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Tick saliva modulates host responses during a blood feeding process. We identified a novel chemokine binding protein 1-like (HLCBP1-like) gene from the salivary glands of the Asian longhorned tick, Haemaphysalis longicornis. The HLCBP1-like protein, lacking a well-defined conserved domain, showed structural similarity to evasin, a chemokine binding protein from the brown dog tick, Rhipicephalus sanguineus. A preliminary knockdown study of HLCBP1-like revealed that ticks with reduced expression of this gene, halted feeding in the early feeding phase, and did not fully-engorge, unlike the control dsRNA (malE) injected ticks. Also, knockdown ticks induced cellular immune responses in the host skin, similar to control dsmalE-injected ticks, but did not show hemorrhage. These findings suggest that HLCBP1-like may play a modulatory role in the slow feeding phase., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This study aims to investigate whether handgrip strength can predict all-cause mortality following transcatheter edge-to-edge repair (TEER), and whether it improves after TEER., Methods: The OCEAN-Mitral Registry includes 2077 patients who had handgrip strength test before TEER. Scores were divided into quartiles according to the handgrip strength. Additionally, 371 of them had follow-up handgrip strength test 1 year after TEER., Results: Quartile 4 (weakest) were more likely to be older, smaller, and more symptomatic due to heart failure than others as baseline characteristics. Multivariate analyses revealed that quartile 3 and 4 were independently associated with increased risk of all-cause mortality after TEER compared with quartile 1 as a referent (adjusted hazard ratio 1.58, 95 % confidence interval 1.06-2.35, p = 0.024 for quartile 3, and adjusted hazard ratio 2.40, 95 % confidence interval 1.62-3.55, P < 0.001 for quartile 4). In subanalysis, in primary MR, handgrip strength did not change in patients with successful MR reduction (MR ≤2+), whereas it significantly decreased in those without successful MR reduction (MR 3+/4+). Conversely, in secondary MR, it significantly increased in those with successful MR reduction, whereas it did not change in those without successful MR reduction., Conclusions: Weaker handgrip strength, one of the good indicators of frailty was associated with all-cause mortality following TEER. Reduction in MR was linked to improvements in frailty. This is the largest and the very first study showing that MR reduction ≤2+ after TEER would be important for improving frailty and keeping their resilience in this population., Condensed Abstract: The handgrip strength test is a quick and inexpensive way to assess the weakness as a part of frailty. The OCEAN-Mitral Registry includes 2077 patients who had handgrip strength test before transcatheter edge-to-edge repair. Weaker handgrip strength was independently associated with all-cause mortality following TEER. Itis useful for predicting mortality because of its ease. Additionally, we saw the change in frailty assessed by handgrip strength after TEER, and therefore MR reduction ≤2+ after TEER would be important for improving frailty or keeping their resilience in this population., Clinical Trials: OCEAN-Mitral registry (UMIN-ID: UMIN000023653)., Competing Interests: Declaration of competing interest Clinical proctor of TEER for Abbott Medical: Drs. Saji, Yamamoto, Asami, Enta, Shirai, Izumo, Mizuno, Watanabe, Amaki, Yamaguchi, Bota, Ohno, Ueno, Mizutani, Kubo, and Hayashida. Lecturer fees from Abbott Medical: Drs. Saji, Yamamoto, Asami, Enta, Shirai, Izumo, Mizuno, Watanabe, Amaki, Kodama, Yamaguchi, Bota, Ohno, and Kubo. Consultant fees from Abbott Medical: Drs. Saji, Yamamoto, Enta, Izumo, Shirai, Mizuno, Watanabe, Amaki, Bota, Ohno, Kubo, and Ohno. Scholarship donation from Abbott Medical: Drs. Isobe, and Yamaguchi. Advisor of Abbott Medical: Dr. Ohno. The other authors have no relationships relevant to the content of this article., (Copyright © 2024. Published by Elsevier B.V.)

Background: Optimal medical therapy for patients with secondary mitral regurgitation (SMR) undergoing transcatheter edge-to-edge mitral valve repair (M-TEER) remains unclear. This study aimed to investigate the association between beta-blocker uptitration and clinical outcomes after M-TEER., Methods: Using data from the Japanese multicenter registry, we examined 1474 patients who underwent M-TEER for SMR between April 2018 and June 2021. Beta-blocker uptitration was defined as an increased dose of beta-blockers 1 month after M-TEER compared with that before M-TEER. The 2-year clinical outcomes were compared between patients with and without beta-blocker uptitration, utilizing multivariable Cox regression analyses and propensity score matching (PSM)., Results: Of the 1474 patients who underwent M-TEER, 272 (18.4 %) were receiving increasing doses of beta-blockers at the 1-month follow-up. These patients had lower left ventricular ejection fraction (LVEF) and higher B-type natriuretic peptide levels. Most patients in the beta-blocker uptitration group received less than the target dose of beta-blockers. Multivariable Cox regression analyses showed that beta-blocker uptitration was significantly associated with a lower risk of all-cause (adjusted hazard ratio [HR]: 0.55; 95 % confidence interval [CI]: 0.36-0.84; P = 0.006) and cardiovascular mortalities (adjusted HR: 0.45, 95 % CI: 0.26-0.79, P = 0.006). PSM analyses revealed consistent findings. Subgroup analyses revealed a significant interaction between beta-blocker uptitration and LVEF≤40 % (interaction P = 0.018)., Conclusions: In patients with SMR, beta-blocker uptitration after M-TEER was associated with better clinical outcomes, especially in the group with an LVEF≤40 %. Efforts to uptitrate guideline-directed medical therapy after M-TEER for SMR may be necessary, even if reaching the target dose proves challenging., Competing Interests: Declaration of competing interest Drs. Kubo, Saji, Izumo, Watanabe, and Amaki are clinical proctors of transcatheter edge-to-edge repair for Abbott Medical and have received consultant fees from Abbott Medical. Dr. Asami is clinical proctors of transcatheter edge-to-edge repair for Abbott Medical and received speaker fees from Abbott Medical. Dr. Kodama is a clinical proctor of transcatheter edge-to-edge repair for Abbott Medical and has received speaker fees from Abbott Medical. Dr. Yamamoto is a clinical proctor of transcatheter edge-to-edge repair for Abbott Medical and have received lecture fees from Abbott Medical. Dr. Yamaguchi is a clinical proctor of transcatheter edge-to-edge repair for Abbott Medical and has received a lecture fee and scholarship donation from Abbott Medical. Dr. Ohno is a clinical proctor of transcatheter edge-to-edge repair for Abbott Medical and has received consultant, advisor, and speaker fees from Abbott Medical. Drs. Enta, Shirai, Mizuno, Ueno, Bota, and Hayashida are clinical proctors of transcatheter edge-to-edge repair for Abbott Medical. The remaining authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Evidence regarding the incidence of prosthesis-patient mismatch (PPM) and long-term mortality after transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve stenosis (AS) is scarce., Objectives: This study sought to assess the incidence and prognostic impact of PPM after TAVR for bicuspid AS compared with that for tricuspid AS., Methods: In total, 7,393 patients who underwent TAVR were prospectively enrolled in the OCEAN-TAVI (Optimized Catheter Valvular Intervention Transcatheter Aortic Valve Implantation) registry, an ongoing Japanese, multicenter registry. We analyzed 7,051 patients (median age = 85 years, 68.4% women) and identified 503 (7.1%) with bicuspid AS. We compared the incidence of PPM and long-term mortality in 497 patients with and 497 without bicuspid AS after one-to-one propensity score matching analysis., Results: Among the 7,051 patients, moderate and severe PPM were observed in 756 (10.7%) and 92 (1.3%) patients, respectively. Upon Kaplan-Meier curve analysis of the overall cohort, severe PPM appeared to be associated with long-term mortality (log-rank test, P = 0.065). After propensity score matching analysis, moderate and severe PPM were more frequently observed among patients with tricuspid AS than patients with bicuspid AS (moderate PPM, 11.7% vs 4.4%; severe PPM, 1.4% vs 1.0%; P = 0.0001)., Conclusions: Severe PPM appeared to be associated with all-cause mortality. Moderate and severe PPM were more frequently observed in patients with tricuspid AS than patients with bicuspid AS., Competing Interests: Funding Support and Author Disclosures The OCEAN-TAVI registry is supported by Edwards Lifesciences, Medtronic, Boston Scientific, Abbott Medical, and Daiichi-Sankyo Company. Dr Yashima is a clinical proctor for Medtronic. Dr Ohno is a clinical proctor for Medtronic. Dr Izumo is a screening proctor for Edwards Lifesciences. Dr Asami is a clinical proctor for Medtronic. Dr Naganuma is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Takagi is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Mizutani is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Tada is a clinical proctor for Edwards Lifesciences, Abbott Medical, and Medtronic. Dr Shirai is a clinical proctor for Edwards Lifesciences, Abbott Medical, and Medtronic. Dr Ueno is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Watanabe is a clinical proctor for Edwards Lifesciences, Abbott Medical, and Medtronic. Dr Yamamoto is a clinical proctor for Edwards Lifesciences, Abbott Medical, and Medtronic. Dr Hayashida is a clinical proctor for Edwards Lifesciences, Abbott Medical, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Lasers have numerous advantageous tissue interactions such as ablation or vaporization, hemostasis, bacterial killing, as well as biological effects, which induce various beneficial therapeutic effects and biological responses in the tissues. Thus, lasers are considered an effective and suitable device for treating a variety of inflammatory and infectious conditions of periodontal disease. Among various laser systems, the Er:YAG laser, which can be effectively and safely used in both soft and hard tissues with minimal thermal side effects, has been attracting much attention in periodontal therapy. This laser can effectively and precisely debride the diseased root surface including calculus removal, ablate diseased connective tissues within the bone defects, and stimulate the irradiated surrounding periodontal tissues during surgery, resulting in favorable wound healing as well as regeneration of periodontal tissues. The safe and effective performance of Er:YAG laser-assisted periodontal surgery has been reported with comparable and occasionally superior clinical outcomes compared to conventional surgery. This article explains the characteristics of the Er:YAG laser and introduces its applications in periodontal surgery including conventional flap surgery, regenerative surgery, and flapless surgery, based on scientific evidence from currently available basic and clinical studies as well as cases reports., Competing Interests: none., (© 2023 The Authors.)

Background: Transcatheter aortic valve replacement (TAVR) using a self-expandable valve (SEV) promotes better hemodynamics compared with a balloon-expandable valve (BEV) in a small aortic annulus (SAA)., Objectives: The authors sought to compare hemodynamic properties and clinical outcomes between the latest-generation BEV and SEV after TAVR for SAA., Methods: We retrospectively analyzed 1,227 patients undergoing TAVR for aortic stenosis with SAA, defined as an annulus area ≤430 mm 2 , using the BEV (SAPIEN3 Ultra RESILIA, Edwards Lifesciences) and SEV (Evolut FX, Medtronic). The impact of valve design on severe prosthesis-patient mismatch, aortic valve mean pressure gradient ≥20 mm Hg, paravalvular leakage (PVL) ≥ mild, new permanent pacemaker implantation (PMI), and modified VARC-3 device success at discharge was evaluated using logistic regression and propensity score analysis., Results: Of 1,227 patients, 798 (65.0%) underwent TAVR with BEV implantation. TAVR using BEV had a relatively higher rate of severe prosthesis-patient mismatch (OR: 1.74; 95% CI: 0.54-5.62) and significantly higher incidence of mean pressure gradient ≥20 mm Hg (OR: 2.05; 95% CI: 0.91-4.62) than that using SEV. By contrast, the BEV showed significantly lower incidence of PVL ≥ mild (OR: 0.19; 95% CI: 0.14-0.26), and new PMI (OR: 0.53; 95% CI: 0.33-0.86). The rate of device success was comparable between the BEV and the SEV. These results were confirmed by propensity score analysis., Conclusions: In TAVR for SAA, SEV demonstrated better hemodynamics than the latest BEV, whereas the latest BEV had lower incidences of PVL ≥ mild and new PMI than the SEV., Competing Interests: Funding Support and Author Disclosures The OCEAN-TAVI registry is supported by Edwards-Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, and Daiichi-Sankyo. Drs Yamamoto, Shirai, Watanabe, Yamasaki, Hachinohe, and Hayashida served as clinical proctors for Edwards Lifesciences, Abbott Medical, and Medtronic. Drs Ohno, Yashima, Asami, and Nishina are clinical proctors for Medtronic. Drs Naganuma, Mizutani, Takagi, Ueno, and Fuku are clinical proctors for Edwards Lifesciences and Medtronic. Dr Izumo is a screening proctor for Edwards Lifesciences. Dr Nishioka is a clinical proctor for Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The data that support the findings of this study are available on request from the corresponding author Dr Masanori Yamamoto., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Agmatine, a natural polyamine also known as 4-aminobutyl-guanidine, is biosynthesized from arginine by decarboxylation. Aspergillus oryzae contains high amounts of agmatine, suggesting highly active arginine decarboxylase (ADC) in this organism. However, genome analysis revealed no ADC homolog in A. oryzae. A. oryzae strain RIB40 has six homologs of phosphatidylserine decarboxylase (PSD), an enzyme that synthesizes phosphatidyl ethanolamine from phosphatidylserine. We previously discovered that one of these homologs, AO090102000327, encodes arginine decarboxylase, which we named ADC1. In the present study, we determined the crystal structures of ligand-free, arginine-treated, and agmatine-treated ADC1 each at 1.9-2.15 Å resolution. Each structure contained four ADC1 molecules (chains A-D) in the asymmetric unit of the cell. Each ADC1 molecule is a heterodimer consisting of the N-terminal region (Asn60-Gly441) and C-terminal region (Ser442-Thr482). In the ligand-free ADC1, the N-terminus of Ser442 was modified to form a pyruvoyl group. In the arginine-treated ADC1, arginine was converted to agmatine, with the pyruvoyl group covalently bound to agmatine by forming a Schiff base. The same structure was observed in agmatine-treated ADC1. These results indicate that ADC1 is a pyruvoyl-dependent decarboxylase and unveils the reaction mechanism of ADC from A. oryzae., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interestsKiyoshi Yasukawa reports financial support was provided by Japan Society for the Promotion of Science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The mechanism and impact of mismatch between residual mitral regurgitation (MR) and postprocedural left atrial pressure (LAP) after transcatheter edge-to-edge repair (TEER), which may adversely affect clinical outcome, is of great interest., Objectives: This study aimed to examine the effect of hemodynamic mismatch after TEER on clinical outcomes in patients with heart failure due to severe MR and investigate the predictive factors for the mismatch using a prospective multicenter registry., Methods: We categorized 1,477 patients into optimal (residual MR grade ≤1 and postprocedural LAP ≤15 mm Hg), mismatched (residual MR grade >1 or postprocedural LAP >15 mm Hg), and poor (residual MR grade >1 and postprocedural LAP >15 mm Hg) groups and examined their prognosis. The primary endpoint was a composite of all-cause mortality and heart failure hospitalization., Results: There were 927 (62.7%), 459 (31.1%), and 91 (6.2%) patients categorized into optimal, mismatched, and poor groups, respectively. Cox regression analysis, referenced to the optimal group, revealed that the mismatched and poor groups exhibited a higher risk for the primary endpoint (HR: 1.55; 95% CI: 1.28-1.88; and HR: 1.95; 95% CI: 1.38-2.74, respectively). Six risk factors were identified as predictors of hemodynamic mismatch after TEER: body mass index, baseline left atrial volume index, atrial fibrillation, tricuspid annular plane systolic excursion value, preprocedural mean left atrial pressure, and postprocedural mean mitral valve pressure gradient., Conclusions: Post-TEER hemodynamic mismatch between residual MR and postprocedural LAP was associated with a poor prognosis. Six readily accessible perioperative parameters predict the hemodynamic mismatch. (OCEAN-Mitral registry; UMIN000023653)., Competing Interests: Funding Support and Author Disclosures The OCEAN-Mitral registry, part of the OCEAN-SHD registry, is supported by Edwards Lifesciences, Medtronic Japan, Boston Scientific, Abbott Medical Japan, and Daiichi-Sankyo Company. Dr Yamaguchi has served as a clinical proctor of transcatheter edge-to-edge repair and received a lecture fee and scholarship donation from Abbott Medical. Drs Yamamoto and Nakajima have served as clinical proctors of transcatheter edge-to-edge repair for and received lecture fees from Abbott Medical. Drs Saji, Kubo, Izumo, Watanabe, and Amaki have served as clinical proctors of transcatheter edge-to-edge repair for and received consulting fees from Abbott Medical. Drs Asami and Kodama have received speaker fees from Abbott Medical. Drs Enta, Shirai, Mizuno, and Bota have served as clinical proctors of transcatheter edge-to-edge repair for Abbott Medical. Dr Ohno has received consulting, advisor, and speaker fees from Abbott Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Early prediction of aorta-related events is important for determining subsequent treatment strategies in patients with acute aortic dissection. However, most studies evaluated long-term aortic growth rates by annual assessment. The purpose of our study was to determine whether the in-hospital growth rate of aortic volume was associated with aorta-related events., Methods: We studied 116 patients with uncomplicated type B acute aortic dissection. We analyzed whether changes in aortic volume were associated with aorta-related events during a 5-year follow-up. According to the growth rate from admission to discharge, patients were divided into two groups: Increase >0 (aortic volume: n = 59, aortic diameter: n = 43) and Reduction ≤0 (aortic volume: n = 57, aortic diameter: n = 73) in maximum aortic diameter or aortic volume. The primary endpoint was the discriminative ability of the growth rate of aortic volume for aorta-related events., Results: According to the evaluation of aortic volume changes, the Increase group had significantly higher aorta-related event rates than those in the Reduction group (49.2 % vs. 3.5 %, respectively; p < 0.001). Receiver operating characteristics analysis showed that the growth rate of aortic volume had a clearly useful discrimination, with an area under the curve of 0.84, whereas the discriminative ability of the growth rate of maximum aortic diameter was poor (area under the curve: 0.53). Multivariate analysis showed that the growth rate of aortic volume from admission to discharge was an independent predictor of aorta-related events (hazard ratio, 26.3; 95 % confidence interval, 2.04-286.49; p = 0.001)., Conclusions: In-hospital evaluation of aortic volume was helpful to predict long-term aorta-related events in patients with uncomplicated type B acute aortic dissection., Competing Interests: Declaration of competing interest Kazuyoshi Kakehi: has no conflict of interest to report. Masafumi Ueno: has no conflict of interest to report. Takayuki Kawamura: has no conflict of interest to report. Nobuhiro Yamada: has no conflict of interest to report. Kuniaki Takahashi: has no conflict of interest to report. Kosuke Fujita: has no conflict of interest to report. Masakazu Yasuda: has no conflict of interest to report. Koichiro Matsumura: has no conflict of interest to report. Tatsuya Miyoshi: has no conflict of interest to report. Kazuki Mizutani: has no conflict of interest to report. Toru Takase: has no conflict of interest to report. Genichi Sakaguchi: has no conflict of interest to report. Gaku Nakazawa: has no conflict of interest to report., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Despite the wide implementation of transcatheter aortic valve implantation (TAVI), the optimal antithrombotic therapy after TAVI has not been established yet. Owing to the accumulating evidence supporting the efficacy and safety of single antiplatelet therapy (SAPT) over dual antiplatelet therapy, the latest guideline recommends life-long SAPT. However, there is scarce evidence supporting SAPT compared with non-antithrombotic therapy. Given the vulnerability of patients undergoing TAVI in terms of high bleeding risk, the benefit of SAPT may be canceled out by its potential increased bleeding risk., Study Design and Objectives: Non-antithrombotic Therapy After Transcatheter Aortic Valve Implantation (NAPT) Trial is a prospective, randomized controlled, open-label blinded endpoint multicenter trial conducted in Japan, testing the non-inferiority of non-antithrombotic therapy compared with aspirin monotherapy in patients who underwent TAVI and had no indications for long-term oral anticoagulation therapy (OAC). Patients who successfully underwent trans-femoral TAVI for severe aortic stenosis with either balloon-expandable or self-expandable valves are eligible for inclusion. Key exclusion criteria are (i) occurrence of perioperative complications (ii) indications of taking antithrombotic drugs for other reasons; (iii) eGFR <30 ml/min/1.73 m2 or hemodialysis or peritoneal dialysis. A total of 360 patients will be randomized (1:1) to aspirin monotherapy vs. non-antithrombotic therapy. The primary outcome is a composite of all-cause mortality, myocardial infarction, stroke, and bleeding. All bleeding events based on the Valve Academic Research Consortium 3 are included as a component of the primary outcome., Conclusion: The NAPT trial will determine the non-inferiority of a non-antithrombotic therapy compared with aspirin monotherapy after TAVI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Drs. Shirai, Yamamoto, and Hayashida are clinical proctors for Edwards Lifesciences, Medtronics, and Abbott Medicals. Drs. Tada, Naganuma, Mizutani, Tabata, Ueno, and Watanabe are clinical proctors for Edwards Lifesciences and Medtronic. Dr. Izumo is a screening proctor for Edwards Lifesciences. Dr. Yashima is a clinical proctor for Medtronic. All other authors have no relationships relevant to the contents of this article to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The present study compared trends in antimicrobial resistance patterns in pathogens isolated from skin and soft-tissue infections (SSTIs) in Japan with those of a nationwide survey conducted in 2013. Three organisms that caused most of the SSTIs were collected from 12 dermatology departments in medical centers and 12 dermatology clinics across Japan between April 2019 and August 2020. A total of 390 strains, including 267 Staphylococcus aureus, 109 coagulase-negative staphylococci (CNS), and 14 Streptococcus pyogenes strains were submitted to a central laboratory for antimicrobial susceptibility testing. Patient demographic and clinical information was collated. Methicillin-resistant S. aureus (MRSA) was detected in 25.8% (69/267) of the S. aureus strains. The prevalence of MRSA between the present study and the 2013 survey did not differ significantly. Furthermore, there were no significant differences in MIC values and susceptibility patterns of the MRSA strains to other agents, regardless of a history of hospitalization within 1 year or invasive medical procedures. Methicillin-resistant CNS (MRCNS) was detected in 48.6% (53/109) of CNS isolates, higher than the 35.4% prevalence in the 2013 survey. This difference could be attributed to the heterogeneity in the members of the MRCNS, which comprises multiple staphylococci species, between the 2013 and 2019 surveys. However, it was noted that the susceptibility profiles of the MRCNS to each antibiotic were not significantly different from those identified in the 2013 survey. Most strains of S. pyogenes were susceptible to each antibiotic, similar to the 2013 survey. Continuous monitoring of trends in pathogen and susceptibility profiles is important to advise local public health efforts regarding the appropriate treatment of SSTIs., Competing Interests: Declaration of competing interest Tetsuya Matsumoto received speaker honoraria from MSD K·K., and Pfizer Japan Inc., Intestu Kobayashi received scholarship donations from Nippon Becton Dickinson Company, Ltd., Tatsuyoshi Kawamura speaker honoraria from Maruho Co., Ltd., and Eli Lilly Japan K.K. and received scholarship donations from AbbVie GK., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Purpose: COVID-19 causes physical and psychological impacts on health care workers (HCWs), especially when it occurs during an outbreak. As there are few reports on outcomes of HCWs infected with COVID-19 during a hospital outbreak, we investigated the physical and psychological impacts on HCWs infected with COVID-19 during an outbreak in our hospital., Methods: During the outbreak in our hospital, 231 people were infected with COVID-19 including patients, HCWs and their families. Among them, 83 HCWs were enrolled in this study. Current quality of life (QOL) was assessed with the EuroQol-visual analogue scales (EQ-VAS), and motivation to keep on working was evaluated by a 10-point analogue scale. Physiological recovery rates including return to work (RTW) period were also analyzed., Results: One nurse quit work due to anxiety regarding re-infection with COVID-19. The median period to RTW from the diagnosis was 14.0 (12.0-17.0) days. Motivation to keep on working was slightly reduced, and the EQ-VAS was 75.0 (65.0-83.6). There were no significant differences in QOL and motivation between male and female HCWs, nurses and other HCWs, treatment and non-treatment group, and supplemental and non-supplemental oxygen group. The most frequent persistent symptoms at 1,3 and 6 months after infection were anosmia followed by fatigue., Conclusion: Although QOL and motivation to keep on working were slightly reduced, only one HCW quit work. No severe persistent symptoms were observed, and the RTW period was relatively short., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Several trials demonstrated that aspirin monotherapy compared with aspirin plus clopidogrel is associated with a lower incidence of bleeding without an increased risk of ischemic events in patients after transcatheter aortic valve replacement (TAVR); however, there remains a paucity of data to prove the necessity of even aspirin monotherapy., Objectives: This study aimed to compare clinical outcomes and valve performance of the 3 different antithrombotic strategies post-TAVR from the OCEAN-TAVI (Optimized transCathEter vAlvular iNtervention) registry., Methods: Patients who received anticoagulation or had procedural complications were excluded. The remaining patients were classified into 3 groups according to the antithrombotic regimen at discharge: 1) nonantithrombotic therapy (None); 2) single-antiplatelet therapy (SAPT); and 3) dual-antiplatelet therapy (DAPT). The primary outcome was the incidence of net adverse clinical events (NACEs) (ie, cardiovascular death, stroke, myocardial infarction, and life-threatening or major bleeding)., Results: Overall, 3,575 TAVR patients were included (None, 293; SAPT, 1,354; DAPT, 1,928). The median follow-up period was 841 days (IQR: 597-1,340 days). The incidence of NACEs did not differ between the groups (None vs SAPT: adjusted HR [aHR]: 1.18; P = 0.45; None vs DAPT: aHR: 1.09; P = 0.67). There was a lower incidence of all bleeding in patients with no antithrombotics (None vs SAPT: aHR: 0.63; P = 0.12; None vs DAPT: aHR: 0.51; P = 0.04). The valve performance was similar among the groups. Leaflet thrombosis was detected in 8.5% of the nonantithrombotic group., Conclusions: Compared with SAPT/DAPT, the nonantithrombotic strategy was not associated with an increased risk of NACEs and potentially reduced the risk of bleeding events. The nonantithrombotic strategy may be an acceptable alternative to SAPT/DAPT in selected patients with TAVR., Competing Interests: Funding Support and Author Disclosures The OCEAN-TAVI registry is supported by the following companies: Edwards Lifesciences, Abbott, Medtronic, Boston Scientific, and Daiichi-Sankyo. Dr Yashima is a clinical proctor for Medtronic. Dr Naganuma is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Mizutani is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Tada is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Shirai is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Tabata is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Ueno is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Takagi is a clinical proctor for Edwards Lifesciences. Dr Watanabe is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Yamamoto is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Hayashida is a clinical proctor for Edwards Lifesciences, Medtronic, and Abbott Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Since neural epidermal growth factor-like-like (NELL) 2 was identified as a novel ligand for the roundabout (Robo) 3 receptor, research on NELL-Robo signaling has become increasingly important. We have previously reported that Robo2 can bind to NELL1/2 in acidic conditions but not at neutral pH. The NELL1/2-binding site that is occluded in neutral conditions is thought to be exposed by a conformational change of the Robo2 ectodomain upon exposure to acidic pH; however, the underlying structural mechanisms are not well understood. Here, we investigated the interaction between the immunoglobulin-like domains and fibronectin type III domains that form hairpin-like structure of the Robo2 ectodomain, and demonstrated that acidic pH attenuates the interaction between them. Alternative splicing isoforms of Robo2, which affect the conformation of the hairpin-like structure, were found to have distinct NELL1/2-binding affinities. We developed Förster resonance energy transfer-based indicators for monitoring conformational change of the Robo2 ectodomain by individually inserting donor and acceptor fluorescent proteins at its ends. These experiments revealed that the ends of the Robo2 ectodomain are close to each other in acidic conditions. By combining these findings with the results of size exclusion chromatography analysis, we suggest that, in acidic conditions, the Robo2 ectodomain has a compact conformation with a loose hairpin-like structure. These results may help elucidate the signaling mechanisms resulting from the interaction between Robo2 and NELL1/2 in acidic conditions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Access-site complications during transfemoral transcatheter aortic valve implantation (TF-TAVI) cause serious issues in the future, if unresolved, but the best strategies to manage these complications remains unclear. This study aimed to comprehensively assess access-site complications during percutaneous TF-TAVI in terms of their management., Methods: Using the prospective, multicentre, observational registry OCEAN (Optimized Transcatheter Valvular Intervention), 1497 patients who underwent percutaneous TF-TAVI between October 2013 and May 2017 were identified. The incidence, predictors, temporal changes, and prognosis of access-site complications along with its treatment strategy and re-intervention rate were evaluated., Results: Access-site complications occurred in 105 patients (7.0%) and was predicted with lower body-mass-index (OR, 0.94; 95% CI; 0.89-0.99; p = 0.03) and higher sheath-to-femoral-artery-ratio (OR, 1.12; 95% CI, 1.03-1.24; p < 0.002). The incidence of access-site complications declined over time, irrespective of the increasing number of percutaneous TF-TAVI cases. Access-site complications were treated by conservative therapy (n = 19, 18%), interventional procedures (n = 42, 40%), rescue surgical repair (SR) (n = 10, 10%), and primary SR (n = 34, 32%). The severity of complications differed but the re-intervention rate was similar among 4 groups (p = 0.46). Re-intervention was not needed, except for a case of common femoral artery stenosis/occlusion induced by ProGlide. The need for all SRs decreased annually. Access-site complications were not associated with 30 days- and 1 year-survival rate., Conclusions: The incidence of access-site complications was not low but has declined annually. Access-site complications are not related to worse outcomes after successful management. Interventional procedure is acceptable as the first-line strategy to treat access-site complications., Competing Interests: Declaration of competing interest Drs. Yamamoto, Tada, Naganuma, Shirai, Mizutani, Tabata, Ueno, and Watanabe are clinical proctors for Edwards Lifesciences and Medtronic. Drs. Takagi and Hayashida are clinical proctors of Edwards Lifesciences. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: In the current guidelines, indications for transcatheter aortic valve implantation (TAVI) are expanded to include several subgroups of asymptomatic patients with severe aortic stenosis (AS), and there is a paucity of data on the prognostic impact of New York Heart Association (NYHA) functional class in patients with severe AS undergoing TAVI., Methods: Among 2588 patients enrolled in the OCEAN-TAVI registry, patients were divided into 4 groups according to baseline NYHA class (class I in 95 patients, class II in 1172 patients, class III in 1126 patients, and class IV in 195 patients)., Results: Median follow-up was 729 days. The cumulative 2-year incidence of all-cause death was significantly higher in patients with NYHA class IV and III than in those with NYHA class II and I. (30.0%, 21.3%, 13.4%, and 11.2%, respectively, P < 0.001). After adjusting confounders, NYHA class IV and III, but not NYHA class II were independently associated with higher mortality compared with NYHA class I (reference) (adjusted HR: 3.43, 95%CI: 1.83-7.15, P < 0.001; adjusted HR: 2.07, 95%CI: 1.15-4.19, P = 0.013; and adjusted HR: 1.50, 95%CI: 0.83-3.04, P = 0.19, respectively). With increasing NYHA class, there was an incremental increase of heart failure hospitalization in the effect size relative to the reference (NYHA class I)., Conclusions: The long-term outcomes of patients with NYHA class I were better than those with NYHA class IV or III in some selected patients undergoing TAVI., Competing Interests: Declaration of competing interest Dr. Yamamoto, Dr. Tada, Dr. Naganuma, Dr. Shirai, Dr. Mizutani, Dr. Watanabe, Dr. Tabata and Dr. Ueno are clinical proctors for Edwards Lifesciences and Medtronic. Dr. Arai, Dr. Takagi, and Dr. Hayashida are clinical proctors of Edwards Lifesciences. The remaining authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The impact of balloon post-dilatation (BPD) on short- and long-term valve performance after Sapien 3 (S3) implantation is unknown. This study aimed to evaluate the impact of balloon post-dilatation (BPD) on short- and long-term valve performance after the implantation of S3., Methods: A total of 846 patients implanted with S3 from the OCEAN-TAVI registry were included in this study. The patients were divided into BPD and non-BPD groups. The clinical outcomes and valve functions were compared., Results: The BPD group included 173 (20.4%) patients and the non-BPD group comprised 673 (79.6%) patients. The prosthesis-patient mismatch (PPM) rates were significantly lower in the BPD group than in the non-BPD group before and after propensity score matching at in-hospital follow-up (before matching: 12 [7.1%] vs. 108 [16.3%], p = 0.002; after matching: 8 [6.3%] vs. 19 [14.8%], p = 0.027) and at 1-year follow-up (before matching: 14 [12.5%] vs. 112 [23.6%], p = 0.010; after matching: 9 [10.5%] vs. 19 [22.1%], p = 0.039). The rates of acute kidney injury, cardiac tamponade, and in-hospital cardiovascular death were significantly higher in the BPD group than in the non-BPD group (acute kidney injury: 22 [12.7%] vs. 33 [4.9%], p < 0.001; cardiac tamponade: 3 [1.7%] vs. 2 [0.3%], p = 0.028; in-hospital cardiovascular death: 4 [2.3%] vs. 3 [0.4%], p = 0.016). After matching, these clinical outcomes were similar between the BPD and non-BPD groups., Conclusions: The BPD group demonstrated better short- and long-term valve performance. Caution is needed to avoid procedure-related complications in patients undergoing BPD., Competing Interests: Declaration of competing interest Drs. Yamamoto, Tada, Naganuma, Shirai, Mizutani, Tabata, Ueno, and Watanabe are clinical proctors for Edwards Lifesciences and Medtronic. Drs. Takagi and Hayashida are clinical proctors of Edwards Lifesciences. The remaining authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Dimethylallyltryptophan synthases (DMATSs) catalyze the prenyl transfer reaction from dimethylallyl pyrophosphate (DMAPP) to an indole ring. IptA, a member of the DMATS family, is involved in biosynthesis of 6-dimethylallylindole-3-carbaldehyde in Streptomyces sp. SN-593 and catalyzes the C6-prenylation of l-Trp. The enzyme exhibits prenyl acceptor promiscuity and can accept various Trp derivatives, as observed in several other DMATS family members. Although many crystal structures of DMATS have been determined to date, the structural basis of substrate promiscuity and the acceptance of alternatives to indole-containing natural substrates remain to be clarified. In this study, we determined the crystal structures of the ternary l-Trp derivative (5-methyl-, 6-methyl-, and Nα-methyl-l-Trp) -DMSPP (dimethylallyl S-thiolopyrophosphate; stable analog of DMAPP) -enzyme complex of IptA, in addition to the substrate-free IptA and ternary l-Trp-DMSPP-IptA complex crystal structures. The overall structure of IptA exhibited a typical ABBA-fold, which is commonly found in DMATS family members, while l-Trp and DMSPP are found in a tunnel located inside the ABBA barrel. The crystal structure of the ternary l-Trp-DMSPP-enzyme complex can explain the electrophilic substitution at the C6 atom of l-Trp, which is assisted by Glu84 and His294, as previously suggested for other DMATSs. Although l-Trp snugly fitted into the active site pocket and the unoccupied space around l-Trp is very limited in the l-Trp-DMSPP-IptA complex structure, the enzyme can accommodate 5-methyl- and 6-methyl-l-Trp by slight relocation of the substrate indole ring and adjacent side chain in the active site, resulting in a higher prenylation activity for 5-methyl-l-Trp and C7 prenylation of 6-methyl-l-Trp. Like many other DMATSs, IptA cannot utilize prenyl donors larger than DMAPP. To enlarge the prenyl donor-binding pocket, the W154A mutation was introduced. As expected, this mutant produced prenylated l-Trp from l-Trp and geranyl- and farnesyl pyrophosphate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Brain tumors often become clinically evident during pregnancy; however, the mechanism has not been well elucidated. Purpose of this study is to investigate the influence of molecular genetic factors on the progression of brain tumors during pregnancy or the postpartum period., Methods: Twelve cases of brain tumors that presented during pregnancy or postpartum period were included: five gliomas, three meningiomas, two vestibular schwannomas, and two chordomas. Tumor samples were investigated by metaphase comparative genomic hybridization and immunohistochemistry, for chromosomal copy number aberration (CNA) and receptor expression of sex hormones and growth factors., Results: The results were correlated with the timing of tumor presentation in relation to the stage of pregnancy. EGFR, VEGFR-1/2, AR, and c-Myc were expressed in gliomas, PgR, ER, HER-2, VEGFR-1, EGF and VEGFR2 in meningiomas, VEGFR-1 in vestibular schwannomas, and EGFR, VEGFR-1/2, and c-Myc in chordomas. The CNAs of the tumors varied. Four of the five gliomas presented in the 2nd trimester, all three meningiomas in the 3rd trimester or postpartum period, and both of the two schwannomas in the late 2nd trimester. Expression of VEGFR-1/2 and EGFR was observed regardless of the timing of tumor presentation, whereas female hormone receptors and HER-2 were exclusively found in meningiomas. Interestingly, one anaplastic astrocytoma (IDH mut, non-codeleted) that progressed from precedent grade 2 tumor harbored amplification of the MYC locus., Conclusion: Progression of brain tumors during pregnancy is associated with various growth factors as well as sex hormones. The timing of presentation is likely dependent on molecular receptors specific to each tumor type., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background /objective: Recent studies have suggested that a recanalization grade of modified Thrombolysis in Cerebral Infarction (mTICI) score ≥2c is strongly related with good clinical outcome rather than the current therapeutic angiography target ≥2b. To achieve better recanalization, additional further maneuvers on distal residual vessel occlusion (RVO) may be required. The aim of this study was to evaluate the safety and efficacy of rescue treatment in RVOs after recanalization of large vessel occlusions in the anterior circulation., Methods: A single-center retrospective review of a prospectively maintained stroke databank was performed. Patients presenting with RVOs after mechanical thrombectomy on the M1/internal carotid artery terminus were included and further divided into treated and untreated groups: the former underwent additional maneuvers on RVOs, whereas the latter did not. Baseline and posttreatment clinical, radiologic, and angiographic data were compared between the 2 groups. End points included good functional outcome (modified Rankin Scale [mRS] score ≤2) rates of hemorrhagic transformations, neurologic deterioration and mortality., Results: RVOs were observed in 183/488 patients (37.5%). 74/183 (40.4%) underwent rescue treatment, showing a better outcome in terms of median 24 hours National Institutes of Health Stroke Scale score (13 vs. 18; P < 0001), 24 hours Alberta Stroke Programme Early CT Score (6 vs. 5; P < 0.001) and 3 months mRS score 0-2 (47.3% vs. 33.1%; P = 0.06). Recanalization of the superior (frontal) branch of the middle cerebral artery was particularly critical in terms of outcome. Hemorrhagic transformation was higher in the untreated group (53.6% vs. 66.6%; P = 0.1) as well as symptomatic intracranial hemorrhage (13.1% vs. 29.4%; P = 0.01). Neurologic deterioration occurred more often among untreated patients (16.2% vs. 25.7%; P = 0.1). Three complications (1.3%) occurred during rescue treatment., Conclusions: When feasible, improving mTICI score 2a-2b recanalization to mTICI 2c/3 is safe and associated with a better clinical outcome, particularly for residual occlusions involving the superior branch of bifurcation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Little is known about changes in nutritional status as an index of frailty on clinical outcomes after transcatheter aortic valve replacement (TAVR). This study aimed to assess the clinical impact of serum albumin changes after TAVR., Methods: Changes in serum albumin levels from baseline to 1 year after TAVR were evaluated in 1524 patients who were classified as having hypoalbuminemia (<3.5 g/dl) and normoalbuminemia (≥3.5 g/dl) at each timepoint. The patients were categorized into 4 groups: NN (baseline normoalbuminemia, 1-year normoalbuminemia: n = 1119), HN (baseline hypoalbuminemia, 1-year normoalbuminemia: n = 202), NH (baseline normoalbuminemia, 1-year hypoalbuminemia: n = 121), and HH (baseline hypoalbuminemia, 1-year hypoalbuminemia: n = 82). We also defined late hypoalbuminemia as hypoalbuminemia identified at the 1-year assessment. Clinical outcomes were compared among 4 groups. Multivariable analysis was driven to assess the variables associated with late hypoalbuminemia and long-term mortality., Results: The cumulative 3-year mortality was significantly different among the 4 groups (NN: 11.4%, HN: 10.7%, NH: 25.4%, HH: 44.4%, p < 0.001). Multivariable Cox regression analysis revealed that the NH group had a higher mortality risk (hazard ratio [HR]; 2.80 and 3.53, 95% confidence interval [CI]; 1.71-4.57 and 2.06-6.06, p < 0.001 and p < 0.001, respectively), whereas the HN group had a similar risk (HR; 1.16, 95% CI; 0.66-2.06, p = 0.61) compared with the NN group. Baseline hypoalbuminemia, low body mass index, liver disease, peripheral artery disease, and hospital readmission within 1 year were predictors of late hypoalbuminemia (all p < 0.05)., Conclusion: Serial albumin assessment may identify poor prognostic subsets in patients with persistent and late acquired malnutrition after TAVR., Competing Interests: Declaration of competing interest Dr. Yamamoto, Dr. Tada, Dr. Naganuma, Dr. Shirai, Dr. Mizutani, and Dr. Watanabe are clinical proctors for Edwards Lifesciences and Medtronic. Dr. Koyama, Dr. Araki, Dr. Tabata, Dr. Takagi, Dr. Higashimori, and Dr. Hayashida are clinical proctors of Edwards Lifesciences. Dr. Ueno is a clinical proctor for Medtronic. The remaining authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to compare long-term all-cause mortality between direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) after transcatheter aortic valve replacement (TAVR)., Background: The optimal anticoagulant agent for patients with AF after TAVR has not been clarified., Methods: OCEAN (Optimized Transcatheter Valvular Intervention) is a prospective, multicenter, observational cohort registry comprising 2,588 patients who underwent TAVR between October 2013 and May 2017. Of these, 403 patients (15.6%) with AF on anticoagulant therapy were identified, of whom 227 (56.3%) were prescribed DOACs and 176 (43.7%) were prescribed VKAs. Patients who successfully discharged after TAVR were stratified into DOAC and VKA groups on the basis of the prescription of anticoagulant agents, and the analyses started from discharge., Results: In total, 33.3% of patients were men. The mean age was 84.4 ± 4.7 years, and the average CHA 2 DS 2 -VASc score was 5.1 ± 1.1. The median follow-up duration was 568 days. A multivariate Cox regression model and inverse probability of treatment weighting based on the propensity score demonstrated that the DOAC group was significantly associated with a lower incidence of all-cause mortality compared with the VKA group (10.3% vs. 23.3%; Cox-adjusted hazard ratio: 0.391; 95% confidence interval: 0.204 to 0.749; p = 0.005; and 10.2% vs. 20.6%; inverse probability of treatment weighting-adjusted hazard ratio: 0.531; 95% confidence interval: 0.294 to 0.961; p = 0.036, respectively)., Conclusions: Compared with VKAs, DOACs might be associated with lower long-term all-cause mortality in patients with concomitant AF who are successfully discharged after TAVR. This finding warrants investigation in ongoing prospective randomized trials., Competing Interests: Author Relationship With Industry The OCEAN-TAVI registry is supported by Edwards Lifesciences, Medtronic, Boston Scientific, and Daiichi-Sankyo Company. Drs. Yamamoto, Tada, Naganuma, Shirai, Mizutani, Tabata, Ueno, and Watanabe are clinical proctors for Edwards Lifesciences and Medtronic. Drs. Takagi and Hayashida are clinical proctors for Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The influence of improved mitral regurgitation (MR) on the outcomes of transcatheter aortic valve replacement (TAVR) is unknown. Our aim was to determine the impact of significant preprocedural MR and the improvement of MR after TAVR., Methods: A population of 1587 patients from the Optimized Catheter Valvular Intervention Transcatheter Aortic Valve Implantation (OCEAN-TAVI) registry were evaluated. Preprocedural MR was mild or less in 1443 patients (90.9%) and moderate or severe in 144 patients (9.1%)., Results: Moderate or severe MR was associated with increased risk for all-cause mortality at 1 year (adjusted hazard ratio, 1.85; 95% confidence interval [CI], 1.20-2.84; P = 0.005) and 2 years (adjusted hazard ratio, 1.64; 95% CI, 1.15-2.34; P = 0.007). At 6 months after TAVR, the MR grade improved in 77.4% of the patients with moderate or severe baseline MR. Multivariate analysis showed that the absence of previous myocardial infarction (odds ratio, 8.00; 95% CI, 1.74-36.8; P = 0.008) and beta-blocker use at baseline (odds ratio, 2.71; 95% CI, 1.09-6.70; P = 0.031) were independently associated with improved MR at 6 months (vs unchanged, worsened MR, or death). Patients with improved MR had a significantly lower rate of midterm readmission for heart failure (11.6%) than those with unchanged or worsened MR (30.8%, P = 0.007)., Conclusions: Moderate or severe MR was associated with increased risk of all-cause mortality 2 years after TAVR. Moderate or severe baseline MR was improved in most patients at 6 months after TAVR. Patients with unchanged or worsened MR had an increased rate of readmission for heart failure., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Endonuclease III (EndoIII) is nearly ubiquitous in all three domains of life. EndoIII family proteins exhibit a bifunctional (glycosylase/lyase) activity on oxidative/saturated pyrimidine bases, such as thymine glycol. Previous studies on EndoIII homologs have reported the presence of important residues involved in substrate binding and catalytic activity. However, a biochemical clarification of the roles of these residues as well as details of their evolutionary conservation is still lacking. This is particularly true for archaeal orthologs. The current study demonstrated the roles of the evolutionarily conserved residues of euryarchaeon Thermococcus kodakarensis EndoIII (TkoEndoIII). We utilized amino acid sequence analysis and homology modeling to identify highly conserved regions with potential key residues in the EndoIII proteins. Using Ala-substituted TkoEndoIII mutant proteins, residues of interest were quantitatively examined via DNA binding, glycosylase/AP lyase/bifunctional activity, and DNA trapping assays. The obtained results allowed us to determine the roles, as well as the significance of these roles in Schiff base formation (Lys140 as a nucleophile and Asp158), Tg recognition (His160), substrate binding (Arg59, Leu101, Trp102, and Gly136), β-elimination activities (Ser57 and Asp62), and [4Fe-4S] cluster formation (Cys208 and Cys215). Interestingly, a critical role played by the highly conserved Lys105 (predicted as being away from the catalytic site) in substrate binding, accompanied by a significant indirect effect on catalytic activity, were detected. Our results suggest that these particular residues play conserved roles among EndoIII orthologs across the domains. In addition to identifying the critical role of the highly conserved Lys105, the study provides a comprehensive understanding of the functions attributable to the evolutionarily conserved residues found in the EndoIII family, from Escherichia coli to humans., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The optimal management of preexisting severe aortic stenosis (AS) in patients undergoing noncardiac surgery (non-CS) remains uncertain. This study aimed to investigate the safety and effectiveness of percutaneous aortic valve intervention (PAVI) in patients with AS before non-CS., Methods: We analyzed pooled data within a multicenter Japanese registry from 118 patients with severe AS who underwent PAVI before non-CS. Sixty patients underwent percutaneous balloon aortic valvuloplasty (BAV) and 58 patients underwent transcatheter aortic valve replacement (TAVR). The groups' baseline characteristics, perioperative complications, and 30-day mortality and midterm mortality after non-CS were compared., Results: The postprocedural mean pressure gradient was higher in the BAV group than in the TAVR group (35.0 ± 11.5 mmHg vs. 11.5 ± 4.8 mmHg, p < 0.001). The non-CS operation risk did not differ between the groups (p = 0.69). One patient in each group experienced a noncardiac death (p = 0.74), and the 30-day mortality rate after non-CS was 1.7%. Heart failure occurred in 2 patients in each group (p = 0.68). One patient in the TAVR group experienced a non-disabling stroke, and no myocardial infarctions occurred. Consequently, the combined adverse events were 5.0% and 6.9% in the 2 groups (p = 0.48). The bleeding rates during the non-CS were similar in both groups (33.3% vs. 25.9%, p = 0.25). There were no differences between the groups regarding midterm mortality (p = 0.60), whereas 53.3% of the patients in the BAV group required invasive treatment of their AS during follow-up., Conclusions: Among patients with severe AS, PAVI before non-CS reduces the AS severity and may contribute to procedural safety during non-CS., Competing Interests: Disclosures Dr. Yamamoto, Dr. Tada, Dr. Naganuma, Dr. Shirai, Dr. Mizutani, and Dr. Watanabe are clinical proctors for Edwards Lifesciences and Medtronic. Dr. Araki, Dr. Tabata, Dr. Takagi, Dr. Higashimori, and Dr. Hayashida are clinical proctors of Edwards Lifesciences. Dr. Ueno is a clinical proctor for Medtronic. The remaining authors have nothing to disclose., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Tolvaptan exerts potent diuretic effects in heart failure patients without hemodynamic instability. Nonetheless, its clinical efficacy for acute decompensated heart failure (ADHF) due to severe aortic stenosis (AS) remains unclear. This study aimed to evaluate the short-term effects of tolvaptan in ADHF patients with severe AS., Methods: The LOw-Dose Tolvaptan (7.5 mg) in Decompensated Heart Failure Patients with Severe Aortic Stenosis (LOHAS) registry is a multicenter (7 centers) prospective registry that assessed the short-term effects of tolvaptan in subjects hospitalized for ADHF with severe AS. A total of 59 subjects were enrolled between September 2014 and December 2017. The primary endpoints were changes in body weight and fluid balance measured daily from baseline up to 4 days., Results: The median [interquartile range] patient age and aortic valve area were 85.0 [81.0-89.0] years and 0.58 [0.42-0.74] cm 2 , respectively. Body weight continuously decreased, and fluid balance was maintained from baseline to day 4 (p < 0.001, p = 0.194, respectively). Median serum B-type natriuretic peptide concentration significantly decreased from 910.5 to 740.0 pg/mL by day 4 (p = 0.002). However, systolic blood pressure and heart rate were non-significantly changed (p = 0.250, p = 0.656, respectively). Hypernatremia (>150 mEq/L) and worsening renal function occurred in 2 (3.4%) and 4 (6.8%) patients, respectively., Conclusions: Short-term treatment with low-dose tolvaptan is safe and effective, providing stable hemodynamic parameters in patients with ADHF and severe AS., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The superficial middle cerebral vein (SMCV) is of clinical importance because of its contribution to the venous drainage of the superficial part of the cerebrum. Sphenoid ridge meningioma (SRM) grows adjacent to the SMCV and its drainage routes, and is thought to occasionally influence the hemodynamics of the SMCV, although this has seldom been suggested in the literature. We investigated the effect of SRM on the SMCV via blood flow analysis using multi-detector computed tomography., Patients and Methods: Overall, 22 patients with SRM who preoperatively underwent contrast-enhanced dynamic computed tomography at our institution were included in this study. We serially measured the Hounsfield units at each point of the SMCV and its adjacent veins on the side on which the tumor was located. We then obtained a time-density curve for each point via gamma distribution fitting. We determined the time-to-peak at each point by calculating the derivative of the time-density curve function and deduced the direction of blood passing through each vein by comparing the time-to-peak values between several points., Results: In total, 26 SMCVs were measured in 19 out of 22 cases. Of the 26 SMCVs, 16 were patent in the medial portion and contributed to normal venous drainage: 4 of them emptied into the cavernous sinus (CS), and 12 of them into the para-cavernous sinus (ParaCS). Out of the 10 that had their medial portions occluded because of the effects of the tumor, 6 SMCVs mainly drained into the vein of Labbé and/or the vein of Trolard retrogradely. However, in 2 of these, the small medial portions of the SMCVs near the occluded portion were maintained anterogradely by the collateral venous structures. In 4 SMCVs, the blood flow through the collateral veins remained anterograde; this was considered to contribute to normal venous drainage., Conclusion: The SRM is likely to cause occlusion or stenosis in the SMCV and influence its hemodynamics. In cases in which the connection between the SMCV and the CS or the ParaCS has been lost, the SMCV may still be involved in normal venous drainage via the collateral veins in some of those cases. Thus, the contribution of these veins to normal venous drainage in the brain should be analyzed preoperatively in careful detail., Competing Interests: Declarations of Competing Interest None., (Copyright © 2020. Published by Elsevier B.V.)

Background: The flow dynamics of the intracranial venous channels are fundamentally important for understanding intracranial physiology and pathophysiology. However, the method clinically applicable to the evaluation of the flow dynamics of the intracranial venous system has not been well described in the reported data. We have developed a new method to evaluate intracranial venous flow direction and velocity using 4-dimensional (4D) computed tomography angiography (CTA). The aim of the present study was to verify the accuracy and validity of 4D-CTA in a clinical setting., Methods: We retrospectively analyzed 97 veins from 26 patients (16 cases of arteriovenous shunt disease, 9 intracranial tumor cases, and 1 cerebral aneurysm case) who had undergone both 4D-CTA and conventional digital subtraction angiography (DSA). Using 4D-CTA, we analyzed the time-density curve with gamma distribution extrapolation and obtained the direction of the flow and flow velocity of each vein. The direction of the flow in 4D-CTA was also collated with that obtained using conventional DSA to verify the experimental method., Results: The direction of the flow determined by 4D-CTA was consistent with that of conventional DSA in 94.8% of cases. The average venous flow velocity was 64.3 mm/second and 81.8 mm/second, respectively, in the antegrade and retrograde channels affected by arteriovenous shunts., Conclusions: The present flow analysis using 4D-CTA enabled us to evaluate the direction and velocity of intracranial venous flow. Other than some limitations, the presented method is reliable and its potential for application in clinical settings is promising., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: We aimed to assess real-world clinical outcomes of transcatheter aortic valve replacement (TAVR) in Japan., Background: Data are limited concerning procedural safety and valve performance following TAVR in Japanese. A program by an on-site proctor and procedure screening system was applied during TAVR introduction., Methods: We consecutively enrolled 1613 patients who underwent TAVR using data from the Optimized CathEter vAlvular iNtervention (OCEAN) Japanese registry, which consists of 14 centers. Baseline characteristics and procedural outcomes including combined early 30-day non-safety, and mortality rates were assessed among 4 groups, divided into quartiles (Q1-Q4)., Results: Most patients were women (70.4%), elderly (84.4 ± 5.1 years), and had a median Society of Thoracic Surgeons score of 6.7(4.7-9.5). The overall 30-day mortality, combined early non-safety, and cumulative 1-year mortality rates were 1.7%, 15.1%, and 11.3%, respectively. Thirty-day mortality was not affected by center experience differences divided into quartiles (1.0%, 2.0%, 2.5%, 1.5%, p = 0.404), whereas 30-day early safety was significantly improved (19.1%, 17.9%, 14.6%, 8.9%, p < 0.001). Thirty-day mortality was 0% under transfemoral on-site proctor. Cox-regression multivariate analysis revealed that male sex, clinical frailty scale, New York Heart Association class, creatinine, albumin, hemoglobin, liver disease, and non-transfemoral approach were independent predictive factors of increased midterm mortality risk., Conclusions: Owning to the global supporting system in Japan, excellent early and midterm outcomes have been achieved to overcome the learning curve of the newly introduced TAVR procedure., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Little evidence is available regarding the risk of peri-procedural stroke detected by diffusion-weighted magnetic resonance imaging (DW-MRI) after transcatheter aortic valve replacement (TAVR). Our purpose was to evaluate stroke risk after TAVR using DW-MRI by enrolling consecutive patients who underwent transfemoral TAVR and post-procedural DW-MRI., Methods: We prospectively enrolled 113 consecutive patients who underwent transfemoral TAVR and post-procedural DW-MRI. We used balloon-expandable valves as first-line therapy and selected self-expandable valves only for patients with narrow sinotubular junctions or annuli. We set the primary endpoint as the number of high intensity areas (HIA) detected by DW-MRI regardless of the size of the area. To evaluate the risks of the primary endpoint, we employed a multivariable linear regression model, setting the primary endpoint as an objective variable and patient and clinical backgrounds as explanatory variables., Results: Median patient age was 84 years, and 36.3% were men. Ninety-three patients underwent balloon-expandable TAVR and 20 underwent self-expandable TAVR. Symptomatic stroke occurred in 6 (5.3%) whereas asymptomatic stroke occurred in 59 (52.2%) patients. The incidence of symptomatic and total stroke was higher in patients who underwent self-expandable TAVR than those who underwent balloon-expandable TAVR (30.0% vs. 0.0%, p<0.001 and 90.0% vs. 50.5%, p=0.001, respectively). A multivariable linear regression model demonstrated an increased primary endpoint when self-expandable TAVR was performed (p<0.001). The other covariates had no significant relationship to the primary endpoint. Akaike information criterion-based stepwise statistical model selection revealed that valve type was the only explanatory variable for the best predictive model., Conclusions: Self-expandable valves were associated with increased numbers of HIA on DW-MRI after TAVR in patients with severe aortic stenosis., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

An understanding of the anatomy and function of the skull base venous channels is fundamentally important for safe performance of endoscopic surgery for skull base lesions. This review focuses on 4 skull base venous channels-namely, the intercavernous sinuses, basilar plexus, osseous veins, and inferior petroclival vein-because these have been less recognized by neurosurgeons than other major venous channels such as the inferior petrosal sinus. We reviewed the literature concerning these 4 venous channels and discussed their anatomy and function. The literature review was mainly based on an electronic search in PubMed using the following terms: "intercavernous sinus," "basilar plexus," "emissary veins," "diploic vein," "basilar plexus," "intraosseous vein," "inferior petroclival/petro-occipital vein," and "transclival." A total of 50 articles were included in this review. Detailed anatomic features of the 4 structures have been elucidated in the literature. All of these venous channels run along the skull base and have multiple connections with surrounding venous structures. Because of their location, they occasionally obstruct the surgical view and are sometimes implicated in intraoperative hemorrhage, air embolism during endoscopic skull base surgery, and postoperative hematoma. They usually function as a venous reservoir of cranial venous drainage; however, they are less often directly involved in normal brain perfusion. Knowledge about the functional and morphologic anatomy of the skull base venous channels is important for neurosurgeons to avoid unexpected complications during endoscopic skull base surgery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The venous outlet of anterior condylar arteriovenous fistulas (AC-AVFs) often empties into the anterior condylar vein (ACV). Hypoglossal nerve palsy is one of the major complications after transvenous embolization (TVE) for the AC-AVF within the hypoglossal canal. However, no studies have investigated the route of the hypoglossal nerve within the hypoglossal canal in AC-AVF. The aim of the current study is to retrospectively verify the anatomical route of the hypoglossal nerve within its canal using dynamic computed tomography angiography (CTA) in order to facilitate the safe TVE for AC-AVF., Patients and Methods: We included five patients with AC-AVF from 2011 to 2017. Dynamic CTA was performed on all patients. When the ACV was well-visualized by dynamic CTA, the hypoglossal nerve could be recognized as a less-intense structure within the surrounding enhanced vasculatures and the nerve route within the canal was analyzed. We also analyzed the location of the fistulas by digital subtraction angiography and cone-beam computed tomography., Results: In all five patients, the filling defect of the hypoglossal nerve ran through the most caudal portion of the hypoglossal canal. The fistulous pouches were located in the hypoglossal canal in three cases, and in the jugular tubercle venous complex in two cases. In all three cases with AC-AVF in the hypoglossal canal, the fistulous pouches were located in the superior wall of the hypoglossal canal, which means superior to the ACV. We performed TVE in four patients and none developed post-therapeutic hypoglossal nerve palsy., Conclusion: In the current study, dynamic CTA is useful for detecting the hypoglossal nerve within the hypoglossal canal. The hypoglossal nerve usually ran the bottom of its canal and the fistulous pouches were usually located at the superior aspect of the canal opposite side to the hypoglossal nerve. Accordingly, the selective embolization within the fistulous pouch located in the superior aspect of the ACV including jugular tubercle venous complex can reduce the risk of hypoglossal nerve palsy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We analyzed the 23S rRNA, gyrA and parC genes of Chlamydia trachomatis DNAs from men with urethritis and determined microbiological outcomes of an extended-release azithromycin (azithromycin-SR) regimen (2 g once daily for 1 day) and a sitafloxacin regimen (100 mg twice daily for 7 days) for chlamydial urethritis to clarify the macrolide and fluoroquinolone resistance status of clinical strains of C. trachomatis. We amplified the portions of 2 alleles of the 23S rRNA gene and the gyrA and parC genes from C. trachomatis DNAs in 284 first-voided urine specimens from men with chlamydial urethritis by PCR and sequenced their PCR products. We enrolled 369 men with chlamydial urethritis, comprising 314 and 55 treated with the azithromycin-SR regimen and the sitafloxacin regimen, respectively. Alleles 1 and/or 2 of the 23S rRNA gene were analyzed in 162 specimens. No mutations were found in the sequenced regions, including the central portion of domain V. The gyrA and parC genes were analyzed in 118 and 113 specimens, respectively. No amino acid changes were found within the quinolone resistance-determining region of the gyrA gene and in the sequenced region of the parC gene. The microbiological outcomes of the azithromycin-SR and sitafloxacin regimens were assessed in 176 and 30 men, respectively. The eradication rates were 96.0% (95% CI 93.1%-98.9%) for the azithromycin-SR regimen and 100% for the sitafloxacin regimen. Clinical strains of C. trachomatis with macrolide and/or fluoroquinolone resistance would be uncommon, and azithromycin or fluoroquinolone regimens could be recommended as treatments for chlamydial infections., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Solitary fibrous tumors (SFTs)/hemangiopericytomas (HPCs) are highly vascularized tumors well known for malignant, invasive, and highly vascular features. To date, several studies have reported the preoperative imaging findings of SFTs/HPCs. In this study, computed tomography (CT) tumor values acquired from dynamic CT scan were selected to determine the tumor pathology of highly vascular tumors, such as SFTs/HPCs., Methods: We conducted a retrospective study on patients with pathologically diagnosed meningiomas and SFTs/HPCs who had undergone a dynamic contrast CT scan. We assessed and compared the CT values of these tumors according to the pathology., Results: From a total of 34 patients, 30 patients with meningiomas and 4 patients with HPCs were included. The mean CT values of SFTs/HPCs and angiomatous meningioma were statistically significantly higher than those of the other meningioma subtypes (P = 0.003). We also performed receiver operating characteristic curve analyses to detect an appropriate cutoff point for the CT value to differentiate tumor pathology, and the calculated threshold was 161 Hounsfield units (HU) (sensitivity, 100%; specificity, 75%; area under the curve, 0.87; 95%, CI 0.75-0.99)., Conclusions: This study showed that obtaining a CT value is useful in determining highly vascular tumor pathology preoperatively. When considering neurosurgical extra-axial tumor removal, and when the CT value of tumors is >161 HU, then highly vascular tumors such as SFTs/HPCs or angiomatous meningiomas are likely, and this should be considered prior to surgical intervention and for risk assessment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: The authors sought to investigate the prevalence, risk factors, and mid-term mortality in Asian patients with prosthesis-patient mismatch (PPM) after transcatheter aortic valve replacement (TAVR)., Background: Little information is available on PPM after TAVR in Asian patients., Methods: The authors included 1,558 patients enrolled in the OCEAN-TAVI (Optimized transCathEter vAlvular iNtervention) Japanese multicenter registry from October 2013 to July 2016 after excluding patients who died following TAVR before discharge. PPM was defined as moderate if ≧0.65 but ≦0.85 cm 2 /m 2 , or severe if <0.65 cm 2 /m 2 at the indexed effective orifice area by post-procedural echocardiography., Results: Of the 1,546 patients, moderate and severe PPM were observed in 138 (8.9%) and 11 (0.7%) patients, respectively. These 149 patients were included in the PPM group. The median age and body surface area were 85 years (interquartile range [IQR]: 81 to 88 years) and 1.41 m 2 (IQR: 1.30 to 1.53 m 2 ), respectively. In our multivariate analysis, younger age, larger body surface area, smaller aortic valve area, smaller annulus area, no balloon post-dilatation, and use of Edwards Sapien 3 (Edwards Lifesciences, Irvine, California) were identified as independent predictors of PPM. The estimated cumulative all-cause mortality at 1 year using the Kaplan-Meier method was similar between the PPM and non-PPM groups (10.2% vs. 8.3%; log-rank; p = 0.41)., Conclusions: The low prevalence of PPM and mortality at 1 year in patients with PPM after TAVR in this Japanese cohort implies that PPM is not a risk factor for mid-term mortality in Asian patients who have undergone TAVR., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Functional venous anatomy in the brain has been mostly understood from the morphological and embryological points of view and no published study has directly evaluated the blood flow volume of cerebral small veins. We developed a method to directly evaluate the relative blood volume in small venous channels using multi-detector computed tomography (CT) and applied it to evaluate the blood volume in each tributary of the cavernous sinus, which plays an important role in cerebral venous drainage., Patients and Methods: Ten patients with small brain tumors who had normal venous anatomy were included in the present study. All of them underwent preoperative 320-row multi-detector CT. After injecting the contrast bolus, we measured the Hounsfield units (HUs) at 10 time point over 60 s in each tributary of the cavernous sinus. The gamma distribution fitting to each HU enabled us to obtain a time-density curve and determine the relative venous volume in each venous channel., Results: In terms of blood volume, the superficial middle cerebral vein and inferior petrosal sinus were the largest inflow and outflow channels of the cavernous sinus and accounted for 36.1% and 24.7% of its inflow and outflow on average, respectively. The superior orbital vein did not contribute to the blood volume passing through the cavernous sinus in the current study., Conclusions: The present study allowed us to determine the relative blood volume in each tributary of the cavernous sinus, which was very useful to understand the physiological actual venous drainage pattern concerning the cavernous sinus in normal anatomy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Of 73 clinical strains of Haemophilus influenzae isolated from the urethra of men with urogenital infections, we enrolled 6 strains (8.2%) with levofloxacin (LVFX) minimum inhibitory concentrations (MICs) of ≥0.03 μg/ml in this study. All the strains were isolated from non-gonococcal urethritis (NGU). We amplified the quinolone resistance-determining region of the gyrA gene and the analogous region of the parC gene from bacterial DNAs by PCR and sequenced the PCR products. Two strains with a LVFX MIC of 0.03 μg/ml had an amino acid change of Asp88 to Gly in GyrA. One with a LVFX MIC of 0.06 μg/ml had a change of Asp88 to Tyr in GyrA. Two with respective LVFX MICs of 0.12 and 0.25 μg/ml had a change of Ser84 to Leu in GyrA. One with a LVFX MIC of 1 μg/ml had changes of Ser84 to Leu in GyrA and of Ser84 to Ile in ParC. Multilocus sequence typing showed two strains with a change of Asp88 to Gly in GyrA had the same sequence type, but the others had sequence types different from each other. Single amino acid changes in GyrA alone or single changes in both GyrA and ParC could contribute to decreased susceptibility to fluoroquinolones in H. influenzae isolates from NGU. Most of the isolates with GyrA and/or ParC alterations would be multiclonal. The prevalence of such isolates would be relatively low, and they would still be susceptible to fluoroquinolones commonly prescribed for treatment of NGU., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

We determined minimum inhibitory concentrations (MICs) of 41 antimicrobial agents for 73 clinical strains of Haemophilus influenzae isolated from the urethra of men with acute urethritis and/or epididymitis and examined the strains for the production of β-lactamase. We also compared their antimicrobial susceptibilities with those of H. influenzae strains from respiratory tract or otorhinolaryngological infections that were reported in Japan. The proportion of β-lactamase-nonproducing ampicillin-resistant strains from acute urethritis and/or epididymitis appeared to be lower, but that of β-lactamase-producing ampicillin-resistant strains appeared to be higher, compared with those from respiratory tract or otorhinolaryngological infections. However, their antimicrobial susceptibilities to a variety of other antimicrobial agents would be similar to those from respiratory tract or otorhinolaryngological infections. Almost all of the strains of H. influenzae from acute urethritis and/or epididymitis were susceptible to the agents, including ceftriaxone, quinolones, macrolides, and tetracyclines, commonly prescribed for treatment of acute urethritis based on the MIC breakpoints recommended by the Clinical and Laboratory Standards Institute. Ceftriaxone and quinolones could be effective on H. influenzae-induced urethritis. However, azithromycin treatment failures were reported in acute urethritis caused by H. influenzae strains considered susceptible to azithromycin. Further studies will be needed to determine MIC breakpoints of antimicrobial agents, which are recommended for treatment of urogenital infections, for H. influenzae strains causing these infections. Nevertheless, this study provides useful data regarding antimicrobial susceptibilities of H. influenzae strains isolated from the urogenital tract, which have rarely been studied., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Exosomes or microvesicles that are secreted from cells are considered to play important roles in tumor microenvironment. Carbonic anhydrase 9 (CA9), which is induced by hypoxia-inducible factor 1 (HIF1) in response to hypoxia, is overexpressed in many types of cancer including renal cell carcinoma (RCC). We examined the expression level of CA9 in several RCC cell lines and found that the basal level of CA9 was much higher in OSRC-2 cells than in Caki-1, KMRC-1 and 786-O cells. Consistent with the intracellular expression levels, CA9 was abundantly detected in exosomes isolated by ultracentrifugation from OSRC-2 cells. Density gradient centrifugation of OSRC-2 and 786-O exosomes confirmed the co-presence of CA9 with exosomal markers. Upon hypoxia and treatment with CoCl 2 , a hypoxia mimic agent, the CA9 level in exosomes was increased for all cell lines. In order to examine the effects of CA9 exosomes on angiogenesis, we generated stably transfected HEK293 cells expressing CA9. Immunocytochemical staining demonstrated the uptake of CA9 exosomes by human umbilical vein endothelial cells (HUVEC). In vitro angiogenesis assays using HUVEC revealed that CA9 exosomes promoted migration and tube formation. Lastly, MMP2 expression was increased by treatment with CA9 exosomes in HUVEC. Taken together, our results suggest the possibility that CA9 exosomes released from hypoxic RCC may enhance angiogenesis in microenvironment, thereby contributing to cancer progression., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We retrieved clinical data of 13 men having herpes simplex virus (HSV)-induced non-gonococcal urethritis (NGU) without visible herpetic lesions. They visited a clinic in Sendai, Japan, between April 2013 and December 2015. All the men complained of dysuria. Meatitis was observed in 9 of the 13 men. Mononuclear cells were observed in the urethral smears from 9 men. The 13 men were treated with azithromycin or sitafloxacin regimen. First-voided urine (FVU) specimens became negative for HSV in 8 of the 10 men who returned to the clinic after antibacterial treatment, and urethritis symptoms were alleviated. However, herpetic lesions were observed at the follow-up visits in 3 men, and 2 of them were still positive for HSV in their FVU. HSV could be a cause of acute urethritis without causing visible herpetic lesions. The shedding of HSV from the urethra would spontaneously cease with alleviation of urethritis symptoms in most cases of HSV-induced NGU without antiviral therapy. However, new herpetic lesions could be developed in some cases. Early antiviral therapy is beneficial for patients with HSV infections. The development of meatitis and the mononuclear cell response in the urethral smear could be helpful to diagnose HSV-induced NGU. Therefore, we should presumptively initiate anti-HSV therapy for patients with signs and symptoms suggestive of HSV-induced NGU at their first presentation., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

We observed fluoroquinolone treatment failures in 2 men with Mycoplasma genitalium-positive non-gonococcal urethritis in Japan. A fluoroquinolone regimen of sitafloxacin 100 mg twice daily for 7 days failed to eradicate M. genitalium. In both cases, M. genitalium had fluoroquinolone resistance-associated amino acid changes both in GyrA and ParC and a macrolide resistance-associated mutation in the 23S rRNA gene. The emergence of such multi-drug resistant strains can threaten antimicrobial chemotherapy for M. genitalium infections in Japan, because we will lose the first- (azithromycin) and second-line (sitafloxacin) antimicrobial agents to treat M. genitalium infections. We prescribed an extended minocycline regimen of minocycline 100 mg twice daily for 14 days for our patients, and the regimen was successful in eradicating the M. genitalium. The extended minocycline regimen might be an option that we can try when treating multi-drug resistant M. genitalium infections in clinical practice., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: The purpose was to assess the early effects of removable partial denture (RPD) placement on abutment teeth in patients with periodontal disease., Methods: Fifteen distal-extension RPDs and 19 abutment teeth were evaluated in 13 patients with moderate-to-severe periodontal diseases. Clinical periodontal records and grey level (GL) score based on digital subtraction radiography were measured on the day of denture placement (baseline) and at 1day, 1 week, 1 month, 3 months, and 6 months after the placement. Occlusal force on total dentition (Ft) and abutment tooth (Fa) were recorded with (baseline) and without denture on the day of the placement, and with denture in the follow-up examinations., Results: No statistically significant difference between a follow-up period and the baseline was found in the clinical periodontal and occlusal force records, except for Ft with denture on the day of the placement, which was significantly lower than the baseline (p<0.05). The GL at distal crestal of the abutment was significantly higher at 1 week after the placement than at the baseline (p<0.05), while the scores of following examinations returned to the baseline level., Conclusions: The distal crestal bone of the abutment tooth transitorily reacts to mechanical stress due to the denture placement, while this does not suggest a detrimental effect within the limitation of the study design with a short-term observation period., Clinical Significance: The RPDs can be safely used for patients with periodontal diseases for at least 6 months if they are properly placed and maintained by professional care., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to report the safety of coronary rotational atherectomy (RA) in patients with severe aortic stenosis (AS). RA in the clinical setting seems challenging because coronary slow flow leads to hemodynamic instability., Methods: Between October 2013 and May 2016, 1401 patients in the Optimized transCathEter vAlvular iNtervention (OCEAN) registry in Japan underwent transcatheter aortic valve implantation (TAVI). The primary study endpoint was procedural success, defined as residual stenosis <20% with final Thrombolysis in Myocardial Infarction flow 3., Results: Twenty-five patients who underwent RA for heavily calcified lesions were included in the study. Low left ventricular ejection fraction (<35%) was present in 3 (12%) patients. The left main stem was involved in 7 (28%) patients. All patients were treated under intravascular image guidance. Intra-aortic balloon pumping was used in 4 (16%) patients. Planned balloon aortic valvuloplasty (BAV) was performed during the same session in 4 (16%) patients. Transvenous catecholamine was used in 10 (40%) patients. The majority of patients underwent drug-eluting stent implantation following RA (n=23, 92%). Procedural success was achieved in all patients. Subsequent device success was achieved in 24 (96%) patients, with no 30-day mortality following TAVI., Conclusions: RA in patients with severe AS seems extremely challenging; however, this procedure appears to be safe if mechanical and drug supports are appropriately utilized and the procedure is performed under intravascular image guidance., (Copyright © 2017 Elsevier Inc. All rights reserved.)