treatment type. Qualitative and quantitative surveys were conducted to assess the feasibility of the app and web system based on the experiences of patients with cancer and healthcare workers., Results: A total of 81 symptoms or variables (chemotherapy-, surgery-, radiotherapy-, rehabilitation-, and health management-related) were selected for management in Smart Cancer Care 2.0. PROs for these symptoms were basically categorized into three severity grades: preventive management, self-treatment, and consultation with a healthcare worker or visit to a healthcare institution. The overall mean scores in the feasibility evaluation by patients and healthcare workers were 3.83 and 3.90 points, respectively, indicating high usefulness., Conclusion: Smart Cancer Care 2.0 leverages the existing information and communication technologies-based platform, Smart Cancer Care, and further includes health behaviors and welfare services. Smart Cancer Care 2.0 may play a crucial role in establishing a comprehensive post-discharge management system for patients with cancer as it provides suitable interventions based on patients' responses and allows the regularly collected PROs to be easily viewed for streamlined care.

Age-related macular degeneration (AMD), often triggered by endothelial barrier disruption through vascular endothelial growth factor (VEGF), is a leading cause of blindness. This study investigated the inhibitory effects of phenolic compounds on VEGF-induced endothelial cell proliferation, migration, angiogenesis, and permeability using human retinal microvascular endothelial cells (hRECs). Thirty-seven polyphenolic compounds were selected from various databases based on their antioxidant properties, abundance in food, and solubility. These compounds significantly reduced migration, tube formation, and endothelial permeability in VEGF-stimulated hRECs. Notably, formononetin, eriodictyol, biochanin A, and p-coumaric acid were more effective in suppressing VEGF-induced angiogenesis and endothelial permeability than lutein. Molecular docking simulations revealed that formononetin, eriodictyol, and biochanin A had relatively lower binding energies with VEGF receptor 2 (VEGFR2) than lutein and sorafenib. These findings highlight the potential of phenolic compounds to be used as VEGFR2 inhibitors and an alternative strategy for preventing AMD., Competing Interests: AUTHOR DISCLOSURE STATEMENT The authors declare no conflict of interest., (© 2024 The Korean Society of Food Science and Nutrition.)

Background: Lipoprotein(a) (Lp[a]) is associated with the development of aortic valve calcification., Objectives: The aim of this study was to evaluate the association between the serum level of Lp(a) and the development of severe degenerative aortic stenosis (AS) and subsequent aortic valve replacement (AVR)., Methods: A total of 44,742 patients with Lp(a) measurements and echocardiography at baseline evaluation between 2000 and 2020 were included from a single tertiary heart center. The primary outcome was the development of severe degenerative AS, defined as a transaortic maximal velocity of ≥4.0 m/s., Results: During a median follow-up period of 6.8 years (Q1-Q3: 2.3-12.4 years), severe degenerative AS was diagnosed in 472 patients (1.1%), and subsequent AVR was performed in 387 patients (0.9%). Lp(a) levels were associated with risk for severe degenerative AS, with levels of 30 to 50, 50 to 100, and >100 mg/dL demonstrating adjusted HRs of 1.02 (95% CI: 0.78-1.34; P  = 0.88), 1.18 (95% CI: 0.91-1.53; P  = 0.22), and 1.96 (95% CI: 1.31-2.94; P  = 0.001) compared to <30 mg/dL. Similarly, the risk for AVR due to severe degenerative AS was significantly associated with higher levels of Lp(a) (>100 mg/dL) (adjusted HR: 2.05; 95% CI: 1.31-3.19; P  = 0.002). Such associations were not observed in the development of severe bicuspid ( P  = 0.63) or rheumatic ( P  = 0.96) AS., Conclusions: Lp(a) levels >100 mg/dL were significantly associated with risk for severe degenerative AS and subsequent AVR, regardless of the baseline severity of AS. Such associations were not observed in other etiologies of severe AS., Competing Interests: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant HC19C0022). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Importance: The appropriate follow-up surveillance strategy for patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) remains unknown., Objective: To assess clinical outcomes in patients with and without ACS who have undergone high-risk PCI according to a follow-up strategy of routine stress testing at 12 months after PCI vs standard care alone., Design, Setting, and Participants: The POST-PCI (Pragmatic Trial Comparing Symptom-Oriented vs Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention) trial was a randomized clinical trial that compared follow-up strategies of routine functional testing vs standard care alone 12 months after high-risk PCI. Patients were categorized as presenting with or without ACS. Patients were enrolled in the trial from November 2017 through September 2019, and patients were randomized from 11 sites in South Korea; data analysis was performed in 2022., Intervention: Patients categorized as presenting with or without ACS were randomized to either a routine functional testing or standard care alone follow-up strategy 12 months after high-risk PCI., Main Outcomes and Measures: The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years following randomization. Kaplan-Meier event rates through 2 years and Cox model hazard ratios (HRs) were generated, and interactions were tested., Results: Of 1706 included patients, 350 patients (20.5%) were female, and the mean (SD) patient age was 64.7 (10.3) years. In total, 526 patients (30.8%) presented with ACS. Compared with those without ACS, patients with ACS had a 55% greater risk of the primary outcome (HR, 1.55; 95% CI, 1.03-2.33; P = .03) due to higher event rates in the first year. The 2-year incidences of the primary outcome were similar between strategies of routine functional testing or standard care alone in patients with ACS (functional testing: 16 of 251 [6.6%]; standard care: 23 of 275 [8.5%]; HR, 0.76; 95% CI, 0.40-1.44; P = .39) and in patients without ACS (functional testing: 30 of 598 [5.1%]; standard care: 28 of 582 [4.9%]; HR, 1.04; 95% CI, 0.62-1.74; P = .88) (P for interaction for ACS = .45). Although a landmark analysis suggested that the rates of invasive angiography and repeat revascularization were higher after 1 year in the routine functional testing group, the formal interactions between ACS status and either invasive angiography or repeat revascularization were not significant., Conclusion and Relevance: Despite being at higher risk for adverse clinical events in the first year after PCI than patients without ACS, patients with ACS who had undergone high-risk PCI did not derive incremental benefit from routine surveillance stress testing at 12 months compared with standard care alone during follow-up., Trial Registration: ClinicalTrials.gov Identifier: NCT03217877.

Background: Artificial intelligence-based quantitative coronary angiography (AI-QCA) has been developed to provide a more objective and reproducible data about the severity of coronary artery stenosis and the dimensions of the vessel for intervention in real-time, overcoming the limitations of significant inter- and intraobserver variability, and time-consuming nature of on-site QCA, without requiring extra time and effort. Compared with the subjective nature of visually estimated conventional CAG guidance, AI-QCA guidance provides a more practical and standardized angiography-based approach. Although the advantage of intravascular imaging-guided PCI is increasingly recognized, their broader adoption is limited by clinical and economic barriers in many catheterization laboratories., Methods: The FLASH (fully automated quantitative coronary angiography versus optical coherence tomography guidance for coronary stent implantation) trial is a randomized, investigator-initiated, multicenter, open-label, noninferiority trial comparing the AI-QCA-assisted PCI strategy with optical coherence tomography-guided PCI strategy in patients with significant coronary artery disease. All operators will utilize a novel, standardized AI-QCA software and PCI protocol in the AI-QCA-assisted group. A total of 400 patients will be randomized to either group at a 1:1 ratio. The primary endpoint is the minimal stent area (mm 2 ), determined by the final OCT run after completion of PCI. Clinical follow-up and cost-effectiveness evaluations are planned at 1 month and 6 months for all patients enrolled in the study., Results: Enrollment of a total of 400 patients from the 13 participating centers in South Korea will be completed in February 2024. Follow-up of the last enrolled patients will be completed in August 2024, and primary results will be available by late 2024., Conclusion: The FLASH is the first clinical trial to evaluate the feasibility of AI-QCA-assisted PCI, and will provide the clinical evidence on AI-QCA assistance in the field of coronary intervention., Clinical Trial Registration: URL: https://www., Clinicaltrials: gov. Unique identifier: NCT05388357., Competing Interests: Conflict of interest Dr. Jung-Min Ahn and Dr. Young-Hak Kim receive consulting fees from Medipixel. Dr. Si-Hyuck Kang receives consulting fees from and owns stock options of Medipixel. Dr. Jihoon Kweon receives consulting fees and research grant support from Medipixel. No other disclosures are reported., (Copyright © 2024. Published by Elsevier Inc.)

2D nanomaterials with ångström-scale thicknesses offer a unique platform for confining molecules at an unprecedentedly small scale, presenting novel opportunities for modulating material properties and probing microscopic phenomena. In this study, mesogen-tethered polyhedral oligomeric silsesquioxane (POSS) amphiphiles with varying numbers of mesogenic tails to systematically influence molecular self-assembly and the architecture of the ensuing supramolecular structures, are synthesized. These organic-inorganic hybrid amphiphiles facilitate precise spatial arrangement and directional alignment of the primary molecular units within highly ordered supramolecular structures. The correlation between molecular design and the formation of superlattices through comprehensive structural analyses, incorporating molecular thermodynamics and kinetics, is explored. The distinct intermolecular interactions of the POSS core and the mesogenic tails drive the preferential formation of a 2D inorganic sublattice while simultaneously guiding the hierarchical assembly of organic lamellae via soft epitaxy. The findings reveal the intricate balance between shape, size, and interaction strengths of the inorganic and organic components, and how these factors collectively influence the structural hierarchy of the superstructures, which consist of multiple sublattices. By controlling this unique molecular behavior, it is possible to modulate or maximize the anisotropy of optical, mechanical, and electrical properties at the sub-nanometer scale for nanotechnology applications., (© 2024 Wiley‐VCH GmbH.)

Purpose: We aimed to investigate the response to balloon pulmonary angioplasty (BPA) in chronic thromboembolic pulmonary hypertension (CTEPH) using semi-quantitative analysis of lung perfusion SPECT/CT., Methods: This is a single-center retrospective study of patients with CTEPH who underwent BPA and pre- and post-BPA lung perfusion SPECT/CT between 2015 and 2022. Segmental defects on SPECT/CT were visually assessed and semi-quantitatively scored as 1 (large defect) or 0.5 (moderate defect) in accordance with modified PIOPED II criteria. The perfusion defect score was defined as (Σ segmental defect scores/18) × 100 (%). Associations between perfusion defect score and hemodynamic or functional parameters including WHO functional class, six-minute walking distance (6MWD), serum B-type natriuretic peptide (BNP), mean arterial pulmonary pressure (mPAP), pulmonary vascular resistance (PVR), and tricuspid regurgitation pressure gradient (TRPG) on echocardiography were statistically analyzed., Results: A total of 24 consecutive patients were included. The perfusion defect score significantly improved after BPA (median 58.3% vs. 47.2%, P  < 0.001), in conjunction with the WHO functional class, 6MWD, serum BNP, mPAP, and TRPG. Perfusion defect scores were significantly correlated with 6MWD ( rho  = - 0.583, P  < 0.001), serum BNP ( rho  = 0.514, P  < 0.001), mPAP ( rho  = 0.583, P  < 0.001), and PVR ( rho  = 0.575, P  < 0.001). The improvement in the perfusion defect score was significantly associated with improvement in mPAP ( rho  = 0.844, P  < 0.001)., Conclusion: Our results suggest that semi-quantitative analysis of lung perfusion SPECT/CT can provide a potential imaging biomarker for monitoring the efficacy of BPA., Supplementary Information: The online version contains supplementary material available at 10.1007/s13139-024-00858-1., Competing Interests: Conflict of InterestShin Ae Han, Sangwon Han, Jinho Lee, Do-Yoon Kang, Jae Seung Lee, Dae-Hee Kim, Duk-Woo Park, Jong-Min Song, Jin-Sook Ryu, Dae-Hyuk Moon declare that they have no conflicts of interest., (© The Author(s), under exclusive licence to Korean Society of Nuclear Medicine 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The relationship between aging and RNA biogenesis and trafficking is attracting growing interest, yet the precise mechanisms are unknown. The THO complex is crucial for mRNA cotranscriptional maturation and export. Herein, we report that the THO complex is closely linked to the regulation of lifespan. Deficiencies in Hpr1 and Tho2, components of the THO complex, reduced replicative lifespan (RLS) and are linked to a novel Sir2-independent RLS control pathway. Although transcript sequestration in hpr1Δ or tho2Δ mutants was countered by exosome component Rrp6, loss of this failed to mitigate RLS defects in hpr1Δ. However, RLS impairment in hpr1Δ or tho2Δ was counteracted by the additional expression of Nrd1-specific mutants that interacted with Rrp6. This effect relied on the interaction of Nrd1, a transcriptional regulator of aging-related genes, including ribosome biogenesis or RNA metabolism genes, with RNA polymerase II. Nrd1 overexpression reduced RLS in a Tho2-dependent pathway. Intriguingly, Tho2 deletion mirrored Nrd1 overexpression effects by inducing arbitrary Nrd1 chromatin binding. Furthermore, our genome-wide ChIP-seq analysis revealed an increase in the recruitment of Nrd1 to translation-associated genes, known to be related to aging, upon Tho2 loss. Taken together, these findings underscore the importance of Tho2-mediated Nrd1 escorting in the regulation of lifespan pathway through transcriptional regulation of aging-related genes., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Aralia elata (Miq.) Seem. (AES; family Araliaceae) is a medicinal plant and has been reported to have various bioactivities, including anticancer and hepatotoxicity protective activities. However, no studies have investigated the biological activities of AES or its extracts on skin. To address this, we aimed to explore the effect of AES-flower-derived absolute-type essential oil (AESFEO) on skin-related biological activities, especially skin wound healing and whitening-related responses in skin cells (human-derived keratinocytes [HaCaT cells] and melanocytes [B16BL6 cells]) and to identify the components of AESFEO. Cell biological activities were analyzed using WST and BrdU incorporation assays, ELISA, or by immunoblotting. In HaCaT cells, AESFEO promoted proliferation, type IV collagen production, and enhanced the phosphorylations of Erk1/2, p38 MAPK, JNK, and Akt. In B16BL6 cells, AESFEO reduced serum-induced proliferation, α-MSH-stimulated increases in melanin synthesis and tyrosinase activity, and α-MSH-induced increases in MITF, tyrosinase, TRP-1, and TRP-2 expressions. In addition, AESFEO inhibited the phosphorylation of Erk1/2, p38 MAPK, and JNK in α-MSH-stimulated B16BL6 cells. Eighteen compounds were identified in AESFEO by GC/MS. These results suggest that AESFEO has beneficial effects on keratinocyte activities related to skin wound healing and melanocyte activities related to inhibition of skin pigmentation. AESFEO may serve as a useful natural substance for developing agents that facilitate skin wound healing and inhibit melanogenesis.

Objective: This study aimed to analyze the effect of Smart Cancer Care program on the quality of life and ease of chemotherapy continuation in cancer patients and the effect of additional tele-management on frequency of use and satisfaction with the Smart Cancer Care program., Methods: 'Smart Cancer Care' is a mobile program that allows cancer patients undergoing chemotherapy to report symptoms of adverse events and receive remote management. In this study, patients were randomly assigned to three groups: Group A, who received only classical face-to-face management; Group B, who used the Smart Cancer Care program as addition; and Group C, who used the Smart Cancer Care program and received telephone management. After 12 weeks of follow-up, the effectiveness of using the Smart Cancer Care program was analyzed by examining the quality of life, ease of maintaining chemotherapy, and unplanned hospital visits in each group. The frequency of use and satisfaction with the Smart Cancer Care program were also analyzed., Results: Cancer patients who used the Smart Cancer Care program had 1.93-fold (1.15-3.25) higher overall quality of life than those who did not. This became 2.33-fold (1.34-4.04) higher when phone care was added. Patients with tele-management were significantly more likely to use the Smart Cancer Care program (odds ratio (OR) = 25.80; 95% confidence interval (CI), 11.28-58.97)., Conclusions: A mobile self-reported management program has a positive effect on the quality of life of cancer patients undergoing chemotherapy. Tele-management is conducive to active and effective use of this program., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

As the main form of digital trade, cross-border e-commerce plays an important role, allowing China to expand its opening-up and promote the optimal foreign trade structure. It also provides opportunities for Chinese enterprises to develop digital technology. From the perspective of the establishment of China's cross-border e-commerce comprehensive pilot zone (CBECPZ), this article uses the multi-period DID method to examine the effects of cross-border e-commerce on enterprise digital technology innovation based on listed companies in the Shanghai and Shenzhen stock markets from 2007 to 2020. The CBECPZ dramatically promotes enterprise digital technology innovation. The mechanism test shows that the CBECPZ promotes digital technology innovation by financing constraint alleviation, digital transformation, and producer service industry agglomeration. The heterogeneity test shows that the direct effect is more significant in the enterprises of large-scale, non-state-owned, with high ICT correlation and in areas with strong government resource allocation capabilities. The research findings have important reference value for how to utilize cross-border e-commerce to promote digital technology innovation, and they also provide directional references for other developing countries to develop cross-border e-commerce., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

To investigate alteration of outer nuclear layer (ONL) and choroidal vascularity index (CVI) in different status of central serous chorioretinopathy (CSC). A retrospective review of 65 CSC eyes with subretinal fluid (manifest CSC) and 40 control eyes was conducted in a single tertiary university hospital. Differences in best-corrected visual acuity (BCVA), ONL, and CVI were compared. CVI was assessed both in the entire choroid (CVI-EC) and around the 1500 μm leakage area (CVI-1500). Measurements were repeated after the subretinal fluid resorption (quiescent CSC), and compared. CSC eyes showed worse BCVA, thinner ONL and greater CVI than controls. Quiescent CSC showed a recovery of ONL compared to the manifest CSC, along with the BCVA improvement. The resolution of the CSC revealed a decrease across all three choroidal areas (total, stromal and luminal), with a more pronounced reduction in the stromal than in the luminal choroidal area, leading to an increase in the CVI. This phenomenon was shown in both CVI-EC and CVI-1500. Conclusively, ONL thickness can be used as a quantitative biomarker for photoreceptor function in CSC. Increased CVI may reflect a disease activity. The stromal choroidal area is particularly sensitive in illustrating leakage from the choroidal vasculature., (© 2024. The Author(s).)

Background: N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT), the representative cocaine derivative used in dopamine transporter imaging, is a promising biomarker, as it reflects the severity of Parkinson's disease (PD). 123 I- and 18 F-labeled FP-CIT has been used for PD diagnosis. However, preclinical studies evaluating [ 18 F]FP-CIT as a potential diagnostic biomarker are scarce. Among translational research advancements from bench to bedside, translating preclinical findings into clinical practice is one-directional. The aim of this study is to employ a circular approach, beginning back from the preclinical stage, progressing to the supplementation of [ 18 F]FP-CIT, and subsequently returning to clinical application. We investigated the pharmacokinetic properties of [ 18 F]FP-CIT and its efficacy for PD diagnosis using murine models., Results: Biodistribution, metabolite and excretion analyses were performed in mice and PD models were induced in rats using 6-hydroxydopamine (6-OHDA). The targeting efficiency of [ 18 F]FP-CIT for the dopamine receptor was assessed through animal PET/CT imaging. Subsequently, correlation analysis was conducted between animal PET/CT imaging results and immunohistochemistry (IHC) targeting tyrosine hydroxylase. Rapid circulation was confirmed after [ 18 F]FP-CIT injection. [ 18 F]FP-CIT reached the highest uptake of 23.50 ± 12.46%ID/g in the striatum 1 min after injection, and it was rapidly excreted within 60 min. The major metabolic organs of [ 18 F]FP-CIT were confirmed to be the intestines, liver, and kidneys. Its uptake in the intestine was approximately 5% ID/g. The uptake in the liver gradually increased, with excretion beginning after reaching a maximum after 60 min. The kidneys exhibited rapid elimination after 10 min. In the excretion study, rapid elimination was verified, with 21.46 ± 9.53% of the compound excreted within a 6 h period. Additionally, the efficacy of [ 18 F]FP-CIT PET was demonstrated in the PD model, with a high correlation with IHC for both the absolute value (R = 0.803, p = 0.0017) and the ratio value (R = 0.973, p = 0.0011)., Conclusions: This study fills the gap regarding insufficient preclinical studies on [ 18 F]FP-CIT, including its ADME, metabolites, and efficiency. The pharmacological results, including accurate diagnosis, rapid circulation, and [ 18 F]FP-CIT excretion, provide complementary evidence that [ 18 F]FP-CIT can be used safely and efficiently to diagnose PD in clinics, although it is already used in clinics., (© 2024. The Author(s).)

The tumor microenvironment (TME) is formed by several immune cells. Notably, tumor-associated macrophages (TAMs) are existed in the TME that induce angiogenesis, metastasis, and proliferation of cancer cells. Recently, a point-mutated variant of IL-32θ was discovered in breast cancer tissues, which suppressed migration and proliferation through intracellular pathways. Although the relationship between cancer and IL-32 has been previously studied, the effects of IL-32θ on TAMs remain elusive. Recombinant human IL-32θ (rhIL-32θ) was generated using an Escherichia coli expression system. To induce M0 macrophage polarization, THP-1 cells were stimulated with PMA. After PMA treatment, the cells were cultured with IL-4 and IL-13, or rhIL-32θ. The mRNA level of M1 macrophage markers (IL-1β, TNFα, inducible nitric oxide synthase) were increased by rhIL-32θ in M0 macrophages. On the other hand, the M2 macrophage markers (CCL17, CCL22, TGFβ, CD206) were decreased by rhIL-32θ in M2 macrophages. rhIL-32θ induced nuclear translocation of the NF-κB via regulation of the MAPK (p38) pathway. In conclusion, point-mutated rhIL-32θ induced the polarization to M1-like macrophages through the MAPK (p38) and NF-κB (p65/p50) pathways., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2024. The Korean Association of Immunologists.)

Background: Quantitative coronary angiography (QCA) offers objective and reproducible measures of coronary lesions. However, significant inter- and intra-observer variability and time-consuming processes hinder the practical application of on-site QCA in the current clinical setting. This study proposes a novel method for artificial intelligence-based QCA (AI-QCA) analysis of the major vessels and evaluates its performance., Methods: AI-QCA was developed using three deep-learning models trained on 7658 angiographic images from 3129 patients for the precise delineation of lumen boundaries. An automated quantification method, employing refined matching for accurate diameter calculation and iterative updates of diameter trend lines, was embedded in the AI-QCA. A separate dataset of 676 coronary angiography images from 370 patients was retrospectively analyzed to compare AI-QCA with manual QCA performed by expert analysts. A match was considered between manual and AI-QCA lesions when the minimum lumen diameter (MLD) location identified manually coincided with the location identified by AI-QCA. Matched lesions were evaluated in terms of diameter stenosis (DS), MLD, reference lumen diameter (RLD), and lesion length (LL)., Results: AI-QCA exhibited a sensitivity of 89% in lesion detection and strong correlations with manual QCA for DS, MLD, RLD, and LL. Among 995 matched lesions, most cases (892 cases, 80%) exhibited DS differences ≤10%. Multiple lesions of the major vessels were accurately identified and quantitatively analyzed without manual corrections., Conclusion: AI-QCA demonstrates promise as an automated tool for analysis in coronary angiography, offering potential advantages for the quantitative assessment of coronary lesions and clinical decision-making., Competing Interests: Declaration of competing interest Jihoon Kweon, Jung-Min Ahn, Young-Hak Kim report a relationship of consulting and advisory with Medipixel. All other authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Acute liver failure is an infrequent yet fatal condition marked by rapid liver function decline, leading to abnormalities in blood clotting and cognitive impairment among individuals without prior liver ailments. The primary reasons for liver failure are infection with hepatitis virus or overdose of certain medicines, such as acetaminophen. Phaeodactylum tricornutum (PT), a type of microalgae known as a diatom species, has been reported to contain an active ingredient with anti-inflammatory and anti-obesity effects. In this study, we evaluated the preventive and therapeutic activities of PT extract in acute liver failure. To achieve our purpose, we used two different acute liver failure models: acetaminophen- and D-GalN/LPS-induced acute liver failure. PT extract showed protective activity against acetaminophen-induced acute liver failure through attenuation of the inflammatory response. However, we failed to demonstrate the protective effects of PT against acute liver injury in the D-GalN/LPS model. Although the PT extract did not show protective activity against two different acute liver failure animal models, this study clearly demonstrates the importance of considering the differences among animal models when selecting an acute liver failure model for evaluation.

Background: TRF1, TRF2, and TERT (Telomerase reverse transcriptase) are telomere-associated factors that regulate telomere length. Genetic changes in these genes may be associated with cancer pathogenesis; however, this relationship has not yet been comprehensively elucidated in lung cancer., Aim: : Exploring the clinicopathologic and prognostic values of TRF1, TRF2, and TERT mRNA expression in non-small cell lung cancers (NSCLC)., Methods: : The clinical significance of TRF1, TRF2, and TERT expression in 141 patients with NSCLC was investigated. Additionally, these findings were supported by the open big data from The Cancer Genome Atlas (TCGA)., Results: : TRF1 and TRF2 expression levels tended to be associated with smoking, and TERT expression was positively correlated with age. The survival analysis showed that TRF1 expression predicted a better prognosis for squamous cell carcinoma (SCC), whereas TRF2 expression was associated with a shorter survival in adenocarcinoma. TCGA data also showed a better prognosis for SCC with TRF1 expression. However, the TRF2 results were not in agreement with our data., Conclusions: : We present the clinical and prognostic values of TRF1, TRF2, and TERT expression in NSCLC tissues and TCGA. Our findings suggest that TRF1 expression is a possible prognostic marker for NSCLC, particularly SCC., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Chae et al.)

Acute coronary syndromes (ACS) often result from the rupture or erosion of high-risk coronary atherosclerotic plaques (ie, vulnerable plaques). Advances in intracoronary imaging such as intravascular ultrasound, optical coherence tomography, or near-infrared spectroscopy have improved the identification of vulnerable plaques, characterized by large plaque burden, small minimal luminal area, thin fibrous cap, and large lipid content. Although pharmacology, including lipid-lowering agents, and intensive risk-factor control are pivotal for management of vulnerable plaques and secondary prevention, recurrent events tend to accrue despite intensive pharmacotherapy. Therefore, it has been hypothesized that local preventive percutaneous coronary intervention may passivate these vulnerable plaques, preventing the occurrence of plaque-related ACS. However, solid evidence is lacking on its use for treatment of non-flow-limiting vulnerable plaques. As such, the optimal management of vulnerable plaques has not been established. Herein, we have reviewed the diagnosis and management of vulnerable plaques, focusing on systematic pharmacology and focal treatments., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Cochlear implantation (CI), a widely employed procedure for individuals with severe hearing loss, can encounter a serious complication in the form of implant exposure. In such instances, surgeons are tasked with deciding between salvage measures or opting for reimplantation with a healthy tissue covering. This case presented a challenge with delayed flap necrosis triggered by an increase in the magnetic force of the external device. Notably, this complication manifested 8 years after the initial operation. Following the removal of the device, it was reconstructed successfully using a superficial temporal fascia V-Y advancement flap., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)