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Lipid mediator, palmitoylethanolamide (PEA) has recently attracted attention as a potential therapeutic option for various inflammatory autoimmune diseases. It has been reported that PEA exerts an inhibitory effect on inflammation triggered by PRRs, particularly Toll-like receptors expressed on myeloid antigen-presenting cells. However, the precise role of PEA in T cell development and function has not yet been elucidated. Here, we found that PEA suppressed the differentiation of Type 1 T helper (Th1) cells and Th17 cells, which are known to cause autoimmune diseases, as well as Th2 cells, which are associated with allergic diseases. This suppression occurs by inhibiting the expression of the master transcription factors crucial for their differentiation in vitro. Notably, PEA had no impact on the process of differentiating regulatory T cells, which play a crucial role in preventing the onset of autoimmune diseases. To further confirm the effect of PEA in vivo, we administered PEA to a Toxoplasma gondii infection model and an ovalbumin-induced allergic rhinitis model. Mice infected with T. gondii, in which Th1 responses are important for pathogen eradication, exhibited enhanced susceptibility. Mice with allergic rhinitis, where Th2 responses contribute to an exacerbation of symptoms, showed alleviated symptoms. Collectively, these findings suggest that PEA has potential applications as a new therapeutic agent for inflammatory autoimmune and allergic diseases based on excessive T cell activity., Competing Interests: Declaration of competing interest The authors have no competing financial interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: VEGF-A concentrations were measured in the blood of bevacizumab-treated cancer patients in previous studies, but a consensus has not formed that would develop VEGF-A into a clinical biomarker. Recently, methods to strictly distinguish between the VEGF-A isoforms have been developed but have not yet been applied to cancer patients undergoing bevacizumab treatment., Methods: An ELISA that strictly distinguishes between VEGF-A121 and VEGF-A165-the major isoforms of VEGF-A-and a commercially available ELISA for VEGF-A are used to determine the concentration of VEGF-A121, VEGF-A165, and VEGF-A in the blood of 12 patients with advanced colorectal cancer receiving bevacizumab therapy., Results: The serum and plasma concentrations of VEGF-A121 increased substantially post-bevacizumab administration; the median increase in serum was 860.8 pg/mL, 95% confidence interval (CI) [468.5, 1128.9], p = 0.0024, and in plasma was 808.6 pg/mL, 95% CI [748.7, 874.0], p = 0.00049. In stark contrast, VEGF-A165 after bevacizumab administration decreased in serum by a medium change of -73.8 pg/mL, 95% CI [-149.4, -10.2], p = 0.0034, with 83.3% of the post-bevacizumab concentrations falling below the high-accuracy threshold of 38 pg/mL; in plasma, all pre and post VEGF-A165 concentrations fell below this threshold. Concentrations of VEGF-A121 and VEGF-A165 in platelets did not change to a statistically significant degree. Adding recombinant VEGF-A121 (and -A165) or bevacizumab to plasma in patients post-bevacizumab administration increased or decreased, respectively, VEGF-A121 and VEGF-A165 levels. The increase in VEGF-A121 in plasma and serum after bevacizumab administration may be due to the dissociation of the complex of tumor-derived VEGF-A121 and bevacizumab when it moves from the stroma into the blood., Conclusions: The VEGF-A121 isoform has been uniquely demonstrated as a clear marker of bevacizumab therapy in both plasma and serum, motivating further research on pursuing these isoforms as biomarkers in cancer care., Competing Interests: No authors have competing interests., (Copyright: © 2024 Okawa 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.)

The oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in GVHD pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients post-hematopoietic cell transplantation associated with increased chronic GVHD (cGVHD) even in patients receiving post-transplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes (LNs) both pre- and post-transplantation activated antigen-presenting cells (APCs), thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increased in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD., (Copyright © 2024 American Society of Hematology.)

Objective: To validate the Japanese below-the-knee (J-BTK) chronic total occlusion (CTO) score for the prediction of successful guidewire crossing (S-GC) in angiographic evaluation., Methods: A prospective, multicenter, nonrandomized study examined 751 consecutive BTK CTOs in 497 patients treated with endovascular therapy in 16 Japanese medical centers from April 2021 to March 2022. The cohort was classified into 2 groups: an S-GC group and a failed guidewire crossing group., Results: The J-BTK CTO score, which assigned one point to "Blunt type at the proximal entry point," one point to "Calcification at the proximal entry point," one point to "Reference vessel diameter <2.0 mm," one point to "CTO length ≥200 mm," and two points to "No outflow of the target vessel," was used to categorize BTK CTOs into 4 grades with varying probabilities of S-GC: grade A (J-BTK CTO score of 0 and 1), grade B (score of 2 and 3), grade C (score of 4 and 5), and grade D (score of 6). Rates of S-GC in each grade (grades A, B, C, and D) were 97.5%, 89.1%, 62.5%, and 27.3%, respectively. The area under the receiver-operating characteristic curve for S-GC was 0.8304. Although the previous J-BTK CTO study enrolled only de novo lesions, both de novo and restenotic lesions were evaluated in this study. De novo lesions have a lower chance of S-GC (odds ratio: 0.24, 95% confidence interval: 0.09-0.67) in the multivariate analysis, and the area under the receiver-operating characteristic curve of the modified J-BTK CTO score, which additionally assigned two points to "De novo lesion," was 0.846. The modified J-BTK CTO score showed an appropriate calibration (Hosmer-Lemeshow P = .957)., Conclusions: The J-BTK CTO score and the modified J-BTK CTO score predict the probability of an S-GC of BTK CTOs and stratify the difficulty of endovascular therapy for BTK CTOs in angiographic evaluation., Competing Interests: Disclosures None., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Toxoplasma gondii (T. gondii) is a zoonotic protozoan parasite that causes congenital toxoplasmosis, including fetal death, abortion, stillbirth, morphological abnormalities, and premature birth. Primary T. gondii infection in pregnant women results in congenital toxoplasmosis. C-C chemokine receptor (CCR) 2 is reportedly a critical host defense factor against T. gondii infection. However, details of the role of CCR2 in the host immune response to T. gondii in congenital toxoplasmosis remain unclear. Here, we infected pregnant CCR2-deficient mice with T. gondii, resulting in stillbirth, embryonic resorption, fetal morphological abnormalities, and preterm delivery at significantly higher rates than those in pregnant wild-type (WT) mice. Consistent with the severity of abnormal pregnancy, a large area of placental hemorrhage and a large number of T. gondii infections around the hemorrhagic area were observed in the placentas of CCR2-deficient mice. In addition, the accumulation of inflammatory monocytes in the placenta was reduced in CCR2-deficient mice during infection. We further confirmed that the adoptive transfer of inflammatory monocytes collected from WT mice into T. gondii-infected pregnant CCR2-deficient mice effectively suppressed placental damage and abnormal pregnancy. Collectively, CCR2 contributes to pregnancy maintenance by regulating the migration of inflammatory monocytes into the placenta of T. gondii-infected pregnant mice., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology.)

Purpose: To reveal the rate of 1-year freedom from restenosis and to determine the factors associated with the restenosis risk in femoropopliteal (FP) lesions treated with a Ranger drug-coated balloon (DCB) in real-world clinical settings., Methods: This multicenter, prospective observational study enrolled 1131 patients and 1453 de novo or restenotic FP lesions (mean age=75±9 years; female=35.3%, mean lesion length=19.2±16.0 cm; chronic total occlusion [CTO]=33.7%; severe calcification=33.7%) that underwent successful Ranger DCB angioplatsy between March 2021 and December 2022., Results: The primary endpoint was 1-year freedom from restenosis and its associated factors. Bail-out stenting was performed in 5.3%. During the follow-up, restenosis was detected in 249 cases. Freedom from restenosis by the Kaplan-Meier analysis was estimated to be 85.2% and 81.0% at 12 and 14 months, whereas freedom from target lesion revascularization (TLR) was 91.7% and 90.0% at 12 and 14 months. The patterns of restenosis were focal (39.2%), tandem (12.3%), diffuse (17.2%), and occlusive (31.3%). Independent risk factors of restenosis were female sex, diabetes mellitus, no runoff, history of revascularization, lesion length ≥25 cm, and CTO., Conclusions: Our study demonstrated that 1-year freedom from restenosis after Ranger DCB for FP lesions in a real-world clinical setting was acceptable. Independent predictors of restenosis were female gender, diabetes mellitus, no runoff, history of revascularization, lesion length ≥25 cm, and CTO., Clinical Impact: Our study demonstrated the true performance of Ranger DCB in real-world practice, with a very low rate of bail-out stenting and no use of atherectomy devices. In addition, it also elucidated morphologies associated with restenosis and the risk factors for restenosis after DCB. Freedom from re-stenosis and TLR at 1-year after Range DCB angioplasty was 84.5% and 91.5%. Two thirds of restenosis had a non-occlusive pattern, and independent predictors of restenosis were female gender, diabetes mellitus, no runoff, history of revascularization, lesion length ≥25 cm, and CTO., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Y.S., Dr O.I., Dr D.K., Dr K.T., and Dr M.F. received honoraria from Boston Scientific Japan. Dr M.T. has no conflicts of interest to report.

Objective: This study aimed to determine the impact of infrapopliteal (IP) revascularisation establishing in line flow to the wound (IFW) on wound healing in chronic limb threatening ischaemia (CLTI), using a core laboratory assessment for wounds and in line flow., Methods: The Wound directed Angiosome RevasculaRIsation apprOach to patients with cRitical limb iSchaemia (WARRIORS) multicentre observational study enrolled patients with CLTI with tissue loss undergoing IP revascularisation in Japan, with scheduled two year follow up. The primary outcome measure was complete wound healing, defined as achievement of complete epithelialisation of all wounds without major amputation. IP revascularisation establishing IFW was defined as revascularisation after which a tibiopedal artery that actually fed an injured pedal unit was patent. The incidence of wound healing was compared between the IFW and non-IFW groups using inverse probability of treatment weighting based on the propensity score., Results: A total of 440 patients with CLTI (median age, 75 years; male, 64.1%; diabetes mellitus, 72.0%; dialysis, 57.7%) with tissue loss (Wound, Ischaemia, and foot Infection stage 4, 66.4%) who underwent IP revascularisation (endovascular procedure, n = 304; bypass grafting, n = 136) between October 2017 and June 2020 were registered. During a median follow up of 23.6 months, 51.1% achieved wound healing. Successful IP revascularisation with IFW was achieved in 68.2%. After analysis, the IFW group had a higher rate of wound healing than the non-IFW group (34.5 vs. 16.1 per 100 person years; p = .030). The association between IFW and wound healing was not statistically different between patients undergoing bypass grafting and those undergoing an endovascular procedure (p for interaction = .38). There was no statistically significant interaction effect between IFW and direct revascularisation for wound healing (p for interaction = .51)., Conclusion: IP revascularisation establishing IFW was statistically significantly associated with a higher wound healing rate in patients with CLTI., (Copyright © 2024 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Background: We previously investigated methods for separating mutagenic contaminants from aqueous solutions using cellulose-bearing covalently bound trisulfo-Cu-phthalocyanine (blue cotton and blue rayon). Mutagenic contaminants with three or more fused aromatic rings in their structures were adsorbed onto blue cotton and rayon. Since Cu-phthalocyanine is considered an unsuitable absorption ligand for byproducts of water chlorination, such as 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (Mutagen X or MX), we investigated the development of a new material for the elimination of MX from aqueous solvents., Results: We selected green cellulose powder bearing ferrous phthalocyanine (FePh), hereafter referred to as green cellulose or GP, as the candidate material. GP is composed of cationized cellulose (white cellulose, WP) and FePh tetracarboxylic acid. The mutagenicity of MX dissolved in buffer or dimethyl sulfoxide (DMSO) solution significantly decreased after treatment with GP. The effects of GP on the elimination of MX from the solvent were very close to being expired after 70 cycles of repeated adsorption of the same GP, and the capacity of GP for MX removal was estimated to be exhausted after 120 cycles of repeated adsorption based on the extrapolation of the obtained result; thus, the interacting ligands on GP may be saturated after complete MX adsorption. The mutagenicity of MX dissolved in aqueous buffer significantly decreased after treatment at pH7.4 but not at pH 4.0. Since MX is dissociated to be the anionic form at pH 6 or higher, the negative charge of MX in the buffer at pH 7.4 may interact with the positive charge of ferrous ions in GP to create a linkage between MX and GP. After GP adsorbed MX, mutagenicity was extracted with water or acetonitrile and recovered in the eluent. Thus, the reversible interaction between MX and FePh may have caused adsorption of MX onto GP., Conclusion: GP could be used as a new eliminator and recovery agent for MX in chlorinated drinking water. Developing new materials for the removal and recovery of agents for the detection of mutagenic contaminant-related chlorination in water is beneficial for environmental health., (© 2024. The Author(s).)

Background: Inflammatory bowel disease (IBD) is a refractory inflammatory disorder of the intestine, which is probably triggered by dysfunction of the intestinal epithelial barrier. Secretory leukocyte protease inhibitor (SLPI) secreted by colon epithelial cells protects against intestinal inflammation by exerting anti-protease and anti-microbial activities. Daikenchuto (DKT) is one of the most commonly prescribed Japanese traditional herbal medicines for various digestive diseases. Although several animal studies have revealed that DKT exerts anti-inflammatory effects, its detailed molecular mechanism is unclear. This study aimed to clarify the anti-inflammatory mechanism of DKT using a murine colitis model, and to evaluate its potential as a therapeutic agent for IBD., Methods: Experimental colitis was induced in wild-type (WT) mice and SLPI-deficient (KO) mice by dextran sulfate sodium (DSS) after oral administration of DKT. The resultant clinical symptoms, histological changes, and pro-inflammatory cytokine levels in the colon were assessed. Expression of SLPI in the colon was detected by Western blotting and immunohistochemistry. Composition of the gut microbiota was analyzed by 16S rRNA metagenome sequencing and intestinal metabolites were measured by gas chromatography-mass spectrometry analysis. Intestinal epithelial barrier function was assessed by oral administration of FITC-dextran and immunostaining of tight junction proteins (TJPs)., Results: Oral administration of DKT increased the number of butyrate-producing bacteria, such as Parabacteroides , Allobaculum , and Akkermansia , enhanced the levels of short-chain fatty acids, including butyrate, in the colon, induced SLPI expression, and ameliorated DSS-induced colitis in WT mice. We found that mouse colon carcinoma cell line treatment with either DKT or butyrate significantly enhanced the expression of SLPI. Moreover, supplementation of DKT protected the intestinal epithelial barrier with augmented expression of TJPs in WT mice, but not in KO mice. Finally, the composition of the gut microbiota was changed by DKT in WT mice, but not in KO mice, suggesting that DKT alters the colonic bacterial community in an SLPI-dependent manner., Conclusion: These results indicate that DKT exerts anti-inflammatory effects on the intestinal epithelial barrier by SLPI induction, due, at least in part, to increased butyrate-producing bacteria and enhanced butyrate levels in the colon. These results provide insight into the mechanism of the therapeutic effects of DKT on IBD., Competing Interests: Authors SI and MN were employed by the company Tsumura & Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Tsumura & Co. The funder had the following involvement in the study: analysis of the gut microbiota., (Copyright © 2024 Ozaka, Sonoda, Kudo, Ito, Kamiyama, Sachi, Chalalai, Kagoshima, Soga, Ekronarongchai, Ariki, Mizukami, Ishizawa, Nishiyama, Murakami, Takeda and Kobayashi.)

Background: Elevated lipoprotein(a) [Lp(a)] levels are a causal risk factor for peripheral artery disease. However, data on their effect on delayed wound healing in patients with chronic limb-threatening ischemia (CLTI) are limited. The present study assessed the association between elevated Lp(a) levels and delayed wound healing in patients with CLTI., Methods and Results: This study included 280 patients who successfully received endovascular therapy for CLTI between September 2016 and August 2021. High Lp(a) levels were defined as those >30 mg/dL. The primary outcome was wound healing. During a median follow-up of 20.4 months (interquartile range 6.8-38.6 months), 146 patients achieved wound healing. The wound healing rate at 24 months was significantly lower in the high Lp(a) than low Lp(a) group (41.1% vs. 86.3%, respectively; P<0.001). The adjusted risk ratio was 0.19 (95% confidence interval 0.13-0.29, P<0.001). Lp(a) levels of 31-50 and >50 mg/dL, but not 16-30 mg/dL, were significantly associated with delayed wound healing relative to Lp(a) levels of ≤15 mg/dL., Conclusions: Elevated Lp(a) levels were independently associated with delayed wound healing in patients with CLTI treated with endovascular therapy.

Background: The impact of very low baseline levels of low-density lipoprotein cholesterol (LDL-C) on patients with coronary artery disease remains unclear., Method: We enrolled 39,439 patients of the pooled population from the CREDO-Kyoto registries Cohorts 1, 2, and 3. The study population consisted of 33,133 patients who had undergone their first coronary revascularization. We assessed the risk for mortality and cardiovascular events according to quintiles of the baseline LDL-C levels., Results: Patients in the very low LDL-C quintile (<85 mg/dL) had more comorbidities than those in the other quintiles. Lower LDL-C levels were strongly associated with anemia, thrombocytopenia, and end-stage renal disease. The cumulative 4-year incidence of all-cause death increased as LDL-C levels decreased (very low: 19.4 %, low: 14.5 %, intermediate: 11.1 %, high: 10.0 %, and very high: 9.2 %; p < 0.001), which was driven by both the early and late events. After adjusting for baseline characteristics, the adjusted risks of the very low and low LDL-C quintiles relative to the intermediate LDL-C quintile remained significant for all-cause death (very low: HR 1.29, 95 % CI 1.16-1.44, p < 0.001; low: HR 1.15, 95 % CI 1.03-1.29, p = 0.01). The excess adjusted risks of the lowest LDL-C quintile relative to the intermediate LDL-C quintile were significant for clinical outcomes such as cardiovascular death (HR 1.17, 95 % CI 1.01-1.35), non-cardiovascular death (HR 1.35, 95 % CI 1.15-1.60), sudden death (HR 1.44, 95 % CI 1.01-2.06), and heart failure admission (HR 1.11 95 % CI 1.01-1.22), while there was no excess risk for the lowest LDL-C quintile relative to the intermediate LDL-C quintile for myocardial infarction and stroke., Conclusions: Lower baseline LDL-C levels were associated with more comorbidities and a significantly higher risk of death, regardless of cardiovascular or non-cardiovascular causes, in patients who underwent coronary revascularization., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Chronic total occlusion (CTO) remains as a major target for endovascular treatment (EVT) in improving symptomatic lower-extremity artery disease (LEAD). However, despite the technical demand and learning curve for the procedure, volume-outcome relationship of EVT targeted for CTO in symptomatic LEAD remains unclear., Materials and Methods: Data were obtained from a nationwide registry for EVT procedures limited to the Japanese Association of Cardiovascular Intervention and Therapeutics between January 2018 and December 2020 from 660 cardiovascular centers in Japan. In total, 96 099 patients underwent EVT for symptomatic LEAD, and 41 900 (43.6%) underwent CTO-targeted EVTs during the study period. Institutional volume was classified into quartiles. The association of institutional volumes with short-term outcomes was explored using the generalized linear mixed model using a logit link function, in which, interinstitution variability was used as a random effect., Results: The median institutional volume for all EVT cases per quartile was 29, 68, 125, and 299 cases/year for the first, second, third, and fourth quartiles, respectively. With each model analysis, the adjusted odds ratios (ORs) for technical success were significantly lower in patients who underwent EVT in institutions within the first quartile (<52 cases/year) than in the other quartiles ( P < .01, respectively). On the contrary, the adjusted ORs for procedural complications were significantly higher in the first and second quartiles than in the third and fourth quartiles ( P < .01, respectively)., Conclusion: In contemporary Japanese EVT practice, a higher institutional volume but not operator volume was associated with a higher technical success rate and a lower procedural complication rate in patients with symptomatic LEAD involving CTO lesions., Clinical Impact: EVT for CTO lesions is still challenging for clinicians because of difficulties of wire/devise crossing or high procedural complications rate. Our study demonstrated that a higher institutional volume but not operator volume was associated with a higher technical success rate and a lower procedural complication rate in patients with symptomatic LEAD involving CTO lesions. In contemporary Japanese practice, a higher institutional experience has better impacts on short-term clinical outcomes. Future research should determine the relationship between institutional volume and long-term clinical outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Clinical trials have demonstrated that high-dose drug-coated balloon (HD-DCB) and polymer-based drug-eluting stent (PB-DES) treatments for femoropopliteal (FP) artery disease have favorable outcomes. However, which one would be better remained unrevealed., Methods: This study used the databases of 2 large-scale multicenter prospective drug-coated balloon (DCB) and drug-eluting stent (DES) registries. The study included 2470 patients with symptomatic FP lesion treated with IN.PACT Admiral DCB or Eluvia DES at 69 centers. A propensity-score-based paired analysis was conducted. Primary endpoint was 1-year restenosis rate. Secondary endpoints were 1-year reocclusion rate, target lesion revascularization (TLR), acute thrombosis, bypass conversion, major amputation, major adverse limb event (MALE), and all-cause death., Results: A total of 1535 patients were treated with HD-DCB, and 935 patients were treated with PB-DES. The propensity-score matching extracted 678 pairs, with no remarkable intergroup difference in baseline characteristics. The 1-year restenosis rate was significantly lower in the PB-DES group than in the HD-DCB group (16.0% vs 22.0%, p=0.016). The other endpoints (reocclusion rate, TLR, acute thrombosis, bypass conversion, major amputation, MALE, and all-cause death) did not differ between the groups. No baseline characteristics had any significant interaction effect on the association of HD-DCB vs PB-DES with restenosis risk (all p>0.05)., Conclusions: This study demonstrated that the 1-year TLR, reocclusion rate, and other endpoints did not differ between the PB-DES group and the HD-DCB group despite the lower restenosis in the PB-DES group., Clinical Impact: One-year restenosis rate was significantly lower in the polymer-based DES group than in the high-dose DCB group for foemoropopliteal disease. However, there is no difference in the other endpoints between two groups., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The safety and effectiveness of the GORE VIABAHN Endoprosthesis for treatment of symptomatic patients with peripheral artery disease (PAD) and complex femoropopliteal (FP) lesions was assessed in a real-world Japanese practice setting. Methods : A prospective, multicenter, postmarket surveillance study was conducted from 2016 to 2017 at 64 sites in Japan. Symptomatic patients with PAD and FP lesions ⩾ 10 cm and reference vessel diameters ranging from 4.0 to 7.5 mm were eligible for enrollment. Outcome measures evaluated at 5 years were primary patency (PP), primary-assisted patency (PAP), secondary patency (SP), freedom from target lesion revascularization (fTLR), occurrence of device- or procedure-related serious adverse events (SAEs), and stent fractures. Results : A total of 321 patients were enrolled and were a mean age of 73.9 ± 8.7 years; 77.3% were men and 26.5% had chronic limb-threatening ischemia (CLTI). The mean lesion length was 23.6 ± 6.6 cm and the frequency with TASC II C/D lesions and chronic total occlusions was 86.6% and 70.4%, respectively. The Kaplan-Meier estimated PP, PAP, SP, and fTLR at 5 years was 62.4%, 74.1%, 82.3%, and 75.9%, respectively. The mean ankle-brachial index was 0.92 ± 0.15 and the mean improvement in Rutherford class was 2.3 ± 1.4, which was maintained through 5 years. The rate of cumulative device- or procedure-related SAEs through 5 years was 19.9% with only 9.3% of those occurring after the first year. No stent fractures were observed through 5 years by x-ray evaluation. Conclusion : The 5-year safety and efficacy outcomes of the endoprosthesis were clinically acceptable for treating complex FP lesions in a real-world cohort of Japanese patients with PAD. ( ClinicalTrials.gov Identifier: NCT04706273) ., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Osamu Iida – advisory boards: Boston Scientific, Cordis; consultant: Boston Scientific, Otsuka Medical; honorarium: Boston Scientific Japan, Becton Dickinson, Cordis, W. L. Gore, Medtronic Japan, Terumo Co., Ltd. Takao Ohki – consultant: W. L. Gore. Yoshimitsu Soga – honorarium: Boston Scientific, Cordis, Kaneka Medics, Medtronic Japan, Terumo Co., Ltd. Tatsuya Nakama – advisory boards: Asahi Intecc; consultant: Becton Dickinson, Boston Scientific, COOK Medical, Century Medical Inc., Cordis, NIPRO, OrbusNeichi; honorarium: Abbott Vascular, KANEKA, Medtronic, Terumo Co., Ltd. Terutoshi Yamoaka – consultant: JAPAN LIFELINE; honorarium: W. L. Gore, Boston Scientific Japan, Kaneka Medix. Kazuki Tobita – honorarium: W. L. Gore, Boston Scientific, Medtronic, Terumo, Kaneka Medics, Becton Dickinson. The other authors have no conflicts of interest to declare.

Background: Sirolimus-coated balloons (SCB) for the treatment of femoropopliteal (FP) lesions have not been systematically studied, but initial outcomes from early studies are promising., Objectives: The authors sought to evaluate the safety and efficacy of the SELUTION SLR SCB, composed of proprietary microreservoir technology combining sirolimus and biodegradable polymer, when used to treat mild-to-moderate FP disease in a Japanese population., Methods: This multicenter, prospective, single-arm study (SELUTION SFA JAPAN) enrolled 134 patients with FP disease. It was independently adjudicated by an imaging core laboratory and clinical events committee. The primary endpoint was 12-month primary patency, defined as peak systolic velocity ratio ≥2.5 by duplex ultrasound and compared against a prespecified performance goal of 60% based on established angioplasty data., Results: The mean age was 73.8 ± 6.9 years, and 60.3% of patients had diabetes mellitus. The mean lesion length was 127.4 ± 59.7 mm, 17.2% were chronic total occlusions, and 47.8% involved the popliteal artery. Data on 12-month restenosis were available in 127 patients (94.8%). The 12-month primary patency rate was 87.9%, and the freedom from clinically driven target lesion revascularization (CD-TLR) was 97.0% per Kaplan-Meier estimate. The major adverse event rate was 6.7%, driven by 4 CD-TLRs and 5 deaths, none of which were related to the device or procedure. Ankle-brachial index data improved significantly from 0.73 ± 0.16 at baseline to 0.96 ± 0.14 at 30 days postprocedure and was sustained through 12 months (0.94 ± 0.13)., Conclusions: The SELUTION SFA JAPAN trial demonstrated that a novel SELUTION SCB is a safe and effective treatment option for FP disease in symptomatic patients., Competing Interests: Funding Support and Author Disclosures This study was sponsored by MedAlliance Japan K.K. Dr Iida has served on advisory boards for Boston Scientific and Cordis; is a consultant for Boston Scientific, Otsuka Medical Devices, and Nipro; and has received honoraria from Boston Scientific, Becton Dickinson, Cordis, W.L. Gore, Medtronic, Terumo, and Kaneka Medix. Dr Soga has received honoraria from Boston Scientific, Cordis, Kaneka Medix, Medtronic, and Terumo. Dr Mano has received research support from Abbott Vascular. Dr Hayakawa has received honoraria from Terumo, Kaneka Medix, Medicos Hirata, Boston Scientific, Medtronic, and Becton Dickinson. Dr Ichihashi has received honoraria from Boston Scientific, Becton Dickinson, Cordis, W.L. Gore, Medtronic, and Terumo. Dr Kawasaki is a consultant for Cordis and Nipro. Dr Yamaoaka is a consultant for Japan Lifeline; and has received honoraria from W.L. Gore, Boston Scientific, and Kaneka Medix. Dr Nakama is on Asahi Intecc’s advisory board; is a consultant for Becton Dickinson, Boston Scientific, Cook Medical, Century Medical. Cordis, Nipro, and Orbus Neich; and has received honoraria from Abbott Vascular, Kaneka Medix, Medtronic, and Terumo. Dr Fujihara is a consultant for Century Medical, Nipro, Terumo, and Cordis; and has received honoraria from Boston Scientific, Medtronic, W.L. Gore, and Terumo. Dr Nakamura has received endowed department from Boston Scientific Japan, Kaneka, Terumo, Nipro, Otsuka Medical, Japan Lifeline, Asahi Intecc, and Biotronik Japan. Dr Lansky is on the advisory boards and has received honoraria from Cordis, Abiomed, Sinomed, Microport, and Boston Scientific; and has received institutional research support from Bard, Silkroad Medical, Abbott Vascular, Emboline, and Filterlex. 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.)

The objective of the study is to investigate the difference in 1-year late lumen loss (LLL) between the high- (IN.PACT Admiral) and low-dose (Lutonix) paclitaxel-coated balloon (PCB). Although a recent randomized clinical trial demonstrated no difference in efficacy endpoint between high- and low-dose PCB, it remains unclear whether high-dose PCB was superior to low-dose PCB in actual clinical practice. We enrolled 64 patients with 67 de novo femoropopliteal lesions who underwent PCB angioplasty at Kokura Memorial Hospital from May 2014 to March 2020 and subsequent follow-up angiography after 1 year. The primary endpoint was 1-year LLL, whereas the secondary endpoints were binary restenosis and clinically driven target lesion revascularization (CD-TLR) after 1 year. The high- and low-dose PCB groups had 45 and 22 lesions, respectively. Although the low-dose PCB group had higher rates of coronary artery disease, hemodialysis, and chronic limb-threatening ischemia than the high-dose PCB group, the latter had a longer lesion length and more lesions with a TASC classification C or D than the former. The high-dose PCB group had a significantly lower LLL than the low-dose PCB group (0.40 ± 1.05 vs. 1.19 ± 1.03 mm; P = 0.003, respectively). Moreover, the high-dose PCB group had significantly lower rates of binary restenosis at 1 year than the low-dose PCB group (22.2% vs. 50.0%; P = 0.02, respectively). Moreover, negative LLL was only observed in the high-dose PCB group (33.3% vs. 0%, P = 0.005). The high-dose PCB group had a significantly lower LLL than the low-dose PCB group., (© 2024. The Author(s).)

Background: Pulmonary vein (PV) stenosis (PVS) is a serious complication of atrial fibrillation (AF) ablation. The objective of this study was to describe interventional treatments for PVS after AF ablation and long-term outcomes in Japanese patients., Methods and results: This multicenter retrospective observational study enrolled 30 patients (26 [87%] male; median age 55 years) with 56 severe PVS lesions from 43 PV interventional procedures. Twenty-seven (90%) patients had symptomatic PVS and 19 (63%) had a history of a single AF ablation. Of the 56 lesions, 41 (73%) were de novo lesions and 15 (27%) were retreated. Thirty-three (59%) lesions were treated with bare metal stents, 14 (25%) were treated with plain balloons, and 9 (16%) were treated with drug-coated balloons. All lesions were successfully treated without any systemic embolic event. Over a median follow-up of 584 days (interquartile range 265-1,165 days), restenosis rates at 1 and 2 years were 35% and 47%, respectively. Multivariate Cox regression analysis revealed devices <7 mm in diameter (hazard ratio [HR] 2.52; 95% confidence interval [CI] 1.04-6.0; P=0.040) and totally occluded lesions (HR 3.33; 95% CI 1.21-9.15; P=0.020) were independent risk factors for restenosis., Conclusions: All PVS lesions were successfully enlarged by the PV intervention; however, restenosis developed in approximately half the lesions within 2 years.

Aim: Use long-term follow-up data from the IMPERIAL study to determine whether drug-eluting polymer-based nitinol stent treatment can delay the time to repeat intervention for femoropopliteal artery disease and how such a delay may result in cost savings in a value-based episode of care. Patients & methods: The IMPERIAL randomized controlled trial was an international study of a paclitaxel-eluting polymer-coated stent (Eluvia, Boston Scientific, MA, USA) versus a polymer-free paclitaxel-coated stent (Zilver PTX, Cook Corporation, IN, USA) for treating lesions of the femoropopliteal arterial segment. Study patients (n = 465) had symptomatic lower limb ischemia. Safety and efficacy assessments were performed through 5 years. Mean time to first reintervention was calculated in post-hoc analysis for patients who underwent a clinically driven target lesion revascularization (CD-TLR) through 3 or 5 years following the index procedure. To simulate potential cost savings associated with differential CD-TLR burden over time, a cost-avoidance analysis using input parameters from IMPERIAL and US 100% Medicare standard analytical files was developed. Results: Among patients with a first CD-TLR through 3 years of follow-up, mean time to reintervention was 5.5 months longer (difference 166 days, 95% CI: 51, 282 days; p = 0.0058) for patients treated with Eluvia (n = 56) than for those treated with Zilver PTX (n = 30). Through the 5-year study follow-up period, CD-TLR rates were 29.3% (68/232) for Eluvia and 34.2% (39/114) for Zilver PTX (p = 0.3540) and mean time to first reintervention exceeded 2 years for patients treated with Eluvia at 737 days versus 645 days for the Zilver PTX group (difference 92 days, 95% CI: -85, 269 days; p = 0.3099). Simulated savings considering reinterventions occurring over 1 and 5 years following initial use of Eluvia over Zilver PTX were US $1,395,635 and US $1,531,795, respectively, when IMPERIAL CD-TLR rates were extrapolated to 1000 patients. Conclusion: IMPERIAL data suggest initial treatment with Eluvia extends the time patients spend without undergoing reintervention. This extension may be associated with cost savings in relevant time frames.

Bovine herpesvirus 4 (BoHV-4) is an indigenous virus in cattle prevalent mainly in North and South American countries and European countries, but the genomic sequences and genetic characteristics of Japanese strains have not been reported. BoHV-4 is suspected, but not proven, to be associated with various diseases. In the present study, we isolated BoHV-4 from a 10-month-old Japanese Black calf with respiratory symptoms in Japan. To identify the genetic characteristics of the isolate named strain SG20, complete genome sequencing was performed using a combination of next-generation and Sanger sequencing technologies. The complete long unique coding region (LUR) of SG20 was found to comprise 108,819 nucleotides with 41.4% GC content and contain at least 78 open reading frames. It shares 83.4 to 99.3% overall nucleotide identity with six BoHV-4 strains available in the database. The deduced amino acid sequence alignment revealed that SG20 contains genotype 1-specific features of BoHV-4, such as amino acid substitutions and insertions within the glycoprotein B region. Phylogenetic analyzes based on the nucleotide sequences of ORF20 indicated that the virus belonged to genotype 1 (Movar 33/63-like group). The strain was also analyzed using the complete LUR and placed in the same clade as a strain recently isolated from China, but it was distinct from American and European BoHV-4 strains of genotype 1. Although further genomic and epidemiologic information is needed, our results help elucidate the molecular epidemiology of BoHV-4 and provide a foundation for future studies.

Purpose: In the present trial, the 24-month safety and effectiveness of the TCD-17187 drug-coated balloon (DCB) for the treatment of atherosclerotic lesions in the superficial femoral artery (SFA) and proximal popliteal artery (PA) were evaluated in Japanese patients., Methods: This was a prospective, multicenter, core laboratory-adjudicated, single-arm trial. From 2019 to 2020, 121 patients with symptomatic peripheral artery disease were enrolled. The primary effectiveness outcome measure was primary patency. The safety outcome measure was the major adverse event (MAE) rate., Results: Age was 74.5 ± 7.3 years, and diabetes mellitus was present in 67.5%. Lesion length and reference vessel diameter (RVD) were 106.0 ± 52.6 mm and 5.2 ± 0.8 mm, respectively. Chronic total occlusion (CTO) and bilateral calcification rate (Grade 3 and 4 by peripheral arterial calcium scoring system (PACSS)) were 17.5% and 50.8%, respectively. The 24-month primary patency rate by duplex ultrasound was 71.3%, while freedom from clinically driven target lesion revascularization (CD-TLR) was 87.0%. The MAE rate was 13.2% and all events consisted of CD-TLR. There were no instances of device- or procedure-related deaths major amputations throughout the 24 months. Multivariate Cox proportional hazards regression analysis revealed significant differences associated with loss of primary patency in the following characteristics: CTO, restenotic lesion and RVD., Conclusion: This trial confirmed the safety and effectiveness of TCD-17187 DCB for atherosclerotic lesions of the SFA and/or proximal PA for up to 24 months., Level of Evidence: Level 3, Cohort study., Clinical Trial Registration: URL: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000038612&type=summary&language=J:Registration ID: UMIN000034122. Registration Date: September 13, 2018., (© 2024. The Author(s).)

Background and Aims: Patients undergoing revascularization for lower extremity arterial disease (LEAD) may face a higher risk of mortality than those with coronary artery disease (CAD). This study aimed to characterize the difference in mortality risk between patients undergoing revascularization for LEAD and CAD and identify associated factors., Methods: The 1-year database of 10 754 patients undergoing revascularization for CAD (n = 6349) and LEAD (n = 4405) was analysed. Poisson regression models were used to characterize interpopulation differences in mortality, adjusting for baseline clinical features, including age, sex, polyvascular disease, comorbidities, medications, and vulnerabilities., Results: Individuals with LEAD were older, were more likely to have polyvascular disease, had more comorbidities, and received fewer cardioprotective drugs than those with CAD. Vulnerabilities remained more common in the LEAD group even after adjusting for these clinical features. The crude risk ratio of mortality incidence for LEAD vs. CAD was 2.91 (95% confidence interval, 2.54-3.34), attenuated to 2.14 (1.83-2.50) after controlling for age, sex, and polyvascular disease. The percentage attenuation in the excessive mortality associated with LEAD was 29%. The stepwise addition of comorbidities, medications, and vulnerabilities as adjusting factors attenuated the incidence risk ratio to 1.48 (1.26-1.72), 1.33 (1.12-1.58), and 1.17 (0.98-1.39), respectively, and increased the percentage attenuation to 64%, 73%, and 86%, respectively., Conclusions: Mortality risk was almost three-fold higher in patients undergoing revascularization for LEAD than in those with CAD. The excessive mortality was considerably attributable to inter-group differences in baseline characteristics, including potentially clinically or socially modifiable factors., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Perioperative oral management contributes to the prevention of dental/systemic complications. However, a professional dental checkup before surgery is generally not performed and relies on the patient's answer to a simple question by medical professionals other than dentists: "Do you have any concerns regarding your mouth related to undergoing surgery?" Here, we evaluated the sensitivity and specificity of this question for predicting perioperative oral health problems in patients with primary esophageal and primary lung cancer., Methods: We performed an oral cavity check in all patients before scheduled surgery for primary esophageal and lung cancer. A total of 183 patients were enrolled (M, 112; F, 71; 24-88 years, median, 69 years), consisting of 61 with primary esophageal cancer (M, 46; F, 15; 24-85 years, median, 69 years) and 122 with primary lung cancer (M, 66; F; 56; 33-88 years, median, 69 years). All subjects provided a response to this question, and an oral cavity check was performed by dentists. The sensitivity and specificity of this question for detecting oral health problems were evaluated retrospectively., Results: Overall sensitivity and specificity for detecting oral health problems were 0.263 and 0.898, respectively. There were no significant differences by sex or disease (primary esophageal or lung cancer)., Conclusion: This simple question has low sensitivity but high specificity for detecting oral health problems. Although challenging to detect surgical patients with oral health problems by simply asking questions, the results indicated that patients with oral complaints are more likely to have problems during surgery., (© 2024. The Author(s).)

Background: Various cardiovascular diseases cause acquired von Willebrand syndrome (AVWS), which is characterized by a decrease in high-molecular-weight (large) von Willebrand factor (VWF) multimers. Mitral regurgitation (MR) has been reported as a cause of AVWS. However, much remains unclear about AVWS associated with MR., Objectives: To evaluate VWF multimers in MR patients and examine their impact on clinical characteristics., Methods: Moderate or severe MR patients ( n  = 84) were enrolled. VWF parameters such as the VWF large multimer index (VWF-LMI), a quantitative value that represents the amount of VWF large multimers, and clinical data were prospectively analyzed., Results: At baseline, the mean hemoglobin level was 12.9 ± 1.9 g/dL and 58 patients (69.0%) showed loss of VWF large multimers defined as VWF-LMI < 80%. VWF-LMI in patients with degenerative MR was lower than in those with functional MR. VWF-LMI appeared to be restored the day after mitral valve intervention, and the improvement was maintained 1 month after the intervention. Seven patients (8.3%) had a history of bleeding, 6 (7.1%) of whom had gastrointestinal bleeding. Gastrointestinal endoscopy was performed in 23 patients (27.4%) to investigate overt gastrointestinal bleeding, anemia, etc. Angiodysplasia was detected in 2 of the 23 patients (8.7%)., Conclusion: Moderate or severe MR is frequently associated with loss of VWF large multimers, and degenerative MR may cause more severe loss compared with functional MR. Mitral valve intervention corrects the loss of VWF large multimers. Gastrointestinal bleeding may be relatively less frequent and hemoglobin level remains stable in MR patients., (© 2024 The Authors.)

Multiple sclerosis (MS) is an incurable chronic autoimmune disease affecting the central nervous system (CNS). Although IL-17-producing helper T (Th17) cells are thought to be one of the exacerbating factors in MS, the underlying pathogenic mechanism is incompletely understood. TNF receptor-associated factor 6 (TRAF6) deficient T cells exhibited enhanced Th17 cell differentiation, however, the physiological relevance of TRAF6 in T cells remains unknown. Here, we induced experimental autoimmune encephalomyelitis (EAE) in T cell-specific TRAF6 deficient (TRAF6ΔT) mice to investigate the role of TRAF6 in T cells during the course of MS using an EAE model. Although Th17 cell differentiation was enhanced in TRAF6ΔT mice, mutant mice were resistant to EAE. In contrast, TRAF6 loss did not affect regulatory T-cell differentiation. Consistent with the severity of EAE, a small number of infiltrating T cells and a small area of demyelination were observed in the CNS of TRAF6ΔT mice. Moreover, myelin oligodendrocyte glycoprotein-induced IL-17 production in TRAF6-deficient T cells was significantly suppressed. We further confirmed lower levels of CD69 and granulocyte-macrophage colony-stimulating factor in Th17 cells of TRAF6ΔT mice than in wild-type mice. In contrast, the expression of IL-10 and cytotoxic T-lymphocyte-associated protein 4 in T cells was significantly elevated in the absence of TRAF6 because of enhanced T-cell receptor signaling. Collectively, TRAF6 signaling in T cells contributes to the pathogenesis of EAE by regulating the pathogenicity and autoantigen reactivity of Th17 cells., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although the 1-year clinical outcomes of fluoropolymer-based drug-eluting stents (FP-DES) were favorable for the treatment of real-world femoropopliteal lesions in symptomatic peripheral artery disease (PAD), their performance beyond 1 year remained unknown. The current study determined the 3-year clinical course of FP-DES implantation for real-world femoropopliteal lesions., Methods: This multicenter, prospective, observational study evaluated 1204 limbs (chronic limb-threatening ischemia, 34.8%; mean lesion length, 18.6 ± 9.9 cm, chronic total occlusion: 53.2%) of 1097 patients with PAD (age, 75 ± 9 years; diabetes mellitus, 60.8%) undergoing FP-DES implantation for femoropopliteal lesions. The primary outcome measure was 3-year restenosis. The secondary outcome measures included 3-year occlusive restenosis, stent thrombosis, target lesion revascularization (TLR), and aneurysmal degeneration., Results: The 3-year cumulative occurrence of restenosis was 27.3%, whereas that of occlusive restenosis, stent thrombosis, and TLR was 16.1%, 7.3%, and 19.6%, respectively. The annual occurrence of restenosis decreased by 12.0%, 9.5%, and 5.8% in the first, second, and third year, respectively ( p < 0.001). Similarly, the rates of occlusive restenosis and stent thrombosis decreased ( p < 0.001 and p = 0.007, respectively), whereas the rate of TLR remained unchanged for 3 years ( p = 0.15). The incidence of aneurysmal degeneration at 3 years (15.7%) did not significantly differ from that at 1 and 2 years ( p = 0.69 and 0.20, respectively)., Conclusions: This study highlights the favorable long-term clinical course of FP-DES in real-world practice, emphasizing the importance of monitoring for occlusive restenosis and stent thrombosis while considering the potential onset of aneurysmal degeneration., Competing Interests: Declaration of conflicting interestsDrs Iida and Soga are consultants who received honoraria from Boston Scientific. Drs Yamaoka, Fujihara, Kawasaki, and Ichihashi received remuneration from Boston Scientific Japan KK. Dr Mano received a research grant from Abbott Vascular Japan. Dr Sakata received an honorarium from Otsuka Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Medtronic Japan, and Boehringer Ingelheim Japan; a research grant from Edwards Lifesciences, FUJIFILM RI Pharma, REGiMMUNE, and Roche Diagnostics; and a scholarship (educational) grant/endowed chair from Otsuka Pharmaceutical, Johnson & Johnson, St Jude Medical Japan, Daiichi Sankyo, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma Limited, Boehringer Ingelheim Japan, Bayer Yakuhin, BIOTRONIK Japan, Boston Scientific, and Medtronic Japan. The remaining authors have no conflicts of interest to declare.

Background: Whether intraluminal drug-coated balloon (DCB) angioplasty is superior to subintimal DCB angioplasty regarding femoropopliteal (FP) chronic total occlusion (CTO) outcomes has not been systematically determined., Objectives: The aim of this study was to compare the 1-year clinical outcomes of intraluminal and subintimal DCB angioplasty for the treatment of patients with symptomatic FP CTO., Methods: This subanalysis of POPCORN (Prospective Multi-Center Registry of Drug-Coated Balloon for Femoropopliteal Disease) evaluated 469 lesions in 469 symptomatic patients with lower extremity artery disease who presented with FP CTO and underwent DCB treatment. Wire passage (intraluminal vs subintimal) was evaluated using intravascular ultrasound. The outcome measure, 1-year freedom from restenosis, was compared between subintimal and intraluminal DCB angioplasty groups after propensity score matching analysis. The Institutional Review Boards of participating centers approved this study. Informed consent was obtained from the participants or their families., Results: During the median follow-up period of 14.2 months, restenosis occurred in 140 patients. After propensity score matching, the subintimal group had a significantly lower 1-year rate of freedom from restenosis than the intraluminal group (77.0% vs 84.2%, respectively; P = 0.024). Interaction analysis revealed a more marked increased risk for restenosis in the subintimal DCB angioplasty group in patients with severe calcification, low-dose DCB use, or smoking., Conclusions: The present study revealed that intraluminal DCB angioplasty was superior to subintimal DCB angioplasty for FP CTO treatment, with a significantly better 1-year rate of freedom from restenosis., Competing Interests: Funding Support and Author Disclosures The POPCORN study was supported by the Research Association for Lower Limb Artery Revascularization. Drs Soga, Iida, Kawasaki, and Kozuki have received honoraria from Bard Japan and Medtronic Japan. Drs Tobita and Fujihara have received honoraria from Medtronic Japan. Dr Tanaka has received honoraria from Bard Japan. 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.)

Purpose: Drug-coated balloon (DCB) has been established as first-line therapy in femoropopliteal (FP) intervention, and successful vessel preparation (VP) is considered a key element. However, the clinical impact of successful VP remains unknown. This retrospective study examined the clinical impact of successful VP in DCB FP intervention., Methods: In total, 268 patients (308 limbs) who underwent successful FP intervention using DCB without atherectomy devices for symptomatic lower extremity artery disease between March 2018 and December 2019 were included in this study (high-dose DCB: 69.8%; low-dose DCB: 30.2%). Successful VP was defined as <50% residual stenosis and

The patient received endovascular therapy for a superficial femoral artery occlusion. Placement of a SMART stent distal to the lesion was successful, but deployment issues occurred with the Innova stent, requiring forceful retraction and causing elongation. The "cut and peel technique" was developed as a bailout strategy for such cases., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Effective and durable options for infrapopliteal artery revascularization for patients with chronic limb-threatening ischemia (CLTI) are limited., Methods: The SAVAL trial is a prospective, multicenter, randomized trial of patients with CLTI and infrapopliteal artery lesions with total lesion length ⩽ 140 mm, stenosis ⩾ 70%, and Rutherford category 4-5 assigned 2:1 to treatment with the SAVAL self-expandable paclitaxel drug-eluting stent (DES) or percutaneous transluminal angioplasty (PTA) with an uncoated balloon. The primary effectiveness endpoint was primary vessel patency (i.e., core lab-adjudicated duplex ultrasound-based flow at 12 months in the absence of clinically driven target lesion revascularization or surgical bypass of the target lesion). The primary safety endpoint was the 12-month major adverse event (MAE)-free rate; MAEs were defined as a composite of above-ankle index limb amputation, major reintervention, and 30-day mortality. The endpoints were prespecified for superiority (effectiveness) and noninferiority (safety) at a one-sided significance level of 2.5%., Results: A total of 201 patients were enrolled and randomly assigned to treatment ( N = 130 DES, N = 71 PTA). Target lesion length was 68.1 ± 35.2 mm for the DES group and 68.7 ± 49.2 mm for the PTA group, and 31.0% and 27.6% of patients, respectively, had occlusions. The 12-month primary patency rates were 68.0% for the DES group and 76.0% for the PTA group (P superiority = 0.8552). The MAE-free rates were 91.6% and 95.3%, respectively (P noninferiority = 0.0433)., Conclusion: The SAVAL trial did not show benefit related to effectiveness and safety with the nitinol DES compared with PTA in infrapopliteal artery lesions up to 140 mm in length. Continued innovation to provide optimal treatments for CLTI is needed. (ClinicalTrials.gov Identifier: NCT03551496) ., Competing Interests: Declaration of conflicting interestsHans van Overhagen, MD, PhD, serves as a consultant for Boston Scientific and Cordis. Masato Nakamura, MD, PhD, serves as a consultant for Terumo Co. and Boston Scientific; has received honoraria from Boston Scientific and Terumo Co. Patrick J Geraghty, MD, holds stock or stock options in MedAlliance SA, Aveera, Protexa, and Pulse Therapeutics. Sid Rao, MD, serves as a consultant for Cardiovascular Systems, Inc. and Philips. Max Arroyo, MD, has no conflicts of interest to declare. Yoshimitsu Soga, MD, serves as an advisor to Boston Scientific. Osamu Iida, MD, serves as a consultant for Boston Scientific. Ehrin Armstrong, MD, serves as a consultant for Abbott Vascular, Boston Scientific, Gore, Medtronic, Philips, and Shockwave Medical. Tatsuya Nakama, MD, serves as a consultant for Boston Scientific, BD, Cook Medical, Cordis, Kaneka, NIPRO, and OrbusNeichi. Masahiko Fujihara, MD, serves as a consultant for Boston Scientific. Mohammad M Ansari, MD, serves as an advisory board member for Boston Scientific, Medtronic, and Cordis; a steering committee member for Philips; a consultant for Boston Scientific, Terumo, Edwards, Gore, Abbott, Bard, and Medtronic; has research trials with Boston Scientific, Terumo, Gore, Abbott, and Reflow Medical. Santhosh J Mathews, MD, MS, serves as a consultant and advisory board member for Philips, Boston Scientific, Abbott Vascular, and Reflow Medical; a consultant for Penumbra, Cordis, and Shockwave. Yann Gouëffic, MD, PhD, has received research funding from Abbott, Boston Scientific, General Electric, Veryan, WL Gore, and personal fees and grants from Abbott, Bard, Biotronik, Boston Scientific, Cook, General Electric, Medtronic, Penumbra, Terumo, Veryan, and WL Gore. Michael R Jaff, DO, is an employee of Boston Scientific, is a board member of Access Vascular; serves as a consultant for Gilde Healthcare; has an equity investment in R3 Vascular and EFemoral. Ido Weinberg, MD, serves as a consultant to Magneto Thrombectomy Solutions and Penumbra, Inc.; is an employee of VasCore. Duane S Pinto, MD, MPH, serves as a consultant to Abbott Vascular, Abiomed, Biotronik, Boston Scientific, Magenta Medical, Medtronic, NuPulseCV, Terumo; has employment with JenaValve Technology. Norihiko Ohura, MD, serves as a consultant for Boston Scientific. Kara Couch, MS, CRNP, CWCN-AP, FAAWC, serves as a consultant for Boston Scientific and vTail; is on the speaker’s bureau for 3M, Urgo Medical North America, and Organogenesis, Inc. Jihad A Mustapha, MD, serves as a consultant to Angiodynamics, BD Bard, Cardiovascular Systems, Inc., Medtronic, Philips; a consultant and researcher for Avinger, Boston Scientific, Endologix, and Terumo; is Chief Medical Officer for Micromedical; has equity ownership and is a researcher and board member of CardioFlow; has equity ownership of Iatri; is a researcher and has stock options in Reflow Medical.

Background: Severe aortic stenosis (AS) causes acquired von Willebrand syndrome by the excessive shear stress-dependent cleavage of high molecular weight multimers of von Willebrand factor (VWF). While the current standard diagnostic method is so-called VWF multimer analysis that is western blotting under nonreducing conditions, it remains unclear whether a ratio of VWF Ristocetin co-factor activity (VWF:RCo) to VWF antigen levels (VWF:Ag) of <0.7, which can be measured with an automated coagulation analyzer in clinical laboratories and is used for the diagnosis of hereditary von Willebrand disease., Objectives: To evaluated whether the VWF:RCo/VWF:Ag is useful for the diagnosis of AS-induced acquired von Willebrand syndrome., Methods: VWF:RCo and VWF:Ag were evaluated with the VWF large multimer index as a reference, which represents the percentage of a patient's VWF high molecular weight multimer ratio to that of standard plasma in the VWF multimer analysis., Results: We analyzed 382 patients with AS having transaortic valve maximal pressure gradients of >30 mmHg, 27 patients with peripheral artery disease, and 46 control patients free of cardiovascular disease with osteoarthritis, diabetes, and so on. We assumed a large multimer index of <80% as loss of VWF large multimers since 59.0% of patients with severe AS had the indices of <80%, while no control patients or patients with peripheral artery disease, except for 2 patients, exhibited the indices of <80%. The VWF:RCo/VWF:Ag ratios, measured using an automated blood coagulation analyzer, were correlated with the indices (r s  = 0.470, P  < .001). When the ratio of <0.7 was used as a cut-off point, the sensitivity and specificity to VWF large multimer indices of <80% were 0.437 and 0.826, respectively., Conclusion: VWF:RCo/VWF:Ag ratios of <0.7 may indicate loss of VWF large multimers with high specificity, but low sensitivity. VWF:RCo/VWF:Ag ratios in patients with AS having a ratio of <0.7 may be useful for monitoring the loss of VWF large multimers during their clinical courses., (© 2023 The Author(s).)

Purpose: Although the optimal treatment for femoropopliteal (FP) drug-coated balloon (DCB) restenosis lesions remains debatable, the effectiveness of DCB repetition for DCB restenosis has been reported. However, the optimal DCB repetition strategy is not yet established. Thus, this study aimed to compare the clinical outcomes of high-dose DCB repetition with those of low-dose DCB repetition for FP DCB restenosis lesions., Materials and Methods: This single-center, observational study used a clinical database of 677 consecutive patients undergoing FP endovascular intervention for symptomatic peripheral artery disease between December 2018 and December 2021. Of these patients, 89 cases treated with DCB repetition for FP DCB restenosis lesions were analyzed. The primary endpoint was recurrent restenosis (re-restenosis) and the secondary endpoints were recurrent target-lesion revascularization (TLR), re-occlusion, and major adverse limb events (MALE) obtained using propensity score matching. Interaction analysis was also performed to explore the effects of the baseline characteristics on the association between high- and low-dose DCB with restenosis risk., Results: After propensity score matching, high-dose DCB demonstrated a significantly higher freedom from re-restenosis compared with low-dose DCB repetition at 1 year (90.4% vs 40.9%, p=0.034). In addition, freedom from re-TLR and MALE at 1 year was significantly higher in the high-dose DCB group (95.0% vs 53.3%, p=0.025; 95.0% vs 54.7%, p=0.025, respectively). Conversely, freedom rates from re-occlusion were not significantly different between the 2 groups (100.0% vs 84.0%, p=0.99). No baseline characteristics or perioperative outcomes had any significant interaction effect on the association of high-dose DCB versus low-dose DCB with restenosis risk., Conclusion: For FP DCB restenosis lesions, high-dose DCB repetition offered more favorable outcomes than low-dose DCB repetition., Clinical Impact: This study revealed that for femoropopliteal drug-coated balloon (DCB) restenosis lesions, high-dose DCB repetition obtained more favorable outcomes than low-dose DCB repetition. In addition, there was no significant interaction effect on the association of high- versus low-dose DCB with re-restenosis risk for the baseline characteristics and perioperative outcomes. This finding might be also a reason for choosing high-dose DCB repetition for FP DCB restenosis lesions in daily clinical practice., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To investigate the 1-year and 2-year clinical outcomes of interwoven stent (IWS) implantation for symptomatic femoropopliteal arterial disease with calcification., Material and Methods: This prospective multicenter study evaluated 308 limbs (63% with the peripheral arterial calcium scoring system 3 and 4 severe calcification and 87% with ≥180° calcification on intravascular ultrasound) of 299 patients (diabetes in 66.9%, chronic renal failure in 52.8%, and dialysis in 49.2%) who underwent IWS (Supera; Abbott, Abbott Park, Illinois) implantation after sufficient predilation (residual stenosis < 30%) for calcified femoropopliteal lesions. The primary outcome measure was primary patency (freedom from restenosis) at 1 and 2 years, whereas the secondary outcome measure included freedom from clinically driven target lesion revascularization (CD-TLR). Clinical parameters associated with loss of patency were explored., Results: Kaplan-Meier analysis showed that primary patency was 88.2% (95% confidence interval [CI], 84.5%-92.1%) at 1 year and 80.8% (95% CI, 76.1%-85.8%) at 2 years. The CD-TLR-free rate was 96.5% and 94.8% at 1 and 2 years, respectively. The characteristics associated with loss of patency were restenotic lesion with and without stent implantation (adjusted hazard ratio, 1.96 and 2.40; P = .047 and .041, respectively), chronic total occlusion (adjusted hazard ratio, 1.88; P = .022), and popliteal involvement (adjusted hazard ratio, 2.60; P = .002)., Conclusions: The implantation of IWS after sufficient predilation for calcified femoropopliteal atherosclerotic disease demonstrated clinically acceptable primary patency., (Copyright © 2023 SIR. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to reveal the prevalence of sodium-glucose co-transporter 2 (SGLT2) inhibitor treatment and its association with restenosis risk in patients with diabetes mellitus undergoing endovascular therapy for symptomatic peripheral artery disease., Methods: We used the database of a multicenter prospective study registering patients with symptomatic peripheral artery disease undergoing femoropopliteal drug-coated balloon treatment in Japan. The current analysis included 1058 patients with diabetes mellitus free from end-stage renal disease. The association of clinical characteristics with SGLT2 inhibitor use was investigated using the logistic regression model. The propensity score matching was adopted to compare the primary patency, i.e., freedom from restenosis, after endovascular therapy between patients treated with and without a SGLT2 inhibitor., Results: The proportion of SGLT2 inhibitor treatment at revascularization was 14.8% (95% confidence interval, 12.8-17.1%). Younger age, increased body mass index, and increased hemoglobin A1c levels were independently associated with SGLT2 inhibitor use (all P < 0.05). The proportion of SGLT2 inhibitor reached 38.2% (95% confidence interval, 25.4-52.3%) in patients with the three associated factors. The propensity score-matching analysis demonstrated that primary patency was not different between patients treated with a SGLT2 inhibitor and those without it (72.0% [95% confidence interval, 64.1-80.9%] versus 67.8% [62.7-73.3%] at 2 years; P = 0.45)., Conclusions: SGLT2 inhibitors were not rarely used in patients with diabetes mellitus who underwent femoropopliteal endovascular therapy using a drug coated balloon for symptomatic peripheral artery disease in real-world settings. SGLT2 inhibitor treatment was not associated with an increased risk of restenosis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Although favorable results of fluoropolymer-based drug-eluting stent (FP-DES) treatment for femoropopliteal lesions have been reported, it is unclear whether minimal lumen area (MLA) after FP-DES implantation affects clinical outcomes. This study aimed to reveal the association between intravascular ultrasound (IVUS)-evaluated MLA and the 1-year risk of restenosis and aneurysmal degeneration after FP-DES implantation for femoropopliteal lesions., Methods: A subanalysis of the CAPSICUM (Contemporary outcomes After Paclitaxel-eluting peripheral Stent implantation for symptomatic lower limb IsChemia with sUperficial feMoral or proximal popliteal lesion) study analyzed 718 limbs in 686 patients with available IVUS-evaluated MLA data. The association of MLA with the 1-year risk of restenosis and aneurysmal degeneration was analyzed using the generalized propensity score method., Results: The 1-year incidence rate of restenosis was estimated to be 8.8% (95% CI, 6.1% to 12.5%) for the upper quartile of MLA (21.1 mm 2 ) versus 14.3% (95% CI, 10.7% to 18.7%) for the lower quartile of MLA (15.2 mm 2 ), with an odds ratio of 0.58 (95% CI, 0.36 to 0.93; p = 0.024), whereas the 1-year incidence rate of aneurysmal degeneration was 23.8% (95% CI, 19.5% to 28.8%) for the upper quartile versus 16.8% (95% CI, 12.6% to 22.0%) for the lower quartile, with an odds ratio of 1.55 (95% CI, 1.04 to 2.32; p = 0.031)., Conclusion: A large MLA after FP-DES implantation for femoropopliteal lesions was associated with decreased restenosis risk but increased aneurysmal degeneration risk. These findings suggest that MLA is a valuable predictor of clinical outcomes., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Osamu Iida and Yoshimitsu Soga are consultants who received honoraria from Boston Scientific. Terutoshi Yamaoka, Masahiko Fujihara, Daizo Kawasaki, Shigeo Ichihashi, and Amane Kozuki received remuneration from Boston Scientific Japan. The remaining authors have no conflicts of interest to report.

Clinical trials have demonstrated the efficacy of a balloon-expandable covered stent (CS) for aortoiliac occlusive disease (AIOD). However, the real-world clinical outcomes and the underlying factors remain unclear. We assessed the clinical outcomes and factors associated with primary patency after implantation of a balloon-expandable CS for patients with complex AIOD. This prospective multicenter observational study enrolled 149 consecutive patients undergoing VIABAHN ® VBX-CS (W.L. Gore & Associates, Flagstaff, AZ) implantation for complex AIOD (age, 74 ± 9 years; male, 74%; diabetes mellitus, 46%; renal failure on dialysis, 23%; chronic limb-threatening ischemia, 26%). The primary study endpoint was 1-year primary patency, and the secondary endpoints were procedural complications, freedom from occlusion, clinical-driven target lesion revascularization (CD-TLR), and surgical revision at 1 year. Risk factors for restenosis were explored using random survival forest analysis. The median follow-up period was 13.1 months (interquartile range 9.7-14.0 months). Procedural complications were observed in 6.7% of the patients. The 1-year primary patency was 94.8% (95% confidence interval 91.0-98.6%), while the 1-year freedom rate from occlusion, CD-TLR, and surgical revision rates were 96.5% (93.5-99.5%), 94.7% (90.9-98.6%), and 97.8% (95.4-100%), respectively. The presence of chronic total occlusion, aortic bifurcation lesion, the number of disease regions, and TASC-II classification was significantly associated with the restenosis risk. In contrast, the calcification severity, IVUS use, IVUS parameters were not associated with restenosis risk. We observed excellent 1-year real-world outcomes after implantation of a balloon-expandable CS for complex AIOD; only a few perioperative complications occurred., (© 2023. Springer Nature Japan KK, part of Springer Nature.)

Aim: Although recent advances in endovascular devices have markedly improved clinical outcomes of femoropopliteal endovascular therapy, lesions located in the popliteal artery are still a major challenge. This study aimed to determine the association of cardiovascular risk factors, including smoking, diabetes mellitus, and dialysis-dependent renal failure, with the location of atherosclerotic lesions in femoropopliteal artery disease., Methods: We used a multicenter prospective study database registering patients with symptomatic femoropopliteal artery disease undergoing drug-coated balloon treatment. The analysis included 1912 patients with de novo femoropopliteal lesions. The association of clinical characteristics with popliteal lesions was investigated using the logistic regression model. In addition, the femoropopliteal artery was divided into six segments (the proximal, middle, and distal portions of the superficial femoral artery and P1, P2, and P3 segments of the popliteal artery), and the association of clinical characteristics with the presence of atherosclerotic lesions in the respective arterial segments was investigated., Results: Smoking and dialysis-dependent renal failure showed a statistically significant inverse and positive association with the presence of popliteal lesions, respectively (adjusted odds ratio, 0.66 [95% confidence interval, 0.51-0.85] and 2.01 [1.62-2.49]; P=0.001 and P＜0.001), whereas diabetes mellitus did not (P=0.17). The subsequent per-segment analysis presented similar results., Conclusions: Smoking was inversely associated with popliteal lesions, whereas renal failure on dialysis was positively associated in patients with symptomatic femoropopliteal artery disease who underwent drug-coated balloon treatment. Diabetes mellitus was not significantly associated.

Aim: The present study investigated the effects of additional cilostazol administration on the 12-month risk of restenosis after femoropopliteal heparin-bonded stent graft implantation., Methods: This study was a sub-analysis of the Viabahn stent graft placement for femoropopliteal disease reQUIring endovaScular tHerapy (VANQUISH) study, which was a prospective multicenter study investigating patients who received Viabahn stent graft (W.L. Gore & Associates, Flagstaff, AZ, USA) and dual-antiplatelet therapy with aspirin and a thienopyridine. The comparison of clinical outcomes between subgroups with and without cilostazol treatment were performed using the propensity score-matching method to minimize the intergroup differences in baseline characteristics., Results: Cilostazol-treated patients had a lower 12-month proportion of restenosis than cilostazol-free patients (8.2% vs 27.3%). The odds ratio of cilostazol for the 12-month restenosis was 0.27 [95% CI, 0.08 to 0.97] (p=0.045). Furthermore, the cumulative incidence rates of surgical reconstruction, target lesion revascularization and acute thrombotic occlusion (p values by the log-rank test) were 2.6% versus 1.8% (P=0.43), 5.3% versus 20.5% (P=0.067), and 0.0% versus 11.8% (P=0.0499), respectively. The rates of surgical reconstruction and target lesion revascularization (TLR) were not significantly different between both groups., Conclusions: Our study revealed the clinical impact of additional cilostazol treatment on the risk of restenosis and acute thrombotic occlusion following heparin-bonded stent graft implantation, while TLR and surgical reconstruction were not significantly different.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a pivotal role in the induction of inflammatory responses not only in innate immune cells but also in non-immune cells, leading to the activation of adaptive immunity. Signal transduction mediated by TRAF6, along with its upstream molecule MyD88 in intestinal epithelial cells (IECs) is crucial for the maintenance of mucosal homeostasis following inflammatory insult. The IEC-specific TRAF6-deficient (TRAF6ΔIEC) and MyD88-deficient (MyD88ΔIEC) mice exhibit increased susceptibility to DSS-induced colitis, emphasizing the critical role of this pathway. Moreover, MyD88 also plays a protective role in Citrobacter rodentium (C. rodentium) infection-induced colitis. However, its pathological role of TRAF6 in infectious colitis remains unclear. To investigate the site-specific roles of TRAF6 in response to enteric bacterial pathogens, we infected TRAF6ΔIEC and dendritic cell (DC)-specific TRAF6-deficient (TRAF6ΔDC) mice with C. rodentium and found that the pathology of infectious colitis was exacerbated with significantly decreased survival rates in TRAF6ΔDC mice, but not in TRAF6ΔIEC mice, compared to those in control mice. TRAF6ΔDC mice showed increased bacterial burdens, marked disruption of epithelial and mucosal structures with increased infiltration of neutrophils and macrophages, and elevated cytokine levels in the colon at the late stages of infection. The frequencies of IFN-γ producing Th1 cells and IL-17A producing Th17 cells in the colonic lamina propria were significantly reduced in TRAF6ΔDC mice. Finally, we demonstrated that TRAF6-deficient DCs failed to produce IL-12 and IL-23 in response to C. rodentium stimulation, and to induce both Th1 and Th17 cells in vitro. Thus, TRAF6 signaling in DCs, but not in IECs, protects against colitis induced by C. rodentium infection by producing IL-12 and IL-23 that induce Th1 and Th17 responses in the gut., Competing Interests: Declaration of competing interest The authors have no competing financial interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Drug-coated balloons (DCBs) have significantly changed endovascular therapy (EVT) for femoropopliteal artery (FPA) disease, in terms of the expansion of indications for EVT for symptomatic lower extremity arterial disease (LEAD). However, whether there is a difference in the performance among individual DCBs has not yet been fully discussed. The present sub-analysis of real-world data from a prospective trial of first-generation DCBs compared the clinical outcomes between high- and low-dose DCBs using propensity score matching methods. The primary endpoint was the restenosis-free and revascularization-free rates at 1 year., Results: We compared 592 pairs matched for patient and lesion characteristics using propensity score matching among a total of 2,507 cases with first-generation DCBs (592 and 1,808 cases in the Lutonix low-dose and In.PACT Admiral high-dose DCB groups, respectively). There were no differences in patient/lesion characteristics, procedural success rates, or complications between the two groups. First-generation low-dose DCB had significantly lower patency (73.3% [95% confidence interval, 69.6%-77.3%] in the low-dose DCB group versus 86.2% [84.1%-88.3%] in the high-dose DCB group; P < 0.001) and revascularization-free (84.9% [81.9%-88.1%] versus 92.5% [90.8%-94.1%]; P < 0.001) rates. Chronic kidney disease on dialysis, cilostazol use, anticoagulant use, and severe calcification had a significant interaction effect in the association (all P < 0.05)., Conclusions: EVT to FPA with first-generation DCBs had inferior low-dose patency outcomes as compared with high-dose outcomes in the present cohort., Level of Evidence: Sub analysis of a prospective multicenter study., (© 2023. Cardiovascular and Interventional Radiological Society of Europe (CIRSE) and Springer International Publishing AG.)

Introduction: Perioperative oral management (POM) was introduced into the Japanese universal health insurance system in 2012. Collaboration with dental clinics is important for hospitals without a dentistry department. A dental hygienist newly assigned as a member of the patient flow management centre led a seminar to promote collaboration via the web. This study represents the first step to explore the possible role of the hospital-based dental hygienist in the field of regional medical-dental cooperation of POM by assessing their willingness to participate in providing this type of care by a survey., Methods: The rate of attendees' satisfaction and the current problems of the collaboration for POM were evaluated through a questionnaire survey after the web seminar., Results: All respondents reported satisfaction with the web seminar although it was the first experience of an online seminar for half of the respondents. All hospital dentists, but only 47.8% of dentists working at clinics, had participated in POM. Dental hygienist tended to show greater desire to participate in POM than dentists. All respondents appreciated the role played by the dental hygienist as a key manager of medical-dental collaboration between the hospital and local clinics., Conclusion: The hospital-based dental hygienist can play a role in planning and management of web seminars for POM, to raise awareness and promote regional medical-dental cooperation of POM., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The scope of clinical guidelines for the management of chronic limb-threatening ischemia (CLTI) is limited to atherosclerotic disease of the lower-extremity arteries. This study aimed to reveal the clinical features and prognoses of CLTI due to inflammatory nonatherosclerotic etiologies undergoing revascularization., Methods: DECOPON (DatabasE of ChrOnic limb-threatening ischemia Presenting ischemic ulcer and gangrene due to nON-atherosclerotic disease) is a multicenter retrospective study that evaluated 465 limbs of 414 patients with CLTI undergoing revascularization for ischemic tissue loss with inflammatory nonatherosclerotic etiologies between 2010 and 2020. Clinical features and prognoses were compared with 930 limbs of 809 patients with atherosclerotic CLTI during the same period., Results: The frequency of conventional atherosclerotic risk factors was significantly lower in the inflammatory nonatherosclerotic group. The inflammatory nonatherosclerotic group had more severe WIfI (wound, ischemia, and foot infection) W and fI grades, and more frequent infrapopliteal and inframalleolar artery diseases with a rarer presence of arterial calcification (all p < 0.05). Adjunctive therapy was more frequently performed in the inflammatory nonatherosclerotic group ( p < 0.05). The inflammatory nonatherosclerotic group had a lower incidence rate of wound healing (0.64-fold, p < 0.001) and a higher incidence rate of major reintervention (2.30-fold, p = 0.006), whereas the risk ratio of all-cause mortality was 0.83-fold ( p = 0.067). The association of inflammatory nonatherosclerotic disease with the delayed wound healing and the susceptibility to major reintervention remained significant even after adjustment for covariates (both p < 0.001)., Conclusions: Patient, limb, and lesion characteristics of inflammatory nonatherosclerotic CLTI were considerably different from those of atherosclerotic CLTI. Inflammatory nonatherosclerotic CLTI was less likely to heal than atherosclerotic CLTI.

Purpose: The value of intravascular ultrasound (IVUS) guidance during peripheral vascular revascularization procedures is incompletely understood. Moreover, data on long-term clinical outcomes and costs are limited. The objective of this study was to compare outcomes and costs between IVUS and contrast angiography alone in patients undergoing peripheral revascularization procedures in Japan., Materials and Methods: This retrospective comparative analysis was performed using the Japanese Medical Data Vision insurance claims database. All patients undergoing revascularization for peripheral artery disease (PAD) between April 2009 and July 2019 were included. Patients were followed until July 2020, death, or a subsequent revascularization procedure for PAD. Two patient groups were compared: one undergoing IVUS imaging or the other contrast angiography alone. The primary end point was major adverse cardiac and limb events, including all-cause-mortality, endovascular thrombolysis, subsequent revascularization procedures for PAD, stroke, acute myocardial infarction, and major amputations. Total health care costs were documented over the follow-up and compared between groups, using a bootstrap method., Results: The study included 3956 patients in the IVUS group and 5889 in the angiography alone group. Intravascular ultrasound was significantly associated with reduced risk of a subsequent revascularization procedure (adjusted hazard ratio: 0.25 [0.22-0.28]) and major adverse cardiac and limb events (0.69 [0.65-0.73]). The total costs were significantly lower in the IVUS group, with a mean cost saving over follow-up of $18 173 [$7 695-$28 595] per patient., Conclusion: The use of IVUS during peripheral revascularization provides superior long-term clinical outcomes at lower costs compared with contrast angiography alone, warranting wider adoption and fewer barriers to IVUS reimbursement for patients with PAD undergoing routine revascularization., Clinical Impact: Intravascular ultrasound (IVUS) guidance during peripheral vascular revascularization has been introduced to improve the precision of the procedure. However, questions over the benefit of IVUS in terms of long-term clinical outcome and over cost have limited its use in everyday clinical practice. This study, performed in a Japanese health insurance claims database, demonstrates that use of IVUS provides a superior clinical outcome over the long term at a lower cost compared to angiography alone. These findings should encourage clinicians to use IVUS in routine peripheral vascular revascularization procedures and encourage providers to reduce barriers to use.

Mobile intrinsic localized modes (ILMs) in balanced nonlinear capacitive-inductive cyclic transmission lines are studied by experiment, using a spatiotemporal driver under damped steady-state conditions. Without nonlinear balance, the experimentally observed resonance between the traveling ILM and normal modes of the nonlinear transmission line generates lattice drag via the production of a lattice backwave. In our experimental study of a balanced running ILM in a steady state, it is observed that the fundamental resonance can be removed over extended, well-defined driving frequency intervals and strongly suppressed over the complete ILM driving frequency range. Because both of these nonlinear capacitive and inductive elements display hysteresis our observation demonstrates that the experimental system, which is only partially self-dual, is surprisingly tolerant, regarding the precision necessary to eliminate the ILM backwave. It appears that simply balancing the cell dual nonlinearities makes the ILM envelope shape essentially the same at the two locations in the cell, so that the effective lattice discreteness seen by the ILM nearly vanishes., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Vascular endothelial growth factor A (VEGF-A) plays pivotal roles in regulating tumor angiogenesis as well as physiological vascular function. The major VEGF-A isoforms, VEGF-A121 and VEGF-A165, in serum, plasma, and platelets have not been exactly evaluated due to the lack of the appropriate assay system. Antibodies against human VEGF-A121 and VEGF-A165 (hVEGF-A121 and hVEGF-A165) were successfully produced and Enzyme-Linked ImmunoSorbent Assay (ELISA) for hVEGF-A121 and hVEGF-A165 were separately created by these monoclonal antibodies. The measurement of recombinant hVEGF-A121 and hVEGF-A165 by the created ELISA showed no cross-reaction between hVEGF-A121 and hVEGF-A165 in conditioned media from HEK293 cells transfected with either hVEGF-A121 or hVEGF-A165 expression vector. The levels of VEGF-A121 and VEGF-A165 in serum, plasma, and platelets from 59 healthy volunteers proved that VEGF-A121 level was higher than VEGF-A165 in both plasma and serum in all the cases. VEGF-A121 or VEGF-A165 in serum represented higher level than that in plasma. In contrast, the level of VEGF-A165 was higher than VEGF-A121 in platelets. The newly developed ELISAs for hVEGF-A121 and hVEGF-A165 revealed different ratios of VEGF isoforms in serum, plasma, and platelets. Measuring these isoforms in combination provides useful information as biomarkers for diseases involving VEGF-A121 and VEGF-A165., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yamakuchi 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: It remains unclear whether the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria could apply to peripheral artery disease (PAD) patients undergoing endovascular therapy (EVT)., Aims: We sought to evaluate the application of the ARC-HBR criteria to PAD patients undergoing EVT with contemporary drug-coated devices (DCD) for femoropopliteal artery lesions., Methods: Between May 2012 and December 2019, 542 consecutive patients undergoing EVT with DCD for femoropopliteal artery lesions were retrospectively analysed. The primary study endpoint was major bleeding events, defined as Bleeding Academic Research Consortium type 3 or 5., Results: Of 542 patients, 435 (80.3%) were stratified into the HBR group. The cumulative 5-year incidence of major bleeding events was significantly higher in the HBR group than in the non-HBR group (31.9% vs 2.3%; p<0.001). The 5-year major bleeding event rate gradually increased with the number of ARC-HBR criteria (≥2 major criteria: 48.6%, 1 major: 33.1%, ≥2 minor: 12.9%, and non-HBR: 2.3%; p<0.001). Major bleeding events were associated with a 5.4-fold increased risk of mortality (adjusted hazard ratio: 5.42, 95% confidence interval: 2.91-10.1; p<0.001). Severe chronic kidney disease, heart failure, and severe anaemia were predictors of major bleeding events., Conclusions: 80.3% of PAD patients undergoing EVT for femoropopliteal artery lesions with contemporary drug-coated devices met the ARC-HBR criteria. Given that major bleeding events remarkably increased the risk of mortality after EVT, the ARC-HBR criteria might be helpful for the risk stratification of PAD patients who undergo EVT with contemporary DCD.

Although excessive immune responses by Th17 cells, a helper T cell subset, are implicated in the pathogenesis of inflammatory bowel disease (IBD), the mechanism by which its localization in an inflamed colon is regulated remains unclear. Chemokines and their receptors are involved in the pathogenesis of IBD, however, the relative significance of each receptor on Th17 cells remains unknown. We generated C-C motif chemokine receptor 2 (CCR2) knockout (KO) and CCR6 KO mice in the syngeneic background using the CRISPR/Cas9 system and found that the phenotypes of experimental colitis worsened in both mutant mice. Surprisingly, the phenotype of colitis in CCR2/CCR6-double knockout (CCR2/6 DKO) mice was opposite to that of the single-deficient mice, with significantly milder experimental colitis (p < .05). The same was true for the symptoms in CCR6 KO mice, but not in wild type mice treated with a CCR2 inhibitor, propagermanium. Colonic CCR2 + CCR6 + Th17 cells produced a potentially pathogenic cytokine GM-CSF whose levels in the gut were significantly reduced in CCR2/6 DKO mice (p < .05). These results suggest that GM-CSF-producing CCR2 + CCR6 + Th17 cells are pathogenic and are attracted to the inflamed colon by either CCR2 or CCR6 gradient, which subsequently exacerbates experimental colitis in mice., (© 2023 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

A well-known feature of a propagating localized excitation in a discrete lattice is the generation of a backwave in the extended normal mode spectrum. To quantify the parameter-dependent amplitude of such a backwave, the properties of a running intrinsic localized mode (ILM) in electric, cyclic, dissipative, nonlinear 1D transmission lines, containing balanced nonlinear capacitive and inductive terms, are studied via simulations. Both balanced and unbalanced damping and driving conditions are treated. The introduction of a unit cell duplex driver, with a voltage source driving the nonlinear capacitor and a synchronized current source, the nonlinear inductor, provides an opportunity to design a cyclic, dissipative self-dual nonlinear transmission line. When the self-dual conditions are satisfied, the dynamical voltage and current equations of motion within a cell become the same, the strength of the fundamental, resonant coupling between the ILM and the lattice modes collapses, and the associated fundamental backwave is no longer observed.

Aim: This study aimed to report injury precipitating tissue loss and to provide updated information on the time from tissue loss occurrence to referral to a vascular center for patients who developed chronic limb-threatening ischemia (CLTI) in Japan., Methods: We examined 450 patients who developed CLTI with tissue loss and were registered in a multicenter prospective study between October 2017 and June 2020. They were referred to the participating vascular centers for revascularization. Information on the injury precipitating tissue loss and time to referral was collected at registration. The severity of tissue loss was evaluated using the Wound, Ischemia, and foot Infection classification., Results: Injury precipitating tissue loss was absent in 52.0% (95% confidence interval, 47.3%-56.6%) of the patients. The absence was associated with lower albumin levels and preserved pressure sensation. Although the time to referral was significantly shorter in cases without a history of prereferral revascularization, 16.8% (12.8%-20.7%) of the patients were referred to the vascular centers more than 3 months after tissue loss occurrence. Time to referral, but not the lack of a clear precipitant for tissue loss, was significantly associated with the severity of tissue loss., Conclusion: A clear precipitant for tissue loss was often lacking, particularly in patients with low albumin levels and preserved pressure sensation. Delayed referral to a vascular center is still common.

Assistance by family members or friends plays important roles in the course of treating patients with chronic limb-threatening ischemia (CLTI), both during hospitalization and after discharge. The aim of this study was to reveal the prevalence of social isolation and to explore relevant clinical backgrounds in patients with CLTI presenting with tissue loss and requiring revascularization. We analyzed 413 patients registered in a multicenter study in whom revascularization were scheduled for CLTI with tissue loss. Social isolation was analyzed by assessing the residence status of the patients and the involvement of a trusted family member or friend in their daily lives and during hospitalization. Patients living alone accounted for 24.5% (95% confidence interval [CI] 20.1-28.8%) of the study population. Patients receiving welfare were more likely to live alone (P < 0.001). For patients living alone, 21.8% (95% CI 12.8-30.8%) met a trusted family member or friend in their daily lives less than once per year. Younger age and receiving welfare were independently associated with lower frequency of meeting the trusted person in their daily lives (both P < 0.05). The adjusted odds ratio of age and receiving welfare was 0.44 (95% CI 0.29-0.67) per 10-year increase and 3.47 (95% CI 1.43-8.44), respectively. During hospitalization, 9.9% (95% CI 6.8-13.0%) of the patients had no hospital visits by a trusted family member or friend on three key occasions: the patient's first hospital visit, the preoperative explanation regarding the planned operation, and the day of the operation. Younger age and receiving welfare were independently associated with lower frequency of hospital visits by a family member or friend (both P < 0.05). The adjusted odds ratio of age and receiving welfare for no visit versus ≥ 1 visit was 0.51 (0.36-0.74) per 10-year increase and 5.29 (2.46-11.4), respectively. In conclusion, social isolation is common among patients with CLTI, especially younger patients and those on welfare. Practical countermeasures against social isolation are warranted in the management of CLTI., (© 2023. The Author(s).)

Multiple sclerosis is an autoimmune disease in which the immune system attacks the nerve myelin sheath. The balance between pathogenic Th17 cells and regulatory Treg cells, both of which express the chemokine receptor CCR6 is critical for determining disease activity. It has been postulated that CCL20, the cognate ligand of CCR6, produced by the blood-brain barrier attracts these immune cells to the central nervous system (CNS). However, the pathological phenotypes of the experimental model of multiple sclerosis in CCR6-knockout (KO) mice are inconclusive, while this has not been addressed in CCL20-KO mice. To address this, we generated CCL20-KO and CCR6-KO mice using the CRISPR/Cas9 system. Clinical phenotypes of experimental autoimmune encephalomyelitis (EAE) in the chronic phase were slightly exacerbated in both mutant mice relative to those in wild-type (WT) mice. Inflammatory cell infiltration and demyelination in the CNS were similar in the KO and WT mice. CNS CD4 + T cell counts were the same for mutant and WT mice. The mutant and WT mice did not differ significantly in the proportions of Th17 and Treg cells in the CNS, or in IL-17 and TGF-β mRNA expression in the CNS. These findings suggest that CCL20/CCR6-mediated cell migration is not necessarily required for the onset of EAE, and may be compensated for by other chemokine signals., Competing Interests: Declaration of competing interest The authors have no competing financial interest to declare in relation to the content of this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)