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INTRODUCTION: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased on average 7.3 ml/min per 1.73 m(2) in the avacopan group and 4.1 ml/min per 1.73 m(2) in the prednisone group (P = 0.029) at week 52. This new analysis examines the results in the patient subgroup with severe renal insufficiency at enrollment into the trial, i.e., eGFR ≤20 ml/min per 1.73 m(2). METHODS: eGFR was determined at baseline and over the course of the trial. Changes in eGFR were compared between the 2 treatment groups. RESULTS: In ADVOCATE, 27 of 166 patients (16%) in the avacopan group and 23 of 164 patients (14%) in the prednisone group had a baseline eGFR ≤20 ml/min per 1.73 m(2). At week 52, eGFR increased on average 16.1 and 7.7 ml/min per 1.73 m(2) in the avacopan and prednisone groups, respectively (P = 0.003). The last eGFR value measured during the 52-week treatment period was ≥2-fold higher than baseline in 41% of patients in the avacopan group compared to 13% in the prednisone group (P = 0.030). More patients in the avacopan group versus prednisone group had increases in eGFR above 20, 30, and 45 ml/min per 1.73 m(2), respectively. Serious adverse events occurred in 13 of 27 patients (48%) in the avacopan group and 16 of 23 patients (70%) in the prednisone group. CONCLUSION: Among patients with baseline eGFR ≤20 ml/min per 1.73 m(2) in the ADVOCATE trial, eGFR improved more in the avacopan group than in the prednisone group.

Original Article

We examined the motility characteristics of sperm from sex-sorted bull semen as a model for low-quality (expected low conception rate) sperm compared to that of sperm from non-sorted semen (expected average conception rate) using cluster analysis followed by discriminant analysis. The results indicated that sex-sorted semen contained sperm with hyperactivation-like motility as the main subpopulation immediately after thawing, and this subpopulation decreased after 2 h of incubation. The main subpopulation in the non-sorted semen had progressive motility that was maintained during incubation. A conventional comparison of the mean values of kinematic parameters could not distinguish the samples. In conclusion, discriminant analysis using data from a cluster analysis of motile sperm may accurately describe differences in the structures of sperm motility subpopulations between low and normal fertility semen.

Background: During cardiomyocyte maturation, the centrosome, which functions as a microtubule organizing center in cardiomyocytes, undergoes dramatic structural reorganization where its components reorganize from being localized at the centriole to the nuclear envelope. This developmentally programmed process, referred to as centrosome reduction, has been previously associated with cell cycle exit. However, understanding of how this process influences cardiomyocyte cell biology, and whether its disruption results in human cardiac disease, remains unknown. We studied this phenomenon in an infant with a rare case of infantile dilated cardiomyopathy (iDCM) who presented with left ventricular ejection fraction of 18% and disrupted sarcomere and mitochondria structure. Methods: We performed an analysis beginning with an infant who presented with a rare case of iDCM. We derived induced pluripotent stem cells from the patient to model iDCM in vitro. We performed whole exome sequencing on the patient and his parents for causal gene analysis. CRISPR/Cas9-mediated gene knockout and correction in vitro were used to confirm whole exome sequencing results. Zebrafish and Drosophila models were used for in vivo validation of the causal gene. Matrigel mattress technology and single-cell RNA sequencing were used to characterize iDCM cardiomyocytes further. Results: Whole exome sequencing and CRISPR/Cas9 gene knockout/correction identified RTTN , the gene encoding the centrosomal protein RTTN (rotatin), as the causal gene underlying the patient’s condition, representing the first time a centrosome defect has been implicated in a nonsyndromic dilated cardiomyopathy. Genetic knockdowns in zebrafish and Drosophila confirmed an evolutionarily conserved requirement of RTTN for cardiac structure and function. Single-cell RNA sequencing of iDCM cardiomyocytes showed impaired maturation of iDCM cardiomyocytes, which underlie the observed cardiomyocyte structural and functional deficits. We also observed persistent localization of the centrosome at the centriole, contrasting with expected programmed perinuclear reorganization, which led to subsequent global microtubule network defects. In addition, we identified a small molecule that restored centrosome reorganization and improved the structure and contractility of iDCM cardiomyocytes. Conclusions: This study is the first to demonstrate a case of human disease caused by a defect in centrosome reduction. We also uncovered a novel role for RTTN in perinatal cardiac development and identified a potential therapeutic strategy for centrosome-related iDCM. Future study aimed at identifying variants in centrosome components may uncover additional contributors to human cardiac disease.

BACKGROUND: A few studies have been reported on the influence of fetal hiccups on umbilical artery. The aim of this study is to clarify the influence of fetal hiccups on Doppler blood flow waveform (DBFW) of some fetal arteries, and to show the difference in these influences among fetal arteries. OBJECTIVE: DBFW of umbilical artery, descending aorta, and middle cerebral artery were recorded at hiccups in normal fetuses between 34th and 40th gestational weeks. The changes on DBFW were classified into three shapes by the direction and the size of the changes. Shape 1: sharp decrease but not to the baseline, Shape 2: sharp decrease to the baseline (absence), and Shape 3: reverse flow. RESULTS: At all hiccups, the changes on DBFW of these arteries were observed. These changes were classified into three shapes. Changes of umbilical artery were widely distributed in three shapes depending on when hiccup occurred during cardiac cycle. On the other hand, most changes of the descending aorta and middle cerebral artery were Shape 3 whenever the hiccup occurred during cardiac cycle. CONCLUSION: The changes on DBFW of fetal arteries were observed at all hiccups. Changes of umbilical artery were widely distributed in three shapes depending on when hiccup occurred during cardiac cycle. On the other hand, most changes of descending aorta and middle cerebral artery were Shape 3. This is the first study clarified the influence of fetal hiccups on DBFW of some fetal arteries, and showed the difference in these influences among fetal arteries.

Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan.A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information.Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma.Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

本実践報告では，看護専門学校の初年次教育科目を対象に試みた，LTD 授業モデルに依拠した授業改善について報告する。参加学生は122名であり，30の小グループにランダムに割り当てられた。授業科目は基礎段階，習熟段階，応用段階で構成されていた。基礎段階では協同学習の基本的な考え方と技法を教えた。習熟段階では基礎段階で獲得した学習技法の熟達を意図し，論理的な言語技術と絵図の読解法を指導した。応用段階では，前2段階の学習内容を活用した問題解決型学習を実践した。授業を評価するたために協同認識尺度とディスカッション= スキル尺度，授業記録紙および最終レポートを用いた。これらの資料を検討した結果，授業全体として期待する方向の成果を得ることができた。特に，基礎段階では協同を基盤とした学びの姿勢と技法の獲得が確認できた。また，基礎段階と習熟段階での学びが応用段階での学びを促す可能性が示唆された。This case report describes an attempt to improve a first-year experience course at a nursing school using the LTD teaching model. The 122 participating students were randomly assigned to 30 small groups. The course consisted of a foundation stage, a proficiency stage, and an application stage. In the foundation stage, the students were taught the basic concepts and techniques of cooperative learning. In the proficiency stage, students were taught logical language skills and pictorial reading comprehension skills with the intention of mastering the learning techniques acquired in the foundation stage. In the application stage, problem-solving learning was practiced using the learning content of the previous two stages. To evaluate the lessons, we used the Cooperative Awareness Scale, the Discussion Skills Scale, class notes, and the final report. The results showed that the class as a whole achieved the expected results. In particular, the acquisition of cooperative learning attitudes and techniques was confirmed. It was also suggested that learning in the foundation and proficiency stages could promote learning in the application stage.

The Acetyl Salicylic Elimination Trial (ASET) Japan pilot study is a multicentre, single-arm, open-label, proof-of-concept study with a stopping rule based on the occurrence of definite stent thrombosis. This study aims to demonstrate the feasibility and safety of low-dose prasugrel monotherapy following percutaneous coronary intervention (PCI) in Japanese patients presenting with chronic coronary syndromes (CCS) or non-ST-elevation acute coronary syndromes (NSTE-ACS). Four hundred patients with a SYNTAX score

近年，土木計画の分野においては，インフラの更新コストの削減や長寿命化，地域 交通の維持や流域治水の推進，少子高齢と気候変動への対応といった複数の課題に対 し，地域環境としての社会資本を構築し，マネジメントすることが求められるように なっている。2022 年以降に高等学校教育において必修化される地理総合では，持続可 能な地域づくりとしてまちづくりや都市計画が重視され，小中学校で取り組まれてき た総合的学習での地域学習から連続して，地域のあり方を考える機会が提供されるこ ととなる。工学系高等教育においては，これらを踏まえ，技術者として地域にどのよ うに関わるべきか，地域の将来像を踏まえて議論するための基礎的な素養を身につけ ることの重要性が増していると考えられる。本稿では，総合学習での地域学習の事例 とともに，金沢工業大学（以下本学）における地域環境デザインに関する演習活動を 通じ，大学教育，地域双方にとっての，継続・発展的な取り組みとするための展望と 課題を整理する。;In the field of civil engineering planning, building and management of social capital as a regional environment is required to address multiple issues, such as reducing infrastructure replacement costs and extending the service life of infrastructure, maintaining regional transportation, promoting watershed flood control, and addressing low birthrates and aging populations and climate change. On the other hand, geography integrated studies, which will become compulsory in high school from 2022, will focus on town planning and urban planning for sustainable regional development and will provide opportunities to think about the state of the region in a manner that is continuous with integrated studies conducted in elementary and junior high schools. Therefore, in engineering higher education, it will be increasingly important to acquire basic knowledge to discuss how engineers should relate to the region, based on the region's future vision. This paper discusses the prospects for making this a continuous effort for both university education and local communities through practice and practical activities for local environmental design at engineering universities.

The bone ring technique is applied for vertical augmentation, in which the dental implant and autogenous block bone graft are simultaneously inserted. We investigated the healing of bone around implants placed simultaneously using the bone ring technique with and without membrane placement after a 12-month healing period. Vertical bone defects were created on both sides of the mandible of Beagle dogs. Implants were inserted into the defects through bone rings and fixed with membrane screws as healing caps. The augmented sites on one side of the mandible were covered with a collagen membrane. Samples were harvested 12 months after implantation and assessed histologically and by microcomputed tomography analysis. All implants remained throughout the healing period; however, except for 1 implant, they showed lost caps and/or exposure to the oral cavity. The implants had contact with newly formed bone despite frequent bone resorption. The surrounding bone appeared mature. The medians of bone volume and percentages of total bone area and bone-to-implant contact within the bone ring were slightly higher in the group with membrane placement than in that without membrane placement. Nevertheless, none of the evaluated parameters were significantly affected by the membrane placement. In the present model, soft tissue complication was frequent, and the membrane application did not reveal the effect at 12 months after implant placement using the bone ring technique. Sustained osseointegration and maturation of surrounding bone were observed in both groups after a 12-month healing period.

Oral mucositis is highly prevalent among the elderly, for whom oral care is often difficult. Oral mucositis, such as candidiasis, can induce systemic fungemia. Antifungal prophylaxis may be useful in such cases to prevent systemic fungemia; however, studies on this are limited. The objective of this study was to demonstrate the effectiveness of antifungal prophylaxis to prevent systemic Candida dissemination compared to oral care using a mice model. Oral candidiasis was induced using chemotherapy and inoculation with C. albicans in 8-week-old male mice. Group A was given oral care, Group B was orally administered an antifungal drug, Group C was intravenously administered an antifungal drug, and Group D was used as the negative control group. Macroscopic features of the tongue surface, colony forming units (CFU) on the tongue, and blood culture for C. albicans were evaluated. CFU was significantly higher in Group A than in Groups B and C. The oral care group, but not the groups administered antifungal agents, showed significantly higher positive numbers of animals with C. albicans in the blood as compared to the control group, indicating the effectiveness of antifungal prophylaxis over oral care. Antifungal prophylaxis may be an option for the prevention of systemic fungemia in individuals with difficulty in oral care.

Background: Synovial sarcoma (SS) has limited treatment options and there is an urgent need to develop a novel therapeutic strategy to treat SS. Blue light (BL) has been shown to inhibit the growth of several cancer cells. However, the efficacy of BL in soft tissue sarcomas such as SS has not been demonstrated, and the detailed mechanism underlying the antitumor activity of BL is not fully understood. In this study, we investigated the antitumor effect of BL on SS. Methods: Human SS cell lines were continuously irradiated with BL using light-emitting diodes (LEDs) in an incubator for in vitro analysis. The chicken chorioallantoic membrane (CAM) tumors and xenograft tumors in mice were subjected to daily BL irradiation with LEDs. Results: BL caused growth inhibition of SS cells and histological changes in CAM tumors. BL also suppressed the migration and invasion abilities of SS cells. The type of cell death in SS cells was revealed to be apoptosis. Furthermore, BL induced excessive production of reactive oxygen species (ROS) in mitochondria, resulting in oxidative stress and malfunctioned mitochondria. Reducing the production of ROS using N-acetylcysteine (NAC), a ROS scavenger, attenuated the inhibitory effect of BL on SS cells and mitochondrial dysfunction. In addition, BL induced autophagy, which was suppressed by the administration of NAC. The autophagy inhibitor of 3-methyladenine and small interfering RNA against the autophagy marker light chain 3B facilitated apoptotic cell death. Moreover, BL suppressed tumor growth in a mouse xenograft model. Conclusion: Taken together, our results revealed that BL induced apoptosis via the ROS-mitochondrial signaling pathway, and autophagy was activated in response to the production of ROS, which protected SS cells from apoptosis. Therefore, BL is a promising candidate for the development of an antitumor therapeutic strategy targeting SS.

The advancement of genome sequencing technology has unveiled whole DNA sequences of individuals. Comparison of the genome sequences has uncovered differences among human population which may relate to the differences in the susceptibility to diseases of each person. The wisdom acquired by the stateof- the-art technology should be shared in the society, especially among the next generation to advance their quality of life. We developed an easy-to-use web interface to promote the idea of genome sequence variation, effect on protein structures and the relationship between the variations and diseases in humans. We used the web tool in the Super Science High School Program class and assessed the impact of using the tools for the promotion of understanding among high school pupils.

Background: Although the fit-for-purpose approach has been proposed for biomarker assay validation, practical data should be compiled to facilitate the predetermination of acceptance criteria. Methods: Immunoaffinity LC–MS was used to analyze glucagon-like peptide-1 as a model biomarker in six laboratories. Calibration curve, carryover, parallelism, precision, relative accuracy and processed sample stability were evaluated, and their robustness among laboratories was assessed. The rat glucagon-like peptide-1 concentrations in four blinded samples were also compared. Results: The obtained results and determined concentrations in the blinded samples at all laboratories were similar, with a few exceptions, and robust, despite the difference in optimization techniques among laboratories. Conclusion: The results provide insights into the predefinition of the acceptance criteria of immunoaffinity LC–MS-based biomarker assays.

Background Nanoparticle albumin-bound paclitaxel (nab-PTX) is a promising antibody partner for anti-human epidermal growth factor receptor 2 (HER2). We performed neoadjuvant chemotherapy (NAC) for HER2-positive breast cancer (BC) using nab-PTX plus trastuzumab (T-mab) and pertuzumab (P-mab), followed by epirubicin and cyclophosphamide (EC). Methods In this multicenter phase II clinical trial (January 2019–July 2020), patients with stage I (T1c)-IIIB HER2-positive primary BC were treated with four cycles of nab-PTX plus T-mab and P-mab, followed by four cycles of EC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints were clinical response rate (RR), adverse events (AE), and tumor-infiltrating lymphocytes (TILs) in biopsy samples. Results In total, 43 patients were enrolled (mean age, 54 years). Twenty-two patients had HER2, and 21 patients had luminal/HER2-subtypes. The overall pCR rate was 53.5% (23/43, 95% CI: 42.6–64.1%, p = 0.184), whilst the pCR for HER2 was 68.2% (15/22, 95% CI: 45.1–86.1) and 38.1% for luminal/HER2 (8/21, 95% CI: 18.1–61.6%). The RR was 100% [clinical (c) CR:25, partial response (PR): 18]. AEs (≥ G3) included neutropenia (23.3%), leukopenia (7.0%), liver dysfunction (7.0%), and peripheral neuropathy (4.7%) when nab-PTX was administered. EC administration resulted in leukopenia (34.2%), neutropenia (31.6%), and febrile neutropenia (15.8%). The TILs in preoperative biopsy samples were significantly higher in pCR compared to non-pCR samples. Conclusion Nab-PTX plus T-mab and P-mab induced a high pCR rate in HER2-positive BC, particularly in the HER2-subtype. Given that AEs are acceptable, this regimen is safe and acceptable as NAC for HER2-positive BC.

In manufacturing industries, customers demand a wide variety of products, with high quality and fast delivery. Production scheduling systems have become critical for efficient operation. However, scheduling problems in manufacturing are generally large and complex with many constraints. It is difficult to create an optimal production schedule that satisfies all constraints within a reasonable timeframe. This study targets a factory with multiple working machines and two overhead cranes. Our research aims to obtain a solution algorithm to avoid interference of overhead cranes and machine competition and a production plan that minimizes the total makespan for each job. As the problem must be solved within a reasonable timeframe, we have developed the solution algorithm using metaheuristics and scheduling simulation. In general, metaheuristic algorithms must strike a balance between an intensive search for good solutions and a search for diverse solutions. Accordingly, we propose a new algorithm using path relinking in a scatter search. This method was demonstrated to be effective in obtaining good solutions with little variation in numerical experiments. In this paper, we describe previous research, our target process, and new solution algorithm and discuss algorithm design methods based on computer experiments.

Hypoxia during supramaximal exercise reduces aerobic metabolism with a compensatory increase in anaerobic metabolism without affecting exercise performance. A similar response is elicited by preexercise voluntary hypocapnic hyperventilation, but it remains unclear whether hypocapnic hyperventilation and hypoxia additively reduce aerobic metabolism and increase anaerobic metabolism during supramaximal exercise. To address that issue, 12 healthy subjects (8 males and 4 females) performed the 30-second Wingate anaerobic test (WAnT) after (1) spontaneous breathing in normoxia (control, ∼21% fraction of inspired O2 [FiO2]), (2) voluntary hypocapnic hyperventilation in normoxia (hypocapnia, ∼21% FiO2), (3) spontaneous breathing in hypoxia (hypoxia, ∼11% FiO2), or (4) voluntary hypocapnic hyperventilation in hypoxia (combined, ∼11% FiO2). Mean power output during the 30-second WAnT was similar among the control (561 [133] W), hypocapnia (563 [140] W), hypoxia (558 [131] W), and combined (560 [133] W) trials (P = .778). Oxygen uptake during the 30-second WAnT was lower in the hypocapnia (1523 [318] mL/min), hypoxia (1567 [300] mL/min), and combined (1203 [318] mL/min) trials than in the control (1935 [250] mL/min) trial, and the uptake in the combined trial was lower than in the hypocapnia or hypoxia trial (all P P

Background : The KOJI AWARENESS™ screening test is a self-administered screening tool for assessment of mobility, stability, and strength. It provides corrective exercises corresponding to the individual’s answers to the KOJI AWARENESS™ test questions. However, there is no evidence of the effectiveness of corrective exercises in improving KOJI AWARENESS™ screening test scores and activity-related pain. Methods : Twenty- six healthy subjects (11 female and 15 male ; age 20–50 years) were selected for participation. In a controlled laboratory setting, subjects were administered the KOJI AWARENESS™ test and were provided with individualized exercise programs based on the results of this first test. KOJI AWARENESS™ results were checked on the first day immediately after the first exercise session, and then again after the two-week program. Pain intensity was also assessed during daily training using a numerical rating scale. Results : Compared to pre-intervention, KOJI AWARENESS™ scores were significantly higher immediately after the first corrective exercise session and after 2 weeks of intervention (p < 0.001). Moreover, pain intensity was significantly lower after 2 weeks of intervention (p < 0.001). Conclusions : Individualized KOJI AWARENESS™ corrective exercises were effective immediately on the first day and also after the two-week program in improving the KOJI AWARENESS™ score and reducing pain intensity during daily training.

We report three cases of methotrexate (MTX) -induced oral erosions and ulcers mimicking Stevens-Johnson syndrome (SJS) in older women with rheumatoid arthritis, although they did not had conjunctivitis. Furthermore, age, dehydration, and renal dysfunction could trigger adverse reactions of MTX, but one patient underwent dialysis, which is a contraindication for MTX. It is sometimes very difficult to differentiate the toxicity of MTX from SJS. Learning from the three cases, we propose that oral mucosal erosions without conjunctive mucosal inflammation, leukopenia, and thrombocytopenia differentiate MTX toxicity from SJS. Furthermore, our patients nearly recovered from myelosuppression within seven days and recovered from mucosal erosions characteristic of MTX toxicity within 14 days. These clinical courses could also be characteristic for MTX toxicity rather than SJS, although quick recovery does not happen in all cases. Therefore, physicians who prescribe MTX must accurately know MTX-induced adverse reactions to recognize them early. Furthermore, as seen in our patients, oral mucosal erosions occur often. Therefore, dermatologists or others who examine these symptoms should consider that mucosal erosions mimicking SJS could be an adverse reaction of MTX, regardless of whether or not SJS/toxic epidermal necrolysis is suspected.