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Background: Although clinical guidelines recommend self-care assessment for patients with chronic heart failure (CHF), its prognostic significance remains controversial. This study aimed to compare the prognostic significance of self-care behavior on mortality between patients with and without a history of recent hospitalization for heart failure (HF)., Methods: We analyzed consecutive 1907 CHF patients from a Japanese multicenter registry (January 2020-June 2023) using the 9-item European Heart Failure Self-care Behavior Scale (EHFScBS-9) at enrolment. Suboptimal self-care behavior was defined as a score < 70 on the EHFScBS-9. Patients were divided into recent (within 30 days post-discharge, n = 664) and no recent hospitalization for HF groups (n = 1263), respectively. The primary outcome was a composite of all-cause death and rehospitalization for HF., Results: During a median follow-up period of 427 (interquartile range 273-630) days, the primary outcome occurred in 100 patients. Patients with suboptimal self-care behavior exhibited a higher incidence of the primary outcome in the recent hospitalization for HF group (p = 0.020) but not in the no recent hospitalization for HF group (P = 0.16). Multivariable regressions showed suboptimal self-care behavior was independently associated with the primary outcome in the recent hospitalization for HF group with a significant interaction (P = 0.029)., Conclusion: In patients recently hospitalized for HF, but not in those without a recent hospitalization history for HF, suboptimal self-care behavior was associated with adverse events. This indicates the importance of self-care education for these patients., Competing Interests: Declaration of competing interest Dr. Toshiyuki Nagai is an associate editor of “International Journal of Cardiology”. Dr. Toshiyuki Nagai received a research grant from Mitsubishi Tanabe Pharma Corp. and honoraria from Kyowa Kirin Co., Ltd., Bayer Yakuhin, Ltd., Viatris Inc., and Boehringer Ingelheim Japan Co., Ltd. Dr. T.A. received a research grant from Daiichi Sankyo Co., Ltd., scholarship funds from Biotronik Japan Co., Ltd., Medtronic Japan Co., Ltd., Win International Co., Ltd., Medical System Network Co., Ltd., and Hokuyaku Takeyama Holdings, Inc. and honoraria from Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan Co., Ltd., Bayer's Pharmaceuticals Co., Ltd., and Bristol-Myers Squibb Co., Ltd. The remaining authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The combination of platinum-based chemotherapy and an antibody to PD-1 or to its ligand PD-L1, with or without an antibody to CTLA-4, has improved the survival of individuals with metastatic non-small-cell lung cancer (NSCLC). However, no randomised controlled trial has evaluated the survival benefit of adding a CTLA-4 inhibitor to platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor., Methods: This open-label, randomised, phase 3 trial was conducted at 48 hospitals in Japan. Eligible patients were aged 20 years or older with previously untreated advanced NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with known driver oncogenes were excluded. Participants were randomly assigned (1:1) to receive platinum-based chemotherapy (four cycles) plus pembrolizumab (pembrolizumab group) or platinum-based chemotherapy (two cycles) plus nivolumab-ipilimumab (nivolumab-ipilimumab group). The primary endpoint was overall survival and assessed in all randomly assigned patients on an intention-to-treat basis. The trial is registered in the Japan Registry for Clinical Trials, jRCTs031210013, and is now closed to new enrolment and is ongoing., Findings: Between patient accrual initiation on April 6, 2021, and discontinuation of the trial on March 30, 2023, 11 (7%) of 148 patients in the nivolumab-ipilimumab group had a treatment-related death. Because of the high number of treatment-related deaths, patient accrual was terminated early, resulting in 295 patients (236 [80%] male and 59 [20%] female) enrolled; the primary analysis was done on the basis of 117 deaths (fewer than the required 329 deaths). By May 25, 2023 (data cutoff), overall survival did not differ significantly between the nivolumab-ipilimumab group and the pembrolizumab group (median 23·7 months [95% CI 17·6-not estimable] vs 20·5 months [17·6-not estimable], respectively; hazard ratio 0·98 [90% CI 0·72-1·34]; p=0·46). Non-haematological adverse events of grade 3 or worse occurred in 87 (60%) of 146 patients in the nivolumab-ipilimumab group and 59 (41%) of 144 patients in the pembrolizumab group. The pembrolizumab group tended to have a better quality of life compared with the nivolumab-ipilimumab group., Interpretation: The safety and efficacy data suggest an unfavourable benefit-risk profile for nivolumab-ipilimumab combined with platinum-based chemotherapy relative to pembrolizumab combined with platinum-based chemotherapy as a first-line treatment for patients with advanced NSCLC, although a definitive conclusion awaits an updated analysis of overall survival., Funding: The National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development., Competing Interests: Declaration of interests YoS has received grants from Chugai Pharmaceutical; and personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Taiho Pharmaceutical, and Kyowa Kirin, all outside of the submitted work. ShN has received grants from AstraZeneca, Chugai Pharmaceutical, and MSD; consulting fees from Asahi Kasei Pharma; and personal fees from AstraZeneca, Bayer, Chugai Pharmaceutical, Asahi Kasei Pharma, Kyowa Hakko Bio, and MSD, all outside of the submitted work. SS has received grants from AnHeart Therapeutics, AstraZeneca, Chugai Pharmaceutical, MSD, Daiichi Sankyo, Bristol Myers Squibb, Nippon Boehringer Ingelheim, Ono Pharmaceutical, AbbVie, Amgen, Taiho Pharmaceutical, Takeda, Accerise, and Parexel International; and personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly, Novartis, Kyowa Kirin, Takeda, Nippon Kayaku, Merck, Amgen, AbbVie, Otsuka, Thermo Fisher Scientific, Towa Pharmaceutical, Sysmex, and Eisai, all outside of the submitted work. HidehH has received research fundings from MSD, AbbVie, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Janssen, Chugai Pharmaceutical, and Roche; personal fees from AstraZeneca, MSD, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, Roche, Amgen, and Abbvie; and personal fees from AstraZeneca, Chugai Pharmaceutical, Roche, Ono Pharmaceutical, Bristol Myers Squibb, and AbbVie (served on the advisory board), all outside of the submitted work. YaY has received personal fees from Taiho Pharmaceutical and Takeda, all outside of the submitted work. HidetH has received grants from IQVIA Services Japan, Eisai, Syneos Health Clinical, EP-CRSU, EPS, Shionogi, Nippon Kayaku, Otsuka Pharmaceutical, Takeda, GSK, MSD, Sanofi, Amgen, Chugai Pharmaceutical, Taiho Pharmaceutical, Nippon Boehringer Ingelheim, Bristol Myers Squibb, SRL Medisearch, Janssen Pharmaceutical, PRA Health Sciences, CMIC, Astellas Pharma, Pfizer R&D Japan, Ascent Development Services, Labcorp Development Japan, Eisai, Kobayashi Pharmaceutical, Bayer, and Pfizer Japan; royalties or licenses from Sysmex; personal fees from Ono Pharmaceutical, Merck, Daiichi Sankyo, 3H Clinical Trial, AstraZeneca, Novartis Pharma, Chugai Pharmaceutical, Bristol Myers Squibb, Eli Lilly Japan, Amgen, MSD, Sysmex, Pfizer Japan, Takeda, Nippon Boehringer Ingelheim; and personal fees for serving on an advisory board from Daiichi Sankyo, Nippon Boehringer Ingelheim, AstraZeneca, Amgen, Chugai Pharmaceutical, Novocure, Eli Lilly Japan, Gilead Science, and Blueprint Medicine, all outside of the submitted work. KA has received lecture fees from AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, MSD, Bristol Myers Squibb, and Takeda, all outside of the submitted work. SN has received grants from GSK, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Teijin, Kyowa Kirin, Shionogi, Boehringer Ingelheim, Daiichi Sankyo, Kyorin, and Nippon Kayaku; personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, MSD, Ono Pharmaceutical, Eisai, Kyorin, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Novartis, Amgen, Merck, Nippon Kayaku, and Kyowa Kirin; and personal fees for serving on advisory boards from AstraZeneca and Daiichi Sankyo, all outside of the submitted work. RM has received personal fees from Daiichi Sankyo, Chugai Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Eli Lilly Japan, MSD, Amgen, and Merck; and personal fees for serving on an advisory board from Daiichi Sankyo, all outside of the submitted work. MY has received grants from Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Kayaku, Taiho Pharmaceutical, and Takeda; and personal fees from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Johnson & Johnson, MSD, Nippon Kayaku, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical, all outside of the submitted work. TY has received grants from MSD, Chugai Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim Japan, Takeda, Delta-Fly Pharma, Janssen, AbbVie, Daiichi Sankyo, and Parexel International; and personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, Pfizer Japan, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Nippon Kayaku, MSD, Novartis, and Merck, all outside of the submitted work. KY has received grants from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Lilly, MSD, Pfizer, Taiho Pharmaceutical, and Takeda; and personal fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Janssen, Kyowa Kirin, Lilly, Merck Serono, Novartis, Ono Pharmaceutical, Otsuka, Taiho Pharmaceutical, and Takeda, all outside of the submitted work. TakayK has received grants from AstraZeneca, Amgen, MSD, Janssen, Takeda, and Daiichi Sankyo; and personal fees from AstraZeneca, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, MSD, Pfizer, and Nippon Kayaku, all outside of the submitted work. HO has received grants from Bristol Myers Squibb, MSD, and Taiho Pharmaceutical, all outside of the submitted work. TakasK has received personal fees from MSD, AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol Myers Squibb, all outside of the submitted work. KK has received personal fees from AstraZeneca, MSD, Chugai Pharmaceutical, Eli Lilly Japan, and Taiho Pharmaceutical; payment for expert testimony from Eli Lilly Japan; and personal fees for serving on advisory boards from Eli Lilly Japan and AstraZeneca, all outside of the submitted work. YF has received personal fees from AstraZeneca, Amgen, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical; payment for expert testimony from Chiome Bioscience, Otsuka Pharmaceutical, and Ono Pharmaceutical; and personal fees for serving on advisory boards from AstraZeneca, Daiichi Sankyo, Micron, and Ono Pharmaceutical, all outside of the submitted work. SM has received grants from AstraZeneca, Takeda, Chugai Pharmaceutical, Sanofi, MSD, Daiichi Sankyo, Ono Pharmaceutical, and Janssen; and personal fees from AstraZeneca, Chugai Pharmaceutical, Takeda, Eli Lilly, MSD, Pfizer, Novartis, and Taiho Pharmaceutical, all outside of the submitted work. SK has received personal fees from Boehringer Ingelheim Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, MSD, Ono Pharmaceutical, and Guardant Health Japan, all outside of the submitted work. HA reports grants from Amgen and Chugai Pharmaceutical; personal fees from Amgen, AstraZeneca, Boehringer Ingelheim Japan, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical; personal fees for serving on advisory boards from Amgen, MSD, Janssen, and Sandoz; and a role on the WCLC Patient Advocacy Committee, all outside of the submitted work. HK has received grants from Eli Lilly; and personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Novartis, Eli Lilly Japan, Ono Pharmaceutical, and Takeda, all outside of the submitted work. ToshiK has received grants from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Kyowa Hakko Kirin, Merck, Daiichi Sankyo, Amgen, AbbVie, Sanofi, Eisai, Labcorp Development Japan, IQVIA Services Japan, Gilead Sciences, Pfizer, and Bayer; consulting fees from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Pfizer Japan, Daiichi Sankyo, Bayer, and AbbVie; and personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Pfizer Japan, Kyowa Hakko Kirin, Nippon Boehringer Ingelheim, Merck, Nippon Kayaku, Novartis, Daiichi Sankyo, Takeda, Bayer, Sawai, Amgen, and Eisai, all outside of the submitted work. HF has received grants from the National Cancer Center Research and Development Fund; and lecture fees from Kyowa Kirin, Chugai Pharmaceutical, and CMIC, all outside of the submitted work. YO reports grants from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, LOXO, Kirin, Sumitomo, Pfizer, Taiho Pharmaceutical, Novartis, Takeda, Kissei, Daiichi Sankyo, and Janssen; personal fees from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Hakko Kirin, Eisai, and Daiichi Sankyo; payment for expert testimony from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics, and PharmaMar; personal fees for serving on an advisory board from Haihe Biopharma; and roles in the Japanese Society of Medical Oncology, Japan Lung Cancer Society, and Japan Clinical Oncology Group, all outside of the submitted work. IO has received grants from the National Cancer Center Research and Development Fund and Japan Agency for Medical Research and Development during the conduct of the study; grants from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Astellas, Bristol Myers Squibb, Novartis, Chugai Pharmaceutical, Pfizer, and AbbVie; consulting fees from AstraZeneca, Bristol Myers Squibb, and AbbVie; and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Bristol Myers Squibb, Novartis, Chugai Pharmaceutical, and Pfizer, all outside of the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The serotonergic neurons in the raphe nucleus are implicated in various cognitive functions such as learning and emotion. In vertebrates, the raphe nucleus is divided into the dorsal raphe and the median raphe. In contrast to the abundance of knowledge on the functions of the dorsal raphe, the roles of the serotonergic neurons in the median raphe are relatively unknown. The studies using zebrafish revealed that the median raphe serotonergic neurons receive input from the two distinct pathways from the habenula and the IPN. The use of zebrafish may reveal the function of the Hb-IPN-median raphe pathway. To clarify the functions of the median raphe serotonergic neurons, it is necessary to distinguish them from those in the dorsal raphe. Most median raphe serotonergic neurons originate from rhombomere 2 in mice, and we generated the transgenic zebrafish which can label the serotonergic neurons derived from rhombomere 2. In this study, we found the serotonergic neurons derived from rhombomere 2 are localized in the median raphe and project axons to the rostral dorsal pallium in zebrafish. This study suggests that this transgenic system has the potential to specifically reveal the function and information processing of the Hb-IPN-raphe-telencephalon circuit in learning., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Biodegradable synthetic nerve conduits have become widely used for peripheral nerve injuries. Recently, bioabsorbable collagen conduits filled with collagen fibers (Renerve®) are commercially available in Japan. We investigated the clinical efficacy and safety of Renerve® conduits for digital nerve repair., Patients and Methods: We retrospectively reviewed data of patients who underwent digital nerve repair using Renerve® conduits between August 2017 and February 2022 at our hospital and were followed up for at least 12 months. Seventeen patients (20 nerves) with a median age of 46.5 years (interquartile rage: 26-48 years) were included in the analysis. We analyzed sensory nerve function recovery and residual pain or uncomfortable tingling, as well as safety outcomes. The relationship between nerve defect length and sensory function data was assessed using Spearman's rank correlation., Results: Sensory nerve function at 12 months postoperatively was excellent in six, good in 10, and poor in four nerves, and that at the final follow-up (median period, 24 months; range, 12-30 months) was excellent in nine, good in 10, and poor in one nerve. All nerves with a defect length of <12 mm had excellent or good sensory outcomes. At 12 months postoperatively, the correlation coefficients between nerve defect length and Semmes-Weinstein monofilament test results, static two-point discrimination, and dynamic two-point discrimination were 0.35 (p = 0.131), 0.397 (p = 0.0827), and 0.451 (p = 0.0461), respectively. Residual pain or tingling sensation were observed in four nerves at the final follow-up. No postoperative complications were observed in any of the patients., Conclusions: This study demonstrated the clinical efficacy and safety of Renerve® conduits for digital nerve repair. Our results will be useful in clinical practice because of the scarcity of real-world data on the use of Renerve® conduits for digital nerve repair., Competing Interests: Declaration of competing interest The authors declare the existence of a financial competing interest from NIPRO Corporation., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

N-glycosylation and proper processing of N-glycans are required for the function of membrane proteins including cell surface receptors. Fibroblast growth factor receptor (FGFR) is involved in a wide variety of biological processes including embryonic development, osteogenesis, angiogenesis, and cell proliferation. Human FGFR3 contains six potential N-glycosylation sites, however, the roles of glycosylation have not been elucidated. The site-specific profiles of N-glycans of the FGFR3 extracellular domain expressed and secreted by CHO-K1 cells were examined, and glycan occupancies and structures of four sites were determined. The results indicated that most sites were fully occupied by glycans, and the dominant populations were the complex type. By examining single N-glycan deletion mutants of FGFR3, it was found that N262Q mutation significantly increased the population with oligomannose-type N-glycans, which was localized in the endoplasmic reticulum. Protein stability assay suggested that fraction with oligomannose-type N-glycans in the N262Q mutant is more stable than those in the wild type and other mutants. Furthermore, it was found that ligand-independent phosphorylation was significantly upregulated in N262Q mutants with complex type N-glycans. The findings suggest that N-glycans on N262 of FGFR3 affect the intracellular localization and phosphorylation status of the receptor., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Thiopurine is metabolized to 6-thio-(deoxy) guanosine triphosphate (6-thio-(d) GTP), which is then incorporated into DNA or RNA and causes cytotoxicity. Nudix hydrolase 15 (NUDT15) reduces the cytotoxic effects of thiopurine by converting 6-thio-(d) GTP to 6-thio-(d) guanosine monophosphate (6-thio-(d) GMP). NUDT15 polymorphisms like the Arg139Cys variant are strongly linked to thiopurine-induced severe leukocytopenia and alopecia. Therefore, measurement of NUDT15 enzymatic activity in individual patients can help predict thiopurine tolerability and adjust the dosage. We aimed to develop a quantitative assay for NUDT15 enzymatic activity in human blood samples. Blood samples were collected from donors whose NUDT15 genetic status was determined. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assess the 6-thio-GTP metabolic activity in cell extracts. Because 6-thio-guanosine diphosphate (6-thio-GDP) and 6-thio-GMP were generated upon incubation of 6-thio-GTP with human blood cell extracts, the method detecting 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP was validated. All three metabolites were linearly detected, and the lower limit of quantification (LLOQ) of 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP were 5 μM, 1 μM, and 2 μM, respectively. Matrix effects of human blood cell extracts to detect 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP were 99.0 %, 100.5 %, and 101.4 %, respectively, relative to the signals in the absence of blood cell extracts. The accuracy and precision of the method and the stability of the samples were also assessed. Using this established method, the genotype-dependent differences in NUDT15 activities were successfully determined using cell extracts derived from human blood cells with NUDT15 wild-type (WT) or Arg139Cys variant and 6-thio-GTP (100 μM) as a substrate (18.1, 14.9, and 6.43 μM/h/10 6 cells for WT, Arg139Cys heterozygous, and homozygous variant, respectively). We developed a method for quantifying intracellular NUDT15 activity in peripheral blood mononuclear cells (PBMCs), which we defined as the conversion of 6-thio-GTP to 6-thio-GMP. Although PBMCs preparation takes some time, its reproducibility in experiments makes it a promising candidate for clinical application. This method can tell the difference between WT and Arg139Cys homozygous blood samples. Even in patients with WT NUDT15, WT samples showed variations in NUDT15 activity, which may correlate with variations in thiopurine dosage., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Yusuke Miyatani reports financial support was provided by Japan Foundation for Applied Enzymology]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: According to the results of the KEYNOTE-407 trial, pembrolizumab plus platinum-based chemotherapy is the standard of care for patients with previously untreated advanced squamous non-small-cell lung cancer (NSCLC). Ubenimex, a potent aminopeptidase inhibitor, is an oral drug with immunostimulatory and antitumor activities. We aim to assess the safety and efficacy of ubenimex in combination with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC., Patients and Methods: This prospective, single-arm, multicenter, phase II clinical trial is conducted to confirm the tolerability and efficacy of the tested drugs. Patients with previously untreated advanced squamous NSCLC will receive a predetermined daily dose of ubenimex orally plus 4 cycles of pembrolizumab, nab-paclitaxel, and carboplatin, followed by continuous administration of ubenimex and pembrolizumab for a maximum of 2 years. To confirm tolerability, the daily dose of ubenimex will begin at level 1 (30 mg), which will be increased to levels 2 (60 mg) and 3 (120 mg) according to the escalation criteria, with a standard 3 + 3 design for achieving the target dose-limiting toxicity rate of 33%. The efficacy, safety, and tolerability of ubenimex at the determined dose level will be analyzed. The primary endpoint of the efficacy evaluation will be the objective response rate assessed by an independent review committee., Conclusions: This is the first study to evaluate the efficacy and safety of ubenimex combined with pembrolizumab, nab-paclitaxel, and carboplatin in patients with previously untreated advanced squamous NSCLC. The results will help devise future treatment strategies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Diabetes in pregnancy is a major risk factor for adverse perinatal outcomes such as congenital anomalies, hypertensive disorders of pregnancy (HDP), and macrosomia. For the mechanism of onset of type 1 and type 2 diabetes are different, we focused on the difference in perinatal outcomes between the type 1 and type 2 diabetes groups., Materials and Methods: We retrospectively reviewed 22 pregnancies with type 1 diabetes and 15 pregnancies with type 2 diabetes, who were managed in our single center, with regard to maternal diabetes conditions during pregnancy and neonatal birthweight and blood glucose level. Furthermore, we checked the effect of continuous glucose monitoring and continuous subcutaneous insulin injection in pregnancies with type 1 diabetes., Results: Type 1 diabetes in pregnancy was less controllable and increased neonatal birth weight and neonatal hypoglycemia within 2 h after birth after neonatal care unit admission. Continuous glucose monitoring and continuous subcutaneous insulin injection that are convenient to use, had a similar effect in the management of type 1 diabetes during pregnancy, compared with conventional diabetes treatment. In contrast, maternal BMI and HDP were increased in women with type 2 diabetes., Conclusion: In the management of pregnancy with diabetes, we should pay attention to the difference in pregnancy prognosis between type 1 and type 2 diabetes., Competing Interests: Conflicts of interest The authors declare no conflicts of interest related to this manuscript., (Copyright © 2023. Published by Elsevier B.V.)

Background: Posterior mitral leaflet (PML) bending is a cause of atrial functional mitral regurgitation (AFMR). We aimed to investigate differences in clinical and echocardiographic features and outcomes between AFMR patients with and without PML bending., Methods: We retrospectively examined 118 AFMR patients with atrial fibrillation (AF), mild or greater MR without degenerative mitral valve changes, and left ventricular ejection fraction ≥50 %. Patients were classified by the presence of PML bending: PML bending (n=24) and no PML bending (n=94). PML bending was defined as PML-to-anterior mitral leaflet angle ratio ≥3.1 calculated using receiver operating characteristics analysis for eccentric MR jet toward left atrial posterior wall. The study endpoint was a composite of cardiac death, admission for heart failure, and mitral valve surgery., Results: Overall, a total of 88 patients (75 %) had mild MR. There were no between-group differences in clinical and echocardiographic characteristics including AF duration and cardiac cavities size except for the length of inward bending of the left ventricular posterobasal wall and the mitral annular area. The 36-month event-free survival for the composite endpoint was significantly lower in the PML bending group (63 % vs. 78 %; Log-rank p=0.047). In multivariate analysis, PML bending was also associated with the composite outcome., Conclusions: AFMR patients with PML bending may have worse outcomes than those without PML bending despite similar clinical features., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The purpose of this study is to justify the result of the modified Stand-Up test (MSUT) in Little League baseball players and to clarify the association with sports related disorders in the elbow., Methods: A total of 245 (240 boys and 5 girls) Little League baseball players aged 9 to 12 underwent physical examination, elbow ultrasonography and questionnaires during a routine medical checkup. In addition, the MSUT, based on the Japanese Orthopaedic Association (JOA)'s original Stand-Up test to evaluate the risk of Locomotive syndrome, was performed., Results: Seventeen osteochondritis dissecans (OCD) of capitellum and 4 medial epicondylar fragmentation (MEF) cases were diagnosed with ultrasonography in 242 players. Based on the MSUT, five boys could not stand up from 40 cm platform with the single leg stance, two of whom complained of current elbow pain, three of whom diagnosed with a positive finding with ultrasonography. Odds ratio (95% confidence limits) of risk factors for failing to the 40 cm-MSUT with the single leg stance were: incidence of current elbow pain 5.7 (0.9-35.5); OCD (Grade 1b and 2) 8.2 (0.8-83); and MEF 19.5 (1.7-230)., Conclusion: Two percent of Little League baseball players were unable to stand up from a 40 cm high platform/stool with the single leg stance by the MSUT and it was associated with an increase in MEF or OCD diagnosis by ultrasonography and presence of elbow pain. These results suggest that players who failed to the 40 cm-MSUT with the single leg stance are at risk of elbow disorders. Also, these results are consistent with previous research on throwing injuries that have associated poor control in the legs or trunk with pain and injury involving the upper extremities. MSUT, a relatively simple procedure, may be a helpful adjunct for screening to estimate readiness for resuming general physical activity in Little League baseball players., Competing Interests: Declaration of competing interest There is no conflict of interest associated with this study., (Copyright © 2021 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Introduction: This study was conducted to evaluate the population pharmacokinetics of prophylactic cefmetazole sodium (CMZ) based on the serum concentrations and establish a pharmacodynamics target concentration exceeding the minimum inhibitory concentration (MIC) to design the re-dosing interval., Methods: Serum (n = 362) samples from 107 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index obtained was regarded as the probability of maintaining CMZ serum trough exceeding the minimal inhibitory concentration (MIC) of 2 mg/L. This MIC was chosen to account for methicillin-susceptible Staphylococcus aureus (MSSA), E. coli, and Klebsiella pneumoniae RESULTS: The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance and body weight were identified as significant covariates influencing the central clearance and volume of distribution in the central compartment. The probability of achieving serum concentrations exceeding the MIC 90 for MSSA, E. coli, and Klebsiella pneumoniae for a 1 g dose with a 10 min intravenous infusion was above 90% except for good renal function (CLcr ≧ 95 mL/min) at 2 h after the initial dose. For patients with good renal function (CLcr ≧ 95 mL/min), a CMZ of 2 g re-dosing interval seemed necessary to meet the achievement probability. In patients with impaired renal function (CLcr ≤20 mL/min), the probability of achievement exceeded 90% even when the dosing interval was extended to 8 h., Conclusions: We evaluated re-dosing intervals based on the population pharmacokinetics. Re-dosing intervals should be determined based on renal function., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objective: The current study aims to propose the auto-segmentation model on CT images of head and neck cancer using a stepwise deep neural network (stepwise-net)., Material and Methods: Six normal tissue structures in the head and neck region of 3D CT images: Brainstem, optic nerve, parotid glands (left and right), and submandibular glands (left and right) were segmented with deep learning. In addition to a conventional convolutional neural network (CNN) on U-net, a stepwise neural network (stepwise-network) was developed. The stepwise-network was based on 3D FCN. We designed two networks in the stepwise-network. One is identifying the target region for the segmentation with the low-resolution images. Then, the target region is cropped, which used for the input image for the prediction of the segmentation. These were compared with a clinical used atlas-based segmentation., Results: The DSCs of the stepwise-net was significantly higher than the atlas-based method for all organ at risk structures. Similarly, the JSCs of the stepwise-net was significantly higher than the atlas-based methods for all organ at risk structures. The Hausdorff distance (HD) was significantly smaller than the atlas-based method for all organ at-risk structures. For the comparison of the stepwise-net and U-net, the stepwise-net had a higher DSC and JSC and a smaller HD than the conventional U-net., Conclusions: We found that the stepwise-network plays a role is superior to conventional U-net-based and atlas-based segmentation. Our proposed model that is a potentially valuable method for improving the efficiency of head and neck radiotherapy treatment planning., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Dermatomyositis (DM) is a chronic acquired autoimmune disorder strongly associated with cancer development. Until now, identifying predictive markers indicating a high risk of cancer has challenged clinicians. Although anti-TIF1γ antibody is a major serological indicator for cancer-associated DM, many anti-TIF1γ antibody-positive DM patients lack malignancy., Objectives: To determine clinical and laboratory parameters that support cancer prediction in anti-TIF1γ antibody-positive DM patients., Methods: Clinical and laboratory data were collected from cancer-associated and unassociated DM patients with anti-TIF1γ antibodies. Serum cytokine concentrations were measured with a cytokine array assay. The values of inflammatory cytokines in cancer prognosis were determined with a receiver operating characteristic curve analysis., Results: The cancer group had a significantly higher frequency of males, older mean age and higher anti-TIF1γ antibody levels. Some inflammatory cytokines, particularly tumour necrosis factor (TNF) and TNF receptor superfamilies, had increased levels in sera that were correlated with myositis markers, cutaneous severity and DM disease activity. Moreover, these cytokines had an area under the curve (AUC) ≥0.8 and high sensitivity and specificity at their specific cut-off, even higher than anti-TIF1γ levels in cancer prediction in our DM patients., Conclusions: Our results suggest a close pathophysiological relationship among myositis, cancer and skin involvements in DM patients with anti-TIF1γ antibodies and the potential clinical significance of anti-TIF1γ antibody levels in evaluating disease severity and prognosis in DM patients. Some inflammatory cytokines, particularly TNF and TNF receptor superfamilies including BAFF, sTNF-R1 and sTNF-R2, may support cancer prediction in DM patients with anti-TIF1γ antibodies., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021. Published by Elsevier B.V.)

The onset of circulation in a developing embryo requires intact blood vessels to prevent hemorrhage. The development of endothelial cells, and their subsequent recruitment of perivascular mural cells are important processes to establish and maintain vascular integrity. These processes are genetically controlled during development, and mutations that affect endothelial cell specification, pattern formation, or maturation through the addition of mural cells can result in early developmental hemorrhage. We created a strong loss of function allele of the zebrafish GDP-mannose 4,6 dehydratase (gmds) gene that is required for the de novo synthesis of GDP-fucose, and homozygous embryos display cerebral hemorrhages. Our data demonstrate that gmds mutants have early defects in vascular patterning with ectopic branches observed at time of hemorrhage. Subsequently, defects in the number of mural cells that line the vasculature are observed. Moreover, activation of Notch signaling rescued hemorrhage phenotypes in gmds mutants, highlighting a potential downstream pathway that requires protein fucosylation for vascular integrity. Finally, supplementation with fucose can rescue hemorrhage frequency in gmds mutants, demonstrating that synthesis of GDP-fucose via an alternative (salvage) pathway may provide an avenue toward therapeutic correction of phenotypes observed due to defects in de novo GDP-fucose synthesis. Together, these data are consistent with a novel role for the de novo and salvage protein fucosylation pathways in regulating vascular integrity through a Notch dependent mechanism., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We conducted a study to examine the effect of COVID-19 on the acute exacerbation of interstitial lung disease (AE-ILD) early in the COVID-19 epidemic (January 1-April 30, 2020). An online questionnaire survey was conducted, which was completed by 134 hospitals. During this period, 854 patients with AE-ILD (including 12 cases of COVID-AE-idiopathic pulmonary fibrosis were hospitalized at 128 hospitals. In comparison, the total number of AE-ILD hospitalizations during the same period in 2019 was 894. The number of hospitalizations increased at 17 hospitals, decreased at 27, and remained the same at 88 hospitals in 2020 compared to the same period in 2019. In 2020, COVID-19-related acute exacerbations had a significantly worse prognosis than non-COVID-19-related acute exacerbations in both 30-day and 90-day mortality. Because the prognosis of AE-ILD associated with COVID-19 is extremely poor, prevention of COVID-19 is especially important for patients with ILD., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare for this article., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P < 0.05). Serum interleukin-1β was increased but to a lesser extent in response to LPS injection in rAT-treated mice than in control mice. Lectin staining and ultrastructural studies showed a notable attenuation of injury to the endothelial glycocalyx after rAT treatment. Microarray analysis further showed an up-regulation of gene sets corresponding to DNA repair, such as genes involved in DNA helicase activity, regulation of telomere maintenance, DNA-dependent ATPase activity, and ciliary plasm, after rAT treatment. Thus, rAT treatment may promote DNA repair, attenuate inflammation, and promote ciliogenesis, thereby attenuating the acute respiratory distress syndrome caused by endothelial injury., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Recent reports have revealed that patients who experienced early rehospitalization for heart failure (HF) had worse prognoses in terms of all-cause and cardiovascular deaths as compared to those who did not. However, precipitating factors for early rehospitalization for HF remain unknown. In this study, we assessed the precipitating factors for early rehospitalization and their impact in patients with HF., Methods and Results: We consecutively included 242 patients (mean age: 80.4 years, females: 46.3%) with a history of rehospitalization for HF. They were divided into 2 groups: the early rehospitalization group (71 patients who were readmitted within 3 months of discharge) and the late rehospitalization group (171 patients who were readmitted after more than 3 months following discharge). During the mean follow-up period of 1,144 days (range: 857-1,417 days), 121 patients (50.0%) died. Kaplan-Meier analysis revealed that patients in the early rehospitalization group had worse prognosis (all-cause death and cardiovascular death) than those in the late rehospitalization group (log-rank p<0.001). As the major precipitating factor for rehospitalization, poor compliance with the doctor's instructions on fluid and physical activity restrictions (determined by the patients or their families admittance of non-compliance with the instructions given at the time of discharge) was higher in the early rehospitalization group than in the late rehospitalization group [poor compliance with fluid restriction: 19.7% vs. 7.6% (p = 0.006), poor compliance with physical activity restriction: 21.1% vs. 9.4% (p = 0.013)]., Conclusions: We concluded that early hospital readmission in patients with HF was associated with higher mortality rates. Compared to late rehospitalization, precipitating factors for early rehospitalization were more strongly dependent on the self-care behaviors of the patients. A more effective approach, such as multidisciplinary intervention, is essential to prevent early hospital readmission and subsequent poor prognosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Objectives: Sustaining benefits of an exercise program is difficult as adherence is often poor after supervised intervention is over. This study aimed to determine whether the effects of active learning education on physical activity, dietary habits, and physical function were maintained 24 weeks after intervention termination in older adults., Design: Non-randomized controlled trial., Setting and Participants: Community-dwelling older adults aged ≥65 years who were independent in activities of daily living., Methods: The intervention group (n = 36) underwent 24 weeks of active learning education. The control group (n = 59) attended a health education class didactically. In both groups, the education program focused on exercise, diet and nutrition, and cognitive activity for health promotion. Active learning included exploratory learning, group work, and self-planning for behavior change that promoted healthy lifestyles. Outcome measures were obtained at baseline (pre), 24 weeks (post), and 48 weeks (follow-up). Physical activity was objectively measured as physical activity level (PAL) using a triaxial accelerometer. Food intake was assessed by obtaining a dietary variety score. Physical function, including gait speed and Timed Up & Go score, was tested as secondary outcome. We used a linear mixed model to estimate the effects of intervention in intention-to-treat analyses., Results: All outcomes in the intervention group significantly improved compared with the control group at 24 weeks, and the improvements were sustained over a 48-week follow-up period. For PAL, between-group difference in change from baseline was 0.043 (95% confidence interval = 0.007, 0.080) at 24 weeks and 0.061 (0.023, 0.099) at 48 weeks., Conclusions and Implications: Active learning education is effective in enhancing healthy lifestyles and physical function sustainability beyond intervention cessation. A randomized controlled trial with a larger sample size is needed to conclusively clarify the beneficial effects of active health education learning on sustainable behavior change and functional improvement., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Social subordination, which causes severe stress in animals, can affect animal's behaviors, homeostasis, and mental health. In rodents, experiences of repeated social defeats, but not a single defeat, induce a depression-like state. However, it is unclear whether such experiences similarly affect behaviors of other model animals than rodents. Here, we established a behavioral paradigm for repeated social defeats with zebrafish, an emerging model for behavioral neuroscience and pharmacological analysis. We put fish into repeated social subordination for 6 consecutive days. Using behaviors during fighting as indicators, we observed that experiencing repeated social defeats led to a reduction in fight frequency and duration. The continuously-defeated zebrafish failed to win even against the transgenic fish with an impaired winning-associated neural pathway. These results suggest that repeated social defeats led to demotivation to fight and to win against opponents. Moreover, they showed strong activity in the ventral habenula, an evolutionary homolog of the mammalian lateral habenula. However, unlike the mice model, the continuously-defeated zebrafish showed no change in anxiety level and sociability. Our established behavioral paradigm will be a new tool to investigate neural mechanisms underlying social defeats., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Interstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with NSCLC and a known risk factor for pneumonitis. Atezolizumab monotherapy is an established treatment for recurrent NSCLC and reported to have a lower risk of pneumonitis than programmed cell death protein 1 inhibitors. This study aimed to assess the safety and efficacy of atezolizumab monotherapy in patients with pretreated advanced or recurrent NSCLC with idiopathic IP., Methods: Patients with advanced or recurrent NSCLC with comorbid idiopathic, chronic fibrotic IP with % forced vital capacity of greater than 70% and no history of immune checkpoint inhibitors were enrolled. The patients received atezolizumab (1200 mg) every 3 weeks until the discontinuation criteria were met. The primary end point of this study was the 1-year survival rate. A sample size of 38 patients was set., Results: This study was terminated early owing to high incidence of pneumonitis. A total of 17 patients were enrolled, with a median age of 70 years. The median % forced vital capacity and % diffusing capacity for carbon monoxide at baseline were 85.4% and 54.4%, respectively. The incidence of pneumonitis was 29.4% (5 of 17) for all grades, 23.5% (4 of 17) for grade greater than or equal to 3, and 5.9% (1 of 17) for grade 5. A total of 57.1% patients (4 of 7) with honeycomb lung developed pneumonitis with a grade greater than or equal to 3, whereas only one patient (10%) without honeycomb lung (n = 10) with grade 1 pneumonitis was found., Conclusions: Patients with NSCLC with comorbid IP as defined by the selection criteria for this study might have an increased risk of immune checkpoint inhibitor-induced pneumonitis., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

We describe the treatment rationale and design of our randomized phase III study, the ACHILLES trial (Japan Registry of Clinical Trials: jRCTs031180175). The aim of this study is to investigate the superiority of afatinib over chemotherapy as first-line treatment in patients with advanced nonsquamous non-small-cell lung cancer with sensitizing uncommon or compound epidermal growth factor receptor (EGFR) mutations, with the exception of de novo T790M mutations and exon 20 insertions. Eligible patients will be randomized at a 1:2 ratio to receive either chemotherapy or afatinib until disease progression or unacceptable toxicity. Patients in the chemotherapy arm will receive pemetrexed 500 mg/m 2  + cisplatin 75 mg/m 2 or carboplatin area under the curve (AUC) 5 or 6 every 3 weeks × 4 cycles, followed by pemetrexed 500 mg/m 2 every 3 weeks. In the afatinib arm, investigators will choose the starting dose of afatinib (30 mg or 40 mg orally daily). The primary endpoint is progression-free survival. A total of 106 patients will be enrolled in this trial over a 30-month registration period with a 15-month follow-up. Enrollment began in March 2019. The results of this trial will establish the superiority of afatinib over chemotherapy in a cohort with a large variety of EGFR mutations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Sleeve resection and double-barreled reconstruction are very rarely adopted for peripheral bronchial tumors. This surgical procedure was used for a carcinoid tumor in the bifurcation of the left upper and lower lobe bronchi. Bronchoplasty was accomplished by suturing the upper and basal bronchi together and anastomosing them to the left main bronchus. The techniques for double-barreled reconstruction described in this report obtained a successful result. These manipulations may be applicable to resection of other bronchial and tracheal bifurcations., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: While many patients with lower limb ischemia also have severe infections, few studies have investigated whether the presence of preoperative sepsis affects patient prognosis following lower limb amputation (LLA). Therefore, we investigated the factors (including sepsis as defined in SEPSIS-3) that contribute to the acute mortality rate in patients who underwent LLA due to arteriosclerosis obliterans (ASO) or diabetes mellitus (DM)., Methods: In this retrospective, single-center, 10-year chart review study, 122 adult patients who underwent LLA due to ASO and/or DM were identified from 56,438 surgery cases. Patient characteristics, including co-morbidities, surgical conditions, the presence/absence of sepsis, and acute physiological condition after surgery, were investigated in patients who died within 30 days of LLA and those who survived. Univariate analysis between groups was performed using the chi-square test. Comparisons of age and American Society of Anesthesiologists-Physical Status classification between groups were performed using the Mann-Whitney U test. Risk factors for 30-day mortality after LLA were examined using stepwise logistic regression (backward elimination). Statistical results were considered significant at P < 0.05., Results: Eight cases of mortality (6.6%) were found; we identified the causes as sepsis, myocardial infarction, fatal arrhythmia, and mesenteric artery occlusive disease in 5 (62.5%), 1 (12.5%), 1 (12.5%), and 1 (12.5%) cases, respectively. Using univariate analysis, we identified that age (≥74), delirium, sepsis, intensive care unit admission, non-DM (ASO only), hemodialysis, and acute kidney injury were significantly higher in the mortality group. In logistic regression analysis, non-DM (odds ratio [OR]: 35.2, 95% confidence interval [CI]: 2.8-432) and sepsis (OR: 80.7, 95% CI: 6.7-959) were potential risk factors for 30-day mortality., Conclusions: This study suggests that cases resulting in amputation due to ASO pathology alone might have poor prognosis and that preoperative sepsis can increase perioperative mortality; hence, the decision to amputate must be considered before the development of sepsis., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: We devised a novel trigone-based sizing method, setting the trigones at one-quarter of the annular circumference, and used it for mitral annuloplasty in patients with mitral regurgitation (MR)., Methods: Between 1999 and 2017, 436 patients with degenerative (n = 192), nonischemic functional (n = 124), or ischemic (n = 120) MR underwent mitral valvuloplasty at our institution using an incomplete ring. The intertrigonal distance and prerepair and postrepair annular diameter were measured. Then the diameters predicted from body surface area, the intertrigonal distance, and the ratios of these diameters to observed data were computed. We investigated the influence of these measurements on MR recurrence, transmitral pressure gradient, and systolic anterior motion., Results: Initial repair was successful in 433 patients (99%), but 3 patients with systolic anterior motion and MR required conversion to valve replacement. After 1, 5, and 10 years (mean follow-up, 6.3 years), the rate of freedom from grade 2 or higher recurrent MR was 96%, 92%, and 86% in the degenerative group, 99%, 97%, and 90% in the nonischemic functional group, and 95%, 90%, and 79%, respectively, in the ischemic group (P = .052). The observed/body surface area predicted diameter ratio was negatively correlated with the mean transmitral pressure gradient (mm Hg); 12.3 - 8.2 × (ratio) (R = -0.37, P < .001), despite a smaller ratio (<0.9) not being associated with less recurrence of MR. In the degenerative group, systolic anterior motion developed in 7 of 71 patients (10%) with an observed/intertrigonal distance predicted diameter ratio of less than 0.9 (P < .001)., Conclusions: Our trigone-based sizing method achieved satisfactory control of MR, while avoiding functional mitral stenosis and systolic anterior motion., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Sarcoidosis is a systemic granulomatous disease characterized by the combination of Th1 and Th17 responses. Recently, several arguments have suggested a potential involvement of B cells as well as T cells in the pathogenesis of sarcoidosis. Follicular helper CD4 + T (T FH ) cells are specialized in interacting with and helping B cells, and play a crucial role in the formation of germinal centers., Objective: We sought to explore the status of T FH cells and investigate their possible pathogenic role in sarcoidosis., Methods: T FH cells and B cells in peripheral blood were examined by flow cytometry, and serum samples were studied by cytokine arrays. Immunohistochemistry was performed to check for the presence of T FH cells in sarcoidosis skin lesions. Gene expression in isolated T FH cells was analyzed by quantitative RT-PCR., Results: The proportion of circulating T FH cells was decreased. CD4 + CXCR5 + T FH cells were observed in cutaneous lesions in sarcoidosis. Gene expression in circulating T FH cells and serum cytokine concentrations related to Th17 were increased in sarcoidosis patients. Gene expressions of B cell differentiation cytokines in T FH cells were not altered in sarcoidosis patients., Conclusion: We herein describe a decrease of circulating T FH cells and their migration to affected tissues. Circulating T FH cells are one of the potential cell types capable of producing IL-17 and enhancing Th17 responses, and may promote the chronic inflammation. We could not demonstrate a direct linkage between the imbalance of T FH cells and abnormal B cell differentiation in sarcoidosis., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatitis E is a global public health problem. Ribavirin (RBV) and pegylated interferon alpha are currently administered to cure hepatitis E. Recently, in combination with RBV, sofosbuvir (SOF), an anti-hepatitis C virus nucleotide analog, is also given to patients with chronic hepatitis E. However, this combinatorial therapy sometimes fails to achieve a sustained virological response. In this study, we used 27 antiviral compounds, including 15 nucleos(t)ide analogs, for in vitro screening against a genotype 3 HEV strain containing a Gaussia luciferase reporter. RBV, SOF, 2'-C-methyladenosine, 2'-C-methylcytidine (2CMC), 2'-C-methylguanosine (2CMG), and two 4'-azido nucleoside analogs (R-1479 and RO-9187) suppressed replication of the reporter genome, while only RBV, SOF, 2CMC and 2CMG inhibited the growth of genotype 3 HEV in cultured cells. Although 2CMG and RBV (2CMG/RBV) exhibited a synergistic effect while SOF/RBV and 2CMC/RBV showed antagonistic effects on the reporter assay, these three nucleos(t)ide analogs acted additively with RBV in inhibiting HEV growth in cultured cells. Furthermore, SOF and 2CMG, with four interferons (IFN-α2b, IFN-λ1, IFN-λ2 and IFN-λ3), inhibited HEV growth efficiently and cleared HEV in cultured cells. These results suggest that, in combination with RBV or interferons, SOF and 2CMG would be promising bases for developing anti-HEV nucleos(t)ide analogs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In order to evaluate the in vivo effect of inhaled formulations, it is a gold standard to create a lung metastasis model by intravenously injecting cancer cells into an animal. Because the cancer grows from the blood vessel side, there is a possibility of underestimating the effect of an inhaled formulation administered to the lung epithelium side. In addition, the metastasis model has disadvantages in terms of preparation time and expense. The present study aimed to establish a new method to evaluate the effect of an inhaled small interfering RNA (siRNA) formulation that is more correct, more rapid, and less expensive. We investigated whether siRNA can suppress gene expression of plasmid DNA (pDNA) by serial pulmonary administration of siRNA and pDNA powders prepared by spray-freeze-drying. We revealed that formulations of dry siRNA powder significantly suppressed gene expression of pDNA powder compared with a control group with no siRNA. Naked siRNA inhalation powder with no vector showed the suppression of gene expression equivalent to that of an siRNA-polyethyleneimine complex without damaging tissues. These results show that the present method is suitable for evaluating the gene-silencing effect of inhaled siRNA powders., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Sarcoidosis is a systemic disorder characterized by the accumulation of lymphocytes and monocyte/macrophage lineage cells that results in the formation of non-caseating granulomas. Thymus- and activation-regulated chemokine (TARC)/CCL17 is an important chemokine in the amplification of Th2 responses, which are achieved by recruiting CCR4-expressing CD4 + T lymphocytes. TARC concentrations are known to increase in the serum of sarcoidosis patients; however, its role in the assessment of severity and prognosis of sarcoidosis remains unknown. The objective of this study is to elucidate the role of TARC in sarcoidosis by investigating its expression in peripheral blood and at inflammatory sites. We also examined its relationship with clinical features., Methods: Serum levels of TARC, soluble interleukin 2 receptor, angiotensin-converting enzyme, and lysozyme were measured in 82 sarcoidosis patients. The Th1 and Th2 balance in circulating CD4 + T cells was evaluated by flow cytometry. The immunohistochemical staining of TARC and CCR4 was performed in order to identify the source of TARC in affected skin tissues., Results: TARC serum levels were elevated in 78% of patients and correlated with disease severity. The percentage of CCR4 + cells and the CCR4 + /CXCR3 + cell ratios were significantly higher in sarcoidosis patients than in normal subjects (P = 0.002 and P = 0.015, respectively). Moreover, TARC was expressed by monocyte/macrophage lineage cells within granulomas. The abundancy as well as distribution of TARC staining correlated with its serum levels., Conclusions: The present results suggest that elevations in TARC drive an imbalanced Th2- weighted immune reaction and might facilitate prolonged inflammatory reactions in sarcoidosis., (Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Introduction: In the phase III JCOG0301 trial, chemoradiotherapy (CRT) with daily low-dose carboplatin showed significant benefits in elderly patients with locally advanced non-small-cell lung cancer (NSCLC) compared with radiotherapy (RT) alone. However, the long-term patterns and cumulative incidences of toxicity associated with CRT and RT in elderly patients are not well elucidated. We report long-term survival data and late toxicities after a minimum follow-up of 6.4 years., Patients and Methods: Eligible patients were older than 70 years and had unresectable stage III NSCLC. They were randomly assigned to RT or CRT. Prognosis and adverse events data were collected beyond those in the initial report. Late toxicities were defined as occurring more than 90 days after RT initiation., Results: From September 2003 to May 2010, 200 patients (RT arm, n = 100; CRT arm, n = 100) were enrolled. Consistent with the initial report, the CRT arm had better overall survival than the RT arm (hazard ratio, 0.743; 95% confidence interval, 0.552-0.998; 1-sided P = .0239). The proportion of Grade 3/4 late toxicities were 7.4% (heart 2.1%, lung 5.3%) in the RT arm (n = 94) and 7.5% (esophagus 1.1%, lung 6.5%) in the CRT arm (n = 93). No additional cases of late toxicity (Grade 3/4) and treatment-related death have been seen since the initial report that was published., Conclusion: Long-term follow-up confirmed the survival benefits of CRT for elderly patients with locally advanced NSCLC. There was no observed increase in late toxicity with CRT compared with RT alone., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Ras related (R-Ras), a small GTPase, is involved in the maintenance of apico-basal polarity in neuroepithelial cells of the zebrafish hindbrain, axonal collapse in cultured murine hippocampal neurons, and maturation of blood vessels in adult mice. However, the role of R-Ras in neural tube formation remains unknown. Using antisense morpholino oligonucleotides (AMOs), we found that in the spinal cord of zebrafish embryos, the lumen was formed bilaterally in rras morphants, whereas it was formed at the midline in control embryos. As AMO can cause off-target effects, we generated rras mutant zebrafish lines using CRISPR/Cas9 technology. Although these rras mutant embryos did not have a bilateral lumen in the spinal cord, the following findings suggest that the phenotype is unlikely due to an off-target effect of rras AMO: 1) The rras morphant phenotype was rescued by an injection of AMO-resistant rras mRNA, and 2) a bilaterally segregated spinal cord was not observed in rras mutant embryos injected with rras AMO. The results suggest that the function of other ras family genes may be redundant in rras mutants. Previous research reported a bilaterally formed lumen in the spinal cord of zebrafish embryos with a mutation in a planar cell polarity (PCP) gene, van gogh-like 2 (vangl2). In the present study, in cultured cells, R-Ras was co-immunoprecipitated with Vangl2 but not with another PCP regulator, Pricke1. Interestingly, the interaction between R-Ras and Vangl2 was stronger in guanine-nucleotide free point mutants of R-Ras than in wild-type or constitutively active (GTP-bound) forms of R-Ras. R-Ras may regulate neural tube formation in cooperation with Vangl2 in the developing zebrafish spinal cord., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study aimed at developing a novel analytical method to identify optimal inhalation flow patterns for commercial dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs). As typical commercial DPI and pMDI, Pulmicort ® Turbuhaler ® , and Sultanol ® Inhaler were evaluated by an in vitro inhalation performance testing system with a flow pattern simulator. An 8-stage Andersen cascade impactor (ACI) or twin stage liquid impinger (TSLI) was applied to determine the inhalation performance. The peak flow rate (PFR) of the inhalation flow pattern was set from 15 to 80 L/min in reference to our previous study. From TSLI test results, a higher PFR improved the inhalation performance of the DPI, while the performance of the pMDI was less affected by the PFR. Conversely, from ACI test results, the pMDI performance decreased with a higher PFR, while the DPI followed a similar pattern as in the TSLI test results, because ACI is a finer aerodynamic classification apparatus than TSLI. These results suggested that our in vitro system using a human inhalation flow pattern simulator successfully detected different optimal inhalation patterns between DPI and pMDI. That is, the higher PFR is better for Pulmicort ® Turbuhaler ® (DPI). Conversely, lower PFR is desirable for Sultanol ® Inhaler (pMDI)., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: The number of intermediate monocytes (CD14 ++ CD16 + ) increases in many inflammatory conditions. However, it is not yet known which functional markers expressed by these populations are linked to the pathogenesis of psoriasis., Objectives: We evaluated the expression of functional markers on circulating intermediate monocytes. Our goal was to correlate specific populations and their markers with the clinical severity of psoriasis., Methods: A cohort of 43 psoriatic patients was subjected to analysis. The proportion of intermediate monocytes with CD86 expression was evaluated by flow cytometry. Serum beta defensin-2 levels were measured by ELISA. Immunofluorescent staining was performed in order to identify the presence of CD14 + CD16 + cells that co-expressed CD86 in affected skin tissues., Results: Upregulated expression of CD86 on the intermediate subset (but not the number of intermediate monocytes) correlated with clinical severity as measured by PASI scores and serum beta defensin-2 levels. Immunostaining also showed the presence of CD86 + CD14 + CD16 + cells in the epidermis and dermis of psoriatic plaques, which was associated with increased epidermal proliferation., Conclusion: These results suggest that the expression of CD86 on circulating intermediate monocytes could be used as an index in clinical practice and provide novel insights into how these cells join a complex immune network under the pathological conditions of psoriasis., (Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Introduction: The safety and efficacy of using artificial collagen nerve conduits filled with collagen filaments to treat nerve defects has not been fully studied in humans. We conducted a multicenter, controlled, open-label study to compare the safety and efficacy of artificial nerve conduit grafts with those of autologous nerve grafts., Methods: We included patients with a sensory nerve defect of ≤30 mm, at the level of the wrist or a more distal location, with the first-line surgical methods selected according to a patient's preference. We compared sensory recovery using static two-point discrimination and adverse events between the artificial collagen nerve conduit and autologous nerve grafting., Results: The artificial nerve conduit group included 49 patients, with a mean age of 42 years and nerve defect of 12.6 mm. The autologous nerve graft group included 7 patients, with historical data of an additional 31 patients, with a mean age of 36 years and nerve defect of 18.7 mm. The rate of recovery of sensory function at 12 months was 75% (36/49) for the artificial nerve conduit group and 73.7% (28/38) in the autologous nerve group. No serious adverse events directly associated with use of the artificial nerve conduit were identified., Conclusions: The treatment of nerve defects ≤30 mm using artificial collagen nerve conduits was not inferior to treatment using autologous nerve grafts. Based on our data, the new artificial collagen nerve conduit can provide an alternative to autologous nerve for the treatment of peripheral nerve defects., (Copyright © 2018 Elsevier Ltd. All rights reserved.)