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Glia, which was formerly considered to exist just to connect neurons, now plays a key function in a wide range of physiological events, including formation of memory, learning, neuroplasticity, synaptic plasticity, energy consumption, and homeostasis of ions. Glial cells regulate the brain's immune responses and confers nutritional and structural aid to neurons, making them an important player in a broad range of neurological disorders. Alzheimer's, ALS, Parkinson's, frontotemporal dementia (FTD), and epilepsy are a few of the neurodegenerative diseases that have been linked to microglia and astroglia cells, in particular. Synapse growth is aided by glial cell activity, and this activity has an effect on neuronal signalling. Each glial malfunction in diverse neurodegenerative diseases is distinct, and we will discuss its significance in the progression of the illness, as well as its potential for future treatment.

Abstract.: Mechanisms for the atria-specific action potential-prolonging action of NIP-142 ((3R*,4S*)-4-cyclopropylamino-3,4-dihydro-2,2-dimethyl-6-(4-methoxyphenylacetylamino)-7-nitro-2H-1-benzopyran-3-ol), a benzopyran compound that terminates experimental atrial arrhythmia, was examined. In isolated guinea-pig atrial tissue, NIP-142 reversed the shortening of action potential duration induced by either carbachol or adenosine. These effects were mimicked by tertiapin, but not by E-4031. NIP-142 concentration-dependently blocked the human G protein-coupled inwardly rectifying potassium channel current (GIRK1/4 channel current) expressed in HEK-293 cells with an EC50 value of 0.64 µM. At higher concentrations, NIP-142 blocked the human ether a go-go related gene (HERG) channel current with an EC50 value of 44 µM. In isolated guinea-pig papillary muscles, NIP-142 had no effect on the negative inotropic effect of carbachol under β-adrenergic stimulation, indicating lack of effect on the muscarinic receptor and Gi protein. These results suggest that NIP-142 directly inhibits the acetylcholine-activated potassium current. Keywords:: NIP-142, antiarrhythmic agent, action potential duration, GIRK1/4 channel, atrial fibrillation

Osteotomy is often necessary for the repair of post-traumatic nasal bone deformities. Typically, tools such as chisels are used for osteotomies; however, we performed osteotomies using Kirschner wires without making a skin incision. Between April 2011 and July 2022, we performed rhinoplasty with external perforated osteotomy using Kirschner wires in 13 patients with post-traumatic nasal bone deformities (9 males and 4 females; mean age, 34 years, range 12-51 years), all of whom exhibited improvement, with only one case showing mild residual cosmetic deformity. None of the patients requested further revision, and all were satisfied with their functional results. The non-incisional external perforated technique is a reasonable method that allows for bone osteotomies along the fracture line and is well-controlled, predictable, and reproducible., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

The purpose of this study was to analyze and elucidate the mechanisms of non-obese diabetes-experimental autoimmune encephalomyelitis (NOD-EAE), an animal model of progressive multiple sclerosis (MS), and to compare the pathological features with those observed in human progressive MS. Pathological analysis, flow cytometry analysis, immunohistochemical staining, and transcriptome analysis were performed at each pathological stage of the NOD-EAE mice to characterize each pathological stage in the lesion. The NOD-EAE mice showed a biphasic pattern of disease progression once in remission. The longitudinal profile of demyelination and inflammatory cell infiltration in the spinal cord was consistent with the pathological score. In the chronic phase of the disease, fibrosis and lymph follicle formation, characteristic of progressive human MS, were observed. Here we describe the pathological profile and transcriptome analysis of the NOD-EAE mice and verify that this model has similar features to those of human progressive MS. Our findings suggest that this model recapitulates lymph follicle formation, a disease hallmark of progressive MS, and fibrosis, a feature complicating the pathogenesis of MS in the chronic phase. This model may be useful for evaluating the efficacy of therapeutic agents and for mechanistic analysis., Competing Interests: Declaration of Competing Interest S.H., Toshiki Y., M.M. and A.I. are employees of Japan Tobacco Inc. Toshihide Y. declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Chronic kidney disease (CKD) induces cardiac inflammation and fibrosis and reduces survival. We previously demonstrated that G protein-coupled receptor 68 (GPR68) promotes cardiac inflammation and fibrosis in mice with 5/6 nephrectomy (5/6Nx) and patients with CKD. However, no method of GPR68 inhibition has been found that has potential for therapeutic application. Here, we report that Cephalotaxus harringtonia var. nana extract and homoharringtonine ameliorate cardiac inflammation and fibrosis under CKD by suppressing GPR68 function. Reagents that inhibit the function of GPR68 were explored by high-throughput screening using a medicinal plant extract library (8,008 species), and we identified an extract from Cephalotaxus harringtonia var. nana as a GPR68 inhibitor that suppresses inflammatory cytokine production in a GPR68 expression-dependent manner. Consumption of the extract inhibited inflammatory cytokine expression and cardiac fibrosis and improved the decreased survival attributable to 5/6Nx. Additionally, homoharringtonine, a cephalotaxane compound characteristic of C. harringtonia, inhibited inflammatory cytokine production. Homoharringtonine administration in drinking water alleviated cardiac fibrosis and improved heart failure and survival in 5/6Nx mice. A previously unknown effect of C. harringtonia extract and homoharringtonine was revealed in which GPR68-dependent inflammation and cardiac dysfunction were suppressed. Utilizing these compounds could represent a new strategy for treating GPR68-associated diseases, including CKD., Competing Interests: Declaration of competing interest All 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. All the authors have read and approved the submission for publication., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In the field of oligonucleotides drug discovery, phosphorothioate (PS) modification has been recognized as an effective tool to overcome the nuclease digestion, and generates 2 n of possible diastereomers, where n equals the number of PS linkages. However, it is also well known that differences in drug efficacy and toxicity are caused by differences in stereochemistry of oligonucleotides. Therefore, the development of a high-resolution analytical method that enables stereo discrimination of oligonucleotides is desired. Under this circumstance, capillary electrophoresis (CE) using polyvinylpyrrolidone (PVP) is considered as one of the useful tools for the separation analysis of diastereomers. In this study, we evaluated the several oligonucleotides with the structural diversities in order to understand the separation mechanism of the diastereomers by CE. Especially, five kinds of 2'-moieties were deeply examined by CE with PVP 1,300,000 polymer solution. We found that different trend of the peak shapes and the peak resolution were observed among these oligonucleotides. For example, the better peak resolution was observed in 6 mer PS3-DNA compared to the rigid structure of 6 mer PS3-LNA. As for this reason, the computational simulation revealed that difference of accessible surface area caused by the steric structure of thiophosphate in each oligonucleotide is one of the key attributes to explain the separation of the diastereomers. In addition, we achieved the separation of sixteen peak tops of the diastereomers in 6 mer PS4-DNA, and the complete separation of fifteen diastereomers in 6 mer PS4-RNA. These knowledge for the separation of the diastereomers by CE will be expected to the quality control of the oligonucleotide drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tubulin C-terminal tail (CTT) is a disordered segment extended from each tubulin monomer of αβ tubulin heterodimers, the building blocks of microtubules. The tubulin CTT contributes to the cellular function of microtubules such as intracellular transportation by regulating their interaction with other proteins and cell shape regulation by controlling microtubule polymerization dynamics. Although the mechanical integrity of microtubules is crucial for their functions, the role of tubulin CTT on microtubule mechanical properties has remained elusive. In this work, we investigate the role of tubulin CTTs in regulating the mechanical properties of microtubules by estimating the persistence lengths and investigating the buckling behavior of microtubules with and without CTT. We find that microtubules with intact CTTs exhibit twice the rigidity of microtubules lacking tubulin CTTs. Our study will widen the scope of altering microtubule mechanical properties for its application in nano bio-devices and lead to novel therapeutic approaches for neurodegenerative diseases with altered microtubule properties., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Asthma is characterized by phenotypes of different clinical, demographic, and pathological characteristics. Identifying the profile of exhaled volatile organic compounds (VOCs) in asthma phenotypes may facilitate establishing biomarkers and understanding asthma background pathogenesis. This study aimed to identify exhaled VOCs that characterize severe asthma phenotypes among patients with asthma., Methods: This was a multicenter cross-sectional study of patients with severe asthma in Japan. Clinical data were obtained from medical records, and questionnaires were collected. Exhaled breath was sampled and subjected to thermal desorption gas chromatography-mass spectrometry (GC/MS)., Results: Using the decision tree established in the previous nationwide asthma cohort study, 245 patients with asthma were divided into five phenotypes and subjected to exhaled VOC analysis with 50 healthy controls (HCs). GC/MS detected 243 VOCs in exhaled breath samples, and 142 frequently detected VOCs (50% of all samples) were used for statistical analyses. Cluster analysis assigning the groups with similar VOC profile patterns showed the highest similarities between phenotypes 3 and 4 (early-onset asthma phenotypes), followed by the similarities between phenotypes 1 and 2 (late-onset asthma phenotypes). Comparisons between phenotypes 1-5 and HC revealed 19 VOCs, in which only methanesulfonic anhydride showed p < 0.05 adjusted by false discovery rate (FDR). Comparison of these phenotypes yielded several VOCs showing different trends (p < 0.05); however, no VOCs showed p < 0.05 adjusted by FDR., Conclusions: Exhaled VOC profiles may be useful for distinguishing asthma and asthma phenotypes; however, these findings need to be validated, and their pathological roles should be clarified., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Primary analysis of the multicenter, open-label, single-arm, phase II DESTINY-Breast01 trial (median follow-up 11.1 months) demonstrated durable antitumor activity with trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab emtansine (T-DM1). We report updated cumulative survival outcomes with a median follow-up of 26.5 months (data cut-off 26 March 2021)., Patients and Methods: Patients with HER2-positive mBC resistant or refractory to T-DM1 received T-DXd 5.4 mg/kg intravenously every 3 weeks until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR). Secondary endpoints included overall survival (OS), duration of response (DoR), progression-free survival (PFS), and safety., Results: The ORR by ICR was 62.0% [95% confidence interval (CI) 54.5% to 69.0%] in patients who received T-DXd 5.4 mg/kg every 3 weeks (n = 184). Median OS was 29.1 months (95% CI 24.6-36.1 months). Median PFS and DoR were 19.4 months (95% CI 14.1-25.0 months) and 18.2 months (95% CI 15.0 months-not evaluable), respectively. Drug-related treatment-emergent adverse events (TEAEs) were observed in 183 patients (99.5%), and 99 patients (53.8%) had one or more grade ≥3 TEAEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 15.8% of patients (n = 29), of which 2.7% (n = 5) were grade 5., Conclusions: These updated results provide further evidence of sustained antitumor activity of T-DXd with a consistent safety profile in heavily pretreated patients with HER2-positive mBC., Competing Interests: Disclosure CS reports consulting or advisory roles for AstraZeneca, AX’Consulting, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann-La Roche Ltd, ISSECAM, Medical Statistics Consulting, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche Farma, Seagen, and Zymeworks and a leadership role for SOLTI. SM reports consulting or advisory roles for AstraZeneca, Daiichi Sankyo, Genentech, GlaxoSmithKline, Macrogenics, Novartis, and Seagen; research funding from AstraZeneca (inst) and Daiichi Sankyo (inst); and honoraria from AstraZeneca, Daiichi Sankyo, Genentech, Macrogenics, and Seagen. IK reports consulting or advisory roles for AstraZeneca, Bristol Meyers Squibb, Daiichi Sankyo, Genentech, Macrogenics, Merck, Novartis, Roche, Seagen, and Taiho Oncology; research funding from Genentech (inst), Macrogenics (inst), Pfizer (inst), and Roche (inst); honoraria from AstraZeneca; and a leadership role with PureTech. YHP reports consulting or advisory roles for AstraZeneca, Daiichi Sankyo, Eisai, Roche, MSD, Novartis, Pfizer, and Lilly; research funding from AstraZeneca, Gencurix, Novartis, Pfizer, and Roche; and honoraria from Pfizer, Roche, MSD, and Novartis. SBK reports consulting or advisory roles for AstraZeneca, Beigene, Dae Hwa Pharmaceutical Co, Ltd, Daiichi Sankyo, IUS Abxis, Lilly, and Novartis and research funding from DongKook Pharm (inst), Novartis (inst), and Sanofi-Aventis (inst). HI reports consulting or advisory roles for AstraZeneca, Chugai, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, and Sanofi and honoraria from AstraZeneca, Chugai, Daiichi Sankyo, Lilly, MSD, and Pfizer. JT reports consulting or advisory roles for AstraZeneca and Daiichi Sankyo; research funding from Chugai (inst), Daiichi Sankyo (inst), Eisai (inst), Lilly (inst), Nihon Kayaku (inst), and Taiho (inst); honoraria from Chugai, Daiichi Sankyo, Eisai, Lilly, Kyowa Kirin, and Taiho; has received support for attending meetings and/or travel from Chugai, Daiichi Sankyo, and Eisai; a leadership role with West Japan Oncology Group; and receipt of equipment, materials, drugs, medical writing, or other services from Daiichi Sankyo. JS reports research funding from AstraZeneca (inst), Boehringer Ingelheim (inst), Lilly (inst), GSK (inst), MSD (inst), Novartis (inst), Pfizer (inst), Roche (inst), and Sanofi (inst) and stock for Daiichi Sankyo. EM, YL, JC, and JS report employment and stock and other ownership interest with Daiichi Sankyo. TY reports research funding from Chugai (inst), Kyowa Kirin (inst), Nippon Kayaku (inst), and Taiho (inst) and honoraria from AstraZeneca, Chugai, Daiichi Sankyo, MSD, Eisai, Lilly, Nippon Kayaku, Kyowa Kirin, Novartis, Pfizer Japan, and Taiho. KT has declared no conflicts of interest. Data sharing Anonymized individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org. In cases where clinical study data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo, Inc, will continue to protect the privacy of our company and our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human intestinal organoids (HIOs) have been reported to exert their functions in a way that mimics living organs, and HIOs-derived monolayers are expected to be applied to in vitro intestinal pharmacokinetic studies. However, HIOs are established from human tissue, which raises issues of availability and ethics. In the present study, to solve these problems, we have established intestinal organoids using commercially available cryopreserved human intestinal epithelial cells (C-IOs), and compared their functions with biopsy-derived human intestinal organoids (B-IOs) from a pharmacokinetic point of view. Both C-IOs and B-IOs reproduced the morphological features of the intestinal tract and were shown to be composed of epithelial cells. Monolayers generated from C-IOs and B-IOs (C-IO-2D, B-IO-2D, respectively) structurally mimic the small intestine. The C-IOs showed gene expression levels comparable to those of the B-IOs, which were close to those of adult human small intestine. Importantly, the C-IOs-2D showed levels of pharmacokinetics-related protein expression and activity-including cytochrome P450 3A4 (CYP3A4) and carboxylesterase 2 (CES2) enzymatic activities and P-glycoprotein (P-gp) transporter activities -similar to those of B-IOs-2D. This study addresses the difficulties associated with B-IOs and provides fundamental characteristics for the application of C-IOs in pharmacokinetic studies., Competing Interests: Declaration of interest The authors declare no competing interests., (© 2023 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Aims: The popularity of B-line-guided congestion assessment by lung ultrasound (LUS) has been increasing. However, the ability of novice residents to detect residual congestion with B-line-guided assessment by LUS after decongestion treatment is poorly understood. In this study, we investigated whether novice residents (no prior echocardiography experience) can acquire the skills for B-line-guided residual congestion assessment and whether the range of variation in assessment is acceptable in actual clinical use., Methods and Results: The study included 30 postgraduate first-year novice residents and an expert. The residents underwent training for LUS. At the end of the training session, a set of 15 LUS videos was provided to the residents, and they were asked to estimate the number of B-lines in each video. When the residents' answers greatly differed from the correct answer, we provided feedback to raise awareness of the discrepancies. After the training session, the residents performed residual congestion assessment by LUS after decongestion treatment in patients hospitalized with acute heart failure. The residents identified residual congestion in 57% of the patients. The sensitivity and specificity to identify residual congestion by the residents were 90% and 100%, respectively. The inter-operator agreement between the residents and the expert was substantial (κ = 0.86). The Spearman rank correlation coefficient for the B-lines between the expert and each resident was very high at 0.916 (P < 0.0001)., Conclusions: After a brief lecture, novice residents can achieve proficiency in quantifying B-lines on LUS and can reliably identify residual congestion on LUS., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Establishing the appropriate rivaroxaban dose in older patients with non-valvular atrial fibrillation (NVAF) is important because of the high risk of adverse events. In this EXPAND study subanalysis, we examined the safety and efficacy of standard-dose (15 mg/day) and non-recommended reduced-dose (10 mg/day) rivaroxaban in patients aged ≥65 years with NVAF and preserved renal function., Methods: The entire analysis population (ALL cohort [n = 3982]; ≥65 years) was divided into early elderly (ELD) (65-74 years [n = 1444]) and late ELD (≥75 years [n = 2386]) sub-cohorts. Each sub-cohort was divided into reduced-dose and standard-dose groups. Kaplan-Meier survival curves with adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were used to assess efficacy (thromboembolic events) and safety (hemorrhagic events) outcomes., Results: The aHR for major bleeding did not differ between the dosages in any of the cohorts (aHRs: 0.86-0.93). There were no significant differences in the occurrence of stroke + systemic embolism (SE) or stroke + SE + myocardial infarction (MI) + cardiovascular (CV) death among the cohorts. The aHR for MI/unstable angina + interventional/CV surgery + CV death was higher with 10-mg/day rivaroxaban than 15-mg/day rivaroxaban in the ALL cohort (aHR: 1.56 [95% CI 1.02-2.37], p = 0.039) and the late ELD sub-cohort (aHR: 1.86 [95% CI 1.01-3.42], p = 0.045)., Conclusions: Reduced-dose rivaroxaban may increase the risk of coronary artery events. The use of rivaroxaban 15 mg/day in patients with NVAF aged ≥75 years with preserved renal function was supported., Competing Interests: Declaration of Competing Interest All authors have received funding support from Bayer Yakuhin Ltd. throughout the implementation of the EXPAND Study, including reporting of this sub-analysis. Other disclosures are as follows; WS has received honoraria from Daiichi-Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Bayer Yakuhin Ltd., Pfizer Co. Ltd., and Bristol-Myers Squibb K. K.; TU has received consulting fees from LSI Medience, Inc.; HA has received honoraria from Daiichi-Sankyo Co. Ltd.; HI has received honoraria from Daiichi-Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Bayer Yakuhin Ltd., and Bristol-Myers Squibb K. K.; TK has received honoraria from Daiichi-Sankyo Co. Ltd. and Bayer Yakuhin, Ltd., and scholarship from Takeda Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Asahi Kasei Medical Co., Ltd., Shionogi & Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma, Ltd., Kowa Co. Ltd., Bayer Yakuhin, Ltd., Eisai Co., Ltd., Sumitomo Pharma Co., Ltd., Daiichi-Sankyo Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Torii Pharmaceutical Co., Ltd., AbbVie GK, EA Pharma Co.,Ltd., Kyowa Kirin Co., Ltd., Zeria Pharmceutical Co., Ltd., Eli Lilly Japan K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Mochida Pharmaceutical Co.,Ltd., Ono Pharmaceutical Co., Ltd., and Novo Nordisk Pharma Ltd.; TY has received consulting fees from Daiichi-Sankyo Co. Ltd., Novartis Pharma K. K., and Toa Eiyo Ltd., and honoraria from Daiichi-Sankyo Co., Ltd., Bayer Yakuhin Ltd., and Bristol-Myers Squibb K. K., and Novartis Pharma K. K.; TI has received grants from Daiichi-Sankyo Co. Ltd., and honoraria from Bayer Yakuhin Ltd., Daiichi-Sankyo Co. Ltd., and Pfizer Japan Inc.; MK has received honoraria from Daiichi-Sankyo Co. Ltd. and had board participations on a trial sponsored by Daiichi-Sankyo Co. Ltd.; KK has grants from Bayer Yakuhin Ltd., Daiichi-Sankyo Co. Ltd., Abbott Medical Co. Ltd. and honoraria from Bayer Yakuhin Ltd., Daiichi-Sankyo Co. Ltd., Novartis Pharma AG., and Otsuka Pharmaceutical Co. Ltd., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The number of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients persists even under nucleos(t)ide analogues (NAs) treatment. Aldo-keto reductase family 1 member B10 (AKR1B10) expression has been reported in advanced chronic liver diseases as well as cancer tissues. We observed an association between related to HCC incidence and serum AKR1B10 by analyzing patients under treatment with NAs. Serum AKR1B10 levels measured by ELISA were higher in HCC cases under NA treatment compared with non-HCC cases and were associated with lamivudine- and adefovir pivoxil-, but not entecavir- or tenofovir alafenamide-treated cases. The latter drugs did not increase AKR1B10 values even in HCC cases, suggesting that they influence the reduction of AKR1B10 in any cases. This analysis was supported by in-vitro examination, which showed reduced AKR1B10 expression by entecavir and tenofovir via immunofluorescence staining. In conclusion there was a relationship between HBV-related HCC incidence and AKR1B10 under nucleos(t)ide analogues, especially in the use of lamivudine and adefovir pivoxil, but entecavir and tenofovir had suppressive effects of AKR1B10., 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 © 2023 Elsevier Inc. All rights reserved.)

Background: No study thus far has compared tunnel enlargement between double-bundle and triple-bundle anterior cruciate ligament reconstruction. We compared tibial tunnel enlargement and rate of tibial tunnel coalition between these two reconstructions, hypothesizing that tibial tunnel enlargement in triple-bundle reconstruction is less than that in double-bundle reconstruction, and that the tunnel coalition rate is equal between the two procedures., Methods: This prospective randomized clinical trial included 25 patients who underwent computed tomography 2 weeks and 1 year postoperatively. Eleven patients underwent double-bundle anterior cruciate ligament reconstruction and 14 underwent triple-bundle anterior cruciate ligament reconstruction. Tunnel positions and tunnel coalition at the tibial tunnel aperture were assessed using three-dimensional computed tomography. Tunnel enlargement rate was calculated by measuring the sagittal and axial widths of the tibial bone tunnel 10 mm from the tibial tunnel aperture. These parameters were then compared between the groups., Results: The changes in tunnel positions and tunnel coalitions between groups were not significantly different. On both sagittal and axial views, the tunnel enlargement rates of the medial and lateral sections of the anteromedial bundle in the triple-bundle group were significantly smaller than those in the double-bundle group (sagittal view, p = 0.02 and < 0.01, respectively; axial view, p = 0.02 and ≤ 0.05, respectively). The groups did not differ significantly in terms of posterolateral tunnel enlargement., Conclusion: Tunnel widening in the medial and lateral sections of the anteromedial bundle-associated tibial tunnel in triple-bundle anterior cruciate ligament reconstruction was smaller than that of double-bundle reconstruction. The tunnel coalition rates between the two reconstructions were not significantly different., Competing Interests: Conflict of Interest None., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Anterior cruciate ligament reconstruction (ACLR) is reportedly associated with a higher incidence of deep vein thrombosis (DVT) incidence than other arthroscopic surgical procedures. The aim of this study is to retrospectively investigate the incidence and type of DVT and evaluate the relationship between DVT and risk factors among all patients who underwent ACLR under uniform conditions consisting of mechanical prophylaxis, no medical prophylaxis, and preoperative and postoperative lower extremity venous ultrasonography., Methods: Of the 114 patients who underwent arthroscopic primary ACLR at our hospital who did not have a compound ligament injury or revision surgery, 112 patients were included. Two patients were not examined. DVT evaluation consisted of whole-leg ultrasonography at 1 week after surgery. We evaluated age, sex, body mass index, comorbidities, operative time, tourniquet time, presence of concurrent surgery (meniscus repair/resection or osteochondral column grafting), and non-weight-bearing status at 1 week after surgery as risk factors for DVT., Results: DVT was found in 33 (29.5%) of 112 patients. Of these, 22 (19.6%) had distal DVT and 11 (9.8%) had proximal DVT. Non-weight-bearing status at 1 week after surgery was a statistically significant risk factor for proximal DVT (P = .034)., Conclusions: Non-weight-bearing status is an independent risk factor for DVT, suggesting that early weight bearing may reduce the occurrence of DVT., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2022 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Limb immobilization is considered to contribute to limb pain including hyperalgesia. Approximately 50% of patients with such chronic limb pain complain that their abnormal pain worsens after exposure to cold. However, there have been few studies on the relationship between limb immobilization and cold hypersensitivity. The aim of this study was to examine whether limb immobilization induces cold hypersensitivity, and whether physical exercise such as ankle stretching prevents its induction in model mice., Method: We used forty-four 8-week-old male C57Bl/6J mice, consisting of 32 immobilized mice and 12 control mice. The bilateral hind limbs of the mice were immobilized by a thermoplastic cast. After limb-immobilization for 1 week, changes in mechanical, thermal and cold hypersensitivity, and the expression levels of TRPV1, TRPA1, TRPM8, IL-1β, IL-6, and TNFα in the spinal cord, dorsal root ganglia and the affected hind paw were evaluated in comparison with those in the control mice. In addition, we examined the effect of ankle stretching on the hypersensitivity and expression levels in the limb-immobilized mice., Results: Mechanical, thermal and cold hypersensitivity were significantly increased in the limb-immobilized mice. In addition, ankle stretching during the immobilization period significantly prevented the increases in those hypersensitivities. There were no significant differences in the expression levels of TRPV1, TRPA1 and TRPM8 among the control, and limb-immobilized mice with and without ankle stretching. The expression levels of IL-1 and IL-6 were significantly increased in the immobilized hind limb paw. Furthermore, ankle stretching significantly prevented the increases in their expression levels., Conclusion: Limb-immobilization induced cold hypersensitivity as well as mechanical and thermal hypersensitivity, and ankle stretching significantly prevented the hypersensitivity induction in the model mice. It would be of great interest to clarify whether a patient with limb-immobilization experiences cold hypersensitivity and whether ankle stretching might prevent hypersensitivity induction in the future., Competing Interests: Declaration of conflicting interest One of the authors is an endowed chair in the affiliated institution. The other authors declare no conflicts of interest., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Tissue engineers have utilised a variety of three-dimensional (3D) scaffolds for controlling multicellular dynamics and the resulting tissue microstructures. In particular, cutting-edge microfabrication technologies, such as 3D bioprinting, provide increasingly complex structures. However, unpredictable microtissue detachment from scaffolds, which ruins desired tissue structures, is becoming an evident problem. To overcome this issue, we elucidated the mechanism underlying collective cellular detachment by combining a new computational simulation method with quantitative tissue-culture experiments. We first quantified the stochastic processes of cellular detachment shown by vascular smooth muscle cells on model curved scaffolds and found that microtissue morphologies vary drastically depending on cell contractility, substrate curvature, and cell-substrate adhesion strength. To explore this mechanism, we developed a new particle-based model that explicitly describes stochastic processes of multicellular dynamics, such as adhesion, rupture, and large deformation of microtissues on structured surfaces. Computational simulations using the developed model successfully reproduced characteristic detachment processes observed in experiments. Crucially, simulations revealed that cellular contractility-induced stress is locally concentrated at the cell-substrate interface, subsequently inducing a catastrophic process of collective cellular detachment, which can be suppressed by modulating cell contractility, substrate curvature, and cell-substrate adhesion. These results show that the developed computational method is useful for predicting engineered tissue dynamics as a platform for prediction-guided scaffold design. STATEMENT OF SIGNIFICANCE: Microfabrication technologies aiming to control multicellular dynamics by engineering 3D scaffolds are attracting increasing attention for modelling in cell biology and regenerative medicine. However, obtaining microtissues with the desired 3D structures is made considerably more difficult by microtissue detachments from scaffolds. This study reveals a key mechanism behind this detachment by developing a novel computational method for simulating multicellular dynamics on designed scaffolds. This method enabled us to predict microtissue dynamics on structured surfaces, based on cell mechanics, substrate geometry, and cell-substrate interaction. This study provides a platform for the physics-based design of micro-engineered scaffolds and thus contributes to prediction-guided biomaterials design in the future., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Systemic sclerosis (SSc) is divided into diffuse and limited cutaneous SSc (dcSSc and lcSSc). The dcSSc subtype has more severe internal organ damage. This study aimed to assess whether cardiovascular magnetic resonance (CMR) parametric mapping could detect early cardiac involvement and evaluate differences between these two subtypes., Methods: Eighty SSc patients (37 dcSSc and 43 lcSSc) underwent CMR at 3.0 T (Philips Healthcare, Best, The Netherlands) in our hospital between July 2018 and July 2021. We analyzed myocardial damage by CMR parametric mapping and compared it with clinical data., Results: The median duration of the disease was 10.2 months. The left ventricular ejection fraction was preserved in both groups. DcSSc had significantly higher native T1 (1333.4 ± 71.2 ms vs. 1295.0 ± 42.7 ms, p = 0.006) and extracellular volume fraction (32.6 ± 4.1 % vs. 30.3 ± 4.0 %, p = 0.018) in the mid-ventricular septum as compared to lcSSc, although there were no differences in T2 values. Native T1 values were positively correlated with the E/e' ratio and left atrial volume indices evaluated by transthoracic echocardiography in overall SSc and dcSSc, but not in lcSSc. Logistic regression analysis revealed that native T1 was an independent predictor of left ventricular diastolic dysfunction in SSc patients (odds ratio, 1.194; 95 % confidence interval, 1.021-1.396; p = 0.026). Native T1 was higher in SSc patients with progressive skin lesions. Additionally, there were positive correlations between brain natriuretic peptide, New York Heart Association functional classification, and native T1., Conclusions: CMR parametric mapping is a useful tool for detecting myocardial changes. Native T1 was the most sensitive parameter for identifying diffuse myocardial changes in the early stages of SSc and was associated with left ventricular diastolic function. DcSSc had more severe myocardial involvement than lcSSc; therefore, the use of CMR parametric mapping may aid in its prediction., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aimed to establish variants in CBX1, encoding heterochromatin protein 1β (HP1β), as a cause of a novel syndromic neurodevelopmental disorder., Methods: Patients with CBX1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. To investigate the pathogenicity of identified variants, we performed in vitro cellular assays and neurobehavioral and cytological analyses of neuronal cells obtained from newly generated Cbx1 mutant mouse lines., Results: In 3 unrelated individuals with developmental delay, hypotonia, and autistic features, we identified heterozygous de novo variants in CBX1. The identified variants were in the chromodomain, the functional domain of HP1β, which mediates interactions with chromatin. Cbx1 chromodomain mutant mice displayed increased latency-to-peak response, suggesting the possibility of synaptic delay or myelination deficits. Cytological and chromatin immunoprecipitation experiments confirmed the reduction of mutant HP1β binding to heterochromatin, whereas HP1β interactome analysis demonstrated that the majority of HP1β-interacting proteins remained unchanged between the wild-type and mutant HP1β., Conclusion: These collective findings confirm the role of CBX1 in developmental disabilities through the disruption of HP1β chromatin binding during neurocognitive development. Because HP1β forms homodimers and heterodimers, mutant HP1β likely sequesters wild-type HP1β and other HP1 proteins, exerting dominant-negative effects., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Schwann cells are glial cells that myelinate neuronal axons in the peripheral nervous system (PNS). When the PNS is damaged, Schwann cells de-differentiate into p75-positive "repair Schwann cells," which contribute to neural circuit regeneration. Interestingly, Schwann cells in the dorsal roots are known to be reprogrammed to repair Schwann cells even after spinal cord injury (SCI) and then migrate into the injured spinal cord. However, the molecular mechanism underlying the migration of repair Schwann cells remains unknown. Since a recent in vitro study revealed the importance of CXCR4 signaling in Schwann cell migration, we investigated whether CXCR4 signaling is involved in the PNS-to-central nervous system (CNS) migration of repair Schwann cells after SCI. We revealed that repair Schwann cells express CXCR4, and its ligand CXCL12 is upregulated in the injured spinal cord. We also found that the pharmacological inhibition of CXCR4 signaling decreased the infiltration of repair Schwann cells. Moreover, CXCR4 agonist administration effectively increased the infiltration of repair Schwann cells along with improved motor function. These findings strongly suggest the involvement of CXCR4 signaling in the PNS-to-CNS migration of repair Schwann cells after SCI., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd and Japan Neuroscience Society. All rights reserved.)

Background: Data regarding the impact of high transcatheter heart valve (THV) implantation on coronary access after transcatheter aortic valve replacement (TAVR) as assessed by postimplantation computed tomography (CT) are scarce., Objectives: The authors sought to assess the impact of high THV implantation on coronary access after TAVR., Methods: We included 160 and 258 patients treated with Evolut R/PRO/PRO+ and SAPIEN 3 THVs, respectively. In the Evolut R/PRO/PRO+ group, the target implantation depth was 1 to 3 mm using the cusp overlap view with commissural alignment technique for the high implantation technique (HIT), whereas it was 3 to 5 mm using 3-cusp coplanar view for the conventional implantation technique (CIT). In the SAPIEN 3 group, the HIT employed the radiolucent line-guided implantation, whereas the central balloon marker-guided implantation was used for the CIT. Post-TAVR CT was performed to analyze coronary accessibility., Results: HIT reduced the incidence of new conduction disturbances after TAVR for both THVs. In the Evolut R/PRO/PRO+ group, post-TAVR CT showed that the HIT group had a higher incidence of the interference of THV skirt (22.0% vs 9.1%; P = 0.03) and a lower incidence of the interference of THV commissural posts (26.0% vs 42.7%; P = 0.04) with access to 1 or both coronary ostia compared with the CIT group. These incidences were similar between the HIT and CIT groups in the SAPIEN 3 group (THV skirt: 0.9% vs 0.7%; P = 1.00; THV commissural tabs: 15.7% vs 15.3%; P = 0.93). In both THVs, CT-identified risk of sinus sequestration in TAVR-in-TAVR was significantly higher in the HIT group compared with the CIT group (Evolut R/PRO/PRO+ group: 64.0% vs 41.8%; P = 0.009; SAPIEN 3 group: 17.6% vs 5.3%; P = 0.002)., Conclusions: High THV implantation substantially reduced conduction disturbances after TAVR. However, post-TAVR CT revealed that there is a risk for unfavorable future coronary access after TAVR and sinus sequestration in TAVR-in-TAVR. (Impact of High Implantation of Transcatheter Heart Valve during Transcatheter Aortic Valve Replacement on Future Coronary Access; UMIN000048336)., Competing Interests: Funding Support and Author Disclosures Dr Ochiai has received honoraria for lectures from Edwards Lifesciences and Medtronic. Dr Moriyama has received honoraria for lectures from Edwards Lifesciences and Medtronic; and has been a clinical proctor for Edwards Lifesciences and Boston Scientific. Dr Makkar has received grant support from Edwards Lifesciences; has served as a consultant for Abbott Vascular, Cordis, and Medtronic; and owns equity in Entourage Medical. Dr Saito is a clinical proctor for Edwards Lifesciences and Medtronic. 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.)

The scaly-foot gastropod (Chrysomallon squamiferum), which lives in the deep-sea zone of oceans around thermal vents, has a black shell and scales on the foot. Both the black shell and scales contain iron sulfide minerals such as greigite (Fe 3 S 4 ) and pyrite (FeS 2 ). Although pyrite nanoparticles can be used as materials for solar panels, it is difficult to synthesize stable and spherical nanoparticles in vitro. In this study, we extracted organic molecules that interact with nano-pyrite from the shell of the scaly-foot gastropod to develop a low-cost, eco-friendly method for pyrite nanoparticles synthesis. Myoglobin (csMG), a heme protein, was identified in the iron sulfide layer of the shell. We purified recombinant csMG (r-csMG) and demonstrated that r-csMG helped in the conversion of ferric ions, sulfide ions and sulfur into spherical shaped pyrite nanoparticles at 80°C. To reduce the effort and cost of production, we showed that commercially available myoglobin from Equus caballus (ecMG) also induced the in vitro synthesis of pyrite nanoparticles. Using structure-function experiments with digested peptides, we highlighted that the amino acid sequence of r-csMG peptides controlled the spherical shape of the nanoparticle while the hemin molecules, which the peptides interacted with, maintained the size of nanoparticles. Synthesized pyrite nanoparticles exhibited strong photoluminescence in the visible wavelength region, suggesting its potential application as a photovoltaic solar cell material. These results suggest that materials for solar cells can be produced at low cost and energy under eco-friendly conditions. STATEMENT OF SIGNIFICANCE: Pyrite is a highly promising material for photovoltaic devices because of its excellent optical, electrical, magnetic, and transport properties and high optical absorption coefficient. Almost all current pyrite synthesis methods use organic solvents at high temperature and pressure under reducing conditions. Synthesized pyrite nanoparticles are unstable and are difficult to use in devices. The scaly-foot gastropod can synthesize pyrite nanoparticles in vivo, meaning that pyrite nanoparticles can be generated in an aqueous environment at low temperature. In this study, we demonstrated the synthesis of pyrite nanoparticles using a heme protein identified in the iron sulfide layer of the scaly-foot gastropod shell. These results exemplify how natural products in organisms can inspire the innovation of new technology., Competing Interests: Declaration of Competing Interest No competing interest., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Pain transmission and processing in the nervous system are modulated by various biologically active substances, including lysophospholipids, through direct and indirect actions on the somatosensory pathway. Lysophosphatidylglucoside (LysoPtdGlc) was recently identified as a structurally unique lysophospholipid that exerts biological actions via the G protein-coupled receptor GPR55. Here, we demonstrated that GPR55-knockout (KO) mice show impaired induction of mechanical pain hypersensitivity in a model of spinal cord compression (SCC) without the same change in the models of peripheral tissue inflammation and peripheral nerve injury. Among these models, only SCC recruited peripheral inflammatory cells (neutrophils, monocytes/macrophages, and CD3 + T-cells) in the spinal dorsal horn (SDH), and GPR55-KO blunted these recruitments. Neutrophils were the first cells recruited to the SDH, and their depletion suppressed the induction of SCC-induced mechanical hypersensitivity and inflammatory responses in compressed SDH. Furthermore, we found that PtdGlc was present in the SDH and that intrathecal administration of an inhibitor of secretory phospholipase A 2 (an enzyme required for producing LysoPtdGlc from PtdGlc) reduced neutrophil recruitment to compressed SDH and suppressed pain induction. Finally, by screening compounds from a chemical library, we identified auranofin as a clinically used drug with an inhibitory effect on mouse and human GPR55. Systemically administered auranofin to mice with SCC effectively suppressed spinal neutrophil infiltration and pain hypersensitivity. These results suggest that GPR55 signaling contributes to the induction of inflammatory responses and chronic pain after SCC via the recruitment of neutrophils and may provide a new target for reducing pain induction after spinal cord compression, such as spinal canal stenosis., 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 © 2023 Elsevier Inc. All rights reserved.)

Background: Elderly patients with atrial fibrillation (AF) are at a higher risk for all-cause mortality and heart failure. Rate control is an essential component in AF management. This exploratory study assessed the relationship between resting heart rate during AF at baseline and clinical outcomes in Japanese elderly non-valvular AF (NVAF) patients, using the All Nippon AF In the Elderly Registry (ANAFIE) dataset., Methods: This sub-cohort included patients who agreed to participate and presented with AF at enrollment in the ANAFIE study. They were categorized into six groups according to the resting heart rate during AF. Outcomes included 2-year cumulative incidences of stroke/systemic embolic events (SEE), ischemic stroke, major bleeding, cardiovascular (CV) events, CV death, all-cause death, and net clinical outcome, a composite of stroke/SEE, major bleeding, and all-cause death., Results: Of the 8292 patients included in this sub-cohort (paroxysmal, 1496; non-paroxysmal, 6796), 90 % of patients were using anticoagulants. Higher heart rate was more frequently reported in women and in patients with paroxysmal AF and was associated with increased use of direct oral anticoagulants (DOACs) and antiarrhythmic drugs. Heart rate ≥110 beats per minute (bpm) was associated with a significantly higher incidence of cardiac events and numerically higher incidences of CV death and all-cause death compared with a heart rate of 60 to <80 bpm, all of which were driven by an increased risk in patients with non-paroxysmal AF. Hazard ratios by the type of anticoagulant for each clinical outcome were comparable across all heart rate categories, indicating no significant interactions., Conclusions: Elderly Japanese patients with non-paroxysmal NVAF and a heart rate ≥110 bpm have an increased risk of cardiac events. There was no interaction between heart rate category and the relative risk of adverse clinical events in patients taking DOACs compared with those taking warfarin., Competing Interests: Declaration of competing interest Takanori Ikeda received research grants from Daiichi Sankyo, Medtronic Japan, and Japan Lifeline and honoraria from Ono Pharma, Bayer Yakuhin, Daiichi Sankyo, Bristol-Myers Squibb, and Pfizer. Additionally, Takanori Ikeda was a member of the advisory board for Bayer Yakuhin, Bristol-Myers Squibb, and Daiichi Sankyo. Takeshi Yamashita received research funding from Bristol-Myers Squibb, Bayer, and Daiichi Sankyo, manuscript fees from Daiichi Sankyo, and Bristol-Myers Squibb, and remuneration from Daiichi Sankyo, Bayer, Pfizer Japan, Bristol-Myers Squibb, and Ono Pharmaceutical. Masaharu Akao received research funding from Bayer and Daiichi Sankyo, and remuneration from Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Bayer, and Daiichi Sankyo. Hirotsugu Atarashi received remuneration from Daiichi Sankyo. Yukihiro Koretsune received remuneration from Daiichi Sankyo, Bayer, and Nippon Boehringer Ingelheim. Ken Okumura received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic. Wataru Shimizu received research funding from Bristol-Myers Squibb, Daiichi Sankyo, and Nippon Boehringer Ingelheim, and patent royalties/licensing fees from Daiichi Sankyo, Pfizer Japan, Bristol-Myers Squibb, Bayer, and Nippon Boehringer Ingelheim. Hiroyuki Tsutsui received research funding from Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, and IQVA services Japan, remuneration from Daiichi Sankyo, Bayer, Nippon Boehringer Ingelheim, Pfizer Japan, Otsuka Pharmaceutical, and Mitsubishi Tanabe Pharma, scholarship funding from Daiichi Sankyo, Mitsubishi Tanabe Pharma, and Teijin Pharma, and consultancy fees from Novartis Pharma, Pfizer Japan, Bayer, Nippon Boehringer Ingelheim, and Ono Pharmaceutical. Kazunori Toyoda received remuneration from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Takeda, and Nippon Boehringer Ingelheim. Atsushi Hirayama participated in a course endowed by Boston Scientific Japan, and has received research funding from Daiichi Sankyo and Bayer, and remuneration from Bayer, Daiichi Sankyo, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Sanofi, Astellas Pharma, Sumitomo Dainippon Pharma, Amgen Astellas BioPharma, and AstraZeneca, and patent royalties/licensing fees from Toa Eiyo M. Masahiro Yasaka received research funding from Nippon Boehringer Ingelheim, and remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Pfizer Japan, and CSL Behring. Takenori Yamaguchi acted as an advisory board member of Daiichi Sankyo, and received remuneration from Daiichi Sankyo and Bristol-Myers Squibb. Satoshi Teramukai received research funding from Nippon Boehringer Ingelheim and remuneration from Daiichi Sankyo, Sanofi, Takeda, Chugai Pharmaceutical, Solasia Pharma, Bayer, Sysmex, Nipro, NapaJen Pharma, Gunze, and Atworking. Tetsuya Kimura has stock and is an employee of Daiichi Sankyo. Yoshiyuki Morishima and Atsushi Takita are employees of Daiichi Sankyo. Hiroshi Inoue received remuneration from Daiichi Sankyo, Bayer, and Bristol-Myers Squibb, and consultancy fees from Daiichi Sankyo., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Carnosine (β-alanyl-L-histidine) is a natural dipeptide with multiple neuroprotective properties. Previous studies have advertised that carnosine scavenges free radicals and displays anti-inflammatory activity. However, the underlying mechanism and the efficacies of its pleiotropic effect on prevention remained obscure. In this study, we aimed to investigate the anti-oxidative, anti-inflammative, and anti-pyroptotic effects of carnosine in the transient middle cerebral artery occlusion (tMCAO) mouse model. After a daily pre-treatment of saline or carnosine (1000 mg / kg / day) for 14 days, mice (n = 24) were subjected to tMCAO for 60 min and continuously treated with saline or carnosine for additional 1 and 5 days after reperfusion. The administration of carnosine significantly decreased infarct volume 5 days after the tMCAO (*p < 0.05) and effectively suppressed the expression of 4-HNE, 8-OHdG, Nitrotyrosine 5 days, and RAGE 5 days after tMCAO. Moreover, the expression of IL-1β was also significantly suppressed 5 days after tMCAO. Our present findings demonstrated that carnosine effectively relieves oxidative stress caused by ischemic stroke and significantly attenuates neuroinflammatory responses related to IL-1β, suggesting that carnosine can be a promising therapeutic strategy for ischemic stroke., Competing Interests: Declaration of Competing Interest The authors disclose no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: This multicentre, phase 2, randomized, controlled study of allogeneic haematopoietic stem cell transplantation (allo-HSCT) recipients compared the immunogenicity of two anti-pneumococcal vaccine regimens: four doses of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) (3+1+1 experimental group), and three doses of PCV13 followed by PPSV23 (3+0+1 group)., Methods: Allo-HSCT recipients without active graft-versus-host disease at enrolment were eligible. The primary endpoint was the IgG response rate (≥0.20 mg/mL) for all eight measured serotypes at 5 months after the PPSV23 booster., Results: Seventy-two recipients were randomized, and seventy recipients who received over one PCV13 dose were analysed. The mean ages were 47.2 years (standard deviation, 14.4) in the 3+1+1 group (n = 35) and 49.0 years (standard deviation, 14.3) in the 3+0+1 group (n = 35). There was no significant difference in the overall IgG response rate at 5 months after the PPSV23 booster between the 3+1+1 and 3+0+1 groups (100% (26/26) vs. 93% (27/29), respectively, relative risk (RR): 1.07; 95% confidence interval (CI): 0.97-1.19). This rate was high immediately before the PPSV23 booster in the 3+1+1 group (100% (26/26) compared with 81% (21/26), respectively, RR: 1.24; 95% CI: 1.03-1.49), but this difference disappeared 1 month after the PPSV23 booster (100% (26/26) vs. 97% (28/29), respectively, RR: 1.04; 95% CI; 0.97-1.11). No serious adverse events leading to study dropout occurred., Discussion: We were not able to determine the efficacy of the experimental arm based on the IgG response rate at 5 months after the PPSV23 booster in allo-HSCT recipients., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Data on the effectiveness and safety of rivaroxaban for the treatment of patients with venous thromboembolism (VTE) and active cancer are limited in the Japanese real-world setting., Methods: In this subanalysis of the J'xactly study, which was a multicenter, prospective, observational study, we evaluated the effectiveness and safety of rivaroxaban in patients with acute VTE and active cancer (n = 193) versus those without active cancer (n = 823)., Results: Compared with patients without active cancer, those with active cancer demonstrated a significantly different age distribution, with fewer aged <65 and ≥75 years; a lower proportion of women; a lower mean body mass index; and a lower proportion of physical inactivity, injury, thrombophilia, and heart failure. There was no difference in the initial dose distribution of rivaroxaban between patients with and without active cancer. The incidences of recurrence or aggravation of symptomatic VTE and major bleeding were not significantly different [VTE: 1.44 % vs. 2.80 % per patient-year, hazard ratio (HR) 0.50, 95 % confidence interval (CI) 0.18-1.39, p = 0.172; major bleeding: 4.49 % vs. 2.55 % per patient-year, HR 1.80, 95 % CI 0.82-3.95, p = 0.137]. Approximately 10 % of patients with active cancer died at 6 months, with a significantly higher cumulative all-cause mortality rate than those without active cancer (23.29 % vs. 2.03 % per patient-year, HR 11.31, 95 % CI 7.30-17.53, p < 0.001)., Conclusions: In patients with VTE and active cancer, rivaroxaban showed acceptable effectiveness, although clinically significant bleeding remains a concern., Clinical Trial Registration: UMIN Clinical Trials Registry number, UMIN000025072., Competing Interests: Declaration of competing interest S.H. has no relationships relevant to the contents of this paper to disclose. T.I. has received lecture fees from Bayer Yakuhin, Ltd., Bristol-Myers Squibb, and Nippon Boehringer Ingelheim Co., Ltd., and research funding from Daiichi-Sankyo Co., Ltd. Y.O. has received lecture fees, research funding, scholarship funds, and donations from Bayer Yakuhin, Ltd.; lecture fees, scholarship funds, and donations from Daiichi-Sankyo Co., Ltd.; research funding from Bristol-Myers Squibb; scholarship funds and donations from Johnson & Johnson; and is associated with endowed departments sponsored by Boston Scientific Japan, Abbott Medical Japan, Medtronic Japan Co., Ltd., Nihon Kohden Co., Nihon Medi-Physics Co., Ltd., and Japan Lifeline Co., Ltd. I.F. has received lecture fees from Bayer Yakuhin, Ltd., Daiichi-Sankyo Co., Ltd., and Pfizer Japan Inc. M.N. has no relationships relevant to the contents of this paper to disclose. N.Y. has received lecture fees from Bayer Yakuhin, Ltd., Pfizer Japan Inc., and Daiichi-Sankyo Co., Ltd. M.T. has no relationships relevant to the contents of this paper to disclose. H.M. has no relationships relevant to the contents of this paper to disclose. Ta.Y. has received lecture fees, manuscript fees, and research funding from Daiichi-Sankyo Co., Ltd., Bristol-Myers Squibb, and Bayer Yakuhin, Ltd., and lecture fees from Ono Pharmaceutical Co., Ltd., Toa Eiyo, Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd. M.M. has received lecture fees from Bayer Yakuhin, Ltd. Ts.Y. has no relationships relevant to the contents of this paper to disclose. A.H. has received lecture fees from Toa Eiyo, Ltd., Nippon Boehringer Ingelheim Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Amgen Astellas BioPharma, and AstraZeneca Plc.; lecture fees, scholarship funds, and donations from Bayer Yakuhin, Ltd., Sanofi S.A., Astellas Pharma Inc., Bristol-Myers Squibb, and Daiichi-Sankyo Co., Ltd.; scholarship funds, donations, and is associated with endowed departments sponsored by Boston Scientific Japan and Otsuka Pharmaceutical Co., Ltd.; scholarship funds and donations from Takeda Pharmaceutical Co., Ltd., and Nihon Medi-Physics Co., Ltd.; and is associated with endowed departments sponsored by Fukuda Denshi Co., Ltd., Abbott Medical Japan Co., Ltd., Japan Lifeline Co., Ltd., and Medtronic Japan Co., Ltd. T. Yamashita, T.I., and A.H. are members of Circulation Journal's Editorial Team., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cancer antigen 125 (CA125) is one of the mucin family proteins and is a serum tumor marker for various tumors, such as ovarian cancer, endometrial cancer, pancreatic cancer, and bladder cancer. CA125 is used to distinguish between benign and malignant tumors, monitor the response to chemotherapy, and detect relapse after initial treatment. Recently, CA125 was reported to be involved in chemoresistance through the physical characteristics of mucin or by modifying the immune tumor-microenvironment. However, the relationship between CA125 expression and chemoresistance in bladder cancer is still unclear. In this study, the clinicopathologic features of bladder cancer with CA125 expression and the status of the tumor-microenvironment related to gemcitabine/cisplatin resistance were investigated using publicly available data sets (Cancer Genome Atlas Expression, GSE169455 data set) from the cBioPortal website, the National Center for Biotechnology Information website, and an in-house case collection of bladder cancer. The cases with CA125 expression had poorer disease-free and overall survival rates than those without CA125 expression. A mucinous area surrounding cancer cells was frequently detected in cases with CA125 expression (81%; 13/16 cases). CA125 expression was also related to the immunosuppressive tumor-microenvironment through the infiltration of immunosuppressive immune cells, such as regulatory T cells and M2 macrophages. These results suggest that the status of tumor-microenvironment associated with CA125 is involved in gemcitabine/cisplatin resistance in bladder cancer., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

In the drug development process, it is important to assess the contributions of drug-metabolizing enzymes and/or drug transporters to the intestinal pharmacokinetics of candidate compounds. For such assessments, chemical inhibitors are often used in in vitro systems. However, this practice poses two problems: one is the low expression levels of pharmacokinetic-related genes in conventional in vitro systems, such as Caco-2 cells, and the other is the off-target and less-efficient effects of their inhibitors. Here, as a model, we have established human biopsy-derived enteroids deficient in MDR1, a key efflux transporter. The expression levels and activities of other pharmacokinetic-related genes, such as CYP3A4, in the MDR1-knockout (KO) enteroid-derived monolayers were maintained at levels as high as those in the WT enteroid-derived monolayers. The contribution of MDR1 to the cytotoxicity of vinblastine, which CYP3A4 metabolized, was accurately evaluated by using the MDR1-KO enteroid-derived monolayers. In contrast, it could not be evaluated in the WT enteroid-derived monolayers treated by verapamil, a widely used MDR1 inhibitor, due to the off-target effect of verapamil, which also inhibits CYP3A4. The combination of human enteroid-derived monolayers and genome editing technology would be a powerful tool to evaluate the contributions of specific pharmacokinetic-related molecules., (Copyright © 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Rodent-derived intestinal tissues or human colon cancer-derived Caco-2 cells are widely used for in vitro pharmacokinetic tests. However, both entail problems such as species differences from humans and low expression levels of specific pharmacokinetic-related factors, respectively. To solve these problems, many groups, including ours, have been focusing on human biopsy-derived intestinal organoids (b-IOs) and human iPS cell-derived intestinal organoids (i-IOs). However, no reports directly compare the two. Therefore, we established both from a single individual and conducted a comparative study. b-IOs had a shorter doubling time than i-IOs: about 59 h vs 148 h. b-IOs also had higher gene expression levels of major drug transporters and drug-metabolizing enzymes than i-IOs. To evaluate their applicability to pharmacokinetics, both organoids were two-dimensionally cultured. Although the b-IO monolayer had a lower transepithelial electrical resistance than the i-IO monolayer, it had higher gene expression levels of many drug transporters and major drug-metabolizing enzymes than the i-IO monolayer. RNA-seq analysis showed that the i-IOs monolayer had a more complex structure than the b-IOs monolayer because the former contained neuronal and vascular endothelial cells. This study provides basic information for pharmacokinetic applications of human biopsy-derived and human iPS cell-derived intestinal organoids., 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 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background: The impact of body mass index (BMI) on hospital mortality in patients with acute heart failure has been well documented in Asian populations. However, the relationship between BMI, hospital-associated disability (HAD), and hospitalization costs in patients with heart failure is poorly understood. This study aimed to explore the impact of BMI on HAD and hospitalization costs for acute heart failure in Japan., Methods: From April 2012 to March 2020, the Japanese Registry of All Cardiac and Vascular Disease Diagnosis Procedure Combination (JROAD-DPC) database was used to identify patients with acute heart failure. All patients were categorized into five groups according to the World Health Organization Asian BMI criteria. The hospitalization costs and HAD were evaluated., Results: Among the 238,160 eligible patients, 15.7% were underweight, 42.2% were normal, 16.7% were overweight, 19.3% were obese I, and 6.0% were obese II, according to BMI. The prevalence of HAD was 7.43% in the total cohort, and the risk of HAD increased with a lower BMI. Restricted cubic spline analysis showed a U-shaped relationship between BMI and hospitalization costs for all ages. Furthermore, developing HAD was associated with greater costs compared with non-HAD, regardless of BMI category., Conclusions: We found that the lower the BMI, the higher the incidence of HAD. A U-shaped association was confirmed between BMI and hospitalization costs, indicating that hospitalization costs increased for both lower and higher BMI regardless of age. BMI could be an important and informative risk stratification tool for functional outcomes and economic burdens., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier B.V.)

Background: When treating cancer patients, the progression of symptoms is accompanied by the deterioration of systemic conditions and motor function. From a risk-benefit perspective, a certain level of physical function must be maintained to continue cancer treatment. Recently, outpatient cancer treatment has become more common. Motor function is important to determine the feasibility of continuing cancer treatment. The study aimed to evaluate the motor function of patients with visceral cancer using locomo tests established by Japanese Orthopaedic Association., Methods: Locomo tests were performed, and the results were compared with data from non-cancer individuals. Background data were matched by propensity score matching. Data from 53 cancer patients (group C) were compared with that of 75 non-cancer patients (group N)., Results: The average score in the two-step test of group C was lower than that of group N (1.27: 1.37, p = 0.004). The average function in the stand-up test of group C was worse than that of group N (p = 0.001). The average score in the 25-question geriatric locomotive function scale (GLFS) of group C was significantly higher than that of group N (19.92: 5.29, SE 2.21, p < 0.001). Higher 25-question GLFS scores indicate reduced mobility. The proportion of the locomo stage 2 in group C was significantly higher than in group N (51%: 13%, p < 0.001). The results of the two field tests revealed a clinically minimal difference between the two groups, but a statistically significant difference. Locomo tests may be detect potential motor dysfunction in outpatient cancer patients with apparently maintained motor function., Conclusions: Even in cancer patients who attend outpatient clinics, their motor functions could be potentially impaired. Therapeutic interventions to maintain and enhance motor function for cancer patients could be useful for continuing cancer treatment, and furthermore, improving prognosis., Competing Interests: Declaration of competing interest None declared., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a degenerative disorder characterized by the loss of synapses and neurons in the brain, and results in the accumulation of amyloid-based neurotic plaques. Amyloid-β oligomers (AβO) are widely accepted as the main neurotoxin that induces oxidative stress and neuronal loss in AD. In this study, an oxidative stress model of the neuroblastoma SH-SY5Y cell line exposed to AβO was established to simulate an AD cell model. Exposure to AβO significantly reduced the viability of cultured SH-SY5Y cells (p < 0.05) and significantly increased intracellular reactive oxygen species (ROS) (p < 0.01). AβO exposure also induced oxidative stress in SH-SY5Y cells. Furthermore, AβO significantly increased the level of hyperphosphorylation of tau at sites T181 and T205 in SH-SY5Y cells (p < 0.01). Using edaravone, a free radical scavenger with neuroprotective properties, as the control, the possible protective and anti-oxidative effects of curcumin (40 μM) and resveratrol (20 μM) were evaluated. The results suggest that curcumin and resveratrol decreased ROS generation, attenuated oxidative stress, inhibited tau hyperphosphorylation, and protected SH-SY5Y cells from AβO damage. Both curcumin and resveratrol are promising supplements or medicine as therapeutic agents for the treatment of AD., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The subventricular zone (SVZ) of the lateral ventricles represents a main region where neural stem cells (NSCs) of the mature central nervous system (CNS) reside. Bone Morphogenetic Proteins (BMPs) are the largest subclass of the transforming growth factor-β (TGF-β) superfamily of ligands. BMP4 is one such member and plays important roles in adult NSC differentiation. However, the exact effects of BMP4 on SVZ adult NSCs in CNS ischemia are still unknown. Using oxygen and glucose deprivation (OGD) as an in vitro model of ischemia, we examined the behavior of adult NSCs. We observed that anoxia resulted in reduced viability of adult NSCs, and that BMP4 treatment clearly rescued apoptotic cell death following anoxia. Furthermore, BMP4 treatment exhibited a strong inhibitory effect on cellular proliferation of the adult NSCs in normoxic conditions. Moreover, such inhibitory effects of BMP4 treatment were also found in OGD conditions, despite the enhanced cellular proliferation of the adult NSCs that was observed under such ischemic conditions. Increased neuronal and astroglial commitment of adult NSCs were found in the OGD conditions, whereas a reduction in differentiated neurons and an increase in differentiated astrocytes were observed following BMP4 treatment. The present data indicate that BMP4 modulates proliferation and differentiation of SVZ-derived adult NSCs and promotes cell survival in the in vitro model of ischemic stroke., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022 Japan Neuroscience Society and Elsevier B.V. All rights reserved.)

Background and Aims: Gut microbial lipopolysaccharide (LPS) induces endotoxemia, an independent risk factor for cardiovascular disease (CVD). However, no studies have demonstrated how structural differences in each bacterial LPS contribute to endotoxemia. Here, we investigated the effects of different acyl chains in the lipid A moiety of LPS on endotoxemia and the subsequent immune response and atherosclerotic plaque formation., Methods: Apoe -/- mice were intraperitoneally administered 2 mg/kg of Escherichia coli-derived LPS (E. LPS, as a representative of hexa-acylated lipid A), Bacteroides-derived LPS (B. LPS, as a representative of penta- or tetra-acylated lipid A), or saline (control) once a week, six times. An immunohistological assessment was performed on plaque sections., Results: E. LPS administration induced endotoxemia, but B. LPS and saline did not. In E. LPS-treated mice, total plaque areas in the aortic root were significantly increased, and neutrophil accumulation and increased formation of neutrophil extracellular traps (NETs) were observed at the plaque lesions, but not in B. LPS-treated mice. A single dose of E. LPS significantly increased the accumulation of neutrophils in plaque lesions on day 3, and NET formation on day 7. E. LPS also increased interleukin-1 beta (IL-1β) production in plaque lesions on day 7. Furthermore, NET formation and IL-1β production were also observed in human coronary plaques., Conclusions: We identified a previously unknown link between structural differences in LPS and atherosclerosis. Lowering microbial LPS activity may reduce NET formation in plaques and prevent CVD progression., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Idarucizumab, a dabigatran-specific reversal agent, was launched in Japan in 2016. The J-Dabigatran Surveillance 2 study was designed to assess the characteristics and outcomes of dabigatran-treated patients after the launch of idarucizumab., Methods: Patient characteristics and outcomes, including thromboembolic and bleeding events, of dabigatran-naïve patients with non-valvular atrial fibrillation (NVAF) who received dabigatran etexilate [110 mg or 150 mg twice-daily (b.i.d.)] for the prevention of ischemic stroke and systemic embolism were investigated and presented descriptively. Absolute standardized differences (ASD) in baseline characteristics compared with the first J-Dabigatran Surveillance (J-Dabi1; 2011-2013) study were included., Results: In total, 5660 patients were enrolled and 5436 were analyzed in this study; 3516 and 1898 received 110 mg b.i.d. and 150 mg b.i.d. dabigatran, respectively; 22 received other doses. The overall duration of follow-up (mean ± standard deviation) was 287 ± 179 days. Baseline characteristics, including stroke/bleeding-risk scores, were typical of this patient population. Overall, paroxysmal, persistent, permanent, and symptomatic atrial fibrillation were observed for 53.2%, 27.1%, 13.7%, and 53.9% of patients, respectively (J-Dabi1 ASD: 0.2, 0.0, 0.3, and 0.2, respectively). Catheter ablation was selected in 27.9% of patients (J-Dabi1 ASD: 0.6). Rates of clinical outcomes were low in the study (mostly <2%/year). The incidence rate of major bleeding was 1.1%/year (n = 46) and stroke/transient ischemic attack/systemic embolism was 1.7%/year (n = 71). Twelve (0.2%) patients received idarucizumab, commonly for serious bleeding events, and most recovered., Conclusions: Dabigatran continues to be safe and well tolerated in patients with NVAF for stroke and systemic embolism prevention and continues to be prescribed appropriately. Treatment outcomes have not changed since the availability of idarucizumab. Since the J-Dabi1 study, treatment guidelines for anticoagulation use in NVAF have been updated based on emerging clinical evidence, accounting for differences in patient characteristics, and making dabigatran a preference for distinct patient populations., Competing Interests: Declaration of competing interest Takeshi Yamashita has received remuneration from Boehringer Ingelheim, Daiichi Sankyo, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Novartis, Otsuka Pharmaceutical, Ono Pharmaceutical, and Toa Eiyo, and research funding from Boehringer Ingelheim, Bristol-Myers Squibb, Bayer Healthcare, and Daiichi Sankyo; Shinichiro Uchiyama has received remuneration from Boehringer Ingelheim, Bayer Healthcare, Daiichi Sankyo, and Sanofi; Hirotsugu Atarashi has received remuneration from Boehringer Ingelheim and Daiichi Sankyo; Ken Okumura has received remuneration from Boehringer Ingelheim, Bayer Healthcare, Daiichi Sankyo, and Pfizer; Yukihiro Koretsune has received remuneration from Daiichi Sankyo, Boehringer Ingelheim, Bayer Healthcare, Bristol-Myers Squibb, and Pfizer; Masahiro Yasaka has received remuneration from Boehringer Ingelheim, Bayer Healthcare, and Daiichi Sankyo, and research funding from Boehringer Ingelheim; Junichi Wakayama is an employee of EPS Corporation; Taku Fukaya is an employee of Nippon Boehringer Ingelheim; Hiroshi Inoue has received remuneration from Boehringer Ingelheim, Bayer Healthcare, Daiichi Sankyo, and Bristol-Myers Squibb., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The adult mammalian central nervous system has limited regenerative ability, and spinal cord injury (SCI) often causes lifelong motor disability. While regeneration is limited in adults, injured spinal cord tissue can be regenerated and neural function can be almost completely restored in neonates. However, difference of cellular composition in lesion has not been well characterized. To gain insight into the age-dependent cellular reaction after SCI, we performed single-nucleus RNA sequencing, analyzing 4076 nuclei from sham and injured spinal cords from adult and neonatal mice. Clustering analysis identified 18 cell populations. We identified previously undescribed cells with ependymal cell-like gene expression profile, the number of which was increased in neonates after SCI. Histological analysis revealed that these cells line the central canal under physiological conditions in both adults and neonates. We confirmed that they were enriched in the lesion only in neonates. We further showed that these cells were positive for the cellular markers of ependymal cells, astrocytes and radial glial cells. This study provides a deeper understanding of neonate-specific cellular responses after SCI, which may determine regenerative capacity., (Copyright © 2022 Japan Neuroscience Society and Elsevier B.V. All rights reserved.)

Background: Catheter ablation is widely used as first-line therapy for patients with impaired quality of life; however, whether catheter ablation improves survival and other outcomes in atrial fibrillation (AF) cases remains unclear., Objective: The purpose of this study was to evaluate whether catheter ablation reduces adverse clinical outcomes and improves patients' quality of life using data from a contemporary Japanese multicenter registry of patients with early-stage AF., Methods: The Keio Interhospital Cardiovascular Studies-Atrial Fibrillation registered 3318 patients with AF newly diagnosed at or referred to participating hospitals between 2014 and 2018. Propensity score matching based on 47 demographic variables was performed. We extracted 823 pairs who underwent catheter ablation or medical therapy alone. The primary outcome was the composite of all-cause death, stroke, bleeding events, and heart failure hospitalization during a 2-year follow-up period. Additionally, the Atrial Fibrillation Effect on QualiΤy-of-Life scores at baseline and 1-year follow-up were evaluated., Results: Within the matched cohort, the median time since AF diagnosis was 0.3 years (interquartile range [IQR] 0.1‒2.3 years), age was 67.0 years (IQR 59.0‒73.0 years), and the CHA 2 DS 2 -VASc score was 2.0 (IQR 1.0‒2.0). During a median follow-up period of 730 days (IQR 366‒731 days), patients who underwent catheter ablation had a lower risk of primary outcomes (hazard ratio 0.49; 95% confidence interval 0.30‒0.79; P = .004), with a significantly lower risk of heart failure hospitalization (hazard ratio 0.33; 95% confidence interval 0.14-0.77; P = .010) and improved Atrial Fibrillation Effect on QualiΤy-of-Life scores, than did those who received medical therapy., Conclusion: In patients with propensity score-matched, early-stage, real-world AF, catheter ablation was associated with a lower risk of adverse clinical events and improved quality of life as compared with medical therapy., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: In monarchE, abemaciclib plus endocrine therapy (ET) as adjuvant treatment of hormone receptor-positive, human epidermal growth factor 2-negative, high-risk, early breast cancer (EBC) demonstrated a clinically meaningful improvement in invasive disease-free survival versus ET alone. Detailed safety analyses conducted at a median follow-up of 27 months and key patient-reported outcomes (PROs) are presented., Patients and Methods: The safety population included all patients who received at least one dose of study treatment (n = 5591). Safety analyses included incidence, management, and outcomes of common and clinically relevant adverse events (AEs). Patient-reported health-related quality of life, ET symptoms, fatigue, and side-effect burden were assessed., Results: The addition of abemaciclib to ET resulted in higher incidence of grade ≥3 AEs (49.7% versus 16.3% with ET alone), predominantly laboratory cytopenias [e.g. neutropenia (19.6%)] without clinical complications. Abemaciclib-treated patients experienced more serious AEs (15.2% versus 8.8%). Discontinuation of abemaciclib and/or ET due to AEs occurred in 18.5% of patients, mainly due to grade 1/2 AEs (66.8%). AEs were managed with comedications (e.g. antidiarrheals), abemaciclib dose holds (61.7%), and/or dose reductions (43.4%). Diarrhea was generally low grade (grade 1/2: 76%); grade 2/3 events were highest in the first month (20.5%), most were short-lived (≤7 days) and did not recur. Venous thromboembolic events (VTEs) were higher with abemaciclib + ET (2.5%) versus ET (0.6%); in the abemaciclib arm, increased VTE risk was observed with tamoxifen versus aromatase inhibitors (4.3% versus 1.8%). PROs were similar between arms, including being 'bothered by side-effects of treatment', except for diarrhea. At ≥3 months, most patients reporting diarrhea reported 'a little bit' or 'somewhat'., Conclusions: In patients with high-risk EBC, adjuvant abemaciclib + ET has an acceptable safety profile and tolerability is supported by PRO findings. Most AEs were reversible and manageable with comedications and/or dose modifications, consistent with the known abemaciclib toxicity profile., Competing Interests: Disclosure HSR reports grants from Pfizer, Novartis, Eli Lilly and Company, Genentech/Roche, Macrogenics, Merck, Boehringer Ingelheim, Polyphor, OBI, Odonate, Daiichi, Astra Zeneca, Seattle Genetics, Immunomedics, Sermonix; personal fees from Mylan, Puma, Samsung outside the submitted work. JO reports personal fees from AbbVie Inc., Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene Corporation, Clovis Oncology, Daiichi Sankyo, Eisai, G1 Therapeutics, Gilead Sciences, GRAIL, Halozyme Therapeutics, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Eli Lilly and Company, Merck, Myriad, Nektar Therapeutics, Novartis, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Prime Oncology, Roche/Genentech, Samsung Bioepis, Sanofi, Seagen, Seattle Genentech, Syndax Pharmaceuticals, Taiho Oncology, Takeda, Synthon outside the submitted work. FB reports personal fees for honoraria and advisory role for Roche, Pfizer, Eli Lilly and Company, and Novartis outside the submitted work. MT reports research grants from JBCRG association, Astellas, AFI technologies, Shionogi, and GL Science; research grants and personal fees from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, AstraZeneca, Shimadzu, Yakult, and Nippon Kyaku; other fees from Kyowa-Kirin and Daiichi-Sankyo; personal and other fees from Eli Lilly and Company, Konica Minolta, Bristol Myers Squibb, Athenex Oncology, Bertis Terumo, and Kansai Medical Net; personal fees for honoraria from MSD, Exact Science, and Novartis; and serves as a board of director for JBCRG association, Organisation for Oncology and Translational Research, and Kyoto Breast Cancer Research Network, outside the submitted work. IB reports grants and research support to institution: AstraZeneca, Roche and Eli Lilly and Company; personal fees for honoraria and advisory role from AstraZeneca, Roche, Novartis, Eisai, Celgene, Pfizer, Eli Lilly and Company, Pierre Fabre and Bristol-Myers Squibb, Veracyte outside the submitted work. MG reports personal fees from MSD, Novartis, GenDrug, and Amgen, outside the submitted work. TY reports grant and other fees from Chugai, Taiho, Nippon Kayaku, Kyowa Kirin; other fees from Eisai, Novartis Pharma, Astra Zeneca, Eli Lilly and Company, Daiichi Sankyo, and Pfizer Japan outside the submitted work. FZ reports personal fees for honoraria, fees for lectures and advisory role for Astra Zeneca, Daiichi, Eli Lilly and Company, Merck, Novartis, Pfizer, and Roche outside the submitted work. MC reports personal fees from Eli Lilly and Company, Novartis, and GT1; other fees from AstraZeneca, Sanofi, Servier, AbbVie, Accord, Pfizer, Seagen, and Daichii Sankyo, outside of the submitted work. BSA, AS, MH, JB, AZ, RW are full-time employees of Eli Lilly and Company and/or Eli Lilly and Company shareholders. SRDJ reports personal fees from AstraZeneca, Eli Lilly and Company, Novartis, Pfizer, Puma Biotechnology, Eisai, and Roche/Genentech; personal fees and other from AstraZeneca, Eli Lilly and Company, Novartis, Pfizer, Puma Biotechnology, and Roche/Genentech, outside the submitted work. MR reports personal fees from Pfizer, Novartis, Eli Lilly and Company, Roche Pharma AG, AstraZeneca, Daiichi Sankyo, Hexal, Novartis, SOMATEX, Seagen, and Pfizer; other fees from Pfizer, Celgene, and Novartis, outside the submitted work. SMT reports grants and personal fees from Eli Lilly and Company during the conduct of the study; grants and personal fees from AstraZeneca, Eli Lilly and Company, Merck, Nektar, Novartis, Pfizer, Genentech/Roche, Exelixis, Bristol-Myers Squibb, Eisai, Nanostring, Sanofi, Odonate, Immunomedics/Gilead; grants from Cyclacel; personal fees from Puma, Celldex, Seattle Genetics, Silverback Therapeutics, G1 Therapeutics, Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Daiichi Sankyo, CytomX, Samsung Bioepsis Inc., Certara, Mersana Therapeutics, OncoSec, Ellipses Pharma, 4D Pharma, Chugai Pharma, Infinity Therapeutics, BeyondSpring Pharmaceuticals outside the submitted work. All other authors have declared no conflicts of interest. Data sharing Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and European Union or after primary publication acceptance, whichever is later. No expiration date for data requests is set once the data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data-sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data-sharing environment. For details on submitting a request, see the online instructions., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)