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Background and Hypothesis: There are limited data on the long-term outcomes and risk factors for non-recovery after development of rituximab (RTX)-associated persistent hypogammaglobulinaemia among children with idiopathic nephrotic syndrome (NS)., Methods: A nationwide Japanese survey was conducted to determine the prognosis of patients with childhood-onset idiopathic NS who developed persistent hypogammaglobulinaemia after RTX administration. Specifically, predictors of IgG level recovery and risk factors for serious infection were examined., Results: The cohort comprised 118 patients (66.1% boys; median age at initial RTX administration, 7.5 years). Among the 121 patients diagnosed with persistent hypogammaglobulinaemia, only 31 (26.3%) recovered within a median observation period of 2.8 years; approximately 70% of patients continued to exhibit persistent hypogammaglobulinaemia. Among the patients who recovered from hypogammaglobulinaemia, the median time to recovery was 14.1 months. Patients with a history of steroid-resistant NS were less likely to recover from persistent hypogammaglobulinaemia (hazard ratio, 0.28; 95% CI, 0.09-0.87). In addition, of the 118 eligible patients, 18 (15.3%) developed serious infections requiring hospitalization, and the main risk factor for infection during hypogammaglobulinaemia was agranulocytosis (a well-known adverse effect of RTX in children)., Conclusions: A significant portion of patients with RTX-associated persistent hypogammaglobulinaemia did not exhibit recovery even after 1 year. Moreover, the data indicate that patients with a history of steroid-resistant NS have a significantly lower probability of recovering from this condition. Agranulocytosis under hypogammaglobulinaemia was significantly associated with an elevated risk of serious infections., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Aim: Medical institutions restricted visitation to neonatal intensive care units (NICUs) during the coronavirus disease (COVID-19) pandemic. Therefore, this study aimed to investigate the impact of COVID-19 NICU visitor restrictions on parents., Methods: We conducted a questionnaire of 378 parents of infants who were hospitalised for more than 1 week at two NICUs in our area and discharged between 1 April 2020 and 31 March 2022. While the visiting rules for NICUs during this period varied depending on the phase of the COVID-19 epidemic, generally, only parents were allowed to visit the NICUs for a few hours daily., Results: A total of 157 parents (A University Hospital (AMUH), n = 79; AK General Hospital (AKGH), n = 78) responded to the survey (41.3% response rate), with 40% stating that their emotions towards their infants were affected by restrictions due to the COVID-19 pandemic. Parents' feelings towards their infants were influenced by mode of delivery, parity, duration of hospitalisation and opportunities to visit the NICU. More than 70% of respondents felt stressed due to COVID-19 restrictions, and anxiety and emotional stress related to visitor restrictions were significantly affected by the number and duration of visits and allowability of family member visits. Parents felt that the restrictions had a negative impact on breastfeeding, overall infant care and infant-family bonding., Conclusion: As parents felt an impact on the bond with their infant during visitation restrictions, it is essential for facilities to implement measures to protect infant-family bonding during potential future pandemics., (© 2024 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Aim: To assess the preoperative disease characteristics and indications for living donor liver transplantation (LDLT), complications, patient survival, and prognosis after LDLT for fibropolycystic liver disease (FLD) in children., Methods: We undertook a cross-sectional survey of patients who underwent LDLT for FLD between January 2002 and December 2020., Results: A total of 35 patients (22 male and 13 female individuals) with FLD were included in this study, of whom 19 (54.3%) had isolated congenital hepatic fibrosis and 16 (45.6%) had Caroli syndrome. Refractory gastrointestinal bleeding was the most frequent symptom related to the indication for LDLT, being found in 48.6% of our patients, followed by uncontrollable cholangitis and ascites. The median age at the time of LDLT was 8.1 years old. Of the 27 patients presenting with renal involvement, 13 patients required kidney transplantation (KT). Overall, the renal function after LDLT decreased regardless of renal involvement; however, patients with renal involvement had a significantly lower estimated glomerular filtration rate than those without renal involvement throughout the course of this study (p < 0.01). The 5-year overall patient survival rate was 97.1%. Two patients died with a median follow-up of 8.9 years after LDLT; one died due to sepsis 2 weeks after simultaneous liver-kidney transplantation and the other committed suicide 10 years after LDLT., Conclusion: The prognosis of the pediatric patients who underwent LDLT for FLD was excellent. However, an individualized treatment approach based on the status of the renal function and liver disease is important, as a certain proportion of patients require KT., (© 2024 Japan Society of Hepatology.)

Background: Patients with subcutaneous implantable cardioverter-defibrillators (S-ICDs) experience an oversensing episode (OS) more frequently than those with transvenous ICDs. However, no established electrocardiography (ECG) parameters can accurately detect an OS. This study aimed to evaluate the incidence of an OS in real-world clinical practice and the association of synthesized 18-lead ECG (syn18-ECG) parameters with an OS., Methods: We retrospectively included 21 consecutive patients who underwent S-ICD implantation and collected syn18-ECG parameters. We placed the generator in a deep posterior position and defined an OS as an inappropriate charging episode caused by cardiac or noncardiac signals. A SMART pass filter and two tachyarrhythmia zones were programed., Results: The most frequent underlying heart disease was Brugada/J wave syndrome (n = 7). During a median follow-up period of 1188 days, an OS was observed in six patients (28.6%). The QRS amplitude in synthesized V7 lead (synV7) was significantly lower in the OS group than in the non-OS group (0.59 ± 0.17 vs. 0.91 ± 0.35 mV, p = 0.019). The optimal cutoff value of synV7 QRS amplitude was 0.61 mV, with a sensitivity of 80.0% and a specificity of 83.7% for predicting an OS. Univariate logistic analysis showed that a synV7 QRS amplitude of <0.61 mV was only associated with an OS (odd ratio, 20.0; 95% confidence interval, 1.66-241.72; p = 0.018)., Conclusions: In patients with S-ICDs, an OS was not a rare complication during long-term follow-up. A low synV7 QRS amplitude was associated with a high OS incidence., (© 2024 Wiley Periodicals LLC.)

The repeated dose liver micronucleus (RDLMN) assay has been sufficiently validated in terms of the numbers and types of chemicals studied. However, it remains unclear whether aging affects assay results. The OECD Test Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents) indicates that dosing should begin as soon as feasible after weaning and in any event before 9 weeks of age. Therefore, it is particularly important to determine whether there are age-related differences between 6 and 8 weeks of age at the start of dosing when considering the possibility of integrating this assay into a 4-week repeated dose general toxicity study. We evaluated the impact of the rats' age on the RDLMN assay with three chemicals: N-nitrosodipropylamine, quinoline, and carbendazim. There were no significant age-related differences for the first two chemicals, whereas a markedly higher frequency of micronucleated hepatocytes (MNHEPs) was observed in younger rats for carbendazim. However, regardless of the age of animals, micronucleus induction was detected in all three chemicals. Combined with the previous reports on clofibrate and diethylnitrosamine, we concluded that animals of any age from 6 to 8 weeks could be used in the RDLMN assay., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Zigzag-shaped [6]phenacene isomers with fused thiophene rings, fulmineno[2,1- b :10,9- b ']dithiophene (FuDT-α) and fulmineno[1,2- b :9,10- b ']dithiophene (FuDT-β), were syntheized and their p-type organic semicondutor properties were studied. Small effective masses of holes were estimated from the crystal structures of both isomers, which was particularly demonstrated by the hole mobility of 10.5 cm 2 V -1 s -1 for FuDT-α single crystals.

Osteoporosis is a significant health concern for postmenopausal women, necessitating efficient screening methods for bone health. This study explores the potential of muscle function, assessed through the 30-s chair stand test (CS-30), as an indicator for low bone stiffness in this demographic, aiming to establish a practical threshold for large-scale fitness surveillance without the need for specialized tools. We analyzed data from 1055 community-dwelling postmenopausal Japanese women, aged 41-89 years, collected between 2016 and 2019. Participants underwent CS-30 to evaluate muscle function alongside quantitative ultrasound (QUS) measurements to assess bone stiffness. The cohort was divided into two groups for the development and validation of a cutoff point for low bone stiffness, defined as a QUS speed of sound less than 1487.3 m/s. The CS-30 cutoff was determined using receiver operating characteristic (ROC) curve analysis and validated through logistic regression, accounting for age, body mass index, and smoking status. Among 577 postmenopausal women, 16.0% exhibited low bone stiffness. In the development group (n = 382), ROC analysis identified a CS-30 cutoff of 25 repetitions for detecting low bone stiffness, with an area under the curve of 0.744 (P < 0.001). In the validation group (n = 195), participants performing ≥ 25 repetitions had a higher risk of low bone stiffness compared to those performing ≤ 24 repetitions. The CS-30 test is an effective preliminary screening tool for identifying postmenopausal women at risk of low bone stiffness, with a threshold of 25 repetitions. This method could facilitate early detection of individuals at higher osteoporosis risk, promoting timely intervention., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The previous Japanese clinical practice guidelines for multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) were published in 2017. Recently, for the first time in 6 years, the MS and NMOSD guideline development committee revised the Japanese guidelines for MS, NMOSD, and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)., Methods: The committee utilized the Grading of Recommendations Assessment, Development, and Evaluation system based on the "Minds Handbook for Clinical Practice Guideline Development 2020 Ver. 3.0″ with a focus on clinical questions (CQs). The committee also discussed clinical issues other than CQs, categorizing them as a question-and-answer (Q&A) section, including "issues on which experts' opinions agree to a certain extent" and "issues that are important but not included in the CQ"., Results: The committee identified 3, 1, and 1 key CQs related to MS, NMOSD, and MOGAD, respectively, and presented recommendations. A Q&A session regarding disease-modifying therapies and relapse prevention therapies for MS, NMOSD, and MOGAD was conducted. The revised guidelines were published in September 2023., Conclusions: The Japanese guidelines for clinical practice on MS, NMOSD, and MOGAD were updated. Treatment strategies for MS, NMOSD, and MOGAD are changing, and these updated guidelines may assist with treatment decisions for these diseases in clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study., (Copyright © 2024. Published by Elsevier B.V.)

Pediatric condylar fractures are commonly managed conservatively, as the condyle typically exhibits spontaneous remodeling. However, should conservative treatment be administered for severe deviated condylar processes? In a case involving a 7-year-5-month-old girl who fell from a height of 3 m, she sustained a mandibular parasymphysis fracture and bilateral condylar fractures, including a condylar base fracture with 60-degree medial deviation on the right side and a condylar head fracture, Neff type A, on the left side. To address the fractures, internal fixation was performed on the right condyle via a classical retromandibular approach, and a mini-plate was removed four months postsurgery. At a follow-up 12 years and 7 months later, the patient showed normal occlusion, TMJ function, and no visible scars. In addition, there was no facial deviation, although the surgical site condyle was larger than the nonsurgical site, suggesting that the surgical site facilitated normal growth while the nonsurgical site impeded it., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Background: The effect of dual immunotherapy combined with platinum-based chemotherapy on untreated brain metastases derived from non-small cell lung cancer (NSCLC) has remained unclear., Methods: This multicenter single-arm phase 2 study enrolled patients with chemotherapy-naïve advanced NSCLC and at least one brain metastasis ≥ 5 mm in size that had not been previously treated. Patients received nivolumab plus ipilimumab combined with platinum-doublet chemotherapy (two cycles), followed by nivolumab-ipilimumab alone. The primary endpoint of the study was intracranial response rate as determined by modified Response Evaluation Criteria in Solid Tumors (RECIST) for brain metastases of ≥ 5 mm as target lesions., Results: A total of 30 patients from 18 institutions was enrolled in this study. The median age was 66.5 years (range, 47-83 years), and 26 patients (87 %) had a non-squamous cell carcinoma histology. The median size of all target brain lesions was 8.4 mm, with a range of 5-39 mm. The intracranial response rate assessed by modified RECIST was 50.0 % (95 % CI, 33.2-66.8 %), with the rate of complete response being 20.0 %, and the study met its primary endpoint. The systemic response rate was 53.3 % (95 % CI, 36.1-69.8 %), and responses for intracranial and extracranial lesions were generally consistent. The median intracranial progression-free survival was 8.1 months, and both the median intracranial duration of response and time to brain radiotherapy were not reached., Conclusion: Nivolumab plus ipilimumab combined with platinum-based chemotherapy showed promising intracranial activity in NSCLC patients with untreated brain metastases., Trial Registration: jRCT071210019., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Y Tsuchiya-Kawano has received personal fees from Bristol-Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Kyowa hakko Kirin, MSD, Ono Pharmaceutical, and Takeda Pharmaceutical outside the submitted work. Y Shiraishi has received grants and personal fees from Chugai Pharmaceutical as well as personal fees from Ono Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Bristol-Myers Squibb, and Kyowa Kirin outside the submitted work. K Tanaka has received personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, Takeda Pharmaceutical, Pfizer, MSD, Novartis, and Bristol-Myers Squibb outside the submitted work. M Tachihara has received grants from AstraZeneca, Chugai Pharmaceutical, and Eli Lilly as well as personal fees from Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, AstraZeneca, MSD, Novartis Pharmaceuticals, Takeda Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, and Janssen Pharmaceutical outside the submitted work. T Okamoto has received grants from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, MSD, Eli Lilly, and Bristol-Myers Squibb as well as personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Ono Pharmaceutical, MSD, Eli Lilly, and Bristol-Myers Squibb outside the submitted work. I Okamoto has received grants from Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Astellas, Bristol-Myers Squibb, Novartis, Pfizer, and AbbVie; consulting fees from AstraZeneca, Bristol-Myers Squibb, and AbbVie; and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Ono Pharmaceutical, MSD, Eli Lilly, Bristol-Myers Squibb, Novartis, and Pfizer outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background & Aims: Targeting exhausted immune systems would be a promising therapeutic strategy to achieve a functional cure for HBV infection in patients with chronic hepatitis B (CHB). However, animal models recapitulating the immunokinetics of CHB are very limited. We aimed to develop an immunocompetent mouse model of CHB for intrahepatic immune profiling., Methods: CHB mice were created by intrahepatic delivery of the Sleeping Beauty transposon vector tandemly expressing the hepatitis B virus (HBV) genome and fumarylacetoacetate hydrolase (FAH) cDNA into C57BL/6J congenic FAH knockout mice via hydrodynamic tail vein injection. We profiled the viral and intrahepatic immune kinetics in CHB mice with or without treatment with recombinant IFNα or the hepatotropic Toll-like receptor 7 agonist SA-5 using single-cell RNA-seq., Results: CHB mice exhibited sustained HBV viremia and persistent hepatitis. They showed intrahepatic expansion of exhausted CD8+ T (Tex) cells, the frequency of which was positively associated with viral load. Recruited macrophages increased in number but impaired inflammatory responses in the liver. The cytotoxicity of mature natural killer (NK) cells also increased in CHB mice. IFNα and SA-5 treatment both resulted in viral suppression with mild hepatic flares in CHB mice. Although both treatments activated NK cells, SA-5 had the capacity to revitalize the impaired function of Tex cells and liver-recruited macrophages., Conclusion: Our novel CHB mouse model recapitulated the intrahepatic exhausted antiviral immunity in patients with CHB, which might be able to be reinvigorated by a hepatotropic TLR7 agonist., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Some patients undergoing liver resection for hepatocellular carcinoma (HCC) have poor outcomes. Therefore, we aimed to propose a new resectability classification for patients with HCC., Methods: We classified patients into three categories: resectable (R), borderline resectable (BR), and unresectable (UR). Patients (n = 409) who underwent hepatectomy for HCC were assigned to the non-UR (R and BR classes combined; n = 285) and UR-HCC classes (n = 68; training cohort). Patient characteristics in the BR-HCC and R-HCC groups were compared. The new criteria were tested in a validation cohort (n = 295)., Results: Of the 285 patients, 229 and 56 were classified into the R- and BR-HCC classes, respectively, using macrovascular invasion, tumor size, and future liver remnant/modified albumin-bilirubin scores. Patients with BR-HCC demonstrated significantly worse progression-free and overall survival (p < 0.0001 and p < 0.0001, respectively) than patients with R-HCC in the training cohort. Similar results were observed in the validation cohort. Multivariate analysis of the non-UR-HCC group in the training cohort revealed that the tumor number and BR-HCC were independent predictive factors for poor overall survival., Conclusions: This classification can help select patients with BR-HCC for preoperative treatment before considering surgery., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

This review article investigates the relationship between mitochondrial dysfunction and cancer progression, emphasizing the metabolic shifts that promote tumor growth. Mitochondria are crucial for cellular energy production, but they also play a significant role in cancer progression by promoting glycolysis even under oxygen-rich conditions, a phenomenon known as the Warburg effect. This metabolic reprogramming enables cancer cells to maintain an alkaline internal pH and an acidic external environment, which are critical for their proliferation and survival in hypoxic conditions. The article also explores the acidic tumor microenvironment (TME), a consequence of intensive glycolytic activity and proton production by cancer cells. This acidic milieu enhances the invasiveness and metastatic potential of cancer cells and contributes to increased resistance to chemotherapy. Alkalization therapy, which involves neutralizing this acidity through dietary modifications and the administration of alkalizing agents such as sodium bicarbonate, is highlighted as an effective strategy to counteract these adverse conditions and impede cancer progression. Integrating insights from science-based medicine, the review evaluates the effectiveness of alkalization therapy across various cancer types through clinical assessments. Science-based medicine, which utilizes inductive reasoning from observed clinical outcomes, lends support to the hypothesis of metabolic reprogramming in cancer treatment. By addressing both metabolic and environmental disruptions, this review suggests that considering cancer as primarily a metabolic disorder could lead to more targeted and effective treatment strategies, potentially improving outcomes for patients with advanced-stage cancers.

Objectives: The multi-hole self-expandable metal stent (MHSEMS) is a novel SEMS with multiple small side holes on the covering membrane to prevent stent migration while minimizing tumor ingrowth. This study aimed to evaluate the clinical outcomes of MHSEMS in comparison with conventional covered SEMS (c-CMS)., Methods: Consecutive patients with unresectable pancreatic cancer who underwent initial SEMS placement (MHSEMS or c-CMS) for malignant distal biliary obstruction were analyzed. Technical success, clinical success, causes of recurrent biliary obstruction (RBO), non-RBO adverse events, time to RBO (TRBO), and endoscopic reintervention were compared between groups., Results: A total of 65 patients were included (MHSEMS: 27, c-CMS: 38). The technical success, clinical success, and non-RBO adverse event rates were similar between groups. Although stent migration was less frequently observed in the MHSEMS group (0% vs. 17.6%, p = 0.032), overall RBO rates were similar between groups (53.8% vs. 55.9%, p > 0.99). The most common cause of RBO within 14 days in the MHSEMS group was non-occlusion cholangitis. Median TRBO was significantly shorter in the MHSEMS group (101 vs. 227 days, p = 0.030) and MHSEMS was an independent predictor for shorter TRBO in multivariate analysis (hazard ratio, 2.27; 95% confidence interval, 1.06-4.86; p = 0.034). Outcomes after endoscopic interventio were not significantly different between groups. Stent removal was successful in all attempted cases in both groups., Conclusions: MHSEMS was associated with a significantly shorter TRBO compared to c-CMS. Further modifications of the present MHSEMS may be needed., Competing Interests: None., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: There is an increased risk of acute exacerbation of idiopathic interstitial pneumonia when treating patients with advanced non-small cell lung cancer with idiopathic interstitial pneumonia. There is no standard optimal treatment regimen for patients with lung cancer complicated with idiopathic interstitial pneumonia. We aimed to evaluate the efficacy and safety of carboplatin (CBDCA), bevacizumab (Bmab) and weekly paclitaxel (PXT) in patients with idiopathic interstitial pneumonia., Methods: This phase 2 study involved chemotherapy-naïve patients with advanced non-small cell lung cancer with idiopathic interstitial pneumonia. Patients received CBDCA (area under the curve: 5 on day 1), PXT (70 mg/m2 on days 1, 8 and 15) and Bmab (15 mg/kg on day 1) every 4 weeks. The primary endpoint was the overall response rate., Results: Twenty-one patients were enrolled between January 2013 and October 2018 and received at least one course of the protocol treatment. The study was terminated before enrolling the planned number of patients because of poor accrual. The median patient age was 69 (range: 62-79) years, and 19 (90.5%) patients were men. The overall response rate was 61.9% (95% confidence interval [CI], 38.4-81.9), meeting the primary endpoint. The median progression-free survival, time to treatment failure, and overall survival were 9.69 (95% CI, 5.78-11.63), 8.21 (95% CI, 3.75-11.63) and 20.93 (95% CI, 13.17-29.83) months, respectively. There was no acute exacerbation or treatment-related death during protocol treatment., Conclusion: The results indicate that patients with advanced non-squamous, non-small cell lung cancer with idiopathic interstitial pneumonia could be effectively and safely treated using a combination of CBDCA, PXT and Bmab., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Generalized pustular psoriasis (GPP) is a recurrent and sometimes life-threatening sterile pustular disease. Because interleukin (IL)-36 is the central cytokine in disease formation, spesolimab, which interferes with IL-36 receptor signaling, is highly effective. Here, we report a patient with GPP with a heterozygous hypomorphic MPO variant refractory to intravenous spesolimab. Although spesolimab showed excellent clinical efficacy in resolving pre-existing pustules and erythema, it did not suppress the emergence of new pustules and erythema, which did not decrease the peripheral blood neutrophil count, therefore bimekizumab, an anti-IL-17A/IL-17F antibody, was administered after the second spesolimab infusion, which resolved the pustules and erythema. We discuss the possible reasons for the resistance mechanism to spesolimab., (© 2024 Japanese Dermatological Association.)

Sialocele is a common complication of parotid tumour surgery. Aspiration and pressure dressing are the most common conservative treatments for sialoceles. However, they occasionally exhibit a refractory nature. In this case report, a minocycline injection was administered for refractory sialocele following a condylar fracture treated using the retromandibular anterior transparotid approach. Aspiration of the sialocele and the same amount of minocycline injection using three-way stopcocks were performed four weeks after surgery. After the injection, the buccal swelling completely disappeared without complications, including facial palsy. Percutaneous injection of minocycline might be the first choice for postoperative refractory sialocele following condylar fracture., (Copyright © 2024 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Objective: This study explored the interaction among ACTN3 R577X polymorphism, muscle damage, and post-exercise inflammatory response by assessing changes over time in serum creatine kinase and interleukin-6 levels., Design: Ninety-five active Japanese participants (50 men and 45 women: 22.2 ± 2.3 years) who did not perform daily upper limb strength exercises were enrolled. Participants executed five sets of six maximal eccentric elbow flexion exercises. The exercise duration was 9 min, including rest between sets (90 s). Maximum voluntary isometric contraction, range of motion, muscle soreness, and serum creatine kinase and interleukin-6 levels were assessed pre and post and 1, 2, 3, and 5 d after exercise. Genotype groups were classified as RR + RX and XX based on the absence of ACTN3 expression., Results: A significant time and group interaction (p = 0.045) on creatine kinase levels was observed between the groups, indicating that the absence of ACTN3 significantly affects creatine kinase changes. Conversely, no significant interaction on change in interleukin-6, maximum voluntary isometric contraction, range of motion, and muscle soreness was observed between groups., Conclusion: The results highlight an interaction on creatine kinase activity post-exercise by ACTN3 R577X polymorphism, with elevated activity in the XX genotype., Competing Interests: The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We herein report a rare case of hypersensitivity pneumonitis (HP) that was initially demonstrated as solitary pure ground-glass opacity (GGO) on chest computed tomography (CT). A 51-year-old woman with a history of breast cancer underwent follow-up CT, which revealed solitary pure GGO. The patient developed exertional dyspnea after two years, and CT revealed diffuse centrilobular nodules in addition to GGO, which had increased in size. An antigen avoidance test was performed to diagnose HP, leading to the resolution of CT abnormalities, including the GGO. Our findings suggested that nonfibrotic HP can present as solitary pure GGO.

Renal leiomyosarcoma metastasis to the pancreas is exceptionally rare. Here, we present a case of metastatic recurrence in the pancreas seven years after renal leiomyosarcoma resection. A 73-year-old female with a history of renal leiomyosarcoma surgery seven years prior presented with a well-defined 40 × 30 mm pancreatic tail tumor detected by a computed tomography (CT) scan. The tumor exhibited hypo-enhancement in the arterial phase and a progressive enhancement pattern toward the equilibrium phase, similar to pancreatic cancer. Endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) revealed bundles of spindle cells that matched those in the previously resected renal sample. Immunohistochemistry showed positive staining for desmin, confirming the diagnosis of pancreatic metastasis from renal leiomyosarcoma. The patient underwent a distal pancreatectomy to remove the metastatic lesion. The extended interval of seven years before the detection of metastasis underscores the challenges in monitoring and diagnosing metastatic patterns of renal leiomyosarcoma. EUS-FNB can assist in distinguishing metastatic pancreatic leiomyosarcoma from primary pancreatic cancer, thus influencing treatment decisions., (© 2024. Japanese Society of Gastroenterology.)

Background: Hemorrhage management is crucial for surgical resection of pediatric posterior-fossa tumors (PPFTs). Tumor volume and vascularity on preoperative magnetic resonance imaging (MRI) can help predict and control intraoperative blood loss (IBL). The present study aimed to assess the correlation between MRI features and IBL in PPFTs., Methods: Eleven patients treated for PPFTs at our hospital using the transcerebellomedullary fissure approach were enrolled, including five (45.5%) males and six (54.5%) females, with a median age of 10 (range, 4-16) years. Nine patients with medulloblastoma, one with ependymoma, and one with atypical teratoid/rhabdoid tumor were included. Using susceptibility-weighted imaging-based intratumoral susceptibility signal (ITSS) grade as an index of tumor vascularity, we performed univariate analysis of the association of degree of vascularity (ITSS grade 0-2 vs. 3) and multivariate analysis of IBL., Results: Univariate analysis showed that the high vascularity group (ITSS grade 3) had significantly larger tumor volume (p = 0.009) and higher IBL (p = 0.004). In multivariate analysis of age, tumor volume, ITSS grade, cerebral blood volume, and extent of resection, tumor volume was the only significant factor (p = 0.001); however, ITSS grade was also positively associated with IBL (p = 0.074)., Conclusion: In this study, tumor volume and vascularity of PPFTs were strongly correlated, and tumor volume was the sole factor significantly associated with IBL. This study suggests that ITSS grade and tumor volume collaboratively influence IBL in surgical resection of PPFTs. IBL should be assessed based on MRI features, and suitable treatment strategies should be established., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: The importance of multidisciplinary discussion (MDD) for diagnosing interstitial lung disease (ILD) is emphasized by several international guidelines. While initial diagnoses are often provisional and require periodic re-evaluation, there is a lack of literature regarding the role of follow-up MDD in clinical practice., Methods: From September 2020 to January 2022, patients underwent an initial MDD (MDD1) based on clinical, radiological, and pathological evaluations. Each diagnosis was assigned a confidence level. One year later, a second MDD (MDD2) was conducted for re-evaluation, based on subsequent clinical and radiological information. Changes in diagnosis and confidence levels between MDD1 and MDD2 were assessed., Results: Among 52 patients enrolled in both MDDs, the diagnosis for 13 (25%) was revised at MDD2. Of these, 10 patients were initially diagnosed with unclassifiable ILD, and 3 received a low confidence diagnosis of either idiopathic pulmonary fibrosis or idiopathic nonspecific interstitial pneumonia. The most common diagnostic revision was due to the deterioration after antigen exposure or improvement after antigen avoidance, which resulted in a revised diagnosis of HP at MDD2., Conclusions: Our findings underscore the importance of periodic reassessment of MDD to improve the accuracy of ILD diagnosis. This study highlights the significance of longitudinal clinical and radiological evaluation for diagnostic revision, even in situations when rebiopsy is not feasible., Competing Interests: Declaration of competing interest Y.Iijima reports grants from Japan Society for the Promotion of Science. H. Furusawa reports grants from Japan Society for the Promotion of Science outside the submitted work. T.Okamoto reports endowment from Nippon Boehringer Ingelheim Co., Ltd. Y. Miyazaki reports grants from Nippon Boehringer Ingelheim Co., Ltd. and Chugai Pharmaceutical Co., Ltd., and personal fees from Nippon Boehringer Ingelheim Co., Ltd. and AstraZeneca K.K., outside the submitted work. The remaining authors have no disclosures., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Stent migration and sludge formation remain significant problems associated with covered self-expandable metal stents (CSEMSs). The EGIS biliary stent fully covered flare type (EGIS biliary stent), a new type of polytetrafluoroethylene-coated self-expandable metal stent with low axial force and an anti-migration system, was developed to overcome these disadvantages. We conducted this study to evaluate the efficacy and safety of this stent in comparison with conventional CSEMS (c-CSEMS)., Methods: We retrospectively analyzed consecutive patients with unresectable pancreatic cancer who received initial CSEMS for distal malignant biliary obstruction. The primary outcome was time to recurrent biliary obstruction (RBO). Secondary outcomes included technical success rate, functional success rate, stent-related adverse events, causes of RBO, and re-intervention., Results: A total of 40 patients were included (EGIS group: 20; c-CSEMS group: 20). The technical and functional success rates were similar between the two groups. Stent-related adverse event rates (20% vs. 15%, p > 0.99) and overall RBO rates (56% vs. 50%, p > 0.99) were not significantly different between the two groups. Stent migration was the most common cause of RBO in the EGIS group, while stent occlusion was in the c-CSEMS group. The median time to RBO (102 vs. 434 days, p = 0.10) was not significantly different between the two groups. Endoscopic transpapillary re-intervention was successful in most patients in both groups., Conclusions: The EGIS biliary stent was not associated with a longer time to RBO compared to c-CSEMS. Further improvements, especially against stent migration, are needed to improve its efficacy., Competing Interests: Tsuyoshi Takeda received honoraria from Boston Scientific Japan and SB‐Kawasumi Laboratories. Takashi Sasaki received honoraria from Boston Scientific Japan, Century Medical, SB‐Kawasumi Laboratories, JAPAN LIFELINE, and KANEKA MEDIX. Naoki Sasahira received honoraria from SB‐Kawasumi Laboratories., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Hybridization generates biodiversity, and wide hybridization plays a pivotal role in enhancing and broadening the useful attributes of crops. The hybridization barrier between wheat and rice, the two most important cereals, was recently overcome by in vitro production of allopolyploid wheat-rice hybrid zygotes, which can develop and grow into mature plants. In the study, genomic sequences and compositions of the possible hybrid plants were investigated through short- and long-read sequencing analyses and fluorescence in situ hybridization (FISH)-based visualization. The possible hybrid possessed whole wheat nuclear and cytoplasmic DNAs and rice mitochondrial (mt) DNA, along with variable retention rates of rice mtDNA ranging from 11% to 47%. The rice mtDNA retained in the wheat cybrid, termed Oryzawheat, can be transmitted across generations. In addition to mitochondrial hybridization, translocation of rice chromosome 1 into wheat chromosome 6A was detected in a F1 hybrid individual. OryzaWheat can provide a new horizon for utilizing inter-subfamily genetic resources among wheat and rice belonging to different subfamilies, Pooideae and Ehrhartoideae, respectively., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.)

Background: Distant metastases from lung cancer are commonly found in the brain, bone, and liver. Metastases to the breast from non-mammary malignancies are extremely rare, and their clinical presentations remain unclear., Case Presentation: We herein report a case of bilateral breast metastases from anaplastic lymphoma kinase-positive advanced lung cancer in a 51-year-old Japanese male patient. During the course of systemic treatment for advanced lung cancer, computed tomography revealed bilateral breast enlargement without contrast enhancement, a finding consistent with gynecomastia. While other metastatic lesions responded to chemotherapy, both breast masses grew vertically like nodules. The breast masses were immunohistochemically diagnosed as metastases from lung cancer and were removed surgically. Simultaneous bilateral breast metastases from malignancies of other organs, like ones in this case, have rarely been described., Conclusions: It is important to keep in mind that breast metastases from nonmammary malignancies are a possible explanation for unusual breast findings in a patient with a history of malignancies., (© 2024. The Author(s).)

'No evidence of disease activity (NEDA)', judged by clinical and radiological findings, is a therapeutic goal in patients with multiple sclerosis (MS). It is, however, unclear if distinct biological mechanisms contribute to the maintenance of NEDA. To clarify the immunological background of long-term disease stability defined by NEDA, circulating immune cell subsets in patients with relapsing-remitting MS (RRMS) were analyzed using flow cytometry. Patients showing long-term NEDA ( n  = 31) had significantly higher frequencies of non-classical monocytes (NCMs) (6.1% vs 1.4%) and activated regulatory T cells (Tregs; 2.1% vs 1.6%) than those with evidence of disease activity ( n  = 8). The NCM frequency and NCMs to classical monocytes ratio (NCM/CM) positively correlated with activated Treg frequency and duration of NEDA. Co-culture assays demonstrated that NCMs could increase the frequency of activated Tregs and the expression of PD-L1, contributing to development of Tregs, was particularly high in NCMs from patients with NEDA. Collectively, NCMs contribute to stable remission in patients with RRMS, possibly by increasing activated Treg frequency. In addition, the NCM frequency and NCM/CM ratio had high predictive values for disease stability (AUC = 0.97 and 0.94, respectively), suggesting these markers are potential predictors of a long-term NEDA status in RRMS.

Tumor-stroma ratio (TSR) has been recognized as a valuable prognostic indicator in various solid tumors. This study aimed to examine the clinicopathologic relevance of TSR in Merkel cell carcinoma (MCC) using artificial intelligence (AI)-based parameterization of the stromal landscape and validate TSR scores generated by our AI model against those assessed by humans. One hundred twelve MCC cases with whole-slide images were collected from 4 different institutions. Whole-slide images were first partitioned into 128 × 128-pixel "mini-patches," then classified using a novel framework, termed pre-tumor and stroma (Pre-TOAST) and TOAST, whose output equaled the probability of the minipatch representing tumor cells rather than stroma. Hierarchical random samplings of 50 minipatches per region were performed throughout 50 regions per slide. TSR and tumor-stroma landscape (TSL) parameters were estimated using the maximum-likelihood algorithm. Receiver operating characteristic curves showed that the area under the curve value of Pre-TOAST in discriminating classes of interest including tumor cells, collagenous stroma, and lymphocytes from nonclasses of interest including hemorrhage, space, and necrosis was 1.00. The area under the curve value of TOAST in differentiating tumor cells from related stroma was 0.93. MCC stroma was categorized into TSR high (TSR ≥ 50%) and TSR low (TSR < 50%) using both AI- and human pathology-based methods. The AI-based TSR-high subgroup exhibited notably shorter metastasis-free survival (MFS) with a statistical significance of P = .029. Interestingly, pathologist-determined TSR subgroups lacked statistical significance in recurrence-free survival, MFS, and overall survival (P > .05). Density-based spatial clustering of applications with noise analysis identified the following 2 distinct TSL clusters: TSL1 and TSL2. TSL2 showed significantly shorter recurrence-free survival (P = .045) and markedly reduced MFS (P < .001) compared with TSL1. TSL classification appears to offer better prognostic discrimination than traditional TSR evaluation in MCC. TSL can be reliably calculated using an AI-based classification framework and predict various prognostic features of MCC., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

We describe a case of mandibular gingival carcinoma with hypercalcaemia and leukocytosis caused by tumour-derived parathyroid hormone-related protein (PTHrP) and granulocyte colony-stimulating factor (G-CSF). A 54-year-old man presented to our Department of Oral and Maxillofacial Surgery with a chief complaint of a left-sided mandibular gingival ulcer. A 42 mm × 20 mm sized ulcer was found on the left lower molar gingiva. Squamous cell carcinoma was pathologically diagnosed. The patient underwent a hemimandibulectomy, left-sided radical neck dissection, plate reconstruction, pectoralis major musculocutaneous flap reconstruction, and tracheostomy under general anaesthesia. Pathologically, two metastatic lymph nodes were identified. Residual tumour was suspected at the resection margins. Eight weeks after surgery, the patient started postoperative concurrent chemoradiotherapy (CCRT). Two weeks after CCRT, the patient developed hypercalcaemia. Serum levels of PTHrP and G-CSF increased in parallel with the progression of hypercalcaemia and leukocytosis. Immunohistochemical analysis of the surgical specimen showed positivity for G-CSF. Based on these clinical and pathological findings, the patient was diagnosed with hypercalcaemia and leukocytosis associated with malignancy and was treated with denosumab. Irradiation was terminated at 50 Gy because CT showed rapid disease progression. Chemotherapy was initiated, however, four weeks after the start of chemotherapy, a CT scan showed increased metastases and pleural dissemination. Therefore, chemotherapy was discontinued. One week after the chemotherapy was discontinued, the patient died of respiratory failure., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: We recently have reported that individual day-to-day arterial stiffness variations are associated with maximal aerobic capacity. However, the evidence of this phenomenon was not provided sufficiently. The present study aimed to examine whether a decrease in arterial stiffness through static stretching exercise could enhance maximal aerobic capacity., Methods: Twelve healthy young men (age 22±2 years, mean and standard deviation) participated in this study and underwent two separate sessions in a randomized controlled crossover design: a single session of a whole-body static stretching exercise protocol that involved the trunk, upper limb, and lower limb (stretch condition), and sedentary control where they rested in the exercise room. Brachial-ankle pulse wave velocity (baPWV) was measured as an index of systemic arterial stiffness before, immediately after and at 30 min after both conditions. Maximal oxygen uptake (V̇O2max) was assessed using a graded power test on an electronically braked cycle ergometer after these measurements., Results: As we expected, there was a significant decrease in the baPWV at 30 min after the stretch trial compared to baseline values (P=0.01). The baPWV in the stretch condition was lower than that of the control condition, while V̇O2max in the stretch condition was higher than that of the control condition (P=0.03)., Conclusions: Based on these findings, it can be inferred that an acute reduction in arterial stiffness may contribute to change in maximal aerobic capacity.

Introduction: High recurrence rate following curative surgery for non-small cell lung cancer (NSCLC) presents a major clinical challenge. Understanding the site and timing of recurrence and their impact on post-recurrence survival (PRS) is important for optimal postoperative surveillance and therapeutic intervention. In this study, we investigated the influence of the time to recurrence (TTR) and initial recurrence site on PRS., Materials and Methods: This multicentre prospective cohort study included patients who experienced recurrence after NSCLC resection between 2010 and 2015. The relationship between TTR and initial recurrence site, and their impact on PRS, was further evaluated. The hazard ratio (HR) for PRS was analysed using the Cox proportional hazards model., Results: Among 495 patients, the median TTR was 14 (range, 1-158) months; the mode of recurrence was 11 months. Early recurrence within 6 months was observed in 17 % of patients, and 68 % of patients showed recurrence within 2 years post-surgery. The HR for PRS was the highest in patients with a TTR within 6 months, and a noticeable decline was observed after the first 6 months. The HRs of TTRs beyond 2 years were not significantly different. The liver was a significantly unfavourable prognostic site for metastases (HR 2.2; P = 0.01), and metastases frequently recurred within 6 months after surgery. The timing of brain metastasis did not significantly impact the PRS., Conclusion: Earlier recurrence after surgery was associated with shorter PRS. In contrast, recurrences occurring >2 years after surgery do not significantly affect PRS., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (© 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objectives: The objective of this study is to assess the trends in treatment selection for patients with de novo metastatic castration-sensitive prostate cancer in the era of upfront combination therapy., Methods: This multicenter retrospective study included 595 patients treated with either upfront combination therapy (upfront novel hormonal therapies and taxane-based chemotherapy) or vintage therapy (androgen deprivation therapy with or without bicalutamide) between 2016 and 2021. High tumor burden metastatic disease was defined when a patient met the CHAARTED or LATITUDE criteria. We evaluated trends in treatment selection and reasons for selecting vintage therapy., Results: Of the 595, 123 and 472 patients were classified as having low and high tumor-burden disease, respectively. The Use of upfront combination therapy was found to be rapidly increasing with utilization rates of 72% and 54% in 2021 for high and low tumor-burden disease, respectively. Multivariable logistic regression analysis found older age, poor performance status, and nonacademic center were significantly associated with the selection of vintage therapy. Of the 163 patients who received vintage hormone therapy after approval of upfront therapy, 74.2% had a specific reason for avoiding upfront therapy. The reasons for selecting vintage therapy included refusal (39.8%), older age (67.6%), frailty (56.3%), and comorbidity (40.8%). Furthermore, 16.9% of patients declined upfront combination therapy due to cost concerns., Conclusion: Upfront combination therapy use has 72% and 54% prevalence among patients with high and low tumor burden diseases, respectively, in this current practice. Older age, poor performance status, and facility bias were negatively associated with the use of upfront combination therapy., (© 2024 The Author(s). International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Background: This study aimed to identify the prognostic factors after pancreatectomy for borderline resectable pancreatic cancer abutting major arteries (BR-A). Methods: We retrospectively investigated relationship between preoperative and intraoperative variables and overall survival (OS) through univariate and multivariate analyses. The cut-off points of preoperative therapy duration and response rates of serum carbohydrate antigen 19-9 (CA19-9) levels after preoperative therapy were determined through a minimum P -value approach using the log-rank test for OS. Overall survival was compared among patients stratified according to the independent prognostic factors and the presence or absence of pancreatectomy. Results: After pretreatment, 17 patients underwent pancreatectomy and four patients continued chemotherapy without surgery. Multivariate analysis in 17 resected BR-A patients demonstrated decreased serum CA19-9 levels and preoperative therapy duration of ≥4 months were the independent prognostic factors [hazard ratio (HR) 0.01; P = 0.002, HR 0.13; P = 0.02]. Patients who underwent surgery with decreased serum CA19-9 levels after preoperative therapy of ≥4 months had a significantly better prognosis than those without one or both of independent prognostic factors and those who did not undergo surgery (median survival time: not estimated, 23.3 months, 10.5 months, and 10.8 months; P = 0.02, P = 0.004, and P = 0.001, respectively). Furthermore, the prognosis did not significantly differ between the patients who underwent surgery without meeting either one or both criteria and those without surgery. Conclusions: Preoperative therapy duration of ≥4 months and decreased serum CA19-9 levels are independent prognostic factors among BR-A patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: Recent evidence suggests that acute liver failure (ALF) in some patients may reflect a dysregulated immune response, and that corticosteroids improve survival of the native liver in ALF patients with high serum alanine aminotransferase levels, which are an indication of liver inflammation. However, it is unclear whether steroids are effective for pediatric acute liver failure (PALF). The aim of this retrospective case-control study is to examine whether steroid therapy for PALF accompanied by immune activation improves the survival of native liver and to identify factors that predict responses to steroid treatment., Methods: Of 38 patients with PALF treated at Kyoto University Hospital from February 2006 to August 2022, 19 receiving steroids who met the specific criteria for identifying the pathophysiology of immune activity in the liver (the "Steroid group"), and seven steroid-free patients who also met the criteria ("Nonsteroid group") were enrolled. Patients in the "Steroid group" were categorized as "responders" or "nonresponders" according to treatment outcome. Clinical and histological data were analyzed., Results: Survival of the native liver in the Steroid group was significantly higher than that in the Nonsteroid group (68% vs. 0%, respectively; p = 0.0052). Nonresponders were significantly younger, with higher Model for End-stage Liver Disease and pediatric end-stage liver disease scores, higher prothrombin time - international normalized ratio, and higher serum ferritin levels than responders. Massive hepatic necrosis was more common in nonresponders., Conclusion: Steroid therapy is effective for PALF patients with liver inflammation; however, liver transplantation should be prioritized for young children with ALF accompanied by severe coagulopathy or massive hepatic necrosis., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Children with intestinal failure suffer liver damage associated with parenteral nutrition: a condition known as intestinal failure-associated liver disease (IFALD), which requires transplantation of both liver and intestine. In many countries, simultaneous transplantation of these two organs is performed using grafts from a deceased donor, but there have been no such cases in Japan, and the details of the procedure are not clear. Recently, we performed simultaneous split liver and intestinal transplantation in two premature infants with IFALD, using organs from identical deceased donors and achieved good results. These are the first two cases of this procedure being performed in Japan. We report these cases and discuss the important aspects of the surgical and perioperative management., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: In Japan, there has never been a national analysis of pediatric deceased donor liver transplantation (pDDLT) based on donor and recipient factors. We constructed a Japanese nationwide database and assessed outcomes of pDDLT focusing on the pediatric prioritization system introduced in 2018., Methods: We collected data on pDDLTs (<18 years) performed between 1999 and 2021 from the Japan Organ Transplant Network and Japanese Liver Transplantation Society, identified risk factors for graft survival and compared the characteristics and graft survival in pDDLTs conducted before and after the introduction of the pediatric prioritization system., Results: Overall, 112 cases of pDDLT were included, with a 1-year graft survival rate of 86.6%. Four poor prognostic factors were identified: recipient intensive care unit stay, model for end-stage liver disease/pediatric end-stage liver disease score, donor cause of death, and donor total bilirubin. After the introduction of the system, allografts from pediatric donors were more reliably allocated to pediatric recipients and the annual number of pDDLTs increased. The 1-year graft survival rate improved significantly as did pDDLT conditions indicated by the risk factors., Conclusions: Under the revised allocation system, opportunities for pDDLT increased, resulting in favorable recipient and donor conditions and improved survival., (© 2024 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Flaviviridae is a family of positive-stranded RNA viruses, including human pathogens, such as Japanese encephalitis virus (JEV), dengue virus (DENV), Zika virus (ZIKV), and West Nile virus (WNV). Nuclear localization of the viral core protein is conserved among Flaviviridae, and this feature may be targeted for developing broad-ranging anti-flavivirus drugs. However, the mechanism of core protein translocation to the nucleus and the importance of nuclear translocation in the viral life cycle remain unknown. We aimed to identify the molecular mechanism underlying core protein nuclear translocation. We identified importin-7 (IPO7), an importin-β family protein, as a nuclear carrier for Flaviviridae core proteins. Nuclear import assays revealed that core protein was transported into the nucleus via IPO7, whereas IPO7 deletion by CRISPR/Cas9 impaired their nuclear translocation. To understand the importance of core protein nuclear translocation, we evaluated the production of infectious virus or single-round-infectious-particles in wild-type or IPO7-deficient cells; both processes were significantly impaired in IPO7-deficient cells, whereas intracellular infectious virus levels were equivalent in wild-type and IPO7-deficient cells. These results suggest that IPO7-mediated nuclear translocation of core proteins is involved in the release of infectious virus particles of flaviviruses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Itoh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Hypothesis: Male patients with X-linked Alport syndrome (XLAS) generally develop end-stage kidney disease in early or middle adulthood and show distinct genotype-phenotype correlations. Female patients, however, show various phenotypes ranging from asymptomatic to severe with no genotype-phenotype correlations. However, the factors affecting the severity of XLAS in female patients are unclear. Since X-chromosome inactivation (XCI) affects the severity of certain female X-linked diseases, we investigated whether genotype and XCI were associated with XLAS severity in female patients in a large Japanese cohort., Methods: Among 139 female patients with genetically diagnosed XLAS at our institution, we conducted XCI analysis on peripheral blood leukocytes using the human androgen receptor assay method and analyzed two cohorts. In 74 adult female patients, we evaluated the correlation between kidney function (creatinine-estimated glomerular filtration rate [Cr-eGFR] optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis, and in 65 pediatric female patients, we evaluated the correlation between kidney function (Cr-eGFR optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis. We also investigated the correlation between the development of proteinuria (urine protein-to-creatinine ratio above normal for the patient's age) and genotype/XCI using multivariable Cox proportional hazard analysis., Results: In adult female patients, XCI pattern was significantly associated with Cr-eGFR (regression coefficient estimate = -0.53, P = 0.004), whereas genotype was not (P = 0.892). In pediatric female patients, both genotype and XCI pattern were significant independent risk factors for the development of proteinuria (hazard ratio [HR], 3.702; 95% confidence interval [CI], 1.681-8.150; P = 0.001 and HR, 1.043; 95% CI, 1.061-1.070; P = 0.001, respectively), whereas both genotype and XCI pattern were not associated with Cr-eGFR (P = 0.20, P = 0.67, respectively)., Conclusion: Genotype and XCI are factors associated with the severity in females with XLAS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)