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Background: Endovascular treatment has become the preferred approach for managing unruptured cerebral aneurysms, with simple and balloon-assisted coil embolization as the standard first-line therapy. However, recanalization after coil embolization remains a major clinical concern. This study aimed to evaluate the predictive factors for recanalization using time-of-flight magnetic resonance (TOF-MR) angiography., Methods: This retrospective multicenter study analyzed data from 241 patients with unruptured cerebral aneurysms who underwent coil embolization at five stroke centers. Aneurysms were evaluated using TOF-MR angiography within 7 days post-procedure and at follow-up. The study investigated the role of aneurysm characteristics and the Postoperative TOF-MR Angiography (PTMA) classification in predicting recanalization., Results: Of the 241 aneurysms analyzed, 79 (32.7%) exhibited recanalization, and 15 (6.2%) required retreatment. Aneurysms with a maximum diameter of ≥10 mm were associated with a higher risk of recanalization (odds ratio (OR), 3.27; 95% confidence interval (CI), 1.38-7.75; p<0.01). The PTMA classification, which indicated incomplete occlusion (SN/RN/PO), also showed a significant association with recanalization (OR, 4.82; 95% CI, 2.17-10.7; p<0.01). The modified Raymond-Roy classification (Class IIIb) also contributed to the prediction of recanalization (OR, 3.09; 95% CI, 1.50-6.38; p<0.01)., Conclusions: Aneurysm size, the modified Raymond-Roy classification, and PTMA classification within 7 days of coil embolization were significant predictors of recanalization. This study suggests that TOF-MR angiography may be accurate, and that PTMA classification may serve as an appropriate predictor of aneurysm recanalization. Further prospective studies with larger cohorts are required to validate our findings., (Copyright © 2024. Published by Elsevier Inc.)

Soft robotics has emerged as a highly promising field, particularly for handling interactions in unstructured environments such as food factories and agricultural warehouses. This potential is largely attributed to the inherent flexibility and compliance of soft robots. A critical aspect in the development of these robots lies in the selection and utilization of appropriate soft actuators and materials. Nevertheless, the modeling of soft robots presents considerable challenges owing to their intricate properties and continuum nature. In this article, we focus on the design and modeling of a three dimensional (3D) printed soft bellows actuator. The primary objective is to assess its efficacy in creating suitable soft grippers for handling various practical products. We propose an empirical model to predict the output forces of the soft bellows actuator. This model comprehensively integrates parameters such as bellows geometry and material properties, thereby providing valuable insights for the actuator's design and control. To ascertain the precision of our model, we conducted a series of finite element simulations considering different designed parameters of the bellows, and performed experimental validations using 3D printed bellows actuators. The empirical model demonstrated high accuracy in predicting the output forces of the bellows actuator, with average absolute and relative errors of 1.35 N and 3.5 % , respectively. As an application, a robotic gripper with two parallel bellows actuators was developed, and its grasping force was validated using the empirical model. Building on this, a robotic gripper incorporating three bellows actuators was designed and fabricated based on the empirical model, and pick-and-place experiments were effectively conducted for handling a range of products., Competing Interests: Declarations 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., (© 2024. The Author(s).)

Wastewater-based epidemiology (WBE) is an effective, non-invasive method for monitoring the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by tracking viral prevalence in water. This study aimed to investigate the presence of SARS-CoV-2 in surface water in Vietnam over two years. One-step quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays were employed to quantify SARS-CoV-2 and its variant-specific mutation sites (G339D/E484A) and pepper mild mottle virus (PMMoV) from a total of 315 samples (105 samples per site) to compare with reported Coronavirus disease 2019 (COVID-19) cases and environmental factors. SARS-CoV-2 was detected in 38 % (40/105), 43 % (45/105), and 39 % (41/105) of water samples from Sites A, B, and C, respectively, with concentrations of 3.0-5.6 log 10 copies/L. PMMoV concentrations were 5.1-8.9 log 10 copies/L. SARS-CoV-2 levels were higher in winter compared with summer. There was a strong positive association between the mutant type and SARS-CoV-2 concentrations (Spearman's rho = 0.77, p < 0.01). The mean concentrations of mutant and nonmutant types were 2.3 and 1.8 log 10 copies/L, respectively. Peaks in SARS-CoV-2 concentrations preceded reported COVID-19 cases by 2-4 weeks, with the highest association observed at a 4-week delay (Pearson's correlation coefficient: 0.46-0.53). Environmental factors, including temperature, pH, and electrical conductivity, correlated negatively with SARS-CoV-2 (Spearman's rho = -0.21, -0.28, and -0.21, respectively, p < 0.05), whereas average rainfall, humidity, and dissolved oxygen correlated positively (Spearman's rho = 0.20, 0.27, and 0.51, respectively, p < 0.05). These correlations highlight the significance of environmental variables in understanding viral prevalence in water. Our findings confirmed the utility of WBE as an early warning system for long-term monitoring. Future research should incorporate environmental factors to improve prediction accuracy for clinical cases and other waterborne diseases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eiji Haramoto received research funding from Takara Bio Inc. The other authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Facet joint destruction causes postoperative spinal instability, resulting in poor clinical outcomes after lumbar decompression surgery. However, the effect of facet joint destruction on radiographic and clinical outcomes after microendoscopic laminectomy (MEL) is unknown. Therefore, the current study aimed to examine the effect of facet joint resection on radiographic and clinical outcomes after single-level MEL surgery., Methods: This study included 116 patients with lumbar spinal canal stenosis (LSCS) who underwent single-level (L4/5) MEL surgery. Eligible patients were divided into the following groups: group P (facet joint preservation rate = 100%) (n = 70); group PR (50% ≤ the facet joint preservation rate <100%) (n = 27); and group R (the facet joint preservation rate <50%) (n = 19). The demographic characteristics of the patients, surgical data, preoperative and 1-year postoperative radiographic measurements, and clinical outcomes were compared among the 3 groups. Moreover, preoperative and postoperative radiographic and clinical outcomes were compared after adjusting the demographic characteristics of the patients and surgical data by the inverse probability weighting method with propensity scores., Results: The 3 unweighted groups did not significantly differ in terms of demographic characteristics, surgical data, and preoperative and postoperative radiographic and clinical outcomes. Even after adjusting for the demographic characteristics and surgical data, the preoperative and postoperative radiographic and clinical outcomes were comparable among the 3 weighted groups., Conclusions: The extent of facet joint resection might have a minimal impact on radiographic and clinical outcomes at 1 year after single-level MEL surgery., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKIs). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells., Experimental Design: Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho-RTK antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET-fusion-positive lung cancer were analyzed for pre-treatment YAP expression and correlated with treatment outcomes., Results: In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/TEAD inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pre-treatment YAP expression in clinical specimens obtained from patients with RET-fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes., Conclusion: The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.

Objectives: Distal anterior cerebral artery (DACA) aneurysms account for 1%-9% of all intracranial aneurysms. Microsurgical treatment is generally preferred for DACA aneurysms; however, it presents challenges owing to the anatomical complexities. Advances in neuro-interventional techniques have yielded promising results. This study aims to compare the clinical outcomes of DACA aneurysms treated with microsurgery and endovascular treatment (EVT) to elucidate the efficacy of EVT., Materials and Methods: A multicenter observational registry comprising 16 stroke centers was utilized for this study. Data was retrospectively and prospectively analyzed from 166 patients with DACA aneurysms in our database, which included 4,552 consecutive patients with ruptured or unruptured intracranial aneurysms who underwent microsurgical or endovascular treatment between January 2013 and December 2021., Results: Surgical clipping was performed in 115 patients, and 51 underwent coil embolization. The median follow-up duration was 15.3 months. No significant differences were observed in patient characteristics between the two treatment modalities. There were no differences in complication-related morbidity between the microsurgical treatment and EVT groups in either unruptured (10.5% vs. 9.1%, p=1.00) or ruptured aneurysms (5.2% vs. 6.9%, p=0.66). Coil embolization resulted in higher recurrence and retreatment rates than surgical clipping did, especially for ruptured aneurysms (2.6% vs. 27.6%, p<0.01)., Conclusions: Endovascular treatment is an alternative to microsurgery for DACA aneurysms especially in unruptured cases or the patients who have difficulty undergoing craniotomy due to their general condition, albeit with considerations for higher recurrence and retreatment rates, particularly in ruptured cases. Close follow-up is crucial for the effective management of these challenges. Further studies are needed to refine the treatment strategies for DACA aneurysms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The health-related quality of life (HRQL) of people with food allergies should be evaluated to provide high-quality medical care. Currently, there is no available easy-to-use and reliable instrument for assessing HRQL clinically in Japan., Methods: The Food Allergy Quality of Life Questionnaire 10 (FAQLQ10) in English was translated into Japanese, and this was referred to as the Japanese version of the Food Allergy Quality of Life Questionnaire 10 (FAQLQ10-J). Participants aged up to 18 years, who had food allergy, and their parents were instructed to complete the FAQLQ10-J and the Food Allergy Independent Measure, a self-report instrument. For comparison, participants without food allergies were also included in the survey., Results: The FAQLQ10-J, which included forms for individuals aged 8-12 years, teenagers, and caregivers was developed. The responders completed each form within approximately 3 min. An analysis of responses showed that each form had a good internal consistency, test-retest reliability, construct validity, and discriminant validity. Moreover, based on an examination of the relationship between demographic data and FAQLQ10-J scores, items such as possession of an adrenaline auto-injector, participant age, and number of eliminated foods might influence HRQL., Conclusions: We developed the FAQLQ10-J, which is a simple, reliable, and effective tool for assessing HRQL among Japanese individuals with food allergy. Its use may provide a more detailed understanding of HRQL among individuals with food allergy in clinical settings and may facilitate the development of more individual-oriented treatments., Competing Interests: The authors report no competing interests., (© 2024 The Authors.)

Adult-acquired flatfoot causes various deformities. If a patient-specific foot model can be created using the finite element method, it can be used to study the appropriate surgical technique for each patient. Nine patient-specific flatfoot models were created, and loading simulations were performed. To validate the models, the patients' weight-bearing radiographs were compared with the parameters of the models. The CCC values ranged from 0.917 to 0.993 , all exceeding the moderate threshold according to the McBride criteria. Our model reproduces the biomechanics of a patient's foot under loading conditions, which may be useful for investigating patient-specific surgical procedures.

Introduction: Similar to other countries, in Japan, the demand for primary care pediatricians has increased due to the surge in pediatric allergic diseases, and with the change in a paradigm shift regarding the prevention of pediatric allergic disease in the last 20 years, they have had an increased need for retraining. To offer better support to children and their caregivers, educational needs for bridging the gap between knowledge and practice must be met. Therefore, we developed an educational program including practical and interactive approaches for pediatricians in 2012., Methods: To evaluate the effectiveness of a 2-week program, behavioral changes, knowledge and skill improvements in clinical practice, and the satisfaction level of participants before and after the course were investigated. Kirkpatrick's four levels of training evaluation were employed to assess the educational effect. Seven years (April 2014 to March 2021) worth of results were assessed., Results: A total of 65 pediatricians voluntarily participated in the program. Most of them were <40 years old and came from various regions of Japan. Results of pretraining and posttraining questionnaires in terms of their knowledge and skills on a four-point scale revealed significant improvements. Participants also reported their behavioral changes after 6 months of the course and evaluated the program's practicality. Each participant set new goals to be achieved in 6 months, and 36 (76.6%) of them set objectives for implementing oral food challenge tests., Conclusions: The results revealed that the program not only enhanced their knowledge and skills for practice but also changed their behaviors toward clinical practice. In pediatric allergy, where community primary pediatricians have important roles to play, such an educational program should be further developed., Competing Interests: None, (Copyright © Japan Medical Association.)

Haploinsufficiency of the transcriptional repressor ZBTB18/RP58 is associated with intellectual disability. However, the mechanisms causing this disability are unknown, and preventative measures and treatments are not available. Here, we assessed multiple behaviors in Zbtb18/Rp58 heterozygous-knockout mice, and examined local field potentials, DNA fragmentation, mitochondrial morphology, and performed histochemical and transcriptome analyses in the hippocampus to evaluate chronic inflammation. In wild-type mice, object location memory was present at a similar level at 2 and 4-5 months of age, and became impaired at 12-18 months. In contrast, Zbtb18/Rp58 heterozygous-knockout mice displayed early onset impairments in object location memory by 4-5 months of age. These mice also exhibited earlier accumulation of DNA and mitochondrial damage, and activated microglia in the dentate gyrus, which are associated with defective DNA repair. Notably, chronic minocycline therapy, which has neuroprotective and anti-inflammatory effects, attenuated age-related phenotypes, including accumulation of DNA damage, increased microglial activation, and impairment of object location memory. Our results suggest that Zbtb18/Rp58 activity is required for DNA repair and its reduction results in DNA and mitochondrial damage, increased activation of microglia, and inflammation, leading to accelerated declines in cognitive functions. Minocycline has potential as a therapeutic agent for the treatment of ZBTB18/RP58 haploinsufficiency-associated cognitive dysfunction., (© 2024. The Author(s).)

Introduction: This study aimed to compare the outcomes and safety in patients aged ≥75 years and those aged <75 years who underwent stent-assisted endovascular treatment for unruptured cerebral aneurysms, specifically focusing on perioperative antiplatelet therapy (APT)., Methods: This multicenter retrospective study comprised patients who underwent stent-assisted coiling (SAC) or flow diverter stent (FDS) placement for unruptured cerebral aneurysms. The primary outcome was defined as the composite outcomes of perioperative thromboembolic events, bleeding events, or death., Results: Among 632 patients, 533 (84.3%) were aged <75 years and 99 (15.6%) were aged ≥75 years. No significant differences were observed in the dual APT duration. The primary outcome occurred in 14.3% of patients aged <75 years and in 14.1% of those aged ≥75 years, with no significant difference (p = 1.0). The composites of the primary outcome, including thromboembolic events, bleeding events, and death differed insignificantly. Similar findings were observed when the primary outcomes for SAC (12.7% vs. 11.5%, p = 0.95) and FDS (17.5% vs. 18.4%, p = 1.0) were analyzed. The 30-day, 1-year, and 2-year cumulative event-free survival rates for the primary outcome were 89.5, 87.2%, and 85.2%, respectively, in patients aged <75 years, and 90.9%, 88.7%, and 87.0%, respectively, in those aged ≥75 years. These trends were similar (log-rank test, p = 0.92)., Conclusion: No significant differences were observed in the rates of the primary outcomes between patients aged <75 years and those aged ≥75 years. Therefore, refraining from stent-assisted treatment for unruptured aneurysms based solely on age might be inappropriate., (© 2024 S. Karger AG, Basel.)

Wastewater-based epidemiology (WBE) is a critical tool for monitoring community health. Although much attention has focused on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of coronavirus disease 2019 (COVID-19), other pathogens also pose significant health risks. This study quantified the presence of SARS-CoV-2, influenza A virus (Inf-A), and noroviruses of genogroups I (NoV-GI) and II (NoV-GII) in wastewater samples collected weekly (n = 170) from July 2023 to February 2024 from five wastewater treatment plants (WWTPs) in Yamanashi Prefecture, Japan, by quantitative PCR. Inf-A RNA exhibited localized prevalence with positive ratios of 59 %-82 % in different WWTPs, suggesting regional outbreaks within specific areas. NoV-GI (94 %, 160/170) and NoV-GII (100 %, 170/170) RNA were highly prevalent, with NoV-GII (6.1 ± 0.8 log 10 copies/L) consistently exceeding NoV-GI (5.4 ± 0.7 log 10 copies/L) RNA concentrations. SARS-CoV-2 RNA was detected in 100 % of the samples, with mean concentrations of 5.3 ± 0.5 log 10 copies/L in WWTP E and 5.8 ± 0.4 log 10 copies/L each in other WWTPs. Seasonal variability was evident, with higher concentrations of all pathogenic viruses during winter. Non-normalized and normalized virus concentrations by fecal indicator bacteria (Escherichia coli and total coliforms), an indicator virus (pepper mild mottle virus (PMMoV)), and turbidity revealed significant positive associations with the reported disease cases. Inf-A and NoV-GI + GII RNA concentrations showed strong correlations with influenza and acute gastroenteritis cases, particularly when normalized to E. coli (Spearman's ρ = 0.70-0.81) and total coliforms (ρ = 0.70-0.81), respectively. For SARS-CoV-2, non-normalized concentrations showed a correlation of 0.61, decreasing to 0.31 when normalized to PMMoV, suggesting that PMMoV is unsuitable. Turbidity normalization also yielded suboptimal results. This study underscored the importance of selecting suitable normalization parameters tailored to specific pathogens for accurate disease trend monitoring using WBE, demonstrating its utility beyond COVID-19 surveillance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eiji Haramoto received research funding from Takara Bio Inc. The other authors declared 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 Authors. Published by Elsevier B.V. All rights reserved.)

Lazertinib, a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), demonstrates marked efficacy in EGFR-mutant lung cancer. However, resistance commonly develops, prompting consideration of therapeutic strategies to overcome initial drug resistance mechanisms. This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first-line treatment for EGFR mutation-positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL-1 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A combination of genetic predisposition and environmental factors contributes to the development of psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder. Previous studies using mouse models suggested that prolonged high sucrose intake during puberty can serve as an environmental risk factor for the onset of psychiatric disorders. However, the impact of both the duration and timing of high sucrose consumption during different developmental stages on pathogenesis remains poorly defined. We therefore investigated the effects of a long-term high sucrose diet on cognitive deficit, a core symptom of psychiatric disorders, using Disrupted-in-Schizophrenia 1 locus-impairment heterozygous mutant (Disc1 het ) mice as a model for genetic predisposition. First, Disc1 het mice and their littermate control (WT) were fed either a high sucrose diet or a control starch diet for nine weeks starting at weaning (postnatal day 24), and tested for cognitive performance in the object location test (OLT) and the novel object recognition test (NORT) (assessing spatial and recognition memory, respectively). Only Disc1 het mice on a high sucrose diet displayed deficits in OLT (p < 0.0001), demonstrating impaired hippocampus-dependent spatial memory. This behavioral abnormality was accompanied by a decreased proportion of the high parvalbumin-expressing interneurons (High-PV neurons) in the ventral hippocampus, a cell type that regulates neural activity and a variety of learning and memory processes such as spatial and working memory. We further explored the critical developmental period for high sucrose intake to cause cognitive deficits in adulthood by comparing specific feeding periods during puberty (P24-P65) and post-puberty (P65-P90). Compared to those on a standard chow diet, high sucrose intake caused deficits in spatial memory in both WT and Disc1 het mice, with more pronounced effects in Disc1 het mice. In particular, Disc1 het mice on a sucrose diet during adolescence showed more pronounced cognitive deficit than those fed after adolescence. Our results suggest that adolescence is particularly vulnerable to nutritional environmental risk factors, and that high sucrose consumption may cause hippocampus-dependent memory deficits via decreased High-PV interneuron function when combined with Disc1-related genetic predisposition., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest related to this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background Context: Incidental dural tear (DT) during cervical spine surgery is a feared complication. However, its impact on patient-reported outcomes (PROs) remains unclear., Purpose: To determine the influence of DTs on PROs 1 year after cervical spine surgery., Study Design: Retrospective cohort., Patient Sample: Patients undergoing elective cervical spine surgery for cervical spondylosis, ossification of the posterior longitudinal ligament (OPLL), and cervical disc herniation., Outcome Measures: Analysis included patients' characteristics, perioperative complications, and PROs both preoperatively and at 1 year postoperatively., Methods: This study enrolled consecutive patients who underwent elective cervical spine surgery at 13 high-volume spine centers. All patients were required to complete questionnaires both preoperatively and 1 year postoperatively, which included PROs such as numerical rating scales of pain or dysesthesia for each part of the body, Neck Disability Index NDI, and Core Outcome Measures Index. Patients were divided into 2 groups based on the presence (DT+) or absence (DT-) of dural injury. Comparisons were made regarding patient background, perioperative complications, and pre and postoperative PROs. Propensity score matching was also utilized to adjust for patient background, and further comparisons were made regarding complication rates and PROs., Results: Out of 2,704 patients, dural tears were identified in 97 (3.6%) cases. The DT+ group had a significantly higher proportion of fixation surgeries, upper cervical surgeries, OPLL, and revision surgeries. Perioperative complications were significantly higher in the DT+ group, including intraoperative nerve damage, postoperative paralysis, surgical site infections (SSI), and cerebrovascular complications. Outcomes collected from 2,163 patients (79.9%) revealed significantly more severe neck and upper limb pain in the DT+ group. After propensity score matching, significant differences persisted in postoperative paralysis and SSI in the DT+ group, but no significant differences were observed in PROs., Conclusions: Patients with dural tears showed nearly equivalent postoperative outcomes at 1 year following cervical spine surgery compared to those without dural tears. However, the incidence of perioperative complications was higher, emphasizing the need for careful management., 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 Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: Thromboembolism is a serious complication of endovascular treatment for ruptured cerebral aneurysms. The administration of antiplatelet agents before endovascular treatment for ruptured cerebral aneurysms may reduce the risk of thromboembolic complications., Aim: This study aimed to assess the safety and efficacy of preoperative aspirin administration in endovascular treatment for ruptured cerebral aneurysms., Sample Size Estimates: Assuming a 15% incidence rate of both intraoperative thromboembolic morbidity and symptomatic ischemic lesions on magnetic resonance imaging diffusion-weighted imaging scans assessed by an Independent Review Committee, a sample size of 484 will be required to detect a 10% improvement with aspirin administration with 90% power using the Pearson's chi-square test at a two-sided significance level of 2.5% for each primary outcome, after accounting for a 5% dropout rate., Methods and Design: ASTOP is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 484 patients with ruptured cerebral aneurysms receiving coil embolization within 72 h of onset will be randomly assigned 1:1 to receive 200 mg of aspirin or placebo before the procedure., Study Outcomes: The primary outcomes will be the incidence rates of intraoperative thromboembolic complications and symptomatic ischemic lesions on magnetic resonance imaging diffusion-weighted imaging scans evaluated by the Independent Review Committee. The secondary outcomes will be the incidence rate of cerebral ischemic events and all bleeding events within 14 days of enrollment and functional outcomes defined by the modified Rankin Scale score at 90 days., Discussion: This trial will provide valuable data on the role of antiplatelet agents during endovascular treatment for ruptured cerebral aneurysms., Trial Registration: Registration: Japan Registry of Clinical Trials, Identifier: jRCTs031210421., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hirai 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.)

Despite widespread cervical cancer (CC) screening programs, low participation has led to high morbidity and mortality rates, especially in developing countries. Because early-stage CC often has no symptoms, a non-invasive and convenient diagnostic method is needed to improve disease detection. In this study, we developed a new approach for differentiating both CC and cervical intraepithelial neoplasia (CIN)2/3, a precancerous lesion, from healthy individuals by exploring CC fatty acid metabolic reprogramming. Analysis of public datasets suggested that various fatty acid metabolizing enzymes were expressed at higher levels in CC tissues than in normal tissues. Correspondingly, 11 free fatty acids (FFAs) showed significantly different serum levels in CC patient samples compared with healthy donor samples. Nine of these 11 FFAs also displayed significant alterations in CIN2/3 patients. We then generated diagnostic models using combinations of these FFAs, with the optimal model including stearic and dihomo-γ-linolenic acids. Receiver operating characteristic curve analyses suggested that this diagnostic model could detect CC and CIN2/3 more accurately than using serum squamous cell carcinoma antigen level. In addition, the diagnostic model using FFAs was able to detect patients regardless of clinical stage or histological type. Overall, the serum FFA diagnostic model developed in this study could be a powerful new tool for the non-invasive early detection of CC and CIN2/3., (© 2024. The Author(s).)

Purpose: The quick establishment of adequate vascular access is essential for the technical success of mechanical thrombectomy (MT). Focusing on shifts in aortic arch geometry and aging-related changes, we propose an imaging parameter for predicting access difficulty using chest CT., Methods: Patients with acute anterior circulation large-vessel occlusion who underwent MT from April 2020 to September 2021 were included in this retrospective multicenter observational study. The distance from the sternum to the ascending aorta (S-AAD) was defined as the surrogate marker of access difficulty. Access was defined as difficult when the time from femoral sheath placement to guiding catheter induction (guiding time: GT) ≥ 30 minutes, and the patients were dichotomized into groups with short GT (sGT: GT < 30 min) and long GT (lGT: GT ≥ 30 min)., Results: One hundred fifteen patients were included. There were 12 patients (10.4 %) in lGT group. The median (IQR) S-AAD was 11.9 mm (6.3, 18.3 mm) in sGT group and 6.6 mm (4.0, 10.3 mm) in lGT group, and a significant difference in S-AAD was observed (P = 0.026). In multivariate analyses, dyslipidemia and S-AAD < 5 mm were significantly associated with difficult access (OR, 5.938 [95 % CI, 1.468, 24.022], P = 0.012 for dyslipidemia; OR, 5.147 [95 % CI, 1.267, 20.917], P = 0.022 for S-AAD < 5 mm)., Conclusion: S-AAD is a simple and reliable imaging parameter to predict access difficulty. This parameter may be helpful in selecting the appropriate devices and access routes in preinterventional practice., Competing Interests: Competing interests The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Lys mutation of the canonical histone H3.1 Glu97 residue (H3E97K) is found in cancer cells. Previous biochemical analyses revealed that the nucleosome containing the H3E97K mutation is extremely unstable as compared to the wild-type nucleosome. However, the mechanism by which the H3E97K mutation causes nucleosome instability has not been clarified yet. In the present study, the cryo-electron microscopy structure of the nucleosome containing the H3E97K mutation revealed that the entry/exit DNA regions of the H3E97K nucleosome are disordered, probably by detachment of the nucleosomal DNA from the H3 N-terminal regions. This may change the intra-molecular amino acid interactions with the replaced H3 Lys97 residue, inducing structural distortion around the mutated position in the nucleosome. Consistent with the nucleosomal DNA end flexibility and the nucleosome instability, the H3E97K mutation exhibited reduced binding of linker histone H1 to the nucleosome, defective activation of PRC2 (the essential methyltransferase for facultative heterochromatin formation) with a poly-nucleosome, and enhanced nucleosome transcription by RNA polymerase II., (© 2024 The Author(s). Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Background: Thoracic epidural analgesia (TEA) and intravenous patient-controlled analgesia (IV-PCA) are widely used to mitigate immediate postoperative pain; however, their effects on long-term disability-free survival are poorly documented. This study aimed to compare the effects of postoperative TEA and IV-PCA on disability-free survival in patients who underwent thoracic or abdominal surgery., Methods: This post hoc analysis of a prospective observational study included 845 inpatients aged ≥55 years that underwent elective thoracic and abdominal surgery between 1 April 2016 and 28 December 2018 in a tertiary care hospital. Inverse probability of treatment weighted (IPTW) using stabilized inverse propensity scores was adopted to minimize bias. The primary outcome in this study was disability-free survival, defined as survival with a 12-item World Health Organization Disability Assessment Schedule 2.0 score of <16%, assessed at 3 months and 1 year after surgery., Results: The final analysis included 601 patients who received TEA and 244 who received IV-PCA. After IPTW, the weighted incidence of disability-free survival at 3 months and 1 year was 60.5% and 61.4% in the TEA group and 78.3% and 66.2% in the IV-PCA group, respectively. The adjusted OR for disability-free survival at 3 months and 1 year was 0.84 (95% confidence interval [CI]: 0.50-1.39) and 1.21 (95% CI: 0.72-2.05), respectively, for the TEA group., Conclusion: No significant differences were observed in the disability-free survival at 3 months and 1 year after elective thoracic and abdominal surgery in patients aged ≥55 years who received TEA or IV-PCA., Significance Statement: This study is the first in our setting to document the long-term effects of patient-controlled analgesia. In a post hoc analysis of our prospective cohort study, we show that although differences in chronic postsurgical pain exist at 3 months post-surgery, disability-free survival rates at 1 year do not differ irrespective of the choice of patient-controlled analgesia. The findings of this study highlight the need for shared decision-making between clinicians and patients., (© 2024 European Pain Federation ‐ EFIC ®.)

Sarcopenia assessed at a single time point is associated with the efficacy of immunotherapy, and we hypothesized that longitudinal changes in muscle mass may also be important. This retrospective study included patients with non-small cell lung cancer (NSCLC) who received durvalumab treatment after concurrent chemoradiotherapy (CCRT) between January 2017 and April 2023. Muscle loss and sarcopenia were assessed based on the lumbar skeletal muscle area. Patients with a decrease in muscle area of 10% or more during CCRT were categorized into the muscle loss group, while those with a decrease of less than 10% were categorized into the muscle maintenance group. We evaluated the relationship between muscle changes during CCRT and the efficacy of durvalumab treatment. Among the 98 patients, the muscle maintenance group had a significantly longer PFS of durvalumab treatment compared to the muscle loss group (29.2 months [95% confidence interval (CI): 17.2-not reached] versus 11.3 months [95% CI: 7.6-22.3]; p = 0.008). The multivariable analysis confirmed that muscle change was a significant predictor of a superior PFS (HR: 0.47 [95% CI: 0.25-0.90]; the p -value was less than 0.05). In contrast, the OS between the groups did not differ significantly (not reached [95% CI: 21.8 months-not reached] and 36.6 months [95% CI: 26.9-not reached]; p = 0.49). Longitudinal muscle changes during CCRT are a predictor of durvalumab's efficacy in patients with NSCLC after CCRT.

We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib-ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T. Yamada received commercial research grants from Ono Pharmaceutical, Janssen Pharmaceutical K.K., AstraZeneca, and Takeda Pharmaceutical Company Limited and speaking honoraria from Eli Lilly and Chugai-Roche. H. Kawachi received personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Eli Lilly Japan, and MSD outside the purview of the submitted work. A. Osoegawa received consultant honoraria from AstraZeneca and speaking honoraria from AstraZeneca, MSD Japan, Chugai Pharmaceutical, Bristol Myers Squibb, and Ono Pharmaceutical. T. Sakai received research grants from Otsuka Pharmaceutical, Taiho Pharmaceutical, and Oncolys BioPharma and a patent fee from JT Pharmaceutical. T. Yasuhiro and R. Kozaki are paid employees of Ono Pharmaceutical. S. Yano received research grants from Chugai-Roche and Boehringer-Ingelheim and speaking honoraria from Amgen, Chugai-Roche, Boehringer-Ingelheim, Novartis, and Pfizer. K. Takayama received research grants from Chugai-Roche and Ono Pharmaceutical and personal fees from AstraZeneca, Chugai-Roche, MSD-Merck, Eli Lilly, Boehringer-Ingelheim, and Daiichi-Sankyo. The other authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Few effective treatments are available for small cell lung cancer (SCLC), indicating the need to explore new therapeutic options. Here, we focus on an antibody-drug conjugate (ADC) targeting the L1 cell adhesion molecule (L1CAM). Several publicly available databases reveal that (1) L1CAM is expressed at higher levels in SCLC cell lines and tissues than in those of lung adenocarcinoma and (2) the expression levels of L1CAM are slightly higher in SCLC tissues than in adjacent normal tissues. We conducted a series of in vitro experiments using an anti-L1CAM monoclonal antibody (termed HSL175, developed in-house) and the recombinant protein DT3C, which consists of diphtheria toxin lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G. Our HSL175-DT3C conjugates theoretically kill cells only when the conjugates are internalized by the target (L1CAM-positive) cells through antigen-antibody interaction. The conjugates (an ADC analog) were effective against two SCLC-N (NEUROD1 dominant) cell lines, Lu-135 and STC-1, resulting in decreased viability. In addition, L1CAM silencing rendered the two cell lines resistant to HSL175-DT3C conjugates. These findings suggest that an ADC consisting of a humanized monoclonal antibody based on HSL175 and a potent anticancer drug would be effective against SCLC-N cells.

Background and Objectives: Although intraprocedural rupture (IPR) is rare, it is a devastating complication of endovascular treatment (EVT) for intracranial aneurysms. Very few studies have been conducted on IPR, and the safety and efficacy of management techniques of IPR have not been investigated., Methods: Patients who experienced IPR during EVT between 2013 and 2022 were enrolled from a multicenter observational registry. We examined the safety and efficacy of the management of IPR using imaging markers, including increased hemorrhage and ischemic lesions, which were evaluated using postoperative computed tomography and diffusion-weighted imaging, respectively., Results: Of the 3269 EVTs for intracranial aneurysms, 74 patients who experienced IPR (2.26%) were analyzed. Fifty-five patients (3.36%) experienced IPR among 1636 EVT cases for ruptured aneurysms. Multivariate analysis revealed that increased hemorrhage was significantly associated with poor outcomes (odds ratio [OR], 6.37 [95% CI, 1.00-40.51], P = .050), whereas ischemic lesions were not. Regarding management techniques of IPR, antihypertensive medication use was significantly associated with increased hemorrhage (OR, 14.16 [95% CI, 2.35-85.34], P = .004). Heparin reversal was an independent factor for ischemic lesions (OR, 8.92 [95% CI, 1.54-51.58], P = .014)., Conclusion: Although the setting of IPR may be miscellaneous, and optimal management varies depending on individual cases, heparin reversal might be associated with ischemic complications, and its role in the successful hemostasis in IPR during EVT for ruptured aneurysms remains unclear., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Objective: Effective thrombectomies in the posterior circulation remain controversial. Previous reports have demonstrated the superiority of contact aspiration in anterior circulation. Aspiration catheters and stent retrievers are often used alone on a global scale, while combined techniques are commonly used in Japan. This study evaluated the effect of first-line contact aspiration with other strategies for the treatment of basilar artery occlusion., Methods: The primary outcome was the frequency of the first-pass effect, and the secondary outcome was the time from puncture to the first-pass effect. A multicenter observational registry including 16 Japanese stroke centers was used. Between December 2013 and February 2021, enrolled patients underwent endovascular thrombectomy for basilar artery occlusion. The efficacy of contact aspiration compared to other methods (including stent retrievers and combined techniques) was evaluated., Results: Eighty-four patients were included, all of whom had achieved effective recanalization. Twenty-six patients were treated with contact aspiration, 13 with combined technique, and 45 with stent retrievers. The two groups: contact aspiration and non-contact aspiration, had different backgrounds. Both had similar frequencies of effective recanalization and first-pass effects. The contact aspiration group experienced better functional outcomes without statistical significance, while this strategy was significantly associated with a shorter puncture-to-recanalization time (38 vs. 55 minutes, P=0.036). In particular, in the 55 patients with the first-pass effect, multivariate Cox proportional hazard analysis showed that contact aspiration was significantly associated with a shorter time from puncture to first-pass effect, independent of age and etiology of large-artery atherosclerosis (hazard ratio 2.02, 95% confidence intervals 1.10-3.69, P=0.023)., Conclusion: This study suggested that contact aspiration for basilar artery occlusion may shorten the puncture-to-first-pass effect, compared to stent retrievers and combined techniques., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The association between pet exposure in infancy, early childhood eczema, and FLG mutations remains unclear., Methods: This was a birth cohort study performed in Tokyo, Japan. The primary outcome was current eczema based on questionnaire responses collected repeatedly from birth to 5 years of age. Generalized estimating equations and generalized linear modeling were used to evaluate the association., Results: Data from 1448 participants were used for analyses. Household dog ownership during gestation, early infancy, and 18 months of age significantly reduced the risk of current eczema. Household cat ownership also reduced the risk of current eczema, albeit without statistical significance. The combined evaluation of children from households with pets, be it cats, dogs or both, the risk of current eczema at 1-5 years of age was lower in those with household pet exposure ownership during gestation (RR = 0.59, 95 % CI 0.45-0.77) and at 6 months (RR = 0.49, 95 % CI 0.36-0.68). , Reduced risks of eczema were also observed at 2-5 (RR = 0.52, 95 % CI 0.37-0.73) and 3-5 years of age (RR = 0.50 95 % CI 0.35-0.74) when the respective household pet ownership were evaluated at 18 months and 3 years of age. These protective associations of reduced risk of eczema were only observed in children without FLG mutations., Conclusions: Household dog and pet (dog, cat, or both) ownership was protective against early childhood eczema in a birth cohort dataset. This protective association was observed only in children without FLG mutations, which should be confirmed in studies with larger cohorts., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Purpose: Adult spinal deformity (ASD) is associated with a combination of back and leg pain of various intensities. The objective of the present study was to investigate the diverse reaction of pain profiles following ASD surgery as well as post-operative patient satisfaction., Methods: Multicenter surveillance collected data for patients ≥ 19 years old who underwent primary thoracolumbar fusion surgery at > 5 spinal levels for ASD. Two-step cluster analysis was performed utilizing pre-operative numeric rating scale (NRS) for back and leg pain. Radiologic parameters and patient-reported outcome (PRO) scores were also obtained. One-year post-operative outcomes and satisfaction rates were compared among clusters, and influencing factors were analyzed., Results: Based on cluster analysis, 191 ASD patients were categorized into three groups: ClusterNP, mild pain only (n = 55); ClusterBP, back pain only (n = 68); and ClusterBLP, significant back and leg pain (n = 68). ClusterBLP (mean NRS back 7.6, mean NRS leg 6.9) was the oldest 73.4 years (p < 0.001) and underwent interbody fusion (88%, p < 0.001) and sacral/pelvic fixation (69%, p = 0.001) more commonly than the other groups, for the worst pelvis incidence-lumbar lordosis mismatch (mean 43.7°, p = 0.03) and the greatest sagittal vertical axis (mean 123 mm, p = 0.002). While NRS back , NRS leg and PRO scores were all improved postoperatively in ClustersBP and BLP, ClusterBLP showed the lowest satisfaction rate (80% vs. 80% vs. 63%, p = 0.11), which correlated with post-operative NRS back (rho = -0.357)., Conclusions: Cluster analysis revealed three clusters of ASD patients, and the cluster with the worst pain back and leg pain had the most advanced disease and showed the lowest satisfaction rate, affected by postoperative back pain., (© 2024. The Author(s).)

Few efficacious treatment options are available for patients with small cell lung carcinoma (SCLC), indicating the need to develop novel therapeutic approaches. In this study, we explored kinesin family member 11 (KIF11), a potential therapeutic target in SCLC. An analysis of publicly available data suggested that KIF11 mRNA expression levels are significantly higher in SCLC tissues than in normal lung tissues. When KIF11 was targeted by RNA interference or a small-molecule inhibitor (SB743921) in two SCLC cell lines, Lu-135 and NCI-H69, cell cycle progression was arrested at the G2/M phase with complete growth suppression. Further work suggested that the two cell lines were more significantly affected when both KIF11 and BCL2L1, an anti-apoptotic BCL2 family member, were inhibited. This dual inhibition resulted in markedly decreased cell viability. These findings collectively indicate that SCLC cells are critically dependent on KIF11 activity for survival and/or proliferation, as well as that KIF11 inhibition could be a new strategy for SCLC treatment.

Medial displacement calcaneal osteotomy (MDCO) is the standard procedure for flatfoot. We investigated the effect of MDCO on the foot using a finite element analysis. Foot models were created from computed tomography data of 8 patients with flat feet. MDCO was performed on each model with bone translation distance of 4, 8, and 12 mm. The morphological changes, plantar pressures, and stress percentage on the talocrural and subtalar joints were evaluated before and after surgery. Morphological evaluation showed improvement in the medial longitudinal arch. The stress percentage of plantar pressure in the medial area decreased, and the stress percentage of plantar pressure in the mid- and lateral forefoot area increased. At the talocrural joint, the medial and middle stress percentage increased, while the lateral and posterior stress percentage decreased. In the subtalar joint, the stress percentage in the middle subtalar joint increased and that in the posterior subtalar joint decreased. Within the posterior subtalar joint, the anterior and medial stress percentage increased, while the posterior and lateral stress percentage decreased. Preoperative simulation using the finite element analysis may be useful in understanding postoperative morphological changes and loading conditions to perform patient-specific surgery., (© 2024. The Author(s).)

Stearoyl-CoA desaturase 1 (SCD1) is an attractive target for cancer therapy. However, the clinical efficacy of SCD1 inhibitor monotherapy is limited. There is thus a need to elucidate the mechanisms of resistance to SCD1 inhibition and develop new therapeutic strategies for combination therapy. In this study, we investigated the molecular mechanisms by which cancer cells acquire resistance to endoplasmic reticulum (ER) stress-dependent cancer cell death induced by SCD1 inhibition. SCD1 inhibitor-sensitive and -resistant cancer cells were treated with SCD1 inhibitors in vitro, and SCD1 inhibitor-sensitive cancer cells accumulated palmitic acid and underwent ER stress response-induced cell death. Conversely, SCD1-resistant cancer cells did not undergo ER stress response-induced cell death because fatty acid desaturase 2 (FADS2) eliminated the accumulation of palmitic acid. Furthermore, genetic depletion using siRNA showed that FADS2 is a key determinant of sensitivity/resistance of cancer cells to SCD1 inhibitor. A549 cells, an SCD1 inhibitor-resistant cancer cell line, underwent ER stress-dependent cancer cell death upon dual inhibition of SCD1 and FADS2. Thus, combination therapy with SCD1 inhibition and FADS2 inhibition is potentially a new cancer therapeutic strategy targeting fatty acid metabolism., (© 2024. The Author(s).)

We report a case of a large vestibular schwannoma in an 80-year-old female patient that shrank after palliative Gamma Knife radiosurgery (GKS). Neurological symptoms included hearing deterioration and facial palsy. The tumor volume was 21.9 mL. Craniotomy was considered high-risk, and conventional GKS was risky, owing to the risk of transient enlargement. Therefore, GKS was performed on only a portion of the tumor. The marginal dose (12 Gy) volume was 3.8 mL (17.4%). The tumor began to shrink after transient enlargement. Sixty months later, the tumor volume was only 3.1 mL, and the patient was able to maintain independent activities of daily living without salvage treatment., Competing Interests: No potential conflict of interest relevant to this article was reported.

Purpose: To investigate the association between adherence to guideline-recommended risk-based postoperative nausea and vomiting (PONV) prophylaxis, the antiemetics used for PONV prophylaxis, and the incidence of PONV in patients who were underwent general anesthesia before and after 5-HT3 receptor antagonists became available., Methods: Patients (≥ 20 years old) who were extubated after scheduled surgery and returned to general wards between January 2021 and February 2022 and between June 2022 and July 2023 were included. Risk factors included age < 50, female, motion sickness, nonsmoker, surgical factors, and postoperative opioid use. Two and three or more prophylaxis were recommended for patients with one or two and three or more risk factors, respectively. The primary outcome was the number of patients who received adequate prophylaxis, and the secondary outcomes were antiemetic agents used during anesthesia and the incidence of PONV on postoperative days 0 and 1. PONV was defined as documented PONV or rescue antiemetic administration., Results: From January 2021 to February 2022 and from June 2022 to July 2023, 2342 and 2682 patients were included, respectively. Before ondansetron became available, more D2 receptor antagonists were used (p < 0.001), and after ondansetron became available, both ondansetron (p < 0.001) and propofol (p < 0.001) were given more frequently. Before and after ondansetron became available, the number of patients with adequate prophylaxis was 3.7% and 9.2%, respectively (p < 0.001), and the incidence of PONV on postoperative days 0 and 1 was 44.6% and 44.0%, respectively (p = 0.67)., Conclusion: The availability of ondansetron increased the number of patients with adequate PONV prophylaxis, but did not decrease the incidence of PONV., (© 2024. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Background: The effectiveness of slow low-dose oral immunotherapy (SLOIT) for cow's milk (CM) allergy has been reported. Most OIT studies have discussed the target populations over 4 years old. Furthermore, no predicting modeling is reported for CM allergy remission by CM-SLOIT under 4 years of age., Objective: We sought to develop a predictive model for CM allergy remission by SLOIT after 3 years in young children who started CM-SLOIT under 4 years of age., Methods: We included young children with cow's milk allergy or cow's milk sensitization (development modeling set with 120 children and validation modeling set with 71 children). We did logistic regression analysis to develop the models. We calculated the area under the receiver operating curves (ROC-AUCs) to evaluate the predictive modeling performance., Results: The model (CM-sIgE before SLOIT + age at beginning SLOIT + serum TARC before starting SLOIT + CM-sIgE titer one year after OIT) showed good discrimination with the ROC-AUC of 0.83 (95% CI:0.76-0.91) on internal validation. Applying the model to the validation set gave good discrimination (ROC-AUC = 0.89, 95% CI:0.80-0.97) and a reasonable calibration (intraclass correlation coefficient = 0.88, 95% CI:0.62-0.97)., Conclusion: We developed and validated predictive modeling for determining the remission rate of CM allergy at 3 years after SLOIT under 4 years of age in children with CM allergy. This predictive model is highly accurate and can support CM allergy management. (226 words)., (© 2024 The Author(s).)

Background and Aims: Precise diagnostic biomarkers are urgently required for pancreatic ductal adenocarcinoma (PDAC). Therefore, the aim of this study was to identify PDAC-specific exosomal microRNAs (Ex-miRs) from pancreatic juice (PJ) and evaluate their diagnostic potential., Methods: Exosomes in PJ and serum were extracted using ultracentrifugation and confirmed morphologically and biochemically. PDAC-specific Ex-miRs were identified using our original miR arrays, in which "Ex-miRs derived from the PJ of patients with chronic pancreatitis (CP)" were subtracted from Ex-miRs commonly expressed in both "human PDAC cell lines" and "the PJ of patients with PDAC." We verified the expression of these miRs using quantitative real-time reverse transcription polymerase chain reaction. Changes in serum Ex-miR levels were assessed in 2 patients with PDAC who underwent curative resection. In situ hybridization was performed to directly visualize PDAC-specific miR expression in cancer cells., Results: We identified novel Ex-miR-4516 and Ex-miR-4674 from the PJ of patients with PDAC, and they showed 80.0% and 81.8% sensitivity, 80.8% and 73.3% specificity, and 90.9% and 80.8% accuracy, respectively. The sensitivity, specificity, and accuracy of a triple assay of Ex-miR-4516/4674/PJ cytology increased to 93.3%, 81.8%, and 88.5%, respectively. In serum samples (n = 88), the sensitivity, specificity, and accuracy of Ex-miR-4516 were 97.5%, 34.3%, and 68%, respectively. Presurgical levels of serum-derived Ex-miR-4516 in 2 patients with relatively early disease stages declined after curative resection. In situ hybridization demonstrated that Ex-miR-4516 expression exclusively occurred in cancer cells., Conclusion: Liquid assays using the in situ-proven Ex-miR-4516 may have a high potential for detecting relatively early-stage PDAC and monitoring its clinical course., (© 2024 The Authors.)

Background: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear., Objective: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis., Patients and Methods: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020., Results: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03)., Conclusions: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge., (© 2024. The Author(s).)

Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor., Competing Interests: Declaration of competing interest T. Yamada received commercial research grants from Pfizer, Ono Pharmaceutical, Janssen Pharmaceutical K.K., AstraZeneca, and Takeda Pharmaceutical Company Limited and has received speaking honoraria from Eli Lilly. H. Kawachi received personal fees from Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Eli Lilly Japan KK, and MSD KK, outside the purview of the submitted work. N. Furuya received personal fees from AstraZeneca, Chugai, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Pfizer, Taiho, and Novartis. S. Watanabe received grants and personal fees from Boehringer Ingelheim and Nippon Kayaku. Personal fees from Lilly, Pfizer, Novartis Pharma, AstraZeneca, Chugai Pharma, Bristol-Myers, Ono Pharmaceutical, Daiichi Sankyo, and Taiho Pharmaceutical. S. Yano received research grants from Chugai Pharmaceutical and Boehringer-Ingelheim and has received speaking honoraria from Amgen, Chugai Pharmaceutical, Boehringer-Ingelheim, Novartis, and Pfizer. T. Sakai received research grants from Otsuka Pharmaceutical, Taiho Pharmaceutical and Oncolys BioPharma, and a patent fee from JT Pharmaceutical. K. Takayama reports receiving research grants from Chugai-Roche Co., and Ono Pharmaceutical Co., and personal fees from AstraZeneca Co., Chugai-Roche Co., MSD-Merck Co., Eli Lilly Co., Boehringer-Ingelheim Co., and Daiichi-Sankyo Co.No potential conflicts of interest were disclosed by the other authors., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: There have been numerous studies of the anterior cruciate ligament (ACL) anatomy, but few have focused on the long axis angle of the femoral ACL footprint. This study investigated the angle between the long axis of the femoral ACL footprint and the bony morphology of the knee., Methods: This study is a cadaveric descriptive study. Thirty non-paired formalin-fixed knees of Japanese cadavers were used. Anteromedial (AM) and posterolateral (PL) bundles were identified according to the tension pattern differences during the complete range of motion of the knee. In the ACL femoral footprint, there is a fold between the mid-substance insertion site and fan-like extension fibers. After identifying AM and PL bundles of mid-substance fibers, the mid-substance and fan-like extension fibers were divided into those bundles and stained. We defined the line passing through the center of the AM and PL bundles as the long axis of the ACL. The center points of each of the four areas and the angle between the long axis of the ACL and the bony morphology of the knee were calculated using Image J software., Results: The mean angle between the axis of the femoral shaft and the long axis of the ACL mid-substance insertion was 28.8 ± 12.2 degrees. The mean angle between the Blumensaat line and the long axis of the mid-substance was 54.2 ± 13.5 degrees., Conclusion: The mean angle between the axis of the femoral shaft and the long axis of the femoral ACL footprint was approximately 29 degrees. There is a wide variation in the long axis of the femoral ACL footprint. To achieve better clinical results through a more anatomically accurate reconstruction, it can be beneficial to replicate the ACL femoral footprint along its native long axis., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© Indian Orthopaedics Association 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Manila, a highly urbanized city, is listed as one of the top cities with the highest recorded number of coronavirus disease 2019 (COVID-19) cases in the Philippines. This study aimed to detect and quantify the RNA of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the Omicron variant in 51 wastewater samples collected from three locations in Manila, namely Estero de Santa Clara, Estero de Pandacan, which are open drainages, and a sewage treatment plant (STP) at De La Salle University-Manila, between July 2022 and February 2023. Using one-step reverse transcription-quantitative polymerase chain reaction, SARS-CoV-2 and Omicron variant RNA were detected in 78 % (40/51; 4.9 ± 0.5 log 10 copies/L) and 60 % (24/40; 4.4 ± 0.3 log 10 copies/L) of wastewater samples collected from all sampling sites, respectively. SARS-CoV-2 RNA was detected frequently at Estero de Santa Clara (88 %, 15/17); its highest concentration was at the STP (6.3 log 10 copies/L). The Omicron variant RNA was present in the samples collected (4.4 ± 0.3 log 10 copies/L) from all sampling sites, with the highest concentration at the STP (4.9 log 10 copies/L). Regardless of normalization, using concentrations of pepper mild mottle virus RNA, SARS-CoV-2 RNA concentrations exhibited the highest positive correlation with COVID-19 reported cases in Manila 5 days after the clinical report. These findings revealed that wastewater-based epidemiology may aid in identifying and monitoring of the presence of pathogens in open drainages and STPs in the Philippines. This paper provides the first documentation on SARS-CoV-2 and the Omicron variant in wastewater from Manila., Competing Interests: Declaration of competing interest Eiji Haramoto received research funding from Takara Bio Inc. Masaaki Kitajima received research funding from Shionogi & Co., Ltd. and AdvanSentinel, Inc. and patent royalties from Shionogi & Co., Ltd. The other authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The association between postoperative patient-reported outcomes (PROs) and patient satisfaction remains poorly defined in patients undergoing surgery for thoracic myelopathy. This study aimed to investigate PROs and patient satisfaction following surgical intervention for thoracic myelopathy., Methods: A prospective cohort of 133 patients who underwent surgery for thoracic myelopathy at 13 hospitals between April 2017 and August 2021 was enrolled. Patient demographics and perioperative complications were recorded. PROs were assessed using questionnaires administered preoperatively and 1 year postoperatively, including the EuroQol-5 dimension, physical and mental component summaries of the 12-item Short-Form Health Survey, Oswestry Disability Index, and numerical rating scales for low back, lower extremity, and plantar pain. Patients were categorized into two groups: satisfied (very satisfied, satisfied, and slightly satisfied) and dissatisfied (neither satisfied nor dissatisfied, slightly dissatisfied, dissatisfied, and very dissatisfied)., Results: The mean age of the patients was 66.5 years, comprising 87 men and 46 women. The most common diagnoses were ossification of the ligamentum flavum (48.8%) and thoracic spondylotic myelopathy (26.3%). Seventy-four (55.6%) and 59 (44.3%) patients underwent decompression surgery and underwent decompression with fusion, respectively. Eight patients required reoperation due to postoperative surgical site infection, hematoma, and insufficient decompression in four, three, and one patient. Ninety (67.7%) patients completed both the preoperative and postoperative PRO questionnaires, all of which demonstrated significant improvement. Among them, 58 (64.4%) and 32 (35.6%) reported satisfaction and dissatisfaction with their treatment, respectively. The satisfied group showed superior improvement in PROs than the dissatisfied group, although there were no significant differences in complication rates between the two groups., Conclusions: The 64.4% satisfaction rate observed in patients undergoing surgery for thoracic myelopathy was lower than that reported in previous studies on cervical or lumbar spine surgery. The dissatisfied group exhibited significantly poorer quality of life (QOL) and higher pain scores than the satisfied group., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2024 The Japanese Society for Spine Surgery and Related Research.)

Background: Several reports have highlighted comparable surgical outcomes between microendoscopic laminectomy (MEL) and open laminectomy (open) for lumbar spinal stenosis. However, the unilateral approach in MEL may present challenges for the upper lumbar levels, where facet joints are located deeper inside. Our objective was to compare surgical outcomes and radiographic evaluations for single-level decompression cases at L1-L2 or L2-L3 between MEL and open laminectomy., Methods: We analyzed patients who underwent single-level decompression for upper lumbar spinal stenosis at 12 distinguished spine centers from April 2017 to September 2021. Baseline demographics, preoperative, and 1-year postoperative patient-reported outcomes, along with imaging parameters, were compared between the MEL and open groups. To account for potential confounding, patients' backgrounds were adjusted using the inverse probability weighting method based on propensity scores., Results: Among the 2487 patients undergoing decompression surgery, 118 patients (4.7%) underwent single-level decompression at L1-L2 or L2-L3. Finally, 80 patients (51 in the MEL group, 29 in the open group) with postoperative data were deemed eligible for analysis. The MEL group exhibited significantly improved postoperative EuroQol 5-Dimension values compared to the open group. Additionally, the MEL group showed a lower facet preservation rate according to computed tomography examination, whereas the open group had a higher incidence of retrolisthesis., Conclusions: Although overall surgical outcomes were similar, the MEL group demonstrated potential advantages in enhancing EuroQol 5-Dimension scores. The MEL group's lower facet preservation rate did not translate into a higher postoperative instability rate., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: Assessing the indication for elective neuro-endovascular treatment (EVT) in older patients requires consideration of the impact of systemic comorbidities on their overall reduced life expectancy. The objective of this study was to determine the long-term outcomes of elective neuro-EVT in patients aged ≥80 years, and to investigate the impact of pre-existing cancer on their long-term outcomes., Methods: Of the patients enrolled in multicenter observational registry, those aged ≥80 years undergoing elective neuro-EVT between 2011 and 2020 were enrolled. A history of cancer was defined as a pre-existing solid or hematologic malignancy at the time of EVT. The primary outcome was time to death from elective neuro-EVT., Results: Of the 6183 neuro-EVT cases implemented at 10 stroke centers, a total of 289 patients (median age, 82 years [interquartile range 81-84 years]) were analyzed. A total of 58 (20.1%) patients had a history of cancer. A total of 78 patients (27.0%) died during follow up. The 5-year survival rate of enrolled patients was 64.6%. Compared with patients without a history of cancer, those with a history of cancer showed significantly worse survival (log-rank test, P = 0.001). Multivariate Cox proportional hazards analysis showed history of cancer was an independent predictor of time to death from elective neuro-EVT (HR 1.74, 95% CI 1.01-3.00, P = 0.047). Cancer was the leading cause of death, accounting for 25.6% of all deaths., Conclusions: The present study showed that history of cancer has a significant impact on time to death from elective neuro-EVT in patients aged ≥80 years. Geriatr Gerontol Int 2024; 24: 211-217., (© 2023 Japan Geriatrics Society.)

Few treatment options exist for pleural mesothelioma (PM), which is a progressive malignant tumor. However, the efficacy of molecular-targeted monotherapy is limited, and further therapeutic strategies are warranted to treat PM. Recently, the cancer cell-cycle checkpoint inhibitors have attracted attention because they disrupt cell-cycle regulation. Here, we aimed to establish a novel combinational therapeutic strategy to inhibit the cell-cycle checkpoint kinase, ATR in PM cells. The siRNA screening assay showed that anexelekto (AXL) knockdown enhanced cell growth inhibition when exposed to ATR inhibitors, demonstrating the synergistic effects of the ATR and AXL combination in some PM cells. The AXL and ATR inhibitor combination increased cell apoptosis via the Bim protein and suppressed cell migration when compared with each monotherapy. The combined therapeutic targeting of AXL and ATR significantly delayed regrowth compared with monotherapy. Thus, optimal AXL and ATR inhibition may potentially improve the PM outcome., (©2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: The surgical Apgar score is useful for predicting postoperative morbidity and mortality. However, its applicability in frail patients with minimal hemodynamic variation remains unknown. This study aimed to investigate the association between frailty and surgical Apgar score., Methods: This secondary analysis included 210 patients ≥ 65 years of age undergoing elective major abdominal surgery for cancer. Frailty was assessed using the Fried Frailty Phenotype Questionnaire and defined as a total score of ≥ 3. The surgical Apgar score (range, 0-10; including mean blood pressure, heart rate, and blood loss volume) was compared between patients with or without frailty using the Mann-Whitney U test. Postoperative severe complications and length of postoperative stay were compared between patients with surgical Apgar scores ≤ 7 and > 7., Results: Among the included patients, 45 were classified as frail. The median [1st quartile, 3rd quartile] surgical Apgar scores in patients with and without frailty were 7.0 [7.0, 8.0] and 8.0 [7.0, 8.0], respectively (P = 0.03). Patients with surgical Apgar score ≤7 had a higher incidence of serious postoperative complications (P = 0.03) and longer hospital stays (P < 0.001) compared with patients with surgical Apgar score >7., Conclusion: Frail patients have lower SAS, and patients with lower SAS have higher postoperative complication rates and longer hospital stays in patients who underwent cancer surgery., (© 2024. The Author(s).)

In cases of moderate to severe atopic dermatitis that does not respond to topical therapy, temporary systemic administration of molecular targeted drugs (biological agents or oral Janus kinase[JAK]inhibitors) may be necessary. However, topical therapy forms the basis of the treatment for atopic dermatitis, and if topical therapy is appropriately established with long-term remission achieved, the use of molecular targeted drugs can be discontinued. In these two cases of severe adolescent atopic dermatitis, successful initiation of remission was achieved through hospitalization, disease education, skincare guidance, and the combined use of appropriate topical therapy and short-term oral JAK inhibitors during the remission induction phase. Subsequently, maintenance of remission was possible with proactive topical therapy alone. As there are many cases where molecular targeted drugs cannot be discontinued, presenting cases where oral JAK inhibitors were successfully discontinued emphasizes the avoidance of indiscriminate long-term use of molecular targeted drugs. This highlights the significance of topical therapy for atopic dermatitis and the importance of avoiding the careless use of molecular targeted drugs, and supporting the transition to adulthood.

We conducted a two-year inhalation study of butyraldehyde using F344/DuCrlCrlj rats. The rats were exposed to 0, 300, 1,000 and 3,000 ppm (v/v) for 6 hr/day, 5 days/ week for 104 weeks using whole-body inhalation chambers. The incidence of squamous cell carcinoma of the nasal cavity was increased in the 3,000 ppm groups of both male and female rats, with Fisher's exact test and the Peto test indicating that the incidence was significant. In addition to squamous cell carcinoma in the nasal cavity, in the 3,000 ppm groups one male had an adenosquamous carcinoma, one male had a carcinosarcoma, one male had a sarcoma NOS (Not Otherwise Specified), and one female had a squamous cell papilloma in the nasal cavity. The combined incidence of squamous cell carcinoma, adenosquamous carcinoma and carcinosarcoma was significantly increased in male rats and the combined incidence of squamous cell papilloma and carcinoma was significantly increased in female. Based on these results, we conclude that there is clear evidence of butyraldehyde carcinogenicity in male and female rats.

To investigate the carcinogenicity of anatase-type nano-titanium dioxide (aNTiO 2 ), F344/DuCrlCrlj rats were exposed to aNTiO 2 aerosol at concentrations of 0, 0.5, 2, and 8 mg/m 3 . The rats were divided into 2 groups: carcinogenicity study groups were exposed for two years, and satellite study groups were exposed for one year followed by recovery for 1 day, 26 weeks, and 52 weeks after the end of exposure. In the carcinogenicity groups, bronchiolo-alveolar carcinomas were observed in two 8 mg/m 3 -exposed males, showing an increasing trend by Peto's test. However, this incidence was at the upper limit of JBRC's historical control data. Bronchiolo-alveolar adenomas were observed in 1, 2, 3, and 4 rats of the 0, 0.5, 2, and 8 mg/m 3 -exposed females and were not statistically significant. However, the incidence in the 8 mg/m 3 -exposed females exceeded JBRC's historical control data. Therefore, we conclude there is equivocal evidence for the carcinogenicity of aNTiO 2 in rats. No lung tumors were observed in the satellite groups. Particle-induced non-neoplastic lesions (alveolar epithelial hyperplasia and focal fibrosis) were observed in exposed males and females in both the carcinogenicity and satellite groups. Increased lung weight and neutrophils of bronchoalveolar lavage fluid were observed in the 8 mg/m 3 -exposed carcinogenicity groups. The aNTiO 2 deposited in the lungs of the satellite group rats was decreased at 26 weeks after the end of exposure compared to 1 day after the end of exposure. At 52 weeks after the end of exposure, the decreased level was the same at 26 weeks after the end of exposure.

Subarachnoid hemorrhage due to the A1 segment of an anterior cerebral artery dissecting aneurysm is rare. Therefore, a standard treatment has not been established. Though several case reports of direct surgery exist, there are few reports on endovascular treatment. This is the first study to describe five patients who underwent endovascular treatment for ruptured A1 dissecting aneurysms. Between January 2001 and December 2022 in our affiliated centers, five cases of SAH-onset A1 dissecting aneurysms were treated with endovascular treatment. We describe in detail two representative cases, briefly summarize the other three, and analyze their complications and outcomes. In the five cases, four were female. Four were in their 50s, and one was in her 80s. The WFNS grades were as follows: three were 2, one was 4, and one was 5. No re-ruptures or symptomatic complications were observed. The modified Rankin Scale scores at the time of discharge were as follows; one was 0, one was 1, two were 2, and one was 5. One in five patients needed retreatment after endovascular trapping because of recanalization. Endovascular treatment may be an effective and viable treatment option for ruptured A1 dissecting aneurysms. Further studies are needed to collect detailed data on complications and outcomes.