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Background: The histological improvement in liver fibrosis in patients with hepatitis C who achieved a sustained virological response (SVR) to direct-acting antiviral (DAA) treatment has not been comprehensively investigated. Therefore, we assessed the histological changes in liver fibrosis among patients with hepatitis C who underwent long-term follow-up after achieving SVR to treatment with DAA., Methods: This retrospective study enrolled 71 patients with hepatitis C who achieved SVR to treatment with DAA. Changes in histological liver fibrosis and fibrosis biomarkers (hyaluronic acid, type 4 collagen 7S, Mac-2 binding protein glycosylation isomer, autotaxin, and Fibrosis-4 index) were assessed before and 5 years after treatment. Transient elastography using the FibroScan® device was performed 5 years after treatment. Advanced fibrosis and cirrhosis were defined as Ishak fibrosis scores of ≥ 4 and ≥ 5, respectively., Results: Histological liver fibrosis significantly regressed after SVR. Fibrosis biomarkers were significantly reduced after SVR. Transient elastography was the most helpful after evaluating the predictive performance of advanced fibrosis and cirrhosis after SVR, with an area under the receiver operating characteristic curve of 0.965 and a cut-off value of 6.75 kPa. The cut-off values of serum fibrosis biomarkers for identifying advanced fibrosis and cirrhosis after SVR were lower than those before treatment., Conclusions: Long-term SVR to treatment with DAA ameliorated histological liver fibrosis. Noninvasive tests helped predict the degree of liver fibrosis after SVR, but their cut-off values should be redefined to avoid underestimation of liver fibrosis., Competing Interests: Declarations. Conflict of interests: Tetsuo Takehara has received research grants from Janssen Pharmaceutical K.K., Gilead Sciences, Inc., Abbie Inc., and Chugai Pharmaceutical Co., Ltd. Tetsuo Takehara and Hayato Hikita have received lecture fees from Gilead Sciences, Inc, Abbie Inc, and Chugai Pharmaceutical Co., Ltd. All other authors declare no conflict of interest. Ethical Approval: This study was approved by the Institutional Review Board of Kansai Rosai Hospital (Approval No. 23E041g) and Osaka University Graduate School of Medicine (Approval No. K23182) and conducted following the Declaration of Helsinki. All patients provided written informed consent for liver biopsy before and after treatment., (© 2024. The Author(s).)

White adipocytes are a major component of white adipose tissue (WAT) and help to maintain systemic metabolic homeostasis by storing energy and secreting adipokines. In mice deficient in the protein WWP1 (WW domain-containing E3 ubiquitin protein ligase 1), oxidative stress in adipocytes increases but insulin resistance induced by obesity improves. However, the specific roles of WWP1 in adipocytes remain unclear. Here, we show that in 3T3L1 adipocytes, WWP1 localized in the Golgi apparatus via its C2 domain, where it protected the Golgi apparatus from monensin-induced disruption. By contrast, WWP1 knockdown by short hairpin RNA failed to protect the Golgi apparatus and enhanced Golgi apparatus disruption by monensin. The Golgi apparatus acts as a central organelle to establish accurate protein glycosylation of proteoglycans containing glycosaminoglycans, including chondroitin sulfate and heparan sulfate (HS). WWP1 overexpression increased chondroitin sulfate and HS levels, whereas WWP1 knockdown decreased them. Furthermore, obesity-related increases in HS were prevented by WWP1 knockout in adipose tissue. In summary, our results demonstrate a novel role for WWP1 in maintaining Golgi apparatus morphology and proteoglycan synthesis in adipocytes., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Aim: The incidence of and factors involved in gastroesophageal varix-related events in hepatitis C virus-related cirrhosis patients, including decompensated cirrhosis, after direct-acting antiviral therapy are unclear., Methods: We conducted a multicenter study using prospective data from 478 hepatitis C virus-related cirrhosis patients treated with direct-acting antiviral therapy from February 2019 to December 2021 at 33 Japanese hospitals. Gastroesophageal varices were classified as F1 (small-caliber), F2 (moderately enlarged), or F3 (markedly enlarged) according to the Japanese criteria. Patients without varix or with F1 without red color signs were defined as low-risk varix, and patients with ≥F2 or red color signs or a history of rupture were defined as high-risk varix. Varix-related events were defined as prophylactic treatment or rupture of gastroesophageal varix., Results: The median age was 70 years, 43% of patients had decompensated cirrhosis, and 16% had high-risk varices (13% in compensated and 33% in decompensated, p < 0.001). Sustained virologic response rates were 94.9% for compensated cirrhosis and 91.3% for decompensated cirrhosis (p = 0.120). Across 35.7 months, 25 patients received prophylactic treatment, and four experienced varix rupture. The 3-year incidence rate of varix-related events was 6.2% (3.5% in compensated and 9.9% in decompensated, p = 0.001). In the multivariate analysis, high-risk varix (p < 0.001), high baseline gamma-glutamyl transpeptidase levels (p < 0.001), and virologic failure (p = 0.004) were significantly involved in varix-related events., Conclusions: The cumulative incidence rate of varix-related events was significantly higher in decompensated cirrhosis than in compensated cirrhosis. Baseline varix status, baseline gamma-glutamyl transpeptidase levels, and virologic response were related to varix-related events after direct-acting antiviral therapy., (© 2024 The Author(s). Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Objective: Healthcare-associated infections (HAIs) pose significant challenges to healthcare systems worldwide. Epidemiological data are essential for effective HAI control; however, comprehensive information on HAIs in Japanese hospitals is limited. This study aimed to provide an overview of HAIs in Japanese hospitals., Methods: A multicenter point-prevalence survey (PPS) was conducted in 27 hospitals across the Aichi Prefecture between February and July 2020. This study encompassed diverse hospital types, including community, university, and specialized hospitals. Information on the demographic data of the patients, underlying conditions, devices, HAIs, and causative organisms was collected., Results: A total of 10,199 patients (male: 5,460) were included in this study. The median age of the patients was 73 (interquartile range [IQR]: 56-82) years, and the median length of hospital stay was 10 (IQR: 4-22) days. HAIs were present in 6.6% of patients, with pneumonia (1.83%), urinary tract infection (1.09%), and surgical site infection (SSI) (0.87%) being the most common. The prevalence of device-associated HAIs was 0.91%. Staphylococcus aureus (17.3%), Escherichia coli (17.1%), and Klebsiella pneumoniae (7.2%) were the primary pathogens in 433 organisms; 29.6% of the Enterobacterales identified showed resistance to third-generation cephalosporins. Pneumonia was the most prevalent HAI in small-to-large hospitals (1.69%-2.34%) and SSI, in extra-large hospitals (over 800 beds, 1.37%)., Conclusions: This study offers vital insights into the epidemiology of HAIs in hospitals in Japan. These findings underscore the need for national-level PPSs to capture broader epidemiological trends, particularly regarding healthcare challenges post-COVID-19.

Introduction: The number of dementia patients is increasing with population aging. Preclinical detection of dementia in patients is essential for access to adequate treatment. In previous studies, dementia patients showed texture recognition difficulties. Onomatopoeia or sound symbolic words (SSW) are intuitively associated with texture impressions and are less likely to be affected by aphasia and description of material perception can be easily obtained. In this study, we aimed to create a test of texture recognition ability expressed by SSW to detect the presence of mild cognitive disorders., Methods: The sound symbolic words texture recognition test (SSWTRT) is constructed from 12 close-up photos of various materials and participants were to choose the best SSW out of 8 choices to describe surface texture in the images in Japanese. All 102 participants seen in Juntendo University Hospital from January to August 2023 had a diagnosis of possible iNPH (age mean 77.9, SD 6.7). The answers were scored on a comprehensive scale of 0 to 1. Neuropsychological assessments included MMSE, FAB, and the Rey Auditory Verbal Learning Test (RAVLT), Pegboard Test, and Stroop Test from the EU-iNPH Grading Scale (GS). In study 1 the correlation between SSWTRT and the neuropsychological tests were analyzed. In study 2, participants were divided into two groups: the Normal Cognition group (Group A, n  = 37) with MMSE scores of 28 points or above, and the Mild Cognitive Impairment group (Group B, n  = 50) with scores ranging from 22 to 27 points, and its predictability were analyzed., Results: In study 1, the total SSWTRT score had a moderate correlation with the neuropsychological test results. In study 2, there were significant differences in the SSWTRT scores between groups A and B. ROC analysis results showed that the SSWTR test was able to predict the difference between the normal and mildly impaired cognition groups., Conclusion: The developed SSWTRT reflects the assessment results of neuropsychological tests in cognitive deterioration and was able to detect early cognitive deficits. This test not only relates to visual perception but is likely to have an association with verbal fluency and memory ability, which are frontal lobe functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kamohara, Nakajima, Nozaki, Ieda, Kawamura, Horikoshi, Miyahara, Akiba, Ogino, Karagiozov, Miyajima, Kondo and Sakamoto.)

Members of the T-cell immunoglobulin and mucin (TIM) family, which is crucial for T-cell function, are implicated in autoimmunity. TIM-1 and -3 play distinct roles in autoimmunity, with TIM-1 acting as a costimulatory molecule and TIM-3 regulating Th1 responses. We investigated the therapeutic potential of anti-TIM-1 (RMT1-10) and anti-TIM-3 (RMT3-23) antibodies in an autoimmune arthritis model. Zymosan A was used to induce arthritis in female SKG mice. The arthritis scores, histology, mRNA expression, cytokine levels, micro-computed tomography, and flow cytometry results were obtained. The application of RMT1-10 reduced the arthritis scores, histological damage, and CD4+ T-cell infiltrations, and it suppressed interleukin (IL)-6 and -17A and reduced TIM-3 mRNA expressions. RMT3-23 also lowered arthritis severity, improved histology, and reduced serum levels of tumor necrosis factor (TNF)-α and IL-17A. RMT3-23 inhibited intracellular TNF-α and IL-6 and early apoptosis. An amelioration of autoimmune arthritis was achieved by blocking the TIM-1 and -3 signaling pathways via RMT1-10 and RMT3-23 administration, leading to a widespread decrease in inflammatory cytokines. Both antibodies exhibited therapeutic effects, suggesting TIM-1 and -3 as potential targets for rheumatoid arthritis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: This study evaluated the effect of coinfections and/or secondary infections on antibiotic use in patients hospitalized with coronavirus disease 2019 (COVID-19)., Method: Days of therapy per 100 bed days (DOT) in a COVID-19 ward were compared between 2022 (Omicron period) and 2021 (pre-Omicron period). Antibiotics were categorized as antibiotics predominantly used for community-acquired infections (CAIs) and antibiotics predominantly used for health care-associated infections (HAIs). Bacterial and/or fungal infections which were proved or assumed on admission were defined as coinfections. Secondary infections were defined as infections that occurred following COVID-19., Results: Patients with COVID-19 during the Omicron period were older and had more comorbidities. Coinfections were more common in the Omicron period than in the pre-Omicron period (44.4% [100/225] versus 0.8% [2/257], respectively, p < 0.001), and the mean DOT of antibiotics for CAIs was significantly increased in the Omicron period (from 3.60 to 17.84, p < 0.001). Secondary infection rate tended to be higher in the Omicron period (p = 0.097). Mean DOT of antibiotics for HAIs were appeared to be lower in the COVID-19 ward than in the general ward (pre-Omicron, 3.33 versus 6.37, respectively; Omicron, 3.84 versus 5.22, respectively). No multidrug-resistant gram-negative organisms were isolated in the COVID-19 ward., Conclusion: Antibiotic use for CAIs was limited in the pre-Omicron period but increased in the Omicron period because of a high coinfection rate on admission. With the antimicrobial stewardship, excessive use of antibiotics for HAIs was avoided in the COVID-19 ward during both periods., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

This is the first case report in which computed tomography (CT) images of a patient with emphysematous pyelonephritis (EPN) capture the time course of emphysema from onset to resolution through conservative treatment. To re-evaluate EPN, including refractory urinary tract infections, CT scans after 72 h might be helpful., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: The effects of aspirin-free strategy on bleeding and cardiovascular events in patients undergoing percutaneous coronary intervention with oral anticoagulation (OAC) have not been fully elucidated., Methods and Results: We conducted the prespecified subgroup analysis based on the use of OAC, including vitamin K antagonist and direct oral anticoagulants, within 7 days before percutaneous coronary intervention in the STOPDAPT-3 (Short and Optimal Duration of Dual Antiplatelet Therapy-3) trial, which randomly compared prasugrel monotherapy (2984 patients) to dual antiplatelet therapy (DAPT) with prasugrel and aspirin (2982 patients) in patients with acute coronary syndrome or high bleeding risk. The coprimary end points were major bleeding events (Bleeding Academic Research Consortium types 3 or 5) and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke) at 1 month. Among 5966 study patients, there were 530 patients (8.9%) with OAC (no aspirin: N=248, and DAPT: N=282) and 5436 patients (91.1%) without OAC (no aspirin: N=2736, and DAPT: N=2700). Regardless of the use of OAC, the effects of no aspirin compared with DAPT were not significant for the bleeding end point (OAC: 4.45% and 4.27%, hazard ratio [HR], 1.04 [95% CI, 0.46-2.35]; no-OAC: 4.47% and 4.75%, HR, 0.94 [95% CI, 0.73-1.20]; P for interaction=0.82), and for the cardiovascular end point (OAC: 4.84% and 3.20%, HR, 1.53 [95% CI, 0.64-3.62]; no-OAC: 4.06% and 3.74%, HR, 1.09 [95% CI 0.83-1.42]; P for interaction =0.46)., Conclusions: The no-aspirin strategy compared with the DAPT strategy failed to reduce major bleeding events irrespective of the use of OAC. There was a numerical excess risk of the no-aspirin strategy relative to the DAPT strategy for cardiovascular events in patients with OAC.

Pasteurellosis is a common zoonotic infection that occurs after an animal bite or scratch (B/S). We compared the clinical features of six patients with non-B/S pasteurellosis with those of 14 patients with B/S infections. Pasteurella multocida was identified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in all six non-B/S infections, whereas 13 of the 14 B/S infections were identified with diagnostic kits. The non-B/S infections were pneumonia (n = 3), skin and soft tissue infections (n = 2), and bacteremia (n = 1). Pneumonia occurred in two patients with underlying pulmonary disease, whereas ventilator-associated pneumonia developed in one patient with cerebral infarction. Pasteurella multocida was isolated from a blood specimen and nasal swab from a patient with liver cirrhosis (Child-Pugh class C) and diabetes. Cellulitis developed in one patient with diabetes and normal-pressure hydrocephalus, who had an open wound following a fall, and in one patient with diabetes and a foot ulcer. Three patients with non-B/S infections had no pet and no episode of recent animal contact. The rate of moderate-to-severe comorbidities was significantly higher in patients with non-B/S infections than in those with B/S infections (100% and 14.3%, respectively, p < 0.001). In conclusion, non-B/S infections can develop in patients with chronic pulmonary disease, invasive mechanical ventilation, or open wounds, or who are immunocompromised, irrespective of obvious animal exposure. In contrast to B/S infections, non-B/S pasteurellosis should be considered opportunistic., Competing Interests: Declaration of competing interest All the authors declare that they have no conflicts of interest., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Purpose: We aimed to evaluate the influence of easing COVID-19 preventive measures following its downgrading to a common infectious disease on COVID-19 occurrence among hospitalized patients., Methods: Nosocomial occurrence of COVID-19 was compared between periods with national infectious disease category 5 versus the preceding category 2 equivalent. Changes in the revised manual included a shorter duration of work restrictions for infected health care practitioners (HCPs); no work restriction for HCPs exposed to SARS-CoV-2 with a negative test on days 1, 3 and 5; discontinuation of universal pre-admission screening; and pre-emptive isolation of patients without screening. Wearing an N95 mask and face shield was required in procedure/care with moderate-to high-risk contact., Results: Although the mean monthly number of infected HCPs increased from 8.1 to 12.7 in the category 5 period (p = 0.034) and that of pre-admission screening decreased to one-fourth, the COVID-19 incidence in hospitalized patients remained similar between the two study periods (1.60 ± 5.59/month versus 1.40 ± 2.63/month, p = 0.358). Clusters, defined as ≥3 COVID-19 patients on the ward, were experienced twice in the preceding period and only once in the category 5 period. The index cases causing nosocomial SARS-CoV-2 transmission mostly involved rehabilitation therapists in the preceding period; five of six index cases were patients in the category 5 period. Following the expanded indication for N95 masks, neither SARS-CoV-2 transmission to patients nor transmission from infected patients was observed in HCPs for 1 year., Conclusion: With sustained, enhanced standard precautions, easing prevention strategies could limit nosocomial SARS-CoV-2 infections., 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 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background/aim: Oncotype DX Breast Recurrence Score ® test (ODx) is a gene profiling assay predicting the benefit of adjuvant chemotherapy for early-stage hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Meanwhile, to avoid unnecessary financial burden on the patient, many studies have attempted to establish alternatives to ODx using conventional clinicopathological factors, but these have not yet been successful. Thus, we retrospectively investigated clinicopathological factors to establish alternatives to ODx., Patients and Methods: Data from 114 Japanese women who underwent ODx were retrospectively examined to investigate the relationship between ODx recurrence score (RS) and clinicopathological features, including MUC1 staining patterns on immunohistochemical assessment. An RS of 0-25 was defined as low, and 26-100 as high., Results: Ninety patients (79%) had low RS and 24 patients (21%) had high RS. Univariate analysis revealed that low tumor grade, high progesterone receptor (PgR) expression, and low Ki67 labeling index (LI) were significantly associated with low RS (p=0.025, p<0.001, and p<0.001, respectively). Tumors with an apical pattern of MUC1 staining also frequently had a low RS (p=0.024). In multivariate analysis, PgR expression and Ki67 LI were independent factors associated with RS (p<0.001, for both). When the ODx results were categorized with a combination of these two factors, only 2% of the PgR-high and Ki67-low group (one in 51 cases) had a high RS., Conclusion: PgR expression and Ki67 LI were independent factors correlated with RS. MUC1 staining pattern also has the potential to be a useful marker. We believe that it is crucial to continue attempts to identify patients who are unlikely to benefit from ODx., Competing Interests: The Authors have no potential conflicts of interest to disclose., (Copyright 2024, International Institute of Anticancer Research.)

Background: Knee osteoarthritis negatively affects the gait of patients, especially that of elderly people. However, the assessment of wearable sensors in knee osteoarthritis patients has been under-researched. During clinical assessments, patients may change their gait patterns under the placebo effect, whereas wearable sensors can be used in any environment., Methods: Sixty patients with knee osteoarthritis and 20 control subjects were included in the study. Wearing shoes with an IMU sensor embedded in the insoles, the participants were required to walk along a walkway. The sensor data were collected during the gait. To discriminate between healthy and knee osteoarthritis patients and to classify different subgroups of knee osteoarthritis patients (patients scheduled for surgery vs. patients not scheduled for surgery; bilateral knee osteoarthritis diagnosis vs. unilateral knee osteoarthritis diagnosis), we used a machine learning approach called the support vector machine. A total of 88 features were extracted and used for classification., Findings: The patients vs. healthy participants were classified with 71% accuracy, 85% sensitivity, and 56% specificity. The "patients scheduled for surgery" vs. "patients not scheduled for surgery" were classified with 83% accuracy, 83% sensitivity, and 81% specificity. The bilateral knee osteoarthritis diagnosis vs. unilateral knee osteoarthritis diagnosis was classified with 81% accuracy, 75% sensitivity, and 79% specificity., Interpretation: Gait analysis using wearable sensors and machine learning can discriminate between healthy and knee osteoarthritis patients and classify different subgroups with reasonable accuracy, sensitivity, and specificity. The proposed approach requires no complex gait factors and is not limited to controlled laboratory settings., Competing Interests: Declaration of competing interest K. Fukushi, C. Huang, K. Ihara, Y. Nozaki, K. Nakahara are employees of the NEC Corporation., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Information regarding the status of surgical antimicrobial prophylaxis (SAP) in Japanese hospitals is lacking. This study aimed to explore the status of SAP prescriptions for surgeries and adherence to Japanese SAP guidelines., Methods: From February to July 2020, a 1-day multicentre point prevalent survey was conducted at 27 hospitals in Aichi Prefecture, Japan. Patients prescribed SAP were included in this study. The appropriateness of the SAP was evaluated based on the guidelines for selection of antimicrobials and their duration. Surgery was defined as appropriate when all the items were appropriate., Results: A total of 728 patients (7.1 %; 728/10,199) received antimicrobials for SAP. Among them, 557 patients (76.5 %, 557/728) underwent the surgeries described in the guidelines. The overall appropriateness of all surgeries was 33.9 % (189/557). The appropriate selection of antimicrobial before/during and after surgery and their durations were 67.5 % (376/557), 67.5 % (376/557), and 43.3 % (241/557), respectively. The overall appropriateness ranged from 0 % (0/37, oral and maxillofacial surgery) to 58.7 % (88/150, orthopaedic surgery) and 27.7 % (36/130, community hospitals with 400-599 beds) to 47.2 % (17/36, specific hospitals). Cefazolin was the most prevalent antimicrobial prescribed before/during (55.5 %, 299/539), and after (45.1 %, 249/552) surgery. In total, 101 oral antimicrobials were prescribed postoperatively., Conclusions: SAP adherence by specific surgical fields and hospitals was shown in this study. Intensive intervention and repeated surveillance are necessary to improve SAP prescriptions in Japanese hospitals., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest relevant to this article., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Acute kidney injury (AKI) and hypokalaemia are common adverse events after treatment with liposomal amphotericin B (L-AMB)., Objectives: Because excess potassium (K) leakage occurs during renal tubular injury caused by L-AMB, measuring the decrease in rate of serum K concentration might be more useful to assess the renal impact of L-AMB than hypokalaemia identified from a one-point measurement. The effects of a decrease in K concentration and duration of hypokalaemia on AKI were investigated., Methods: A ≥ 10% decrease in K concentration from the reference concentration within a 7-day timeframe was evaluated. The hypokalaemia index, which combines the duration of K concentration lower than the reference and a marked low K concentration, was calculated from the area over the concentration curve., Results: Eighty-six patients were included in the study. The incidences of AKI and decrease in K concentration were 36.0% and 63.9%, respectively. Of patients who developed both adverse events, a decrease in K concentration occurred first in 22 of 26 patients, followed by AKI 7 days later. Hypokalaemia did not increase AKI risk whereas a decrease in K concentration was an independent risk factor for AKI. The hypokalaemia index in patients with AKI was significantly higher than those without AKI (5.35 vs. 2.50 points, p = 0.002), and ≥3.45 points was a significant predictor for AKI., Conclusion: A ≥ 10% decrease in the K concentration was a significant factor for AKI in patients receiving L-AMB therapy. In such patients, dose reduction or alternative antifungals could be considered based on the hypokalaemia index., (© 2024 The Author(s). Mycoses published by Wiley‐VCH GmbH.)

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m 2 ): 2893 patients; CKDa group (eGFR 45-60 mL/min/1.73 m 2 ): 551; and CKDb group (eGFR < 45 mL/min/1.73 m 2 ): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09-0.61), IL-6Ri: 0.34 (0.14-0.81), CTLA-4-Ig: 0.36 (0.15-0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m 2 ). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs., (© 2024. The Author(s).)

Aims: To predict preterm birth (PTB) accurately, we conducted a comprehensive cytokine assay using cervicovaginal fluid (CVF) and evaluated the additive effects of cytokine levels on the fetal fibronectin (fFN) test., Methods: A total of 645 CVF samples were collected from 256 asymptomatic pregnant women between 24 and 35 weeks gestation, exhibiting short cervix. After selection based on specific criteria, 17 cytokines in 105 CVF samples were simultaneously measured using multiplex assay. Multivariate logistic regression analysis was performed to evaluate the association between cytokine levels and impending PTB, which is defined as PTB within 2 weeks after CVF collection. Moreover, receiver operating characteristic (ROC) analysis was performed in women with positive fFN results, which was validated using another set of 65 CVF samples., Results: In positive fFN women, the CCL2 level was significantly higher in the impending PTB group than the other group (p < 0.01) and a predictor of impending PTB (adjusted odds ratio 1.020, 95% confidence interval [95% CI] 1.003-1.038, p = 0.020). The cutoff value of CCL2 was 64.8 pg/mL (are under the curve 0.726, p = 0.004, 95% CI 0.593-0.859, sensitivity 45.2%, specificity 91.7%). Additionally, the reliable classification performance of proposed ROC model could be validated. However, measuring cytokine levels could not help in predicting impending PTB in women with negative fFN or normal labor onset in healthy-term women., Conclusion: Comprehensive analysis of CVF cytokines revealed that the CCL2 level significantly improves the prediction of impending PTB in asymptomatic fFN-positive women with a short cervix, which may contribute to better clinical management., (© 2024 Japan Society of Obstetrics and Gynecology.)

Aims: We aimed to elucidate the association between malnutrition and the occurrence of bleeding events in patients with heart failure., Methods and Results: We evaluated the nutritional status of patients with heart failure [n = 2044, median (inter-quartile range) age 69.0 (59.0-78.0) years, 1209 (59.1%) males] using the Geriatric Nutritional Risk Index (GNRI). The primary endpoint was a composite of bleeding events such as haemorrhagic stroke or gastrointestinal bleeding. According to the survival classification and regression tree analysis, the accurate cut-off point of GNRI for predicting the primary endpoint was 106.2. We divided the patients into two groups based on GNRI levels: high GNRI group (GNRI ≥ 106.2, n = 606, 29.6%) and low GNRI group (GNRI < 106.2, n = 1438, 70.4%). We compared the patients' characteristics and prognosis between the two groups. The low GNRI group was older [72.0 (63.0-79.0) vs. 63.0 (53.0-73.0) years, P < 0.001] and had a lower prevalence of male sex (56.9% vs. 64.5%, P = 0.001). There were no differences in the use of antiplatelet agents and anticoagulants between the two groups. Levels of B-type natriuretic peptide were higher [321.1 (123.3-667.4) vs. 111.6 (42.6-235.4) pg/mL, P < 0.001] and levels of haemoglobin were lower [12.4 (10.8-13.7) vs. 14.2 (12.9-15.4) g/dL, P < 0.001] in the low GNRI group. The Kaplan-Meier analysis demonstrated that bleeding event rates were higher in the low GNRI group (log-rank P < 0.001). The multivariable Cox proportional hazard analysis revealed that low GNRI (hazard ratio 1.952, 95% confidence interval 1.002-3.805, P = 0.049) was associated with bleeding events., Conclusions: Heart failure patients with poor nutritional status, determined by GNRI under 106.2, experienced high bleeding event rates. Comprehensive management is required to avoid bleeding event in those populations., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Meningeal carcinomatosis is a condition in which cancer cells diffusely metastasize to the cerebral pia mater in the cerebrospinal membrane or cerebrospinal cavity. It causes a wide array of symptoms according to the site of metastasis. The prognosis is poor, especially in metastasis from solid tumors. This study reports a case of meningeal carcinomatosis caused by advanced gastric cancer, manifested by headache and vision loss. The patient was a 69-year-old man who underwent head computed tomography (CT) and magnetic resonance imaging (MRI) for persistent headaches. No abnormal findings were found; however, his vision declined, convulsions occurred, and cerebrospinal fluid (CSF) cytology showed poorly differentiated adenocarcinoma. Therefore, meningeal carcinomatosis was diagnosed. The patient died after receiving FOLFOX therapy to relieve symptoms and prolong his life. An autopsy showed no invasion of the optic nerve or surrounding tissues. As the frequency of complications of meningeal carcinomatosis in solid cancers is rare, it is crucial to actively suspect and make an early diagnosis., (© 2023. Japanese Society of Gastroenterology.)

The treatment efficiency and predictors of atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma in real-world practice have not been established. This study aimed to assess the efficacy and safety of atezolizumab plus bevacizumab and to investigate predictors of progression-free survival and overall survival. Patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy in 19 hospitals were enrolled before treatment and observed prospectively. The outcomes of 222 patients in this cohort were analyzed. The objective response rate and disease control rate were 22.0% and 70.6%, respectively, whereas the median progression-free survival was 5.7 months. Independent risk factors for shortened progression-free survival were younger age (<75 years; 3.9 months vs. 8.6 months), higher number of intrahepatic tumors (≥5; 4.0 months vs. 7.9 months), macrovascular invasion (2.3 months vs. 6.7 months), and higher neutrophil-to-lymphocyte ratio (≥3.03; 3.0 months vs. 7.8 months). The median overall survival was not reached; however, independent risk factors for shortened overall survival were absence of hyperlipidemia, higher number of intrahepatic tumors (≥5), macrovascular invasion, higher α-fetoprotein level (≥400 ng/mL), worse Child-Pugh score (≥6), and higher neutrophil-to-lymphocyte ratio (≥3.03). Severe adverse events (grade ≥3) were observed in 96 patients (36.0%), with proteinuria being the most frequent. In conclusion, patients with older age, lower number of intrahepatic tumors, absent macrovascular invasion, and lower neutrophil-to-lymphocyte ratio are expected to have better progression-free survival with atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Tetsuo Takehara has received lecture fees and research grants from Chugai Pharmaceutical Co., Ltd, Eisai Co., Ltd. Takahiro Kodama has received lecture fees from Chugai Pharmaceutical Co., Ltd and AstraZeneca K.K. All other authors declare no conflicts of interest., (Copyright: © 2024 Kai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Drug-induced convulsion is a serious concern in drug development, such that the convulsion liability of drug candidates must be evaluated in preclinical safety studies. However, information on the differences among species regarding their sensitivity to convulsions induced by convulsant drugs in humans remains limited. Here, we selected 11 test articles from several pharmacological classes and compared the sensitivities of three types of laboratory animal to convulsion. All 11 test articles were examined in mice via intraperitoneal injection and in rats via intravenous bolus; and 6 of the 11 test articles, selected mainly based on availabilities of data on drug plasma concentrations in humans at convulsion, were examined in non-human primates (NHPs) via intravenous infusion. Plasma concentrations of the test articles shortly after convulsion onset or 5 min after administration were measured. All 11 articles tested in mice, 10 of 11 articles tested in rats, and all 6 articles tested in NHPs induced convulsion with premonitory signs. Although there was a general tendency that rats and NHPs exhibited convulsions at lower plasma drug concentrations than did mice, the plasma concentrations at convulsion onset were generally comparable, within 3-fold differences, across the animal species. We conclude that the mice, rats, and NHPs examined in the present study generally showed similar sensitivities to convulsion induced by the test articles. Thus, each of these laboratory animals can be used for the assessment of convulsion risk in the early stages of drug development, depending on throughput, cost, and test article-specific requirements.

Long-term caloric restriction (CR) is an effective intervention that improves whole-body metabolism, suppresses age-related pathophysiology, and extends lifespan. Although the beneficial effects of caloric restriction mediated by growth hormone/insulin-like growth factor-1 (GH/IGF-1) have been extensively studied, the mechanisms independent of GH/IGF-1 remain largely unknown. In this review, we focus on these GH/IGF-1-independent mechanisms, with a particular emphasis on the role of sterol regulatory element-binding protein 1c (SREBP-1c). CR increases the expression of SREBP-1c through the suppression of leptin signaling and enhances downstream factors involved in fatty acid synthesis in white adipose tissue (WAT). SREBP-1c also directly and indirectly increases the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha, a master regulator of mitochondrial biogenesis, leading to an increase in the number of mitochondria. Furthermore, SREBP-1c elevates expression of mitochondrial intermediate peptidase, which contributes to improving mitochondrial quality through the processing of sirtuin 3 into its mature form. Thus, it appears that CR exerts beneficial effects by modulating mitochondrial quantity and quality in WAT in a GH/IGF-1 signal-independent manner.