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Background: Sarcopenia is a substantial therapeutic target, yet the validity of risk stratification values per the latest Asian Working Group for Sarcopenia in 2019 (AWGS 2019) remains unconfirmed in patients with heart failure. We hypothesized that using the 6-minute walk test (6MWT) to assess physical performance improves risk stratification., Methods: The study included 832 hospitalized patients with heart failure who could walk at discharge. Sarcopenia was diagnosed using both the original AWGS 2019 criteria (AWGS 2019 model) and an alternative method, in which physical performance components were replaced with the 6MWT (modified model). An <300 m 6MWT indicated low physical performance in the modified model. The primary outcome was 2-year mortality., Results: Sarcopenia and severe sarcopenia were identified in 45 and 150 patients with the AWGS 2019 model and in 75 and 108 patients with the modified model, respectively. Over the 2-year follow-up period, 145 (17.4%) deaths occurred. Adjusted Cox proportional hazard analysis showed both sarcopenia and severe sarcopenia were significantly associated with 2-year mortality in the modified model. In the AWGS 2019 model, only severe sarcopenia was significantly related to 2-year mortality. The modified model demonstrated significant net reclassification improvement (NRI) over the AWGS 2019 model (NRI, 0.396; 95% CI, 0.214-0.578; P < 0.001)., Conclusions: In patients with heart failure who were ambulatory at discharge, sarcopenia assessment with the modified AWGS 2019 model using the 6MWT as a physical performance component improved risk stratification compared with the original AWGS 2019 model. Reconsidering the current criteria to improve risk stratification is necessary to ensure timely, appropriate treatment., (Copyright © 2024. Published by Elsevier Inc.)

Human T follicular helper (Tfh) cells play a crucial role in orchestrating B cell differentiation, maturation, and immunoglobulin class switching. Recent studies have underscored the presence of Bcl-6 + Tfh cells not only in secondary lymphoid organs but also within tertiary lymphoid structures at inflammatory sites, emphasizing their pivotal role in disease pathogenesis. Furthermore, Tfh cells have been found to transit between lesion sites, lymph nodes, and peripheral blood, as revealed by T cell receptor repertoire analysis. Among Tfh subsets, Tfh2 cells have emerged as central orchestrators in driving the production of IgE and IgG4 from B cells. Their critical role in diseases such as allergy, malignancy, and IgG4-related disease highlights their profound impact on balancing inflammation and immune tolerance. Our current review provides the molecular characteristics of human Tfh cells, the differentiation pathways of Tfh subsets, mechanisms by which Tfh subsets induce IgE and IgG4 production, and their clinical implications in allergy, malignancy, and IgG4-related disease., Competing Interests: Conflict of interest MA has received speaking fees from AbbVie, Asahi-Kasei, Astellas, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Janssen, Novartis, Pfizer, Taisho, UCB, Gilead Sciences. YK has received research grants from AbbVie, Eisai, Sanofi, Chugai, Mitsubishi-Tanabe, Taisho, and has received scholarship grant from Asahi-Kasei, Eisai, Boehringer Ingelheim, Taisho, and has received speaking fees from AbbVie, Asahi-Kasei, Astellas, Ayumi Pharmaceutical, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Glaxo Smith Kline, Janssen, Novartis, Pfizer, UCB, Gilead Sciences. The rest of the authors have no conflict of interest., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: It is unclear whether inactivated influenza vaccination (IIV) or pneumococcal vaccination are associated with the risk of dementia; however, both types of vaccination are recommended for older adults. Studies have shown that the IIV is negatively associated with incident dementia; however, the uptake of pneumococcal vaccinations has not been considered. We investigated the independent associations of IIV and 23-valent pneumococcal polysaccharide vaccine (PPSV23) with incident dementia in older adults., Methods: Health-related information on older Japanese adults was obtained through a baseline survey conducted in 2013 (baseline survey). The uptake of IIV and PPSV23 was determined in a second survey conducted in 2016 (second wave). Both surveys were conducted among independent Japanese older adults aged ≥ 65 years at the two surveys and who had not been certified as needing long-term care (LTC). In the second wave, 9,865 participants were followed up for 3.5 years (short-term follow-up), and 6,995 participants were followed up for six years and five months (long-term follow-up) until they required LTC due to dementia onset (incident dementia). A competing risk model with stabilized inverse probability weighting (SIPW) was constructed to calculate the hazard ratios (HRs) and 95 % confidence intervals (CIs) of incident dementia., Results: PPSV23 uptake was negatively associated with incident dementia among participants in both the short- and long-term follow-up periods after SIPW (short-term follow-up: HR: 0.77, 95 % CI: 0.63 - 0.95; long-term follow-up: HR: 0.83, 95 % CI: 0.70 - 0.97). Conversely, IIV uptake was not associated with incident dementia among participants in either follow-up group (short-term follow-up: HR: 0.86, 95 % CI: 0.63-1.16; long-term follow-up: HR: 0.99, 95 % CI: 0.76-1.29). The PPSV23 uptake was negatively associated with incident dementia in participants without the IIV uptake (short-term follow-up: HR: 0.44, 95 % CI: 0.24 - 0.81; long-term follow-up: HR: 0.47, 95 % CI: 0.29 - 0.76). Conversely, the IIV uptake was not associated with incident dementia regardless of the PPSV23 status (short-term follow-up: HR: 0.87, 95 % CI: 0.62 - 1.23; long-term follow-up: HR: 1.00, 95 % CI: 0.74 - 1.35)., Conclusion: Our results suggest that the PPSV23 uptake was independently associated with the incidence of dementia. However, the IIV uptake was not associated with the incidence of dementia., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Interstitial lung diseases (ILDs) are a heterogeneous group of disorders, a subset of which develop progressive pulmonary fibrosis (PPF). There is little information on the epidemiology and treatment of PPFs in Japan. This retrospective cohort study estimated the incidence probability of progression to PPFs in patients with fibrosing ILDs other than idiopathic pulmonary fibrosis in a real-world Japanese setting. Management procedures and treatment patterns were also quantified., Methods: Data were extracted from the Medical Data Vision database from 01-Jan-2012 to 28-May-2020, comprising a 6.91-year patient identification period, 1-year pre-index period, and post-index period. The primary outcome was the cumulative incidence probability of progression to PPF up to 24 months. Subgroup analyses were performed by the presence/absence of connective tissue disease-ILD and by pre-specified ILD clinical diagnosis., Results: Of the 34,960 eligible patients (mean age: 71.1 years, males: 52.5%), 14,580 (41.7%) progressed to PPF. The 24-month incidence probability of progression to PPF was 39.5%. A relatively comparable percentage of patients progressed across all ILD subtypes. Oral corticosteroids and tacrolimus were the most common therapies during the pre- and post-index periods. Treatment rates were very low in the post-index period., Conclusions: This is the first claims database study to estimate the incidence probability of progression to PPF in Japan. Progression appeared common in patients with chronic fibrosing ILDs, with comparable percentages of patients across all subtypes developing PPF at 2 years. Future studies should assess the impact of regular monitoring and early intervention on treating fibrotic ILDs and preventing progression., Competing Interests: Declaration of competing interest Yasuhiro Kondoh reports consulting fees from Boehringer Ingelheim, Chugai Pharmaceutical Co., Ltd., Healios K.K., Janssen Pharmaceutical K.K., Shionogi and Co., Ltd., and Taiho Pharmaceutical Co.; payments or honoraria from Boehringer Ingelheim, Bristol-Myers Squibb, Eisai Inc., Janssen Pharmaceutical K.K., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, Novartis Pharma K.K., Shionogi and Co., Ltd., and Teijin Pharma. Tomohiro Ito, Kumiko Saito, Haikun Bao, and Wataru Sakamoto are employees of Boehringer Ingelheim., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of Competing Interest Yousuke Nakai has received research grants by Taiho Pharmaceutical. No funding agency had input into the design and conduct of this study.

Background: It is unknown how accurately the current Japanese classification system for neurodevelopmental delay based on the assessment with the Kyoto Scale of Psychological Development (KSPD) at toddlerhood and pre-school periods predicts cognitive impairment at school age., Methods: This single-center retrospective cohort study enrolled infants born at 22-29 weeks of gestational age. At 18-24 months of corrected age and 3 years of age, the patients were categorized according to the current Japanese criteria for neurodevelopmental delay based on their overall developmental quotient calculated using the KSPD-2001. Cognitive impairment at 6 years of age was classified according to the calculated or estimated full-scale intelligence quotient. The predictability of the current Japanese classification of neurodevelopmental delay for cognitive impairment at 6 years of age was investigated., Results: Of 566 eligible patients, 364 (64 %) completed the protocol. The current classification for the neurodevelopmental delay showed significant agreement with the severity of cognitive impairment at 6 years of age. The sensitivity and specificity of the KSPD-2001-based assessment for any cognitive impairment at 6 years of age were 0.64 and 0.74 at 18-24 months of corrected age and 0.83 and 0.70 at 3 years of age. The corresponding sensitivity and specificity for moderate/severe cognitive impairment were 0.51 and 0.96 at 18-24 months of corrected age and 0.68 and 0.95 at 3 years of age., Conclusion: The KSPD-2001 is a useful tool to predict the severity of cognitive impairment at school age., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Study Aims: The infliximab biosimilar CT-P13 was the first biosimilar drug targeting tumor necrosis factor-α. However, its efficacy and safety in real-world clinical situations have remained insufficient. Therefore, we aimed to verify the efficacy and safety of CT-P13 in bio-naïve patients with Crohn's disease., Patients and Methods: This retrospective multicenter study compared the remission rate at week 54 between patients with Crohn's disease who were treated with originator infliximab or CT-P13. Endoscopic and laboratory findings were assessed in both groups. A total of 184 (156 originator and 28 CT-P13) patients were analyzed. Of these, 138 originator users and 19 biosimilar users completed 54-week administration., Results: The clinical remission rates in patients taking originator infliximab of CT-P13 at week 54 were 92.5 % and 100 %, respectively. The endoscopic scores of each group significantly decreased from baseline at week 54 in both groups, and the mucosal healing rate at week 54 was 53 % and 64 %, respectively. Laboratory data including C-reactive protein, serum albumin, and hemoglobin significantly improved from baseline to week 14 and 54 in both groups. Adverse events were observed more frequently in the CT-P13 group (25 % vs. 4.5 %, p = 0.0015), but severe adverse events were rare in both groups., Conclusion: The efficacy and safety of CT-P13 were comparable with those of originator infliximab in bio-naïve patients with Crohn's disease evaluated by clinical, endoscopic, and laboratory findings. This study establishes the needed groundwork for the development of a strategy for treatment with biologics in patients with Crohn's disease., Competing Interests: Declaration of competing interests 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 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Background: Frailty is associated with a poor prognosis in older patients with heart failure (HF). However, multidomain frailty assessment tools have not been established in patients with HF, and the association between the frailty phenotype and the deficit-accumulation frailty index in these patients is unclear. We aimed to understand this relationship and evaluate the prognostic value of the deficit-accumulation frailty index in older patients with HF., Methods: We retrospectively analyzed FRAGILE-HF cohort, which consisted of prospectively registered hospitalized patients with HF aged ≥ 65 years. The frailty index was calculated using 34 health-related items. The physical, social, and cognitive domains of frailty were evaluated using a phenotypic approach. The primary endpoint was all-cause mortality., Results: Among 1027 patients with HF (median age, 81 years; male, 58.1%; median frailty index, 0.44), a higher frailty index was associated with a higher prevalence in all domains of cognitive, physical, and social frailty defined by the phenotype model. During the 2-year follow-up period, a higher frailty index was independently associated with all-cause death even after adjustment for Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score plus log B-type natriuretic peptide (per 0.1 increase: hazard ratio, 1.21; 95% confidence interval, 1.07-1.37; P = 0.002). The addition of the frailty index to the baseline model yielded statistically significant incremental prognostic value (net reclassification improvement, 0.165; 95% confidence interval, 0.012-0.318; P = 0.034)., Conclusions: A higher frailty index was associated with a higher prevalence of all domains of frailty defined by the phenotype model and provided incremental prognostic information with pre-existing risk factors in older patients with HF., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Hypotaurine, a precursor to taurine, is known for its antioxidant properties and is prominently present in fetal plasma and the placenta. Our previous research revealed that ezrin-knockout mice experience fetal growth retardation, coinciding with reduced hypotaurine levels in fetal plasma. This study aims to elucidate the expression and role of hypotaurine transporters within the placenta., Methods: We employed quantitative RT-PCR to measure mRNA expression of GAT transporter family members in the placenta during mid-to-late gestation. LC/MS/MS was used to analyze the distribution of hypotaurine in different placental subregions. Immunohistochemistry was utilized to examine the localization of GAT2 in mice. Placental hypotaurine uptake from fetal circulation was studied via umbilical perfusion in rats., Results: Among hypotaurine transporters, GAT2 exhibited increased mRNA and protein expression in murine placenta during mid-to-late gestation. Notably, GAT2/Slc6a13 mRNA and hypotaurine were most concentrated in the labyrinth of murine placenta. In contrast, enzymes responsible for hypotaurine synthesis, such as cysteine dioxygenase, cysteine sulfinic acid decarboxylase, and 2-aminoethanethiol dioxygenase, showed minimal expression in the labyrinth. These findings suggest that GAT2 is a key determinant of hypotaurine levels in the placental labyrinth. Immunohistochemical examination unveiled that GAT2 was predominantly localized on the fetal-facing plasma membrane within syncytiotrophoblasts, which co-localized with ezrin. In rat umbilical perfusion experiments, the GAT2/3 and TauT inhibitor, SNAP-5114, significantly reduced hypotaurine extraction from fetal circulation to the placenta., Discussion: The results suggest that GAT2 plays a pivotal role in the concentrative uptake of hypotaurine from fetal plasma within syncytiotrophoblasts of the placenta., 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. 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. Published by Elsevier Ltd.)

The human cerebrum contains a large amount of cortico-cortical association fibers. Among them, U-fibers are short-range association fibers located in white matter immediately deep to gray matter. Although U-fibers are thought to be crucial for higher cognitive functions, the organization within U-fiber regions are still unclear. Here we investigated the properties of U-fiber regions in the ferret cerebrum using neurochemical, neuronal tracing, immunohistochemical and electron microscopic techniques. We found that U-fiber regions can be subdivided into two regions, which we named outer and inner U-fiber regions. We further uncovered that outer U-fiber regions have smaller-diameter axons with thinner myelin compared with inner U-fiber regions. These findings may indicate functional complexity within U-fiber regions in the cerebrum., Competing Interests: Competing interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd and Japan Neuroscience Society. All rights reserved.)

Cervical cancer and its precursor lesion, cervical intraepithelial neoplasia (CIN), are caused by high-risk human papillomavirus (HPV) viral infection and are highly susceptible to host immunity targeting of HPV viral proteins, which include both foreign antigens and cancer antigens expressed by tumors. Immunotherapy that induces Th1 immunoreactivity against viral proteins is expected to take advantage of this immunological regression mechanism. However, although cancer immunotherapies for cervical cancer and CIN have been developed over the past several decades, none have been commercialized. Most of these immunotherapies target the viral cancer proteins E6 and E7, which are generally the same. The reasons for the underdevelopment of HPV-targeted immunotherapy differ depending on whether the target is invasive cancer or CIN. We here summarize the developmental history of cancer immunotherapy for CIN and discuss strategies for solving the problems that led to this underdevelopment. We note that CIN is a mucosal lesion and propose that inducing mucosal immunity may be the key., Competing Interests: Declaration of competing interest GLOVACC Inc. gifted GLBL101c, IGMKK16E7, and placebo, and partially supported this clinical trial., (Copyright © 2023. Published by Elsevier B.V.)

The stochastic behavior of the stutter ratio (SR) in capillary electrophoresis-based DNA typing is currently described and predicted using statistical models in forensic genetics. Clarifying this behavior can help obtain more objective and robust evidence to the court in terms of mixture interpretation. This study aimed to investigate the effect existence of aging on SR via a Bayesian framework. Nail scrapings and clippings were collected from 68 healthy individuals with informed consent. Samples were classified by age-class: young group (0-16 years; n = 36) and older-adult group (>61 years; n = 32). Then, they were compared in terms of their SRs for each simple repeat locus included in GlobalFiler Kit. Bayesian modeling was performed with lognormal distribution model, which implemented multiple linear regression, allele and age-class as explanatory variables. For all simple repeat loci, the median of the posterior distribution of the age-class parameter was a positive value. For CSF1PO and D7S820, the 95% credible interval of the posterior distribution did not include 0. Our data suggested that aging slightly increases the SR. These findings might help elucidate the stochastic behavior of SR., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Where and which countries should receive higher priority for improving inorganic fertilizer use in rice fields in sub-Saharan Africa (SSA)? This study addressed this question by assessing the spatial variation in fertilizer use and its association with rice yield and yield gap in 24 SSA countries through a systematic literature review of peer-reviewed papers, theses, and grey literature published between 1995 and 2021. The results showed a large variation in N, P, and K fertilizer application rates and rice yield and an opportunity for narrowing the yield gap by increasing N and P rates, especially in irrigated rice systems. We identified clusters of sites/countries based on nutrient input and yield and suggested research and development strategies for improving yields and optimizing nutrient use efficiencies. Further research is essential to identify the factors causing low fertilizer use and the poor association between its use and yield in rainfed systems., Competing Interests: 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., (© 2023 The Authors.)

Introduction: We sought to determine whether loss of renal function increases risk of recurrence and metastases in renal cell carcinoma (RCC), and whether this impact was age-related., Materials and Methods: We performed a retrospective analysis of the International Marker Consortium for Renal Cancer (INMARC) registry. Patients were separated into younger (<65 years old) and elder (≥65 years old) age groups, and rates of de novo estimated glomerular filtration rate (eGFR<45 mL/min/1.73m2 [eGFR<45]) were calculated. Multivariable analysis (MVA) was conducted for predictors of progression-free survival (PFS) and all-cause mortality (ACM). Kaplan-Meier Analysis (KMA) was conducted for PFS and overall survival (OS) in younger and elder age groups stratified by functional status., Results: We analyzed 1805 patients (1113 age<65, 692 age≥65). On MVA in patients <65, de novo eGFR<45 was independently associated with greater risk for worsened progression (HR=1.61, P=.038) and ACM (HR=1.82, P=.018). For patients ≥65, de novo eGFR<45 was not independently associated with progression (P=.736), or ACM (P=.286). Comparing patients with de novo eGFR<45 vs. eGFR ≥45, KMA demonstrated worsened 5-year PFS and OS in patients <65 (PFS: 68% vs. 86%, P<.001; OS: 73% vs. 90%, P<.001), while in patients ≥65, only 5-year OS was worsened (77% vs. 81%, P<.021)., Conclusion: Development of de novo eGFR<45 was associated with more profound impact on patients <65 compared to patients ≥65, being an independent risk factor for PFS and ACM. The mechanisms of this phenomenon are unclear but underscore desirability for nephron preservation when safe and feasible in younger patients., (Copyright © 2022. Published by Elsevier Inc.)

Background: No study with an adequate patients' number has examined the relationship/overlap between sarcopenia and cachexia. We examined the prevalence of the overlap and prognostic implications of sarcopenia and cachexia in older patients with heart failure using well-accepted definitions., Methods: This was a post-hoc sub-analysis of the FRAGILE-HF study, a prospective, multicenter, observational study conducted at 15 hospitals in Japan. In total, 905 hospitalized older patients were classified into four groups based on the presence or absence of cachexia and/or sarcopenia, which were defined according to the Evans and Asian Working Group for Sarcopenia criteria revised in 2019, respectively. The primary endpoint was 2-year all-cause mortality., Results: Cachexia and sarcopenia prevalence rates were 32.7% and 22.7%, respectively. Patients were classified into the non-cachexia/non-sarcopenia (55.7%), cachexia/non-sarcopenia (21.7%), non-cachexia/sarcopenia (11.6%), and cachexia/sarcopenia (11.0%) groups. During the 2-year follow-up period after discharge, 158 (17.5%) all-cause deaths (124 cardiovascular deaths [CVD] and 34 non-CVD) were observed. The cachexia/sarcopenia group had the lowest body fat mass and exhibited significantly higher mortality rates (log-rank P < 0.001). Cox proportional hazard analysis revealed that cachexia/sarcopenia was an independent prognostic factor after adjusting for known prognostic factors (versus non-cachexia/non-sarcopenia: hazard ratio, 2.78; 95% confidence interval, 1.80-4.29; P < 0.001). Neither cachexia/non-sarcopenia nor non-cachexia/sarcopenia were significantly associated with all-cause mortality compared with non-cachexia/non-sarcopenia., Conclusions: Cachexia and sarcopenia are prevalent among older hospitalized patients with heart failure; nonetheless, the overlap is not as prominent as previously expected. The presence of cachexia and sarcopenia is a risk factor for all-cause mortality., Competing Interests: Declaration of Competing Interest Yuya Matsue and Takatoshi Kasai are affiliated with a department-sponsored by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi. Yuya Matsue received an honorarium from Otsuka Pharmaceutical Co. and Novartis Japan. Nobuyuki Kagiyama received grants from Philips, Asahi KASEI Corporation, Toho Holdings Co. Ltd., Inter Reha Co. Ltd., and EchoNous. Inc., as well as research grants from AMI Inc. outside of the submitted work. Kentaro Kamiya received research funding from Eiken Chemical Co. Ltd. The other authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The incremental prognostic value of the six-minute walking test over conventional risk factors has not been evaluated in an adequate number of patients with heart failure with preserved ejection fraction (HFpEF). Therefore, we aimed to examine its prognostic significance using data from the FRAGILE-HF study., Methods and Results: A total of 513 older patients who were hospitalized for worsening heart failure were examined. Patients were classified according to the tertiles of six-minute walking distance (6MWD): T1 (<166 m), T2 (166-285 m), and T3 (≥285 m). During the 2-year follow-up period after discharge, 90 all-cause deaths occurred. Kaplan-Meier curves showed that the T1 group had significantly higher event rates than the other groups (log-rank p = 0.007). Cox proportional hazard analysis revealed that the T1 group was independently associated with lower survival, even after adjusting for conventional risk factors (T3: hazard ratio 1.79, 95% confidence interval 1.02-3.14, p = 0.042). The addition of the 6MWD to the conventional prognostic model showed a statistically significant incremental prognostic value (net reclassification improvement 0.27, 95% confidence interval 0.04-0.49; p = 0.019)., Conclusions: The 6MWD is associated with survival in patients with HFpEF and has an incremental prognostic value over conventional well-validated risk factors., Competing Interests: Declaration of Competing Interest Y. M. and T. K. are affiliated with a department sponsored by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi. Y. M. received an honorarium from Otsuka Pharmaceutical Co. and Novartis Japan. N. K. was affiliated with a department endowed by grants from Philips, Asahi KASEI Corporation, Toho Holdings Co., Ltd., and Inter Reha Co., Ltd., received research grants from EchoNous. Inc. and AMI Inc., and received an honorarium from Novartis Japan outside the submitted work. K. K. received funding outside the submitted work from Eiken Chemical Co., Ltd. and SoftBank Cor. Ltd. The other authors have no conflicts of interest to declare. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The skin is a protective interface between the internal organs and environment and functions not only as a physical barrier but also as an immune organ. However, the immune system in the skin is not fully understood. A member of the thermo-sensitive transient receptor potential (TRP) channel family, TRPM4, which acts as a regulatory receptor in immune cells, was recently reported to be expressed in human skin and keratinocytes. However, the function of TRPM4 in immune responses in keratinocytes has not been investigated. In this study, we found that treatment with BTP2, a known TRPM4 agonist, reduced cytokine production induced by tumor necrosis factor (TNF) α in normal human epidermal keratinocytes and in immortalized human epidermal keratinocytes (HaCaT cells). This cytokine-reducing effect was not observed in TRPM4-deficient HaCaT cells, indicating that TRPM4 contributed to the control of cytokine production in keratinocytes. Furthermore, we identified aluminum potassium sulfate, as a new TRPM4 activating agent. Aluminum potassium sulfate reduced Ca 2+ influx by store-operated Ca 2+ entry in human TRPM4-expressing HEK293T cells. We further confirmed that aluminum potassium sulfate evoked TRPM4-mediated currents, showing direct evidence for TRPM4 activation. Moreover, treatment with aluminum potassium sulfate reduced cytokine expression induced by TNFα in HaCaT cells. Taken together, our data suggested that TRPM4 may serve as a new target for the treatment of skin inflammatory reactions by suppressing the cytokine production in keratinocytes, and aluminum potassium sulfate is a useful ingredient to prevent undesirable skin inflammation through TRPM4 activation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background & Aims: Validated surrogate endpoints for overall survival (OS) are important for expediting the clinical study and drug-development processes. Herein, we aimed to validate objective response as an independent predictor of OS in individuals with unresectable hepatocellular carcinoma (HCC) receiving systemic anti-angiogenic therapy., Methods: We investigated the association between objective response (investigator-assessed mRECIST, independent radiologic review [IRR] mRECIST and RECIST v1.1) and OS in REFLECT, a phase III study of lenvatinib vs. sorafenib. We conducted landmark analyses (Simon-Makuch) of OS by objective response at 2, 4, and 6 months after randomization., Results: Median OS was 21.6 months (95% CI 18.6-24.5) for responders (investigator-assessed mRECIST) vs. 11.9 months (95% CI 10.7-12.8) for non-responders (hazard ratio [HR] 0.61; 95% CI 0.49-0.76; p <0.001). Objective response by IRR per mRECIST and RECIST v1.1 supported the association with OS (HR 0.61; 95% CI 0.51-0.72; p <0.001 and HR 0.50; 95% CI 0.39-0.65; p <0.001, respectively). OS was significantly prolonged for responders vs. non-responders (investigator-assessed mRECIST) at the 2-month (HR 0.61; 95% CI 0.49-0.76; p <0.001), 4-month (HR 0.63; 95% CI 0.51-0.80; p <0.001), and 6-month (HR 0.68; 95% CI 0.54-0.86; p <0.001) landmarks. Results were similar when assessed by IRR, with both mRECIST and RECIST v1.1. An exploratory multivariate Cox regression analysis identified objective response by investigator-assessed mRECIST (HR 0.55; 95% CI 0.44-0.68; p <0.0001) and IRR-assessed RECIST v1.1 (HR 0.49; 95% CI, 0.38-0.64; p <0.0001) as independent predictors of OS in individuals with unresectable HCC., Conclusions: Objective response was an independent predictor of OS in individuals with unresectable HCC in REFLECT; additional studies are needed to confirm surrogacy. Participants achieving a complete or partial response by mRECIST or RECIST v1.1 had significantly longer survival vs. those with stable/progressive/non-evaluable disease., Gov Number: NCT01761266., Impact and Implications: This analysis of data taken from a completed clinical trial (REFLECT) looked for any link between objective response and overall survival time in individuals with unresectable HCC receiving anti-angiogenic treatments. Significantly longer median overall survival was found for responders (21.6 months) vs. non-responders (11.9 months). Overall survival was also significantly longer for responders vs. non-responders (based on objective response status at 2, 4, and 6 months) in the landmark analysis. Our results indicate that objective response is an independent predictor of overall survival in this setting, confirming its validity as a rapid marker of efficacy that can be applied in phase II trials; however, further validation is required to determine is validity for other systemic treatments (e.g. immunotherapies), or as a surrogate of overall survival., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Neuropathic pain (NeP) is pain provoked by damage or disease in the nervous system and about one in three Japanese patients with spinal disorders are highly likely to have NeP. The humanistic and economic burden of illness (BOI) of spine-related NeP represents unmet medical needs that should be addressed. The purpose of this targeted literature review was to synthesize the available evidence on the BOI of spine-related NeP in Japanese patients., Methods: PubMed and ICHUSHI were searched for relevant studies published between January 2010 and December 2020, in English or Japanese. The population included patients with one or more of prespecified spinal disorders and NeP, and outcomes of interest were data related to humanistic or economic burden., Results: Out of 32 studies that assessed the BOI of spine-related disorders in Japan, only six specifically assessed spine-related NeP. Among these studies, five different validated questionnaires were used to measure humanistic burden. Spine-related NeP was consistently shown to be related with a poorer health-related quality of life and higher levels of anxiety and depression compared to the general population as well as patients with nociceptive pain. No articles directly evaluating economic burden were identified in this search, so an exploratory analysis was conducted. Reduction in work productivity by people experiencing spine-related NeP in the whole of Japan were estimated to total JPY 172,266,780,480 per year., Conclusions: The humanistic burden of spine-related NeP on Japanese patients is considerable, not only physically but also mentally. Exploratory analysis of the economic burden illustrates the possibility of substantial societal costs associated with NeP. In order to better understand the depth of BOI and the unmet medical need caused by spine-related NeP, further studies on real-world outcomes are recommended., Competing Interests: Declaration of competing interest T Kaito has received consulting fees from Daiichi Sankyo Co., Ltd. K Okuizumi, S Takada, M Yokoyama and K Saito are full-time employees of Daiichi Sankyo Co., Ltd. B Crawford and K Usuba are full-time employees of Syneos Health. Syneos Health received funding from Daiichi Sankyo Co., Ltd. to conduct the data collection, data analysis and manuscript development., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Ribosome biogenesis proceeds with the successive cleavage and trimming of the large 47S rRNA precursor, where the RNA exosome plays major roles in concert with the Ski2-like RNA helicase, MTR4. The recent finding of a consensus amino acid sequence, the arch-interacting motif (AIM), for binding to the arch domain in MTR4 suggests that recruitment of the RNA processing machinery to the maturing pre-rRNA at appropriate places and timings is mediated by several adaptor proteins possessing the AIM sequence. In yeast Saccharomyces cerevisiae, Nop53 plays such a role in the maturation of the 3'-end of 5.8S rRNA. Here, we investigated the functions of PICT1 (also known as GLTSCR2 or NOP53), a mammalian ortholog of Nop53, during ribosome biogenesis in human cells. PICT1 interacted with MTR4 and exosome in an AIM-dependent manner. Overexpression of PICT1 mutants defecting AIM sequence and siRNA-mediated depletion of PICT1 showed that PICT1 is involved in two distinct pre-rRNA processing steps during the generation of 60S ribosomes; first step is the early cleavage of 32S intermediate RNA, while the second step is the late maturation of 12S precursor into 5.8S rRNA. The recruitment of MTR4 and RNA exosome via the AIM sequence was required only during the late processing step. Although, the depletion of MTR4 and PICT1 induced stabilization of the tumor suppressor p53 protein in cancer cell lines, the depletion of the exosome catalytic subunits, RRP6 and DIS3, did not exert such an effect. These results suggest that recruitment of the RNA processing machinery to the 3'-end of pre-5.8S rRNA may be involved in the induction of the nucleolar stress response, but the pre-rRNA processing capabilities themselves were not involved in this process., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masami Nagahama reports financial support was provided by Japan Society for the Promotion of Science., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: We aimed to examine the relationship between D'Amico intermediate-risk and pathological grade group 1 (pGG1) after robot-assisted radical prostatectomy (RARP)., Patients and Methods: In this retrospective multicenter cohort study, D'Amico intermediate-risk prostate cancer patients who did not receive neoadjuvant therapy, and underwent RARP at 10 institutions in Japan were examined for preoperative factors associated with pGG1., Results: In total, we enrolled 1161 D'Amico intermediate-risk prostate cancer patients. The pGG1 and pGG ≥2 groups comprised 73 (6.3%), and 1088 (93.7%) cases, respectively. Biochemical recurrence-free survival (BCRFS) of the pGG1 group was equivalent to that of the D'Amico low-risk patients. Among the 3 D'Amico intermediate-risk factors (IRF), the pGG1-rate was 24% with prostate-specific antigen (PSA) of 10 to 20 ng/mL alone, and 30% with cT2b alone. Both groups had significantly higher pGG1-rates than other groups. Down-grading from biopsy GG ≥2 to pGG1 was relatively rare (3.9%). Patients with pGG1 were further stratified by prostate volume (PV) (cutoff, 40 cc) among patients with one IRF and PSA of 10 to 20 ng/mL. Patients with one IRF, PSA of 10 to 20 ng/mL, and PV >40 cc had a relatively good BCRFS similar to that of the D'Amico low-risk group., Conclusion: Among intermediate-risk prostate cancer patients, those with pGG1 have a good prognosis. Downgrading from biopsy GG ≥2 is rare, and definitive treatment may be recommended for patients with biopsy GG ≥2. Patients with one IRF, PSA of 10 to 20 ng/mL, and PV >40 cc who are eligible for RARP may be candidates for active surveillance., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Growing evidence suggests a broad relationship between individual differences in auditory processing ability and the rate and ultimate attainment of language acquisition throughout the lifespan, including post-pubertal second language (L2) speech learning. However, little is known about how the precision of processing of specific auditory dimensions relates to the acquisition of specific L2 segmental contrasts. In the context of 100 late Japanese-English bilinguals with diverse profiles of classroom and immersion experience, the current study set out to investigate the link between the perception of several auditory dimensions (F3 frequency, F2 frequency, and duration) in non-verbal sounds and English [r]-[l] perception and production proficiency. Whereas participants' biographical factors (the presence/absence of immersion) accounted for a large amount of variance in the success of learning this contrast, the outcomes were also tied to their acuity to the most reliable, new auditory cues (F3 variation) and the less reliable but already-familiar cues (F2 variation). This finding suggests that individuals can vary in terms of how they perceive, utilize, and make the most of information conveyed by specific acoustic dimensions. When perceiving more naturalistic spoken input, where speech contrasts can be distinguished via a combination of numerous cues, some can attain a high-level of L2 speech proficiency by using nativelike and/or non-nativelike strategies in a complementary fashion., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Phencyclidine (PCP) causes mental symptoms that closely resemble schizophrenia through the inhibition of the glutamatergic system. The kynurenine (KYN) pathway (KP) generates metabolites that modulate glutamatergic systems such as kynurenic acid (KA), quinolinic acid (QA), and xanthurenic acid (XA). Kynurenine 3-monooxygenase (KMO) metabolizes KYN to 3-hydroxykynurenine (3-HK), an upstream metabolite of QA and XA. Clinical studies have reported lower KMO mRNA and higher KA levels in the postmortem brains of patients with schizophrenia and exacerbation of symptoms in schizophrenia by PCP. However, the association between KMO deficiency and PCP remains elusive. Here, we demonstrated that a non-effective dose of PCP induced impairment of prepulse inhibition (PPI) in KMO KO mice. KA levels were increased in the prefrontal cortex (PFC) and hippocampus (HIP) of KMO KO mice, but 3-HK levels were decreased. In wild-type C57BL/6 N mice, the PPI impairment induced by PCP is exacerbated by KA, while attenuated by 3-HK, QA and XA. Taken together, KMO KO mice were vulnerable to the PPI impairment induced by PCP through an increase in KA and a decrease in 3-HK, suggesting that an increase in the ratio of KA to 3-HK (QA and XA) may play an important role in the pathophysiology of schizophrenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)