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We investigated the degradation of neutral beam (NB) fast-ion confinement depending on the NB power without magnetohydrodynamics instabilities in the Large Helical Device (LHD). In the LHD deuterium experiment, the neutron emission rate per NB power decreased by up to 20% with increasing injected NBs during a single discharge. Because there were no significant variations in the electron temperature and density, the NB shine-through rate, or the magnetic fluctuation due to the change in NB power, the reduction in the neutron emission rate indicates the degradation of the fast-ion confinement. In this paper, we formulated this degradation depending on the NB power and quantitatively estimated the degraded effective confinement time. In addition, we performed neutron emission rate simulations using the obtained effective confinement time. The simulation and experimental results were in good agreement, suggesting that the degraded effective confinement time is valid.

Recently, experiments on basic plasma physics issues for solving future problems in fusion energy have been performed on a Large Helical Device. There are several problems to be solved in future devices for fusion energy. Emerging issues in burning plasma are: alpha-channeling (ion heating by alpha particles), turbulence and transport in electron dominant heating helium ash exhaust, reduction of the divertor heat load. To solve these problems, understanding the basic plasma physics of (1) wave–particle interaction through (inverse) Landau damping, (2) characteristics of electron-scale (high- k ) turbulence, (3) ion mixing and the isotope effect, and (4) turbulence spreading and detachment, is necessary. This overview discusses the experimental studies on these issues and turbulent transport in multi-ion plasma and other issues in the appendix.

TAE Technologies’ fifth-generation fusion device, C-2W (also called ‘Norman’), is the world’s largest compact-toroid device and has made significant progress in field-reversed configuration (FRC) plasma performance. C-2W produces record breaking, macroscopically stable, high-temperature advanced beam-driven FRC plasmas, dominated by injected fast particles and sustained in steady state, which is primarily limited by neutral-beam (NB) pulse duration. The NB power supply system has recently been upgraded to extend the pulse length from 30 ms to 40 ms, which allows for a longer plasma lifetime and thus better characterization and further enhancement of FRC performance. An active plasma control system is routinely used in C-2W to produce consistent FRC performance as well as for reliable machine operations using magnet coils, edge-biasing electrodes, gas injection and tunable-energy NBs. Google’s machine learning framework for experimental optimization has also been routinely used to enhance plasma performance. Dedicated plasma optimization experimental campaigns, particularly focused on the external magnetic field profile and NB injection (NBI) optimizations, have produced a superior FRC plasma performance; for instance, achieving a total plasma energy of ∼13 kJ, a trapped poloidal magnetic flux of ∼16 mWb (based on the rigid-rotor model) and plasma sustainment in steady state up to ∼40 ms. Furthermore, under some operating conditions, the electron temperature of FRC plasmas at a quiescent phase has successfully reached up to ∼1 keV at the peak inside the FRC separatrix for the first time. The overall FRC performance is well correlated with the NB and edge-biasing systems, where higher total plasma energy is obtained with higher NBI power and applied voltage on biasing electrodes. C-2W operations have now reached a mature level where the machine can produce hot, stable, long-lived, and repeatable plasmas in a well-controlled manner.

Abstract The compact neutron emission spectrometer (CNES) having a tangential sightline was installed to observe a significant Doppler shift of the neutron energy due to the high-energy tangential neutral beam (NB) injections in the Large Helical Device (LHD) for understanding of the energy distribution of fast-ion. The CNES is based on a 1-inch diameter and 1-inch height EJ301 liquid scintillator coupled with a conventional 1-inch photomultiplier tube. The histogram of the integrated pulse signal (Q total) during different NBs heating phases measured by the CNES shows that the edge of Q total changes depending on NB directions. Using the simple derivative unfolding technique, the neutron energy spectra were unfolded from the measured Q total histogram. Peaks of the neutron energy shift to 2.0 MeV, 2.42 MeV, and 3.0 MeV according to the injection direction of NBs. The obtained neutron energy is almost consistent with the virgin deuterium-deuterium neutron energy evaluated by the simple two-body kinematics considering the sightline of CNES, NB injection angle, and NB injection energy.

We measured a set of π±Σ∓, π0Σ0, and π−Σ0 invariant mass spectra below and above the K¯N mass threshold in K−-induced reactions on deuteron. The measured πΣ mass spectral shape is well reproduced via the two-step mechanism, i.e., a neutron knocked out at a forward angle from a deuteron by an incident K−, with the K¯ recoiled backward reacting with the residual nucleon to produce π and Σ. We deduced the S-wave K¯N→πΣ and K¯N→K¯N scattering amplitudes in the isospin 0 channel in the framework of a K¯N and πΣ coupled channel. We find that a resonance pole corresponding to Λ(1405) is located at 1417.7−7.4+6.0 (fitting errors)−1.0+1.1 (systematic errors) + [−26.1−7.9+6.0 (fitting errors)−2.0+1.7 (systematic errors)] i MeV/c2, closer to the K¯N mass threshold than the value determined by the Particle Data Group.

Background: Although a preference for solitude (PS) may mitigate the negative effects of social isolation (SI) owing to the enjoyment of time alone, its impact on mental health and its underlying factors remain unclear., Methods: An Internet survey was conducted with 9000 individuals aged 20-79 years in September 2023 and the analyses were performed across three generations. SI was defined as contact with non-cohabitating family members or relatives and friends/neighbors less than once a week. The PS scale, which was used to assess whether a person preferred spending time alone, stratified respondents into three PS-level groups. Mental health status was evaluated using the K6 (distress symptoms), the WHO-5 (well-being), and the UCLA Loneliness Score (severity of loneliness) as the main outcomes. The mediation analyses assessed whether troublesomeness in socializing, a potential negative aspect of PS, could explain the association between PS and mental health status., Results: A mixed-design two-way analysis of covariance showed that both SI and PS had significant main effects on all outcomes without interactions across generations, indicating that SI and higher PS were associated with poor mental health status. The association between higher PS and poor mental status was mediated by socializing troublesomeness across generations., Limitations: The cross-sectional design prevented making causal inferences from the results. Additionally, sampling bias from Internet surveys may limit the generalizability of the results., Conclusions: The results confirmed that there is no protective effect of PS on social isolation-related poor mental health. The hassle of socializing may partly explain why people with a higher PS experience poor mental status, including greater loneliness., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aim: Tofacitinib and aminosalicylic acid (5-ASA) are commonly used to treat ulcerative colitis (UC). However, evidence on the effect of concomitant 5-ASA use in patients receiving tofacitinib is limited. This study investigated the effects of 5-ASA combined with tofacitinib in UC patients., Methods: This retrospective cohort study used data from the Medical Data Vision database, including patients with UC treated with tofacitinib from May 2018 to April 2022. Patients were grouped according to tofacitinib dosage and assessed for the efficacy of concomitant 5-ASA use. The primary endpoint was clinical relapse., Results: A total of 1213 patients with UC were included in the analysis, with 416 in the 5 mg BID group and 797 in the 10 mg BID group. In the 5 mg BID group, the cumulative relapse-free rate was significantly higher in patients receiving concomitant 5-ASA (P < 0.0001). Multivariate Cox regression analysis confirmed that concomitant 5-ASA use significantly reduced the risk of clinical relapse (adjusted hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.31-0.70). In the 10 mg BID group, no significant difference was noted in the cumulative relapse-free rate between patients treated with and without 5-ASA (P = 0.445). Similarly, multivariate Cox regression analysis indicated that concomitant 5-ASA use did not significantly affect relapse risk (adjusted HR, 0.97; 95% CI, 0.71-1.32)., Conclusions: Concomitant 5-ASA use reduced the risk of relapse in patients on 5 mg tofacitinib BID, suggesting benefits at lower doses. However, no significant benefit was observed with 5-ASA use in those 10 mg tofacitinib BID., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Fosravuconazole L-lysine ethanolate (F-RVCZ) is a prodrug of ravuconazole and a triazole antifungal drug used for the treatment of onychomycosis. It has been reported in previous studies that the kidney injury caused by F-RVCZ is 1% or less., Methods: Serum creatinine levels were compared, and glomerular filtration rate and urine protein were estimated before and after starting the administration of F-RVCZ, as well as after the end of the administration period. The cause of kidney injury was investigated using renal pathology, and risk factors were also investigated., Results: F-RVCZ was administered to 46 patients. Ten of these patients were excluded because three were maintenance dialysis patients and seven were not measured for serum creatinine. Remaining 36 patients were included in the analyses. Kidney injury occurred in 27.8% of patients treated with F-RVCZ; this condition persisted in 10% of patients after the end of the administration period. No changes were observed in the urinalysis after the administration of F-RVCZ. A kidney biopsy was performed in one patient, but no lesions were found that could be the cause of kidney injury. Patients who developed kidney injury were significantly more likely to be receiving angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (odds ratio 18.9, 95% confidential interval: 1.69-210, p = 0.0169)., Conclusion: Kidney injury is caused by F-RVCZ more frequently than previously reported, but the mechanism remains unclear., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Age-related hearing loss (ARHL) and impaired gait both independently heighten the risk of accidental falls among older adults. However, the combined impact of these factors remains unclear. We analyzed the data of 786 community-dwelling Japanese older adults. Hearing was evaluated at frequencies of 1.0 and 4.0 kHz, with participants categorized into ARHL (> 25 dB) and non-ARHL groups. Gait was also assessed, defining slow gait (SG) as speeds one standard deviation below the age- and sex-specific mean. Participants were divided into four groups based on their ARHL and SG statuses and were monitored annually for 8 years to track falls and related injuries. Throughout the follow-up, incidents included 328 single falls (9.6/100 person-years), 117 multiple falls (2.8/100 person-years), 249 minor injuries from falls (6.7/100 person-years), and 55 fractures due to falls (1.3/100 person-years). Cox proportional hazard regression models showed that participants without ARHL but with SG faced a significantly increased risk of frequent falls. Furthermore, ARHL combined with SG significantly raised the risk of both single and frequent falls, and increased the incidence of both minor and severe fall-related injuries, including fractures. In contrast, no significant association was found between ARHL alone and fall-related incidents. These findings suggest that the previously reported risk associated with hearing loss in fall incidents predominantly relates to gait impairment. The co-occurrence of ARHL and SG significantly escalates the risk of falls and related injuries, highlighting the critical need for routine gait monitoring., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Background/aim: Ferroptosis is a nonapoptotic type of cell death that is dependent on iron and involves the accumulation of reactive oxygen species. Ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) are ferroptosis regulators that inhibit ferroptosis through independent pathways. This study assessed the prognostic value of GPX4 and FSP1 expression in colorectal cancer (CRC). We also examined the effects of FSP1 and GPX4 inhibition on cell survival of CRC cells., Materials and Methods: This study included 206 surgical specimens from Stage II or III CRC patients. FSP1 and GPX4 expression was analyzed immunohistochemically, and the association of their expression levels with clinical outcome was evaluated. We also examined the effects of FSP1 and GPX4 inhibitors on the cell proliferative capacity of CRC cell lines., Results: Overall survival and recurrence-free survival were reduced in patients with high expression of FSP1 or GPX4, and those with both GPX4 and FSP1 expression showed worse prognosis. Positivity of both FSP1 and GPX4 was an independent poor prognostic factor for CRC patients. In CRC cells, the combination of GPX4 and FSP1 inhibitors led to more effective cell death than either inhibitor alone., Conclusion: High expression of both GPX4 and FSP1 is a significant poor prognostic factor for CRC. Simultaneous inhibition of GPX4 and FSP1 to induce ferroptosis may be a novel therapeutic strategy in CRC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: Some studies reported a relationship between life-space mobility (LSM) and frailty assessed by physical aspects; however, a more comprehensive discussion of frailty is underdeveloped. In addition, previous studies have focused only on older Euro-American people. Therefore, we aimed to examine LSM-frailty relationships in community-dwelling older Japanese persons using physical and comprehensive frailty indices., Design: A cross-sectional study., Setting and Participants: We used the data of 8898 older adults from a baseline survey of the Kyoto-Kameoka Study in Japan., Methods: The validated life-space assessment (LSA) was used to evaluate LSM and categorized it into quartiles. Two validated indices were used to evaluate frailty: the Kihon Checklist (KCL) and the simple Frailty Screening Index (FSI). Multivariable logistic regression was used to determine the relationships between LSM scores and frailty., Results: The mean age (SD) of the participants was 73.4 (6.3) years, and 53.3% were women. The mean LSM score of the study participants was 53.0. The prevalence of frailty by KCL and FSI was 40.7% and 16.8%, respectively. Significant differences between LSM score and frailty prevalence were observed [KCL: Q1, reference; Q2, odds ratio (OR) 0.53, 95% CI 0.45-0.62; Q3, OR 0.30, 95% CI 0.25-0.35; Q4: OR 0.22, 95% CI 0.18-0.26, P for trend <.001; FSI: Q1, reference; Q2, OR 0.57, 95% CI 0.48-0.68; Q3: OR 0.38, 95% CI 0.31-0.46; Q4: OR 0.35, 95% CI 0.28-0.42, P for trend <.001]. Similar results were observed when LSM scores were examined at 10-point intervals, with LSM and frailty exhibiting an L-shaped relationship. The LSM score dose-response curve at which the OR for frailty plateaued among older individuals was approximately 81-90 score., Conclusions and Implications: LSM score and frailty prevalence exhibited L-shaped relationships in community-dwelling older persons. This study's findings provide useful data for setting LSM targets for preventing frailty in community-dwelling older persons., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Background: HER2-low populations constitute a heterogeneous group, and the cytotoxic anticancer agent efficacy based on HER2 status remains unclear. This study evaluated the clinicopathological features and outcomes of patients with advanced breast cancer showing HER2-low expression treated with eribulin or capecitabine, two treatment options after anthracycline and taxane treatment., Methods: We retrospectively evaluated patients who were treated with eribulin or capecitabine between 2011 and 2015. HER2 status was evaluated according to the ASCO/CAP guidelines., Results: No significant difference was observed in overall survival (OS; eribulin: hazard ratio [HR], 0.66; 95% CI 0.40-1.10; capecitabine: HR, 0.76; 95% CI 0.45-1.30) or progression-free survival (PFS; eribulin: HR, 1.13; 95% CI 0.72-1.78; capecitabine: HR, 0.90; 95% CI 0.56-1.44) between patients receiving eribulin (HER2-null: 35, HER2-low: 44) and those receiving capecitabine (HER2-null: 41, HER2-low: 33). Subgroup analysis revealed no significant differences in OS between the two groups in the hormone-positive and -negative populations for eribulin and capecitabine. HER2-null and HER2-low patients showed objective response rates (ORRs) of 22.5% and 9.1% (p = 0.09) overall, and 32.0% and 10.5% (p = 0.03), respectively, in hormone-positive cases among eribulin-treated patients. No response was observed in hormone-negative patients. Capecitabine treatment in HER2-null and HER2-low patients had overall ORRs of 26.8% and 15.2% (p = 0.23), respectively, with 27.3% and 16.1% (p = 0.28) for hormone-positive cases; and 25.0% and 0% (p = 1.0), respectively, for hormone-negative cases., Conclusions: Eribulin and capecitabine sensitivity may vary based on HER2 expression in patients with HER2-low and HER2-null breast cancer. Prognosis was similar between the HER2-low and the HER2-null groups., (© 2024. The Author(s).)

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.)

Purpose: This study investigated the prognostic value of the geriatric nutritional risk index (GNRI) in patients undergoing curative gastrectomy for remnant gastric cancer (RGC)., Methods: This multicenter retrospective study included 105 patients with RGC of ≥ 65 years of age who underwent curative gastrectomy at 10 institutions in Japan between January 2000 and December 2016. Postoperative complications, overall survival (OS), and disease-specific survival (DSS) were analyzed., Results: Receiver operating curve analyses indicated that the optimal cutoff value of the GNRI for OS was 95.4. Patients were categorized into high and low GNRI groups based on the optimal GNRI cutoff value. The GNRI was significantly correlated with body mass index (p < 0.001), amount of bleeding (p = 0.021), Clavien-Dindo grade 5 postoperative complications (p = 0.040), death caused by primary disease (p = 0.010), and death caused by other diseases (p = 0.002). The OS and DSS were significantly worse in the low GNRI group. A low GNRI and T3 or deeper tumor invasion were independent prognostic factors for OS and DSS., Conclusions: The GNRI is a promising predictor of both short- and long-term outcomes in older patients with RGC., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Purpose: Multiparametric arterial spin labeling (MP-ASL) can quantify cerebral blood flow (CBF) and arterial cerebral blood volume (CBV a ). However, its accuracy is compromised owing to its intrinsically low SNR, necessitating complex and time-consuming parameter estimation. Deep neural networks (DNNs) offer a solution to these limitations. Therefore, we aimed to develop simulation-based DNNs for MP-ASL and compared the performance of a supervised DNN (DNN Sup ), physics-informed unsupervised DNN (DNN Uns ), and the conventional lookup table method (LUT) using simulation and in vivo data., Methods: MP-ASL was performed twice during resting state and once during the breath-holding task. First, the accuracy and noise immunity were evaluated in the first resting state. Second, CBF and CBV a values were statistically compared between the first resting state and the breath-holding task using the Wilcoxon signed-rank test and Cliff's delta. Finally, reproducibility of the two resting states was assessed., Results: Simulation and first resting-state analyses demonstrated that DNN Sup had higher accuracy, noise immunity, and a six-fold faster computation time than LUT. Furthermore, all methods detected task-induced CBF and CBV a elevations, with the effect size being larger with the DNN Sup (CBF, p = 0.055, Δ = 0.286; CBV a , p = 0.008, Δ = 0.964) and DNN Uns (CBF, p = 0.039, Δ = 0.286; CBV a , p = 0.008, Δ = 1.000) than that with LUT (CBF, p = 0.109, Δ = 0.214; CBV a , p = 0.008, Δ = 0.929). Moreover, all the methods exhibited comparable and satisfactory reproducibility., Conclusion: DNN Sup outperforms DNN Uns and LUT with respect to estimation performance and computation time., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Subharmonic-aided pressure estimation (SHAPE) is a technique for determining changes in ambient pressure. We aimed to analyze a novel SHAPE integrated into ultrasound diagnostic equipment to predict patients with liver cirrhosis at high risk of esophagogastric varices (EV)., Methods: This prospective study included 111 patients with liver cirrhosis diagnosed between 2020 and 2023. We obtained liver stiffness measurements (LSM) and spleen stiffness measurements (SSM) using shear wave elastography and hepatic vein-portal vein (HV-PV) gradient using the SHAPE method. The EV risk was determined either as null, low, or high by esophagoscopy and Child-Pugh stage., Results: HV-PV gradient increased concordantly with the increase in EV risk (- 7.0 dB in null-risk, - 4.4 dB in low-risk, and - 2.0 dB in high-risk) with statistically significant difference among any two groups. The most appropriate cut-off value of the HV-PV gradient was - 3.5 dB, and sensitivity, specificity, and positive and negative predictive values were 80.0%, 89.0%, 80.0%, and 88.0%, respectively. The areas under the curve values for predicting the high-risk EV were 0.920, 0.843, and 0.824 for the HV-PV gradient, LSM, and SSM, respectively., Conclusions: The novel SHAPE system demonstrated high accuracy in identifying patients with liver cirrhosis at a high risk of EV., (© 2024. The Author(s).)

Objectives　While Community gathering places known as "kayoi-no-ba" providing communal meals play a crucial role in promoting the health of older adults, the researches supporting their operations and maintenance is limited. Social marketing has been successful in implementing strategic public health programs. This study aimed to identify factors associated with declining participation in kayoi-no-ba providing communal meals using a social marketing framework based on the 4Ps marketing mix (product, promotion, place, and price).Methods　In November 2019, this cross-sectional study surveyed kayoi-no-ba providing communal meals nationwide via a mail. A total of 580 kayoi-no-ba organizers with complete data participated. Changes in the number of participants were assessed using a questionnaire in order to determine the decrease since their establishment. Survey items were organized based on the 4Ps marketing mix framework and treated as independent variables. Multivariate Poisson regression analysis was conducted with participant decrease as the dependent variable, and prevalence ratios (PR) were calculated. The opening period and the number of participants at the time of the survey were included as covariates.Results　A total of 154 kayoi-no-ba experienced the decline in participants (26.6%). Multivariate analysis revealed the following. For product variables, a high frequency of monthly events was significantly associated with a lower PR for participant decrease (0.92). Among promotion variables, kayoi-no-ba with a registration system had a significantly higher PR for participant decrease (1.49). For place variables, a higher population density in the region was significantly associated with a lower PR (0.90), whereas a higher ratio of the population aged 65 years and older was significantly associated with a higher PR (1.05). The price variables did not show a significant association with the decrease in participants.Conclusions　Except price, the other three marketing 4Ps were significantly associated with decreases in participants at kayoi-no-ba providing communal meals. Future efforts should focus on developing and evaluating kayoi-no-ba strategies to ensure sustained participant engagement and promote the health of older adults through communal meals.

Background: Steatotic liver disease, characterized by a combination of metabolic dysfunction, alcohol use, or specific etiologies, is a leading cause of chronic liver disease. However, the role of metabolic dysfunction in chronic liver disease with harmful alcohol use remains unclear. This study aimed to investigate factors associated with hepatic steatosis and fibrosis in patients with harmful alcohol use., Methods: Over a 2-year period, we registered patients with harmful alcohol use, defined by an Alcohol Use Disorders Identification Test score of 8 or higher. We retrospectively analyzed background information, blood test results, ultrasound-guided attenuation parameter (attenuation coefficient), and liver stiffness measurement. Hepatic steatosis was defined as attenuation coefficient ≥0.65 dB/cm/MHz, and fibrosis as liver stiffness measurement ≥7.5 kPa., Results: The study included 131 patients (82% men, median age 59 years). Linear regression analysis revealed significant associations with attenuation coefficient for body mass index ≥23 (0.08, p < 0.0001) and age (-0.002, p = 0.002). Liver stiffness measurement was associated with body mass index ≥23 (2.52, p = 0.001), aspartate aminotransferase (0.02, p = 0.0189), gamma-glutamyl transpeptidase (0.008, p < 0.0001), platelet count (-0.02, p = 0.001), and prothrombin international normalized ratio (26.40, p < 0.0001). Among the four groups classified by the presence or absence of steatosis and fibrosis, patients with fibrosis, but without steatosis, demonstrated the lowest liver reserve. In contrast, patients with both steatosis and fibrosis showed higher aspartate aminotransferase and gamma-glutamyl transpeptidase levels., Conclusions: Body mass index is associated with both hepatic steatosis and fibrosis in patients with harmful alcohol use., (© 2024 Japan Society of Hepatology.)

Background/objectives: Although tyrosine kinase inhibitors (TKIs) targeting EGFR-activating mutations significantly improved the outcome of EGFR-mutant NSCLC, resistance inevitably emerges. Despite the heterogeneity of these resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. While ARAF gene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics., Methods: We conducted a single-center retrospective analysis of the presence of ARAF amplification in re-biopsied samples in patients with EGFR-mutant NSCLC resistant to EGFR-TKIs. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. ARAF amplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients with ARAF amplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC)., Results: ARAF amplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib. ARAF amplification was dominantly observed in female patients with EGFR exon 19 deletion. All ARAF -amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found where ARAF amplification correlated with a histological transformation to SCLC., Conclusions: ARAF amplification was identified in 5-8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation.

Inflammation is a tightly regulated process involving immune receptor recognition, immune cell migration, inflammatory mediator secretion, and pathogen elimination, all essential for combating infection and restoring damaged tissue. However, excessive inflammatory responses drive various human diseases. The autonomic nervous system (ANS) is known to regulate inflammatory responses; however, the detailed mechanisms underlying this regulation remain incompletely understood. Herein, we aimed to study the anti-inflammatory effects and mechanism of action of the ANS in RAW264.7 cells. Quantitative PCR and immunoblotting assays were used to assess lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNFα) expression. The anti-inflammatory effects of catecholamines (adrenaline, noradrenaline, and dopamine) and acetylcholine were examined in LPS-treated cells to identify the receptors involved. Catecholamines inhibited LPS-induced TNFα expression by activating the β2 adrenergic receptor (β2-AR). β2-AR activation in turn downregulated the expression of Toll-like receptor 4 (TLR4) by stimulating protein kinase A (PKA) phosphorylation, resulting in the suppression of TNFα levels. Collectively, our findings reveal a novel mechanism underlying the inhibitory effect of catecholamines on LPS-induced inflammatory responses, whereby β2-AR activation and PKA phosphorylation downregulate TLR4 expression in macrophages. These findings could provide valuable insights for the treatment of inflammatory diseases and anti-inflammatory drug development.

The transcription factor BCL11A is a critical regulator of the switch from fetal hemoglobin (HbF: α 2 γ 2 ) to adult hemoglobin (HbA: α 2 β 2 ) during development. BCL11A binds at a cognate recognition site (TGACCA) in the γ-globin gene promoter and represses its expression. DNA-binding is mediated by a triple zinc finger domain, designated ZnF456. Here, we report comprehensive investigation of ZnF456, leveraging X-ray crystallography and NMR to determine the structures in both the presence and absence of DNA. We delve into the dynamics and mode of interaction with DNA. Moreover, we discovered that the last zinc finger of BCL11A (ZnF6) plays a different role compared to ZnF4 and 5, providing a positive entropic contribution to DNA binding and γ-globin gene repression. Comprehending the DNA binding mechanism of BCL11A opens avenues for the strategic, structure-based design of novel therapeutics targeting sickle cell disease and β-thalassemia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of interests We declare no competing interests.

Background: Immune checkpoint inhibitors (ICIs) occasionally cause immune-related adverse events (AEs), which pose challenges to the continuation of treatment. Although ICIs are widely used in patients with cancer, studies reporting immune-mediated pancreatitis remain scarce., Objectives: We performed a systematic review and meta-analysis to address current knowledge gaps and provide clinical guidance for ICI-associated pancreatitis and lipase elevation., Patients and Methods: We searched PubMed/Medline, Embase, and Web of Science for phase 3 randomized controlled trials (RCTs) evaluating ICIs. The incidence of any-grade and grade 3-5 pancreatitis/lipase elevation was calculated. Then, we performed a random-effect model meta-analysis to pool the odds ratios (ORs) of these outcomes using RCTs evaluating the addition of an ICI to systemic therapy to assess the effect of ICIs on pancreatic AEs. A systematic review of the treatment of ICI-related pancreatitis was also conducted., Results: The incidence analysis included 81 articles (79 RCTs) comprising 36,871 patients. The incidence of treatment-related pancreatitis was 0.68% (any-grade) and 0.32% (grade 3-5). Meta-analysis revealed that the addition of ICI therapy significantly increased any-grade (OR 2.12, 95% confidence interval [CI] 1.45-3.11, p < 0.001) and grade 3-5 pancreatitis (OR 1.76, 95% CI 1.01-3.08, p < 0.05) with low heterogeneity among ICI subtype subgroups (any-grade: I 2 = 0%, p = 0.99; grade 3-5: I 2 = 0%, p = 0.63). In analysis of treatment outcome among 146 patients from 53 articles, glucocorticoids were used in 80.6% (n = 108/134) and ICIs were discontinued in 76.5% (n = 101/132; permanent discontinuation: 62.5% [n = 35/56])., Conclusions: The overall rate of pancreatitis appears low, but the addition of ICI therapy significantly increased the incidence of pancreatitis. These findings provide insight into the incidence and treatment of pancreatitis associated with ICIs., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Glioblastoma (GBM) is the central nervous system tumor with the most aggressive behavior, and no definitive therapy has yet been found. The tumor microenvironment of GBM is immunosuppressive and is considered a 'cold tumor' with low lymphocytic infiltration, but is characterized by a high proportion of glioma-associated macrophages/microglia (GAMs). GAMs promote tumor growth and also affect treatment resistance in GBM. In this review, we describe the origin and classification of GAMs in humans and describe the mechanisms of their activation and the cell-cell interactions between tumor cells and GAMs. We also describe the history of GAM detection methods, especially immunohistochemistry, and discusses the merits and limitations of these techniques. In addition, we summarized chemotactic factors for GAMs and the therapies targeting these factors. Recent single-cell RNA analysis and spatial analysis add new insights to our previous knowledge of GAMs. Based on these studies, GBM therapies targeting GAMs are expected to be further developed.

Background and Objective: Durvalumab plus tremelimumab (Durva/Treme) has recently been approved as a first-line or later-line treatment for patients with unresectable hepatocellular carcinoma (u-HCC) in Japan. We assessed the real-world outcomes of Durva/Treme for u-HCC, with a focus on treatment efficacy and safety., Methods: We retrospectively evaluated 22 patients with u-HCC treated with Durva/Treme at Iwate Medical University during the period from 2023 to 2024, with a comparison of the clinical outcomes between patients who received Durva/Treme as first-line and later-line treatments. We further evaluated changes in the modified albumin-bilirubin (mALBI) grade during treatment., Results: There were 10 patients in the first-line group and 12 patients in the later-line treatment group. During the follow-up with a median duration of 7.6 months, the median progression-free survival (first-line versus later-line: 4.7 months versus 2.9 months, p = 0.85), the objective response rate (0.0% versus 16.7%, p = 0.48), the disease control rate (60.0% versus 58.4%, p = 1.00), and the incidence of any adverse event (50.0% versus 75.0%, p = 0.38) were not statistically different between the two groups. The changes in the mALBI scores were not statistically significant (p = 0.75)., Conclusions: Durva/Treme may be effective and safe for patients with u-HCC, even in patients who receive Durva/Treme as a later-line treatment., (© 2024. The Author(s).)

Neoadjuvant immune checkpoint blockade (ICB) combined with chemotherapy has improved survival outcomes in locally-advanced non-small cell lung cancer (NSCLC). However, its impact on surgery has not been fully elucidated. We performed a systematic review and meta-analysis to compare surgical outcomes between neoadjuvant chemoimmunotherapy and chemotherapy alone in resectable NSCLC. PubMed and Embase were searched to select randomized controlled trials (RCTs) evaluating neoadjuvant ICB therapy for resectable NSCLC. The risk difference (RD) and odds ratio (OR) of outcomes such as surgical and R0 resection rates, overall complication rates, treatment-related adverse events (TRAEs), and AEs leading to cancellation of surgery were pooled using the random-effect model meta-analysis. We also evaluated the correlations between overall survival (OS) and surgical and safety outcomes. Eight RCTs with 3,387 patients were analyzed. Neoadjuvant chemoimmunotherapy was associated with improved surgical resection (RD 4.52 %, 95 % confidence interval [CI] 0.95 %-8.09 %, p = 0.01) and R0 resection (RD 4.04 %, 95 % CI 1.69 %-6.40 %, p = 0.0008) without increasing overall complications (RD -0.13 %, 95 % CI -5.14 %-4.88 %, p = 0.96), but an increase in surgery cancellation due to AEs (RD 1.15 %, 95 % CI 0.25 %- 2.05 %; p = 0.01) and grade 3-4 TRAEs (RD 3.42 %, 95 % CI 0.33 %-6.52 %, p = 0.03). OS did not show a direct significant correlation with surgical outcomes or TRAEs. Neoadjuvant chemoimmunotherapy improves resection rates but increases high-grade TRAEs and AEs leading to surgery cancellation. Nevertheless, incorporating ICB into neoadjuvant approach appears reasonable by improving surgical outcomes, potentially leading to improved survival in patients with locally-advanced NSCLC., Competing Interests: Declaration of Competing Interest None of the authors have a conflict of interest to report for the submitted work. Dr. Nagasaka reports honoraria from AstraZeneca, BMS, Daiichi Sankyo, Novartis, Lilly, Pfizer, EMD Serono, Regeneron, Genentech, Mirati, Takeda, Janssen, and Blueprint Medicine; consulting fees from Caris Life Sciences; travel support from AnHeart Therapeutics., (Copyright © 2024 Elsevier Ltd. All rights reserved.)