Search

Hiroko Otake,1,* Ko Kobayashi,2,* Reita Kadowaki,1 Taiyo Kosaka,1 Mizuki Itahashi,1 Masanobu Tsubaki,1 Masaru Matsuda,2 Norio Iwakiri,2 Eiji Harata,2 Noriaki Nagai1 1Faculty of Pharmacy, Kindai University, Osaka, Japan; 2Life Science Division, NOF CORPORATION, Kanagawa, Japan*These authors contributed equally to this workCorrespondence: Noriaki Nagai, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, Japan, Tel +81 6 4307 3638, Fax +81 6 6730 1394, Email nagai_n@phar.kindai.ac.jpPurpose: We aimed to prepare a β-cyclodextrin (β-CD) polymer using radical polymerization with co-monomers, 6-deoxy-6-(2-methacryloyloxyethylsuccinamide)-β-cyclodextrin (CD-MSAm) and N,N,N-trimethyl-N-(2-hydroxy-3-metacryloyloxopropyl)-ammonium chloride (QA) to design cyclodextrins suitable for use in ophthalmology. In addition, we evaluated their solubility and inclusion properties with rebamipide (REB), a poorly soluble drug, and investigated the usefulness of the β-CD polymer and REB (REB@CDQA) combination in treating dry eye.Methods: The β-CD polymer (CD-MSAm-co-QA, CDQA) based on CD-MSAm/QA was prepared via radical polymerization, and the usefulness of REB@CDQA in treating dry eye was evaluated using a rabbit treated with N-acetylcysteine (dry eye model).Results: The solubility of the CDQA powder was higher than that of the β-CD powder, and 80 nm colloids were observed in the CDQA solution. No corneal toxicity was observed in human corneal epithelial cells or rat corneas treated with 0.2% CDQA solution. The levels of REB dissolved in the CDQA solution were higher than those of the β-CD solution. Moreover, the application of the CDQA solution enhanced REB retention in the cornea and attenuated the transcorneal penetration of REB. In addition, instillation of REB@CDQA enhanced the volume of the lacrimal fluid and normalized the reduced mucin levels in the dry eye model. The extent of tear film breakup was attenuated by REB@CDQA instillation.Conclusion: The CDQA solution enhanced the solubility of REB, and the combination of CDQA and REB enhanced the drug content in the corneal tissue. Moreover, the therapeutic effect on dry eye was higher than that of REB suspensions without CDQA. Keywords: β-cyclodextrin, polymer, cationic group, rebamipide, dry eye

Reita Kadowaki,1 Fumihiko Ogata,1 Miku Nishida,1 Miri Komatsu,1 Hiroko Otake,1 Yosuke Nakazawa,2 Naoki Yamamoto,3 Naohito Kawasaki,1 Noriaki Nagai1 1Faculty of Pharmacy, Kindai University, Higashi-Osaka, Osaka, Japan; 2Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan; 3Support Office for Bioresource Research, Research Promotion Headquarters, Fujita Health University, Toyoake, Aichi, JapanCorrespondence: Noriaki Nagai, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, Japan, Tel +81 6 4307 3638, Fax +81 6 6730 1394, Email nagai_n@phar.kindai.ac.jpPurpose: Medical therapies, such as the use of anti-inflammatory agents, are commonly used for the treatment of oral mucositis (OM). However, these treatments have limited efficacy in treating severe cases of OM. In this study, we aimed to develop a carbopol gel incorporating troxipide (TRO) nanoparticles and methylcellulose (TRO-NP gel) and demonstrate its efficacy in accelerating wound healing in a hamster model of OM (OM model) induced by acetic acid injection.Methods: TRO nanoparticles were prepared using bead milling. The crystalline form was determined by powder X-ray diffraction, and the particle size was measured using a NanoSight LM10 instrument. The drug release was determined using a Franz diffusion cell, and the hamsters injected with acetic acid were selected to evaluate the therapeutic effect of OM.Results: After preparing TRO nanoparticles, we observed a mixture of crystals and amorphous TRO, and the particle size of TRO in the TRO-NP gel ranged from 50 to 280 nm. The TRO-NP gel exhibited a more uniform TRO distribution and viscosity compared to the Carbopol gel containing TRO microparticles (TRO-MP gel). However, the solubility of TRO was comparable in both TRO-MP and TRO-NP gels. The TRO-NP gel released a higher amount of TRO than that from the TRO-MP gel, with detectable release of TRO nanoparticles. TRO levels in the cheek pouches of hamsters treated with TRO-NP gel were higher than those treated with TRO-MP gel. The increased TRO levels in the cheek pouches of hamsters treated with TRO-NP gel were attenuated by treatment with 40 μM dynasore, an inhibitor of clathrin-dependent endocytosis (CME). Moreover, the therapeutic effect of the TRO-NP gel was superior to that of the TRO-MP gel in the hamster model of OM.Conclusion: We have designed a TRO-NP gel, and this gel showed excellent TRO delivery into the cheek pouch tissue through the CME pathway. Moreover, the TRO-NP gel treatment enhanced wound healing after acetic acid injection. Keywords: troxipide, nanoparticle, oral mucositis, hydrogel, endocytosis

Shuya Masuda,1,* Saori Deguchi,1,* Fumihiko Ogata,1 Joji Yoshitomi,1 Hiroko Otake,1 Kazutaka Kanai,2 Naohito Kawasaki,1 Noriaki Nagai1 1Faculty of Pharmacy, Kindai University, Osaka, Japan; 2Department of Small Animal Internal Medicine, School of Veterinary Medicine, University of Kitasato, Aomori, Japan*These authors contributed equally to this workCorrespondence: Noriaki Nagai, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, Japan, Tel +81 6 4307 3638, Fax +81 6 6730 1394, Email nagai_n@phar.kindai.ac.jpPurpose: We designed a 0.05% mometasone furoate (MF) nanocrystal dispersion and investigated whether the application of MF nanocrystals in nasal formulations enhanced local absorption compared to traditional nasal MF formulations (CA-MF).Methods: MF nanocrystal dispersions (MF-NPs) were prepared by bead milling MF microcrystal dispersions (MF-MPs) consisting of MF, 2-hydroxypropyl-β-cyclodextrin, methylcellulose, and purified water. Pluronic F-127 combined with methylcellulose, Pluronic F-68, or carbopol was used as a base for in situ gelation (thickener). MF concentrations were measured using high-performance liquid chromatography, and nasal absorption of MF was evaluated in 6 week-old male Institute of Cancer Research (ICR) mice.Results: The particle size range of MF prepared with the bead mill treatment was 80– 200 nm, and the nanoparticles increased the local absorption of MF, which was higher than that of CA-MF and MF-MPs. In addition, unlike the results obtained in the small intestine and corneal tissue, the high absorption of nanocrystalline MF in the nasal mucosa was related to a pathway that was not derived from energy-dependent endocytosis. Moreover, the application of the in situ gelling system attenuated the local absorption of MF-NPs, owing to a decrease in drug diffusion in the dispersions.Conclusion: We found that nanoparticulation of MF enhances local intranasal absorption, and nasal bioavailability is higher than that of CA-MF. In addition, we demonstrate that viscosity regulation is an important factor in the design of nasal formulations based on MF nanocrystals. These findings provide insights for the design of novel nanomedicines with enhanced nasal bioavailability.Plain Language Summary: Mometasone furoate (MF) is administered nasally to treat nasal inflammatory diseases. In this study, we designed MF nanocrystal dispersions (MF-NPs) and investigated whether the application of MF nanocrystals in nasal MF formulations enhanced local absorption compared to traditional nasal MF formulations. MF-NPs were obtained via bead-milling of dispersions, consisting of MF, 2-hydroxypropyl-β-cyclodextrin, methylcellulose, and purified water, and the MF-NPs with in situ gelation were prepared by the addition of a gel base consisting of Pluronic F-127 combined with methylcellulose, Pluronic F-68, or carbopol. The nasal absorption of MF was evaluated in 6 week-old ICR mice. The bead-milled MF particles in the dispersions were crystalline with sizes of 80– 200 nm. Moreover, MF-NPs exhibited lower viscosity and higher local absorption than commercially available nasal formulations and dispersions containing microcrystalline MF. However, the application of in situ gelling systems attenuated the local absorption of the MF-NPs. This is the first study to investigate the nasal absorption of dispersions containing nanocrystalline MF and the basis of in situ gelation, providing important information for the design of nanomedicines with enhanced nasal bioavailability.Graphical Abstract: Keywords: mometasone furoate, nanocrystal, nasal absorption, drug delivery, in situ gel

Background: Brinzolamide (BRI) suspensions are used for the treatment of glaucoma; however, sufficient drug delivery to the target tissue after eye drop administration is hampered by poor solubility. To address this issue, we focused on nanocrystal technology, which is expected to improve the bioavailability of poor-solubility drugs, and investigated the effect of BRI nanocrystal formulations on corneal permeability and intraocular pressure (IOP)-reducing effect., Methods: BRI nanocrystal formulations were prepared by the wet-milling method with beads and additives. The particle size was measured by NANOSIGHT LM10, and the morphology was determined using a scanning probe microscope (SPM-9700) and a scanning electron microscope (SEM). Corneal permeability was evaluated in vitro using a Franz diffusion cell with rat corneas and in vivo using rabbits, and the IOP-reducing effect was investigated using a rabbit hypertensive model., Results: The particle size range for prepared BRI nanocrystal formulation was from 50 to 300 nm and the mean particle size was 135 ± 4 nm. The morphology was crystalline, and the nanoparticles were uniformly dispersed. In the corneal permeability study, BRI nanocrystallization exhibited higher corneal permeability than non-milled formulations. This result may be attributed to the increased solubility of BRI by nanocrystallization and the induction of energy-dependent endocytosis by the attachment of BRI nanoparticles to the cell membrane. Furthermore, the addition of tyloxapol to BRI nanocrystal formulation further improved the intraocular penetration of BRI and showed a stronger IOP-reducing effect than the commercial product., Conclusions: The combination of BRI nanocrystallization and tyloxapol is expected to be highly effective in glaucoma treatment and a useful tool for new ophthalmic drug delivery., (© 2024. The Author(s).)

Hiroko Otake,1,* Ryoka Goto,1,* Fumihiko Ogata,1 Takumi Isaka,1 Naohito Kawasaki,1 Shinichiro Kobayakawa,2 Toru Matsunaga,3 Noriaki Nagai1 1Faculty of Pharmacy, Kindai University, Higashi-Osaka, Osaka, 577-8502, Japan; 2Department of Ophthalmology, Nippon Medical School, Musashi-Kosugi Hospital, Kawasaki, Kanagawa, 211-8533, Japan; 3Design and Development, SEED Co., Ltd., Kounosu-shi, Saitama, 369-0131, Japan*These authors contributed equally to this workCorrespondence: Noriaki NagaiFaculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka, 577-8502, JapanTel +81 6 4307 3640Fax +81 6 6730 1394Email nagai_n@phar.kindai.ac.jpPurpose: The multi-instillation of three commercially available (CA) eye drops [fluorometholone (FL)-, bromfenac (BF)- and levofloxacin (LV)-eye drops] has been used to manage pain and inflammation post-intraocular surgery. However, the multi-instillation of these three eye drops causes corneal damage, and the FL drops have the disadvantage of low ocular bioavailability. To overcome these problems, we prepared fixed-combination eye drops based on FL nanoparticles (FL-NPs) and BF/LV solution (nFBL-FC), and evaluated the corneal toxicity and transcorneal penetration of the nFBL-FC eye drops.Methods: FL powder was mixed in 2-hydroxypropyl-β-cyclodextrin solution containing benzalkonium chloride, mannitol and methylcellulose, and milled with a Bead Smash 12 (5500 rpm for 30 s× 30 times). The BF/LV solution was then added to the milled-dispersions to be used as nFBL-FC. The FL, BF and LV concentrations were measured by HPLC methods, and transcorneal penetration was evaluated in rabbits.Results: The FL particle size in nFBL-FC was 40– 150 nm, with only 0.0018% in liquid form. No aggregation of FL particles in the nFBL-FC was observed for 1 month. The viability of human corneal epithelial cells treated with nFBL-FC was remarkably higher than that of cells subjected to the multi-instillation of the corresponding three CA-eye drops. In addition, the corneal penetrations (AUC) of the FL, BF and LV in nFBL-FC were 4.9-, 1.8-, and 7.1-fold those of the corresponding CA-eye drops, respectively. Moreover, the caveolae-dependent endocytosis (CavME) inhibitor (nystatin) significantly prevented the transcorneal penetration of these drugs.Conclusion: We prepared fixed-combination eye drops based on FL-NPs and BF/LV solution (nFBL-FC), and show that high levels of FL-NPs and dissolved BF/LV (liquid drugs) can be delivered into the aqueous humor by the instillation of nFBL-FC. Further, we show that CavME is mainly related to the enhancement of transcorneal penetration of both the solid (NPs) and liquid drugs.Keywords: fluorometholone, bromfenac, levofloxacin, fixed-combination eye drops, corneal permeability, endocytosis

Background: Proprotein convertase subtilisin/kexin type 9 inhibitors stabilize vulnerable plaque, reducing cardiovascular events. However, manual optical coherence tomography (OCT) analysis of drug efficacy is challenging because of signal attenuation within lipid plaques., Methods and Results: Twenty-four patients with thin-cap fibroatheroma were prospectively enrolled and randomized to receive alirocumab (75 mg every 2 weeks) plus rosuvastatin (10 mg/day) or rosuvastatin (10 mg/day) alone. OCT images at baseline and 36 weeks were analyzed manually and with artificial intelligence (AI)-aided software. AI-aided OCT analysis showed significantly greater percentage changes in the alirocumab+rosuvastatin vs. rosuvastatin-alone group in fibrous cap thickness (FCT; median [interquartile range] 212.3% [140.5-253.5%] vs. 88.6% [63.0-119.6%]; P=0.006) and lipid volume (median [interquartile range] -30.8% [-51.8%, -16.6%] vs. -2.1% [-21.6%, 4.3%]; P=0.015). Interobserver reproducibility for changes in minimum FCT and lipid index was relatively low for manual analysis (interobserver intraclass correlation coefficient [ICC] 0.780 and 0.499, respectively), but high for AI-aided analysis (interobserver ICC 0.999 and 1.000, respectively). Agreements between manual and AI-aided OCT analyses of FCT and the lipid index were acceptable (concordance correlation coefficients 0.859 and 0.833, respectively)., Conclusions: AI-aided OCT analysis objectively showed greater plaque stabilization of adding alirocumab to rosuvastatin. Our results highlight the benefits of a fully automated AI-assisted approach for assessing drug efficacy, offering greater objectivity in evaluating serial changes in plaque stability vs. conventional OCT assessment.

Background: Coronary artery calcification is an integral part of atherosclerosis. It has been suggested that early coronary artery calcification is associated with active inflammation, and advanced calcification forms as inflammation subsides. Inflammation is also an important factor in plaque vulnerability. However, the relationship between coronary artery calcium burden, vascular inflammation, and plaque vulnerability has not been fully investigated., Objectives: This study aimed to correlate calcified plaque burden (CPB) at the culprit lesion with vascular inflammation and plaque vulnerability., Methods: Patients with coronary artery disease who had both computed tomography angiography and optical coherence tomography were included. The authors divided the patients into 4 groups: 1 group without calcification at the culprit lesion; and 3 groups based on the CPB tertiles. CPB was calculated as calcified plaque volume divided by vessel volume in the culprit lesion. The authors compared pericoronary adipose tissue (PCAT) attenuation for vascular inflammation and optical coherence tomography-derived vulnerable features among the 4 groups., Results: Among 578 patients, the highest CPB tertile showed significantly lower PCAT attenuation of culprit vessel compared with the other groups. The prevalence of features of plaque vulnerability (including lipid-rich plaque, macrophage, and microvessel) was also lowest in the highest CPB tertile. In the patients with calcification, higher age, statin use, and lower PCAT attenuation were independently associated with CPB., Conclusions: Greater calcium burden is associated with a lower level of vascular inflammation and plaque vulnerability. A greater calcium burden may represent advanced stable plaque without significant inflammatory activity. (Massachusetts General Hospital and Tsuchiura Kyodo General Hospital Coronary Imaging Collaboration; NCT04523194)., Competing Interests: Funding Support and Author Disclosures Dr Fujimoto was supported by fellowship grants from the Uehara Memorial Foundation (Tokyo, Japan) and the Fukuda Foundation for Medical Technology (Tokyo, Japan). Dr Ferencik has received consulting fees from Siemens Healthineers, Elucid, Heartflow, and BioMarin; served on the advisory board for Cleerly; and has stock options for Elucid. Dr Jang has received educational grants from Abbott Vascular; his research has been supported by Mrs Gillian Gray through the Allan Gray Fellowship Fund in Cardiology and by Mukesh and Priti Chatter through the Chatter Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Angiography-derived fractional flow reserve (virtual FFR) has shown excellent diagnostic performance compared with wire-based FFR. However, virtual FFR pullback curves have not been validated yet., Objectives: To validate the accuracy of virtual FFR pullback curves compared to wire-based FFR pullbacks and to assess their clinical utility using patient-reported outcomes., Methods: Pooled analysis of two prospective studies, including patients with hemodynamically significant (FFR ≤ 0.80) coronary artery disease (CAD). Virtual and wire-based FFR pullbacks were compared to assess the accuracy of virtual pullbacks to characterize CAD as focal or diffuse. Pullbacks were analyzed visually and quantitatively using the pullback pressure gradient (PPG). Patients underwent PCI, and the Seattle Angina Questionnaire (SAQ) was administered at 3-month follow-up., Results: A total of 298 patients (300 vessels) with both virtual and wire-based pullbacks who underwent PCI were included in the analysis. The mean age was 61.8 ± 8.8, and 15% were female. The agreement on the visual adjudication of the CAD pattern was fair (Cohen's Kappa: 0.31, 95% confidence interval: 0.18-0.45). The mean PPG were 0.65 ± 0.18 from virtual pullbacks and 0.65 ± 0.13 from wire-based pullbacks (r = 0.68, mean difference 0, limits of agreement -0.27 to 0.28). At follow-up, patients with high virtual PPG (>0.67) had higher SAQ angina frequency scores (i.e., less angina) than those with low virtual PPG (SAQ scores 92.0 ± 14.3 vs. 85.5 ± 23.1, p = 0.022)., Conclusion: Virtual FFR pullback curves showed moderate agreement with wire-based FFR pullbacks. Nonetheless, patients with focal disease based on virtual PPG reported greater improvement in angina after PCI., (© 2024 Wiley Periodicals LLC.)

Background: Vulnerable plaque presents prognostic implications in addition to functional significance., Objectives: The aim of this study was to identify relevant features of vulnerable plaque in functionally significant lesions., Methods: In this multicenter, prospective study conducted across 5 countries, including patients who had invasive fractional flow reserve (FFR) ≤0.80, a total of 95 patients with available pullback pressure gradient (PPG) and plaque analysis on coronary computed tomographic angiography and optical coherence tomography were analyzed. Vulnerable plaque was defined as the presence of plaque rupture or thin-cap fibroatheroma on optical coherence tomography. Among the 25 clinical characteristics, invasive angiographic findings, physiological indexes, and coronary computed tomographic angiographic findings, significant predictors of vulnerable plaque were identified., Results: Mean percentage diameter stenosis, FFR, and PPG were 77.8% ± 14.6%, 0.66 ± 0.13, and 0.65 ± 0.13, respectively. Vulnerable plaque was present in 53 lesions (55.8%). PPG and FFR were identified as significant predictors of vulnerable plaque (P < 0.05 for all). PPG >0.65 and FFR ≤0.70 were significantly related to a higher probability of vulnerable plaque after adjustment for each other (OR: 6.75 [95% CI: 2.39-19.1]; P < 0.001] for PPG >0.65; OR: 4.61 [95% CI: 1.66-12.8]; P = 0.003 for FFR ≤0.70). When categorizing lesions according to combined PPG >0.65 and FFR ≤0.70, the prevalence of vulnerable plaque was 20.0%, 57.1%, 66.7%, and 88.2% in the order of PPG ≤0.65 and FFR >0.70, PPG ≤0.65 and FFR ≤0.70, PPG >0.65 and FFR >0.70, and PPG >0.65 and FFR ≤0.70 (P for trend < 0.001), respectively., Conclusions: Among low-FFR lesions, the presence of vulnerable plaque can be predicted by PPG combined with FFR without additional anatomical or plaque characteristics. (Precise Percutaneous Coronary Intervention Plan [P3] Study; NCT03782688)., Competing Interests: Funding Support and Author Disclosures This study received funding from HeartFlow and was also supported by grants from the Patient-Centered Clinical Research Coordinating Center (HI19C0481 and HC19C0305) funded by the Ministry of Health and Welfare and from the Ministry of Food and Drug Safety (RS-2023-00215667), Republic of Korea. Dr Mizukami has received consulting fees from Zeon Medical and HeartFlow; and has received speaker fees from Abbott Vascular. Dr Leipsic is a consultant for and holds stock options in Circle CVI and HeartFlow; has received a research grant from GE; and has received modest speaker fees from GE and Philips. Drs Sonck and Munhoz have received research grants provided by the Cardiopath PhD program. Dr Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow. Dr Otake has received research grants from Abbott Vascular; and has received speaker fees from HeartFlow and Abbott Vascular. Dr Ko has received consulting fees from Canon Medical, Abbott, and Medtronic. Dr Koo has received institutional research grants from HeartFlow. Dr Maeng has received advisory board and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, and Novo Nordics; and has received institutional research grants from Bayer, Philips Healthcare, and Novo Nordisk. Dr Jensen has received unrestricted institutional research grants from Siemens and HeartFlow. Dr Andreini has received research grants from GE Healthcare and Bracco. Dr Shinke has received research grants from Boston Scientific and Abbott Vascular. Dr Barbato has received speaker fees from Boston Scientific, Abbott Vascular, and GE. Dr De Bruyne has received consulting fees from Boston Scientific and Abbott Vascular; has received research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow, Edwards Lifesciences, Bayer, Sanofi, and Celyad. Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, and Abbott Vascular; and has received consulting fees from HeartFlow, OpSens, Abbott Vascular, and Philips Volcano. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The clinical benefits of optical frequency domain imaging (OFDI)-guided percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) remain unclear., Aims: We sought to compare intravascular ultrasound (IVUS)- and OFDI-guided PCI in patients with ACS., Methods: OPINION ACS is a multicentre, prospective, randomised, non-inferiority trial that compared OFDI-guided PCI with IVUS-guided PCI using current-generation drug-eluting stents in ACS patients (n=158). The primary endpoint was in-stent minimum lumen area (MLA), assessed using 8-month follow-up OFDI., Results: Patients presented with ST-segment elevation myocardial infarction (55%), non-ST-segment elevation myocardial infarction (29%), or unstable angina pectoris (16%). PCI procedural success was achieved in all patients, with comparably low periprocedural complications rates in both groups. Immediately after PCI, the minimum stent area (p=0.096) tended to be smaller for OFDI versus IVUS guidance. Proximal stent edge dissection (p=0.012) and irregular protrusion (p=0.03) were significantly less frequent in OFDI-guided procedures than in IVUS-guided procedures. Post-PCI coronary flow, assessed using corrected Thrombolysis in Myocardial Infarction frame counts, was significantly better in the OFDI-guided group than in the IVUS-guided group (p<0.001). The least squares mean (95% confidence interval [CI]) in-stent MLA at 8 months was 4.91 (95% CI: 4.53-5.30) mm 2 and 4.76 (95% CI: 4.35-5.17) mm 2 in the OFDI- and IVUS-guided groups, respectively, demonstrating the non-inferiority of OFDI guidance (pnon-inferiority<0.001). The average neointima area tended to be smaller in the OFDI-guided group. The frequency of major adverse cardiac events was similar., Conclusions: Among ACS patients, OFDI-guided PCI and IVUS-guided PCI were equally safe and feasible, with comparable in-stent MLA at 8 months. OFDI guidance may be a potential option in ACS patients. This study was registered in the Japan Registry of Clinical Trials (jrct.niph.go.jp: jRCTs052190093).

Background: A lesion-level risk prediction for acute coronary syndrome (ACS) needs better characterization., Objectives: This study sought to investigate the additive value of artificial intelligence-enabled quantitative coronary plaque and hemodynamic analysis (AI-QCPHA)., Methods: Among ACS patients who underwent coronary computed tomography angiography (CTA) from 1 month to 3 years before the ACS event, culprit and nonculprit lesions on coronary CTA were adjudicated based on invasive coronary angiography. The primary endpoint was the predictability of the risk models for ACS culprit lesions. The reference model included the Coronary Artery Disease Reporting and Data System, a standardized classification for stenosis severity, and high-risk plaque, defined as lesions with ≥2 adverse plaque characteristics. The new prediction model was the reference model plus AI-QCPHA features, selected by hierarchical clustering and information gain in the derivation cohort. The model performance was assessed in the validation cohort., Results: Among 351 patients (age: 65.9 ± 11.7 years) with 2,088 nonculprit and 363 culprit lesions, the median interval from coronary CTA to ACS event was 375 days (Q1-Q3: 95-645 days), and 223 patients (63.5%) presented with myocardial infarction. In the derivation cohort (n = 243), the best AI-QCPHA features were fractional flow reserve across the lesion, plaque burden, total plaque volume, low-attenuation plaque volume, and averaged percent total myocardial blood flow. The addition of AI-QCPHA features showed higher predictability than the reference model in the validation cohort (n = 108) (AUC: 0.84 vs 0.78; P < 0.001). The additive value of AI-QCPHA features was consistent across different timepoints from coronary CTA., Conclusions: AI-enabled plaque and hemodynamic quantification enhanced the predictability for ACS culprit lesions over the conventional coronary CTA analysis. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary Computed Tomography Angiography and Computational Fluid Dynamics II [EMERALD-II]; NCT03591328)., Competing Interests: Funding Support and Author Disclosures This study received funding from HeartFlow Inc. The company performed the computational fluid dynamics, and artificial intelligence quantitative coronary plaque analysis but was not involved in the study design, collection, analysis, and interpretation of data; the writing of this paper; or the decision to submit it for publication. Dr Koo has received institutional research grants from Abbott, Philips, and HeartFlow Inc. Dr Nam has received institutional research grants from Abbott and Genoss. Dr Merkely has received direct personal payments for speaker fees or studies from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL Behring, Daiichi Sankyo, DUKE Clinical Institute, Medtronic, and Novartis and institutional grants from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CSL Behring, Daiichi Sankyo, DUKE Clinical Institute, Eli Lilly, Medtronic, Novartis, Terumo, and VIFOR Pharma. Dr de Bruyne has received institutional unrestricted research grants from Abbott, Boston Scientific, and Biotronik; has received consulting fees from Abbott, Opsens, and Boston Scientific; and is a shareholder for Siemens, GE, Bayer, Philips, HeartFlow Inc, Edwards Life Sciences, Sanofi, and Omega Pharma. Dr Ko has equity in Artrya and has received honoraria from Medtronic, Abbott Vascular, and Canon Medical. Dr Leipsic is a consultant for and holds stock options in HeartFlow Inc and modest personal core lab fees from Arineta. Dr Shah has received honoraria as a speaker for HeartFlow Inc. Dr Bax has received unrestricted research grants from Abbott and Edwards Lifesciences to the Department of Cardiology, Leiden University Medical Center, the Netherlands. Dr Shaw has received honoraria from HeartFlow Inc and Elucid Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Toshida H, Funaki T, Ono K, et al. Drug Des Devel Ther. 2017;11:1871– 1879 The authors have advised there are some mistakes in the mean changes and standard errors of the paper: 1. The standard errors of groups Placebo and VApal were all the same value for staining and symptom scores in Figure 1 (on page 1875) and Figure 3 (on page 1876), and Table 3 (on page 1877). 2. There were slight discrepancies in the Mean changes of Placebo group at 1, 2 and 4 weeks in Figure 3D. 3. There was a slight discrepancy in the Mean change of foreign body sensation in Placebo group at 1 week in Table 3. The authors have advised the errors were due to: 1. The standard error listed in a different table on the statistical analysis software was adopted. 2. There were typing errors when transferring numerical values from statistical analysis software to graph creation software. 3. There was a mistake when rounding numerical value. Since the statistical analysis had been performed using the original mean values (correct values), all results do not change. The authors apologize for these errors and advise they do not affect the results of the paper. Read the original article

The 88 th Annual Scientific Meeting of the Japanese Circulation Society (JCS2024) was held from Friday, March 8 th to Sunday, March 10 th in Kobe, Japan. The main theme of this 3-day meeting was "The Future of Cardiology: Challenges in Overcoming Cardiovascular Disease". As COVID-19 has been finally conquered, with revision of its categorization under the Infectious Disease Control Law and relaxation of infection prevention measures, it was once again possible to have face-to-face presentations and lively discussion. JCS2024 was a major success, with 19,209 participants and attendees, thanks to the greatly appreciated cooperation and support from all affiliates.

Background: Combining morphological and physiological evaluations might improve the risk stratification of patients who undergo percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) culprit lesions., Aims: We aimed to investigate the clinical utility of morphofunctional evaluation after PCI for identifying ACS patients with increased risk of subsequent clinical events., Methods: We retrospectively studied 298 consecutive ACS patients who had undergone optical coherence tomography (OCT)-guided PCI. We performed OCT-based morphological analysis and quantitative flow ratio (QFR)-based physiological assessment immediately after PCI. The non-culprit segment (NCS) was defined as the most stenotic untreated segment in the culprit vessel. The primary outcome was target vessel failure (TVF), a composite of cardiac death, target vessel-related myocardial infarction, and ischaemia-driven target vessel revascularisation., Results: During a median follow-up period of 990 days, 42 patients experienced TVF. Cox regression analysis revealed that the presence of thin-cap fibroatheroma (TCFA) in the NCS and a low post-PCI QFR, or the presence of TCFA in the NCS and a high ΔQFR in the NCS (QFR NCS ), were independently associated with TVF. The subgroup with TCFA in the NCS and a low post-PCI QFR had a significantly higher incidence of TVF (75%) than the other subgroups, and those with TCFA in the NCS and a high ΔQFR NCS had a significantly higher incidence of TVF (86%) than the other subgroups. The integration of TCFA in NCS, post-PCI QFR, and ΔQFR NCS with traditional risk factors significantly enhanced the identification of subsequent TVF cases., Conclusions: Combining post-PCI OCT and QFR evaluation may enhance risk stratification for ACS patients after successful PCI, particularly in predicting subsequent TVF.

Background: Murray law-based quantitative flow ratio (μQFR) is a novel computational method that enables accurate estimation of fractional flow reserve (FFR) using a single angiographic projection. However, its diagnostic value in patients with severe aortic stenosis (AS) remains unclear., Method: We included 25 consecutive patients who underwent transcatheter aortic valve replacement (TAVR) for severe AS with intermediate or greater (30-90%) coronary artery disease (CAD). Pre- and post-TAVR μQFR, QFR, instantaneous flow reserve (iFR), and post-TAVR invasive FFR values were measured. We evaluated the diagnostic performance of pre-TAVR μQFR, QFR, and iFR using post-TAVR FFR ≤ 0.80 as a reference standard of ischemia., Result: Pre-TAVR μQFR was significantly correlated with post-TAVR FFR (r = 0.73, p < 0.0001). The area under the curve of pre-TAVR μQFR on post-TAVR FFR ≤ 0.8 was 0.91 (95% confidence interval [CI] 0.77-0.98), comparable to that of pre-TAVR iFR (0.86 [95% CI 0.71-0.98], p = 0.97). The accuracy, sensitivity, specificity, and positive and negative predictive values of pre-TAVR μQFR on post-TAVR FFR ≤ 0.8 were 84.2% (95% CI 68.7-93.4), 61.6% (95% CI 31.6-86.1), 96.0% (95% CI 79.6-99.9), 88.9% (95% CI 52.9-98.3), and 82.8% (95% CI 70.6-90.6), respectively. For pre-TAVR iFR, these values were 76.5% (95% CI 58.8-89.3), 90.9% (95% CI 58.7-99.8), 69.6% (95% CI 47.1-86.8), 58.8% (95% CI 42.8-73.1), and 94.1% (95% CI 70.8-99.1), respectively., Conclusion: μQFR could be useful for the physiological evaluation of patients with severe AS with concomitant CAD., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Background: Coronary CT angiography (CCTA) is well-established for diagnosis and stratification of coronary artery disease (CAD). Its usefulness in guiding percutaneous coronary interventions (PCI) and stent sizing is unknown., Methods: This is a sub-analysis of the Precise Percutaneous Coronary Intervention Plan (P3) study (NCT03782688). We analyzed 65 vessels with matched CCTA and pre-PCI optical coherence tomography (OCT) assessment. The CCTA-guided stent size was defined by the mean distal reference lumen diameter rounded up to the nearest stent diameter. The OCT lumen-guided stent size was the mean distal reference lumen diameter rounded to the closest stent diameter. The agreement on stent diameters was determined with Kappa statistics, Passing-Bablok regression analysis, and the Bland-Altman method., Results: The distal reference lumen diameter by CCTA and OCT were 2.75 ​± ​0.53 ​mm and 2.72 ​± ​0.55 ​mm (mean difference 0.06, limits of agreement -0.7 to 0.82). There were no proportional or systematic differences (coefficient A 1.06, 95% CI 0.84 to 1.3 and coefficient B -0.22, 95% CI -0.83 to 0.36) between methods. The agreement between the CCTA and OCT stent size was substantial (Cohen's weighted Kappa 0.74, 95% CI 0.64 to 0.85). Compared to OCT stent diameter, CCTA stent size was concordant in 52.3% of the cases; CCTA overestimated stent size in 20.0% and underestimated in 27.7%., Conclusion: CCTA accurately assessed the reference vessel diameter used for stent sizing. CCTA-based stent sizing showed a substantial agreement with OCT. CCTA allows for PCI planning and may aid in selecting stent diameter., Competing Interests: Declaration of competing interest TM reports receiving consulting fees from Zeon Medical and HeartFlow Inc, and speaker fees from Abbott Vascular. BLN has received an unrestricted institutional research grant from HeartFlow Inc. MM is supported by a grant from the Novo Nordisk Foundation (grant NNF22OC0074083). BKK received an Institutional Research Grant from Abbott Vascular, Boston Scientific Corporation, and Philips. BDB reports receiving consultancy fees from Boston Scientific and Abbott Vascular, research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular, and owning equity in Siemens, GE, Philips, HeartFlow Inc, Edwards Life Sciences, Bayer, Sanofi, Celyad. CC reports receiving research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, Abbott Vascular, and consultancy fees from HeartFlow Inc, OpSens, Abbott Vascular, and Philips Volcano. The other authors have no further disclosures., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: The improvement in flowability and adhesion of starch powder (SP) is essential for using starch as an excipient for lactose intolerant patients. In this study, we attempted to evaluate the usefulness of hydroxypropylcellulose with molecular weight 80,000 (HPC-80) in the preparation of the starch granules (SG) as a substitute for excipient lactose., Methods: Hydroxypropylcellulose with molecular weight 30,000 (HPC-30) and HPC-80 were used as binders to prepare the SG, and defined as HPC-30-SG and HPC-80-SG, respectively. Mean particle size (D50) was measured according to the Method, Optical Microscopy of Particle Size Determination in Japanese Pharmacopoeia, Eighteenth Edition, and storage stability were evaluated by measuring of the physical properties after vortexing the granules for 180 s (physical impact). The product loss rate was calculated from the weight change of the various excipients before and after the one dose packaging (ODP)., Results: The D50 of SP (30 µm) was smaller than that of the lactose powder (115 µm). The granulation with 0.75-3% HPC-30 and HPC-80 increased the particle size of SP, and the D50 in 1.5% HPC-30-SG (255 µm) and HPC-80-SG (220 µm) were higher than that of lactose. The excipient was removed from the heat seal of the ODP, and upon visual inspection, a large amount of starchy material was observed to be adhering to the paper in the SP. On the other hand, the low recovery rate in SP was attenuated by the granulation with HPC-30 and HPC-80. In the both HPC-30 and HPC-80, the improvement in recovery rate reached a plateau at 1.5%, and the levels of recovery rate was similar to that of lactose. The recovery rate in the 0.75-3% HPC-30-SG and 0.75% HPC-80-SG were decreased by the physical impact, however, the recovery rate and amount of 1.5% and 3% HPC-80-SG were not affected by the physical impact, and these levels were similar to that of lactose., Conclusions: The use of HPC-80 as a binder of SG was found to produce a higher quality granule product than conventional HPC-based SG. This finding is useful in streamlining the preparation of starch-based powdered medicine in clinical applications., (© 2024. The Author(s).)

Noriaki Nagai,1 Yoshie Iwai,1 Akane Sakamoto,1 Hiroko Otake,1 Yoshihiro Oaku,2 Akinari Abe,2 Tohru Nagahama2 1Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan; 2Research & Development Laboratories Self-Medication, Taisho Pharmaceutical Co., Ltd., Saitama 331-9530, JapanCorrespondence: Noriaki NagaiFaculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, JapanTel +81 6 4307 3640Fax +81 6 6730 1394Email nagai_n@phar.kindai.ac.jpPurpose: We designed formulations based on minoxidil (MXD) nanoparticles (N-MXD) and examined whether N-MXD can increase drug delivery into the follicles. In addition, we investigated the effect of N-MXD on hair growth in C57BL/6 mice.Methods: N-MXD (1%) was prepared as follows: methylcellulose, p-hydroxyalkylbenzoates, mannitol, and MXD were dispersed in purified water and milled using zirconia beads under refrigeration (5500 rpm, 30 s×15 times, intermittent milling). C57BL/6 mice were used to evaluate hair-growth effects. The expression levels of mRNA and protein for vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) were determined by real-time PCR and ELISA methods, respectively.Results: The ratio of solid-MXD was approximately 60% in N-MXD, and the MXD nanoparticles (90–300 nm) were oblong in shape. For the design of nanomedicines, usability is important. Therefore, we measured the stability and toxicity after N-MXD treatment. No agglutination of MXD nanoparticles was detected for 2 weeks, and no redness or MXD powder residue was observed in the skin after repetitive applications of N-MXD. Next, we evaluated hair-growth effects by N-MXD treatment. MXD contents in the skin tissue from N-MXD were lower than for commercially available MXD formulations (CA-MXD). Conversely, MXD contents in the hair bulbs were higher for N-MXD than for CA-MXD, and the drug efficacy of N-MXD was also higher than that of CA-MXD. In addition, the mRNA and protein levels of IGF-1 and VEGF were enhanced by the repetitive application of N-MXD and CA-MXD, and the enhanced IGF-1 and VEGF levels were significantly higher for N-MXD than for CA-MXD.Conclusion: We designed a novel nanomedicine based on MXD nanoparticles and showed that N-MXD can deliver MXD into hair bulbs via hair follicles and that the therapeutic efficiency for hair growth is higher than for CA-MXD (solution type).Keywords: minoxidil, nanoparticle, androgenetic alopecia, hair follicle delivery, hair growth

Noriaki Nagai,1 Fumihiko Ogata,1 Hiroko Otake,1 Yosuke Nakazawa,2 Naohito Kawasaki1 1Faculty of Pharmacy, Kindai University, Higashi-Osaka 577-8502, Japan; 2Faculty of Pharmacy, Keio University, Minato-ku, Tokyo 105-8512, Japan Purpose: We previously found that ophthalmic formulations containing nanoparticles prepared by a bead mill method lead to an increase in bioavailability in comparison with traditional formulations (solution type). However, the transcorneal penetration pathway for ophthalmic formulations has not been explained yet. In this study, we investigated the mechanism of transcorneal penetration in the application of ophthalmic formulations containing indomethacin nanoparticles (IMC-NPs).Materials and methods: IMC-NPs was prepared by the bead mill method. For the analysis of energy-dependent endocytosis, corneal epithelial (HCE-T) cell monolayers and removed rabbit cornea were thermoregulated at 4°C, where energy-dependent endocytosis is inhibited. In addition, for the analysis of different endocytosis pathways using pharmacological inhibitors, inhibitors of caveolae-mediated endocytosis (54 µM nystatin), clathrin-mediated endocytosis (40 µM dynasore), macropinocytosis (2 µM rottlerin) or phagocytosis (10 µM cytochalasin D) were used.Results: The ophthalmic formulations containing 35–200 nm sized indomethacin nanoparticles were prepared by treatment with a bead mill, and no aggregation or degradation of indomethacin was observed in IMC-NPs. The transcorneal penetration of indomethacin was significantly decreased by the combination of nystatin, dynasore and rottlerin, and the decreased penetration levels were similar to those at 4°C in HCE-T cell monolayers and rabbit cornea. In the in vivo experiments using rabbits, dynasore and rottlerin tended to decrease the transcorneal penetration of indomethacin (area under the drug concentration – time curve in the aqueous humor [AUCAH]), and the AUCAH in the nystatin-treated rabbit was significantly lower than that in non-treatment group. In addition, the AUCAH in rabbit corneas undergoing multi-treatment was obviously lower than that in rabbit corneas treated with each individual endocytosis inhibitor.Conclusion: We found that three energy-dependent endocytosis pathways (clathrin-dependent endocytosis, caveolae-dependent endocytosis and macropinocytosis) are related to the transcorneal penetration of indomethacin nanoparticles. In particular, the caveolae-dependent endocytosis is strongly involved. Keywords: drug delivery system, bead mill, caveolae-dependent endocytosis, clathrin-dependent endocytosis, macropinocytosis

The relationship between high wall shear stress (WSS) and plaque rupture (PR) in longitudinal and circumferential locations remains uncertain. Overall, 100 acute coronary syndrome patients whose culprit lesions had PR, documented by optical coherence tomography (OCT), were enrolled. Lesion-specific three-dimensional coronary artery models were created using OCT data. WSS was computed with computational fluid dynamics analysis. PR was classified into upstream-PR, minimum lumen area-PR, and downstream-PR according to the PR's longitudinal location, and into central-PR and lateral-PR according to the disrupted fibrous cap circumferential location. In the longitudinal 3-mm segmental analysis, multivariate analysis demonstrated that higher WSS in the upstream segment was independently associated with upstream-PR, and thinner fibrous cap was independently associated with downstream-PR. In the PR cross-sections, the PR region had a significantly higher average WSS than non-PR region. In the cross-sectional analysis, the in-lesion peak WSS was frequently observed in the lateral (66.7%) and central regions (70%) in lateral-PR and central-PR, respectively. Multivariate analysis demonstrated that the presence of in-lesion peak WSS at the lateral region, thinner broken fibrous cap, and larger lumen area were independently associated with lateral-PR, while the presence of in-lesion peak WSS at the central region and thicker broken fibrous cap were independently associated with central-PR. In conclusion, OCT-based WSS simulation revealed that high WSS might be related to the longitudinal and circumferential locations of PR., (© 2023. Springer Japan KK, part of Springer Nature.)

Noriaki Nagai,1 Fumihiko Ogata,1 Hiroko Otake,1 Yosuke Nakazawa,2 Naohito Kawasaki1 1Faculty of Pharmacy, Kindai University, Higashi-Osaka, Osaka, Japan; 2Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan Purpose: In the clinical setting, raloxifene, a second-generation selective estrogen receptor modulator, is administered orally; however, the bioavailability (BA) is only 2% because of its poor solubility in aqueous fluids and its extensive first-pass metabolism. Therefore, it is expected that the development of a transdermally delivered formulation may reduce the necessary dose without compromising its therapeutic efficacy. In this study, we designed transdermal formulations containing raloxifene nanoparticles and evaluated their usefulness for osteoporosis therapy. Methods: Raloxifene was crushed with methylcellulose by the bead mill method, and the milled raloxifene was gelled with or without menthol (a permeation enhancer) by Carbopol® 934 (without menthol, Ral-NPs; with menthol, mRal-NPs). The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Results: The mean particle size of raloxifene in the transdermal formulation (Ral-NPs) was 173.7 nm. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. On the other hand, inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted the penetration of raloxifene nanoparticles through the skin. Moreover, macropinocytosis relates to the skin penetration of the formulation including menthol (mRal-NPs), since penetration was inhibited by treatment with 2 µM rottlerin, a macropinocytosis inhibitor. In addition, the application of 0.3% mRal-NPs (once a day) attenuated the decreases in calcium level and stiffness of the bones of ovariectomized rat. Conclusion: We prepared raloxifene solid nanoparticles by a bead mill method and designed a novel transdermal formulation containing nanoparticles and permeation enhancers. These transdermal formulations overcome the barrier properties of the skin and show high drug penetration through the transdermal route (BA 8.5%). In addition, we found that raloxifene transdermal formulations are useful for the treatment of osteoporosis in ovariectomized rat. Keywords: nanomedicine, transdermal delivery system, permeation enhancer, endocytosis, skin

Background: Acute coronary syndrome (ACS) involves plaque-related thrombosis, causing primary ischemic cardiomyopathy or lethal arrhythmia. We previously demonstrated a unique immune landscape of myeloid cells in the culprit plaques causing ACS by using single-cell RNA sequencing. Here, we aimed to characterize T cells in a single-cell level, assess clonal expansion of T cells, and find a therapeutic target to prevent ACS., Methods: We obtained the culprit lesion plaques from 4 patients with chronic coronary syndrome (chronic coronary syndrome plaques) and the culprit lesion plaques from 3 patients with ACS (ACS plaques) who were candidates for percutaneous coronary intervention with directional coronary atherectomy. Live CD45 + immune cells were sorted from each pooled plaque samples and applied to the 10× platform for single-cell RNA sequencing analysis. We also extracted RNA from other 3 ACS plaque samples and conducted unbiased TCR (T-cell receptor) repertoire analysis., Results: CD4 + T cells were divided into 5 distinct clusters: effector, naive, cytotoxic, CCR7 + (C-C chemokine receptor type 7) central memory, and FOXP3 (forkhead box P3) + regulatory CD4 + T cells. The proportion of central memory CD4 + T cells was higher in the ACS plaques. Correspondingly, dendritic cells also tended to express more HLAs (human leukocyte antigens) and costimulatory molecules in the ACS plaques. The velocity analysis suggested the differentiation flow from central memory CD4 + T cells into effector CD4 + T cells and that from naive CD4 + T cells into central memory CD4 + T cells in the ACS plaques, which were not observed in the chronic coronary syndrome plaques. The bulk repertoire analysis revealed clonal expansion of TCRs in each patient with ACS and suggested that several peptides in the ACS plaques work as antigens and induced clonal expansion of CD4 + T cells., Conclusions: For the first time, we revealed single cell-level characteristics of CD4 + T cells in patients with ACS. CD4 + T cells could be therapeutic targets of ACS., Registration: URL: https://upload.umin.ac.jp/cgi-open-bin/icdr&#95;e/ctr&#95;view.cgi?recptno=R000046521; Unique identifier: UMIN000040747., Competing Interests: Disclosures None.

Objective: To assess the accuracy of a virtual stenting tool based on coronary CT angiography (CCTA) and fractional flow reserve (FFR) derived from CCTA (FFR CT Planner) across different levels of image quality., Materials and Methods: Prospective, multicenter, single-arm study of patients with chronic coronary syndromes and lesions with FFR ≤ 0.80. All patients underwent CCTA performed with recent-generation scanners. CCTA image quality was adjudicated using the four-point Likert scale at a per-vessel level by an independent committee blinded to the FFR CT Planner. Patient- and technical-related factors that could affect the FFR CT Planner accuracy were evaluated. The FFR CT Planner was applied mirroring percutaneous coronary intervention (PCI) to determine the agreement with invasively measured post-PCI FFR., Results: Overall, 120 patients (123 vessels) were included. Invasive post-PCI FFR was 0.88 ± 0.06 and Planner FFR CT was 0.86 ± 0.06 (mean difference 0.02 FFR units, the lower limit of agreement (LLA) - 0.12, upper limit of agreement (ULA) 0.15). CCTA image quality was assessed as excellent (Likert score 4) in 48.3%, good (Likert score 3) in 45%, and sufficient (Likert score 2) in 6.7% of patients. The FFR CT Planner was accurate across different levels of image quality with a mean difference between FFR CT Planner and invasive post-PCI FFR of 0.02 ± 0.07 in Likert score 4, 0.02 ± 0.07 in Likert score 3 and 0.03 ± 0.08 in Likert score 2, p = 0.695. Nitrate dose ≥ 0.8mg was the only independent factor associated with the accuracy of the FFR CT Planner (95%CI - 0.06 to - 0.001, p = 0.040)., Conclusion: The FFR CT Planner was accurate in predicting post-PCI FFR independent of CCTA image quality., Clinical Relevance Statement: Being accurate in predicting post-PCI FFR across a wide spectrum of CT image quality, the FFR CT Planner could potentially enhance and guide the invasive treatment. Adequate vasodilation during CT acquisition is relevant to improve the accuracy of the FFR CT Planner., Key Points: • The fractional flow reserve derived from coronary CT angiography (FFR CT ) Planner is a novel tool able to accurately predict fractional flow reserve after percutaneous coronary intervention. • The accuracy of the FFR CT Planner was confirmed across a wide spectrum of CT image quality. Nitrates dose at CT acquisition was the only independent predictor of its accuracy. • The FFR CT Planner could potentially enhance and guide the invasive treatment., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Fractional flow reserve-computed tomography (FFR CT ) has not been validated in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) for coronary artery disease due to theoretical difficulties in using nitroglycerin for such patients., Methods and results: In this single-center study, we prospectively enrolled 21 patients (34 vessels) and performed pre-TAVR FFR CT without nitroglycerin, pre-TAVR invasive instantaneous wave-free ratio (iFR) measurements, and post-TAVR FFR measurements using a pressure wire. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of pre-TAVR FFR CT ≤0.80 to predict post-TAVR invasive FFR ≤0.80 were 82%, 83%, 82%, 71%, and 90%, respectively. A receiver operating characteristic analysis demonstrated an optimal cutoff of 0.78 for pre-TAVR FFR CT to indicate post-TAVR FFR ≤0.80, with an area under the curve (AUC) of 0.84, and the counterpart cutoff of pre-TAVR iFR was 0.89 with an AUC of 0.86., Conclusions: FFR CT without nitroglycerin could be a useful non-invasive imaging modality for assessing the severity of coronary artery lesions in patients with severe AS.

Background and Aims: Coronary hemodynamics impact coronary plaque progression and destabilization. The aim of the present study was to establish the association between focal vs. diffuse intracoronary pressure gradients and wall shear stress (WSS) patterns with atherosclerotic plaque composition., Methods: Prospective, international, single-arm study of patients with chronic coronary syndromes and hemodynamic significant lesions (fractional flow reserve [FFR] ≤ 0.80). Motorized FFR pullback pressure gradient (PPG), optical coherence tomography (OCT), and time-average WSS (TAWSS) and topological shear variation index (TSVI) derived from three-dimensional angiography were obtained., Results: One hundred five vessels (median FFR 0.70 [Interquartile range (IQR) 0.56-0.77]) had combined PPG and WSS analyses. TSVI was correlated with PPG (r = 0.47, [95% Confidence Interval (95% CI) 0.30-0.65], p < 0.001). Vessels with a focal CAD (PPG above the median value of 0.67) had significantly higher TAWSS (14.8 [IQR 8.6-24.3] vs. 7.03 [4.8-11.7] Pa, p < 0.001) and TSVI (163.9 [117.6-249.2] vs. 76.8 [23.1-140.9] m -1 , p < 0.001). In the 51 vessels with baseline OCT, TSVI was associated with plaque rupture (OR 1.01 [1.00-1.02], p = 0.024), PPG with the extension of lipids (OR 7.78 [6.19-9.77], p = 0.003), with the presence of thin-cap fibroatheroma (OR 2.85 [1.11-7.83], p = 0.024) and plaque rupture (OR 4.94 [1.82 to 13.47], p = 0.002)., Conclusions: Focal and diffuse coronary artery disease, defined using coronary physiology, are associated with differential WSS profiles. Pullback pressure gradients and WSS profiles are associated with atherosclerotic plaque phenotypes. Focal disease (as identified by high PPG) and high TSVI are associated with high-risk plaque features., Clinical Trial Registration: https://clinicaltrials,gov/ct2/show/NCT03782688., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Following percutaneous coronary intervention (PCI), optical coherence tomography provides prognosis information. The pullback pressure gradient is a novel index that discriminates focal from diffuse coronary artery disease based on fractional flow reserve pullbacks. We sought to investigate the association between coronary artery disease patterns, defined by coronary physiology, and optical coherence tomography after stent implantation in stable patients undergoing PCI., Methods and Results: This multicenter, prospective, single-arm study was conducted in 5 countries (NCT03782688). Subjects underwent motorized fractional flow reserve pullbacks evaluation followed by optical coherence tomography-guided PCI. Post-PCI optical coherence tomography minimum stent area, stent expansion, and the presence of suboptimal findings such as incomplete stent apposition, stent edge dissection, and irregular tissue protrusion were compared between patients with focal versus diffuse disease. Overall, 102 patients (105 vessels) were included. Fractional flow reserve before PCI was 0.65±0.14, pullback pressure gradient was 0.66±0.14, and post-PCI fractional flow reserve was 0.88±0.06. The mean minimum stent area was 5.69±1.99 mm 2 and was significantly larger in vessels with focal disease (6.18±2.12 mm 2 versus 5.19±1.72 mm 2 , P =0.01). After PCI, incomplete stent apposition, stent edge dissection, and irregular tissue protrusion were observed in 27.6%, 10.5%, and 51.4% of the cases, respectively. Vessels with focal disease at baseline had a lower prevalence of incomplete stent apposition (11.3% versus 44.2%, P =0.002) and more irregular tissue protrusion (69.8% versus 32.7%, P <0.001)., Conclusions: Baseline coronary pathophysiological patterns are associated with suboptimal imaging findings after PCI. Patients with focal disease had larger minimum stent area and a higher incidence of tissue protrusion, whereas stent malapposition was more frequent in patients with diffuse disease.

The early and mid-term arterial healing profile of biodegradable polymer-coated everolimus-eluting stents (BP-EES) is unclear, especially in ST-segment elevation myocardial infarction (STEMI) culprit lesions. This study aimed to compare early- and mid-term arterial healing between durable polymer-coated everolimus-eluting stents (DP-EES) and BP-EES in STEMI patients. In a prospective, multicenter, non-inferiority trial, STEMI patients were randomized to receive BP-EES (n = 60) or DP-EES (n = 60). The primary endpoint of this study was the mean percentage of covered struts (%covered struts) on FD-OCT 2 weeks post-PCI. Key secondary endpoints included the percentage of uncovered struts, frequency of abnormal intra-stent tissue, and percentage of malapposed struts by FD-OCT 2 weeks and 12 months post-PCI. They underwent serial frequency-domain optical coherence tomography (FD-OCT) evaluations immediately after percutaneous coronary intervention, and at 2 weeks and at 12 months after the procedure. The primary endpoint of %covered struts at 2 weeks was 71.4% in BP-EES and 72.3% in DP-EES [risk difference - 0.94%, lower limit of one-sided 95% confidence interval (CI) - 5.6; P non-inferiority  = 0.0756]. At 12 months, the mean percentage of uncovered struts was significantly lower [1.73% (95% CI 0.28-3.17) vs. 4.81% (95% CI 3.52-6.09); p = 0.002], and the average malapposed volume was significantly smaller in the BP-EES group than in the DP-EES group (p = 0.002). At 12 months, BP-EES had a significantly larger average neointimal area with a significantly smaller average intra-stent tissue unevenness score than DP-EES, suggesting more uniform neointimal coverage with BP-EES. Strut coverage was comparable between BP-EES and DP-EES at 2 weeks. Non-inferiority could not be proven because of an insufficient sample size. The significantly better arterial healing with BP-EES at 12 months suggests a safer profile for STEMI culprit lesions.Trial registration: jRCTs022180024 https://jrct.niph.go.jp/en-latest-detail/jRCTs022180024., (© 2022. The Author(s) under exclusive licence to Japanese Association of Cardiovascular Intervention and Therapeutics.)

Hiroshi Toshida,1 Toshinari Funaki,2 Koichi Ono,3 Nobuhito Tabuchi,4 Sota Watanabe,4 Tamotsu Seki,5 Hiroshi Otake,6 Takuji Kato,7 Nobuyuki Ebihara,8 Akira Murakami2 1Department of Ophthalmology, Juntendo University Shizuoka Hospital, Shizuoka, 2Department of Ophthalmology, Juntendo University Graduate School of Medicine, 3Department of Ophthalmology, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, 4Pharmaceutical Research Laboratories, Lion Corporation, Kanagawa, 5Tamagawa Eye Clinic, Tokyo, 6Otake Eye Clinic, Kanagawa, 7Kato Eye Clinic, Tokyo, 8Department of Ophthalmology, Juntendo University Urayasu Hospital, Chiba, Japan Purpose: The purpose of this study was to investigate the efficacy and safety of the administration of retinol palmitate (VApal) ophthalmic solution (500 IU/mL) for the treatment of patients with dry eye. Patients and methods: This study included 66 patients with dry eye. After a 2-week washout period, patients were randomized (1:1) into either a VApal ophthalmic solution or a placebo group, and a single drop of either solution was administered six times daily for 4 weeks. Efficacy measures were 12 subjective symptoms, rose bengal (RB) and fluorescein staining scores, tear film breakup time, and tear secretion. Safety measures included clinical blood and urine analyses and adverse event recordings. Results: In comparisons of the two groups, the mean change in RB staining score from baseline was significantly lower in the VApal group at 2 and 4 weeks (P

A 54-year-old man was admitted with obstructive jaundice. Computed tomography showed common bile duct stricture and a tumor around the celiac artery. Repeated endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endoscopic retrograde cholangiopancreatography (ERCP) as well as a laparotomic biopsy around the celiac artery were diagnostically unsuccessful. Since the bile duct stricture progressed, EUS-FNA and ERCP were performed a third time, finally leading to the diagnosis of diffuse large B-cell lymphoma. The treatment plan and prognosis of obstructive jaundice differ greatly depending on the disease. It is important to conduct careful follow-up and repeated histological examinations with appropriate modifications until a diagnosis is made.

Background: Perivascular inflammation contributes to the development of atherosclerosis and microcirculatory dysfunction. Pericoronary adipose tissue (PCAT) attenuation, measured by coronary computed tomography angiography, is a potential indicator of coronary inflammation. However, the relationship between PCAT attenuation, microcirculatory dysfunction, and periprocedural myocardial injury (PMI) remains unclear., Methods and Results: Patients with chronic coronary syndrome who underwent coronary computed tomography angiography before percutaneous coronary intervention were retrospectively identified. PCAT attenuation and adverse plaque characteristics were assessed using coronary computed tomography angiography. The extent of microcirculatory dysfunction was evaluated using the angio-based index of microcirculatory resistance before and after percutaneous coronary intervention. Overall, 125 consecutive patients were included, with 50 experiencing PMI (PMI group) and 75 without PMI (non-PMI group). Multivariable analysis showed that older age, higher angio-based index of microcirculatory resistance, presence of adverse plaque characteristics, and higher lesion-based PCAT attenuation were independently associated with PMI occurrence (odds ratio [OR], 1.07 [95% CI, 1.01-1.13]; P =0.02; OR, 1.06 [95% CI, 1.00-1.12]; P =0.04; OR, 6.62 [95% CI, 2.13-20.6]; P =0.001; and OR, 2.89 [95% CI, 1.63-5.11]; P <0.001, respectively). High PCAT attenuation was correlated with microcirculatory dysfunction before and after percutaneous coronary intervention and its exacerbation during percutaneous coronary intervention. Adding lesion-based PCAT attenuation to the presence of adverse plaque characteristics improved the discriminatory and reclassification ability in predicting PMI., Conclusions: Adding PCAT attenuation at the culprit lesion level to coronary computed tomography angiography-derived adverse plaque characteristics may provide incremental benefit in identifying patients at risk of PMI. Our results highlight the importance of microcirculatory dysfunction in PMI development, particularly in the presence of lesions with high PCAT attenuation., Registration: URL: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000057722; Unique identifier: UMIN000050662.

Transdermal drug delivery is a formulation in which the drug is absorbed through the skin for systemic action. Its advantages include avoidance of first-pass effects, sustained drug supply, and ease of administration and discontinuation. Drugs administered transdermally transfer into the blood circulation through the stratum corneum, epidermis, and dermis. The stratum corneum on the skin surface plays a barrier function in skin absorption. Therefore, developing of transdermal drug delivery systems requires innovations that overcome the barrier function of the stratum corneum and improve skin permeation. This review examines the usefulness of transdermal formulations based on solid nanoparticles using raloxifene. Milled raloxifene was gelled with (mRal-NPs) or without menthol (Ral-NPs) using Carbopol. The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. The inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted raloxifene nanoparticles to penetrate through the skin. Moreover, macropinocytosis relates to the formulation's skin penetration, including menthol (mRal-NPs). Applying mRal-NPs attenuated the decreases in calcium level and stiffness of bones of ovariectomized rats. This information can support future studies aimed at designing novel transdermal formulations.

A 73-year-old woman was referred to our hospital for persistent liver dysfunction. When the patient was 45 years old, her youngest sister had been diagnosed with Wilson disease (WD). The patient therefore underwent several family screening tests, all of which were unremarkable. She had an annual medical checkup and was diagnosed with liver dysfunction and fatty liver at 68 years old. A liver biopsy and genetic testing were performed, and she was diagnosed with WD; chelation therapy was then initiated. In patients with hepatic disorders and a family history of WD, multiple medical examinations should be conducted, as the development of WD is possible regardless of age.

The solubility and permeability of the Biopharmaceutics Classification System (BCS) class IV drugs, such as furosemide (FUR), are low. Thus, the oral bioavailability of these drugs needs to be augmented. Here, we aimed to design orally disintegrating tablets containing FUR nanoparticles to improve bioavailability after oral administration. The FUR nanoparticles were generated by bead-milling in water containing 0.5% methylcellulose and 0.5% 2-hydroxypropyl-β-cyclodextrin (w/w%). Particle size was approximately 47-350 nm (mean particle size, 188 nm). An orally disintegrating tablet (FUR-NP tablet) comprising FUR nanoparticles (1%) was successfully produced by employing suspensions outlined above that incorporated additives (4% D-mannitol, 0.4% polyvinylpyrrolidone, and 16% gum Arabic, w/w%), followed by freeze-drying. The FUR-NP tablet disaggregated after only 5 s in water, liberating nano-sized FUR particles (172 nm). Experiments using rats showed the absorption of the FUR-NP tablet was significantly improved by comparison with a FUR tablet containing microparticles. In summary, the orally disintegrating tablet containing FUR nanoparticles markedly enhanced the bioavailability of FUR. We anticipate this formulation will also improve the bioavailability of other BCS class IV drugs.

In this updated expert consensus document, the methods for the quantitative measurement and morphological assessment of optical coherence tomography (OCT)/optical frequency domain imaging images (OFDI) are briefly summarized. The focus is on the clinical application and the clinical evidence of OCT/OFDI to guide percutaneous coronary interventions., (© 2022. The Author(s) under exclusive licence to Japanese Association of Cardiovascular Intervention and Therapeutics.)

Background: Gastrointestinal injuries caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is a serious side effect in patients with rheumatoid arthritis (RA). However, effective therapeutic strategies have yet to be established. In this study, we investigated the therapeutic effects of teprenone (TEP), a gastric mucosal protective drug, on NSAID-induced gastrointestinal injuries in rats with RA (AA rats)., Methods: Gastrointestinal injury was induced by oral administration of indomethacin (IMC), a typical NSAID. TEP was orally administered after IMC-induced gastrointestinal bleeding, and the stomach, jejunum, and ileum were excised., Results: On day 14 of IMC administration, lesion areas in the stomach, jejunum, and ileum were significantly larger in AA rats than in normal rats. When TEP was orally administered to AA rats, the lesion areas in the stomach, jejunum, and ileum significantly decreased compared with those in control rats (IMC-induced AA rats). Therefore, we measured NOS2 mRNA and NO levels, which were significantly decreased in rats with IMC-induced AA after treatment with TEP., Conclusions: These results suggest that the oral administration of TEP may be useful for the treatment of NSAID-induced gastrointestinal injuries in patients with RA., (© 2023. The Author(s).)

Background: The interplay between coronary hemodynamics and plaque characteristics remains poorly understood., Objectives: The aim of this study was to compare atherosclerotic plaque phenotypes between focal and diffuse coronary artery disease (CAD) defined by coronary hemodynamics., Methods: This multicenter, prospective, single-arm study was conducted in 5 countries. Patients with functionally significant lesions based on an invasive fractional flow reserve ≤0.80 were included. Plaque analysis was performed by using coronary computed tomography angiography and optical coherence tomography. CAD patterns were assessed using motorized fractional flow reserve pullbacks and quantified by pullback pressure gradient (PPG). Focal and diffuse CAD was defined according to the median PPG value., Results: A total of 117 patients (120 vessels) were included. The median PPG was 0.66 (IQR: 0.54-0.75). According to coronary computed tomography angiography analysis, plaque burden was higher in patients with focal CAD (87% ± 8% focal vs 82% ± 10% diffuse; P = 0.003). Calcifications were significantly more prevalent in patients with diffuse CAD (Agatston score per vessel: 51 [IQR: 11-204] focal vs 158 [IQR: 52-341] diffuse; P = 0.024). According to optical coherence tomography analysis, patients with focal CAD had a significantly higher prevalence of circumferential lipid-rich plaque (37% focal vs 4% diffuse; P = 0.001) and thin-cap fibroatheroma (TCFA) (47% focal vs 10% diffuse; P = 0.002). Focal disease defined by PPG predicted the presence of TCFA with an area under the curve of 0.73 (95% CI: 0.58-0.87)., Conclusions: Atherosclerotic plaque phenotypes associate with intracoronary hemodynamics. Focal CAD had a higher plaque burden and was predominantly lipid-rich with a high prevalence of TCFA, whereas calcifications were more prevalent in diffuse CAD. (Precise Percutaneous Coronary Intervention Plan [P3]; NCT03782688)., Competing Interests: Funding and Author Disclosures The study was sponsored by the Cardiac Research Institute Aalst with unrestricted grants from HeartFlow Inc. Dr Mizukami has received consulting fees from Zeon Medical and HeartFlow Inc; and speaker fees from Abbott Vascular. Dr Leipsic is a consultant and has holding stock options in Circle CVI and HeartFlow Inc; has received a research grant from GE; and modest speaker fees from GE and Philips. Drs Sonck and Munhoz have received research grants provided by the Cardiopath Ph.D. program. Dr Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow Inc. Dr Otake has received research grants from Abbott Vascular; and speaker fees from HeartFlow Inc and Abbott Vascular. Dr Ko has received consulting fees from Canon Medical, Abbott, and Medtronic. Dr Koo has received institutional research grants from HeartFlow Inc. Dr Maeng has received advisory board and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, and Novo Nordisk; and research grants from Bayer and Philips Healthcare. Dr Jensen has received unrestricted institutional research grants from Siemens and HeartFlow Inc. Dr Andreini has received research grants from GE Healthcare and Bracco. Dr Shinke has received research grants from Boston Scientific and Abbott Vascular. CT is an employee of HeartFlow Inc. Dr Barbato has received speaker fees from Boston Scientific, Abbott Vascular, and GE. Dr Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; significant institutional research support from St. Jude Medical (CONTRAST [Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?]; NCT02184117) and Philips/Volcano Corporation (DEFINE-FLOW [Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses]; NCT02328820) for studies using intracoronary pressure and flow sensors; has an institutional licensing agreement with Boston Scientific for the smart-minimum FFR algorithm commercialized under 510(k) K191008; and has pending patents on diagnostic methods for quantifying aortic stenosis and transcatheter aortic valve replacement physiology, as well as algorithms to correct pressure tracings from fluid-filled catheters. Dr De Bruyne has received consultancy fees from Boston Scientific and Abbott Vascular; research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow Inc, Edwards Life Sciences, Bayer, Sanofi, and Celyad. Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and consultancy fees from HeartFlow Inc, OpSens, Abbott Vascular, and Philips Volcano. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is a scarcity of data evaluating contemporary real-world dual antiplatelet therapy (DAPT) strategies after percutaneous coronary intervention (PCI)., Methods and results: In the OPTIVUS-Complex PCI study multivessel cohort enrolling 982 patients undergoing multivessel PCI, including left anterior descending coronary artery using intravascular ultrasound (IVUS), we conducted 90-day landmark analyses to compare shorter and longer DAPT. DAPT discontinuation was defined as withdrawal of P2Y 12 inhibitors or aspirin for at least 2 months. The prevalence of acute coronary syndrome and high bleeding risk by the Bleeding Academic Research Consortium were 14.2% and 52.5%, respectively. The cumulative incidence of DAPT discontinuation was 22.6% at 90 days, and 68.8% at 1 year. In the 90-day landmark analyses, there were no differences in the incidences of a composite of death, myocardial infarction, stroke, or any coronary revascularization (5.9% vs. 9.2%, log-rank P=0.12; adjusted hazard ratio, 0.59; 95% confidence interval, 0.32-1.08; P=0.09) and BARC type 3 or 5 bleeding (1.4% vs. 1.9%, log-rank P=0.62) between the off- and on-DAPT groups at 90 days., Conclusions: The adoption of short DAPT duration was still low in this trial conducted after the release of the STOPDAPT-2 trial results. The 1-year incidence of cardiovascular events was not different between the shorter and longer DAPT groups, suggesting no apparent benefit of prolonged DAPT in reducing cardiovascular events even in patients who undergo multivessel PCI.

Background The prognostic impact of optical coherence tomography-diagnosed culprit lesion morphology in acute coronary syndrome (ACS) has not been systematically examined in real-world settings. Methods and Results This investigator-initiated, prospective, multicenter, observational study was conducted at 22 Japanese hospitals to identify the prevalence of underlying ACS causes (plaque rupture [PR], plaque erosion [PE], and calcified nodules [CN]) and their impact on clinical outcomes. Patients with ACS diagnosed within 24 hours of symptom onset undergoing emergency percutaneous coronary intervention were enrolled. Optical coherence tomography-guided percutaneous coronary intervention recipients were assessed for underlying ACS causes and followed up for major adverse cardiac events (cardiovascular death, myocardial infarction, heart failure, or ischemia-driven revascularization) at 1 year. Of 1702 patients with ACS, 702 (40.7%) underwent optical coherence tomography-guided percutaneous coronary intervention for analysis. PR, PE, and CN prevalence was 59.1%, 25.6%, and 4.0%, respectively. One-year major adverse cardiac events occurred most frequently in patients with CN (32.1%), followed by PR (12.4%) and PE (6.2%) (log-rank P <0.0001), primarily driven by increased cardiovascular death (CN, 25.0%; PR, 0.7%; PE, 1.1%; log-rank P <0.0001) and heart failure trend (CN, 7.1%; PR, 6.8%; PE, 2.2%; log-rank P <0.075). On multivariate Cox regression analysis, the underlying ACS cause was associated with 1-year major adverse cardiac events (CN [hazard ratio (HR), 4.49 [95% CI, 1.35-14.89], P =0.014]; PR (HR, 2.18 [95% CI, 1.05-4.53], P =0.036]; PE as reference). Conclusions Despite being the least common, CN was a clinically significant underlying ACS cause, associated with the highest future major adverse cardiac events risk, followed by PR and PE. Future studies should evaluate the possibility of ACS underlying cause-based optical coherence tomography-guided optimization.

N,N-diethyl-meta-toluamide (DEET) is a widely used insect repellent, with minimal skin permeation and sustained repellent activity in the superficial layers of the skin. In this study, we prepared a 10% DEET formulation consisting of 40% ethanol with or without 2% poly(oxyethylene)/poly(oxypropylene) butyl ether (POE-POP), an amphiphilic random copolymer. Further, we demonstrated the effects of POE-POP on tensile stress (stickiness), hydrophobicity, skin retention, permeation, and repellent activity of DEET. Stickiness was measured in male ICR mice (7-week old), and skin retention and permeation were evaluated in male Wistar rats (7-week old). In addition, female Aedes albopictus were used to measure the repellent action of DEET. The addition of POE-POP did not affect stickiness, volatility, and degradability but decreased logP and increased viscosity of DEET. Next, we demonstrated the behavior of DEET formulations in the rat skin. POE-POP prolonged the retention of DEET in the superficial layers of the rat skin (skin surface and stratum corneum) and decreased the penetration of DEET into rat skin tissues (epithelium and dermis). The repellent effect of DEET was also enhanced by the addition of POE-POP. However, severe skin damage was not observed after repetitive treatment with DEET formulations containing POE-POP for one month (twice a day). In conclusion, we demonstrated that a 10% DEET formulation consisting of 40% ethanol and 2% POE-POP attenuated the skin penetration and prolonged the repellent action of DEET without causing stickiness and skin damage. We conclude that the combination of ethanol and POE-POP is useful as a safe and effective delivery system for the development of insect repellent formulations containing DEET., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kawaguchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Global longitudinal strain (GLS) is reportedly a sensitive marker for early subtle abnormalities in left ventricular (LV) performance of asymptomatic patients with severe aortic stenosis (AS) and preserved LV ejection fraction (LVEF). For symptomatic patients with severe AS and preserved LVEF, however, the association of immediate improvement in GLS after transcatheter aortic valve implantation (TAVI) with long-term outcomes remains uncertain., Methods: This study concerned 151 symptomatic patients with severe AS and preserved LVEF who had undergone TAVI. Echocardiography was performed before TAVI and 7 (7-9) days after TAVI. GLS was determined by means of a two-dimensional speckle-tracking strain using current guidelines. The primary endpoint was defined as a composite endpoint comprising cardiovascular death or re-hospitalization for HF after TAVI over a median follow-up period of 27.7 (11.9-51.4) months., Results: Mean LVEF and GLS were 65 ± 7 % and 12.8 ± 3.4 %, respectively. The Kaplan-Meier curve indicated that patients with acute improvement in GLS after TAVI experienced fewer cardiovascular events than those without such improvement (log-rank P = 0.02). Multivariate analysis showed that non-acute improvement in GLS after TAVI was independently associated with worse outcomes as well as deterioration of the mean transaortic pressure gradient., Conclusion: Assessment of GLS immediately after TAVI is a valuable additional parameter for better management of symptomatic patients with severe AS and preserved LVEF who are scheduled for TAVI., Competing Interests: Conflict of interest H.T. is a consultant for AstraZeneca plc, Ono Pharmaceutical Company, Limited. Pfizer Inc., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, and Novartis International AG. H.O is a consultant for Abbott Vascular Japan and Terumo Co. K.H. has received research funding from Daiichi Sankyo Company, Limited, Actelion Pharmaceuticals Japan, Terumo Corporation, Abbott Vascular Japan, Otsuka Pharmaceutical Company, Limited, Kowa Company, Limited, Takeda Pharmaceutical Company Limited, Nihon Medi-Physics Company Limited, Novartis Pharma Company Limited, Bayer Company Limited, Biotronic Japan Company Limited, FUJIFILM Toyama Chemical Company Limited, Medtronic Japan Company Limited, Sysmex Company Limited. The remaining authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Ltd.)