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Purpose: Diagnostic reference levels (DRLs) are defined as fluoroscopic dose rate measurements that are used for patient dose management in angiography. It is recommended that DRLs be measured at least once a year. This study aimed to evaluate the long-term fluctuations of fluoroscopic dose rate in an angiography system., Methods: An unconnected X-ray output analyzer was used to measure the fluoroscopic dose rate (air kerma rate) at the patient's entrance reference point for a specific angiography system. The target period was from 2015 to 2022, and four measurements per year were made. First, the fluoroscopic dose rate was measured, and the average value and standard deviation for the target period were calculated. Next, the uncertainty of the measured values and the coefficient of variation were calculated. Finally, we calculated the fluoroscopic dose rate measurement error., Results: The average±standard deviation of the fluoroscopic dose rate was 353.29±9.11 µGy/s. The maximum uncertainty and coefficient of variation for each year were 5.41 µGy/s and 0.03, respectively. The maximum measurement error was 4.67%, where the mean measured value was taken as the true value., Conclusion: The fluctuation in the measured value of the fluoroscopic dose rate by an angiography system for 8 years is within ±5%, indicating stable X-ray output.

Objective: The objective of this study is to investigate factors associated with outcomes after 3 months of instructed usage of hand-held digital devices (DD) in patients with acquired comitant esotropia (ACE)., Methods and Analysis: This prospective multicentre observational study included patients with ACE, aged 5-35 years, who used DD within 1 year of onset and were followed up for clinical findings and instructed use of DD. The outcomes were classified into four groups: cured, improved, unchanged and worsened. After the analysis of group differences in the clinical and DD use-related factors by univariate analysis, we used ordinal logistic regression models to identify factors associated with favourable outcomes., Results: Of 156 patients (mean age (SD): 16.4 (7.4) years), 10 (6%), 58 (37%), 67 (43%) and 21 (14%) were classified into the cured, improved, unchanged, and worsened, respectively. In the univariate analysis, consultation within 3 months of onset, small-angle strabismus at distance and good stereoacuity were associated with good outcomes. Ordinal logistic regression analysis on adjusting for age with stereoacuity or successful DD-use time halving showed that small-angle strabismus at distance (OR: 1.02, 95% CI 1.00 to 1.03, p=0.023), good stereoacuity (OR: 1.31; 95% CI 1.10 to 1.56; p=0.003) and successful halving of DD-use time (OR: 0.63; 95% CI 0.43 to 0.92; p=0.016) influenced favourable outcomes., Conclusion: Patients with small-angle esotropia, good stereoacuity on consultation and success in halving DD-use time had a higher chance of recovery through instructional DD usage. Further studies using objectively measurable systems are needed to ensure the accuracy of DD-use time., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: To evaluate the organ-specific therapeutic effect of enfortumab vedotin (EV) after chemotherapy and immunotherapy failed for advanced urothelial carcinoma., Materials Methods: At 6 institutions between December 2021 and July 2023, we retrospectively analyzed patients with metastatic upper and lower urinary tract cancer who received EV monotherapy after platinum-based chemotherapy and immune checkpoint blockade therapy. Objective response rate (ORR) and organ-specific response rate (OSRR) were evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1., Results: This study analyzed 58 patients with 210 tumor lesions, of which 24% were females and 48% had upper urinary tract cancer. The ORR and disease control rate were 53.5% and 74.1%. Moreover, we found 15 target lesions in the primary site, 7 in local recurrence, 93 in the lymph nodes, 46 in the lung, 29 in the liver, and 20 in the bone, with OSRRs of 40%, 71.4%, 61.1%, 70.6%, 90.9%, and 18.2%, respectively. Over time from baseline, the reduction rate (median) in tumor burden was 50% or more in the lymph node, lung, and liver metastases., Conclusion: The organ-specific tumor response to EV in patients with metastatic urothelial carcinoma was almost favorable. The antitumor activity of EV monotherapy may be less in bone metastasis than in other organ sites. Conversely, EV showed remarkably high efficacy against liver metastasis., Competing Interests: Disclosure The authors declare that they have no competing interests in relation to this study., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: An accurate measurement of x-ray beams is expected to reduce the uncertainties associated with estimating radiation risk to patients in clinical settings. To perform assessment tasks based on the readings of a solid-state detector (SSD) using semiconductor technology, the characteristics of the detector should be elucidated. In this study, we evaluated the measurement accuracy of a new SSD under diagnostic x-ray beam conditions in terms of air kerma, tube voltage, and half-value layer (HVL). The performance of the SSD was then compared with those of reference instruments., Methods: The tube voltage was varied within the range of 50-120 kV in steps of 10 kV and the thickness and materials of additional filters were concurrently changed (several combinations were tested). In addition, the dose rate and energy dependence of the SSD were also investigated. These effects were analyzed based on statistical significance tests. Furthermore, the expanded uncertainties in the series of measurements were meticulously calculated., Results: The results showed average relative differences of -3.26 ± 1.33%, 0.44 ± 1.01%, and -2.60 ± 3.31% for air kerma, tube voltage, and HVL, respectively. Furthermore, air kerma did not exhibit any dependence on dose rate and energy, in contrast to tube voltage and HVL measurements., Conclusion: The measurement values of the SSD fall within the acceptable range of uncertainty, highlighting its measurement accuracy and reliability. Furthermore, based on the characteristics elucidated by this study, valuable insights are provided concerning the assurance of appropriate measurement values in clinical settings., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Diagnostic reference level (DRL) for mammography for 2015 and 2020 has been published by J-RIME. More new dose studies are needed to revise the next DRL. In preparation for the next revision of the DRL for mammography, this study investigated data from the Japan Central Organization on Quality Assurance of Breast Cancer Screening on the mean average glandular dose (AGD) for institutional image accreditation in 2019-2023 and the relationship between the average at eligible institutions to date and the type of breast X-ray system. The 95th percentile values of the AGD distributions for the Computed Radiography (CR) and Flat Panel Detector (FPD) systems were 2.5 mGy and 2.0 mGy, respectively. Moreover, it is assumed that AGD is decreasing due to the spread of FPD systems, and it is expected that the further spread of FPD systems and systems with W/Rh target/filter will reduce AGD in future., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Introduction: Carbon dioxide-dependent Proteus mirabilis has been isolated from clinical specimens. It is not clear whether mutations in carbonic anhydrase are responsible for the carbon dioxide dependence of P. mirabilis. The pathogenicity of carbon dioxide-dependent P. mirabilis also remains unclear. The purpose of this study was to determine the cause carbon dioxide dependence of P. mirabilis and its pathogenicity., Methods: The DNA sequence of can encoding carbonic anhydrase of a carbon dioxide-dependent P. mirabilis small colony variant (SCV) isolate was analyzed. To confirm that impaired carbonic anhydrase activity is responsible for the formation of the carbon dioxide-dependent SCV phenotype of P. mirabilis, we performed complementation experiments using plasmids with intact can. Additionally, mouse infection experiments were performed to confirm the change in virulence due to the mutation of carbonic anhydrase., Results: We found that the can gene of the carbon dioxide-dependent P. mirabilis SCV isolate showed had a frameshift mutation with a deletion of 1 bp (c. 173delC). The can of P. mirabilis encodes carbonic anhydrase was also found to function in Escherichia coli. The cause of the carbon dioxide-dependent SCV phenotype of P. mirabilis was an abnormality in carbonic anhydrase. Nevertheless, no changes were observed in virulence due to the mutation of carbonic anhydrase in mouse infection experiments., Conclusions: The can gene is essential for the growth of P. mirabilis in ambient air. The mechanisms underlying this fitness advantage in terms of infection warrant further investigation., Competing Interests: Declaration of competing interest The authors declare that there are 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.)

Background/aim: This study retrospectively evaluated whether enfortumab vedotin (EV) monotherapy is effective as a late-line treatment according to prior treatment type in patients with advanced urothelial carcinoma (UC)., Patients and Methods: We assessed consecutive patients from the Uro-Oncology Group in the Kyushu study population with lower and upper urinary tract cancer treated with EV monotherapy after platinum-based chemotherapy and immune checkpoint inhibitor therapy failure between December 2021 and March 2024. In particular, patients receiving avelumab maintenance or pembrolizumab therapy before EV for advanced UC were analyzed and compared according to the response rate, progression-free survival (PFS), and overall survival (OS)., Results: Of the 80 enrolled patients, 31 and 49 received avelumab and pembrolizumab before EV therapy, respectively. The avelumab and pembrolizumab groups had comparable objective response rates (48.4% vs. 44.9%, p=0.820) and disease control rates (77.4% vs. 67.3%, p=0.448). These two groups showed no significant difference in PFS from the initiation of EV (median: 6.4 months vs. 4.2 months, p=0.184); meanwhile, the avelumab group had better OS from the initiation of EV than the pembrolizumab group (median: 16.0 months vs. 10.2 months, p=0.019). Moreover, the median OS after first-line chemotherapy initiation was longer in the avelumab group than in the pembrolizumab group (40.3 months vs. 24.7 months, p=0.054). On multivariate analysis, avelumab maintenance therapy before EV reduced the mortality risk by 47% (95% confidence interval=0.27-1.03; p=0.059)., Conclusion: EV monotherapy after avelumab maintenance therapy provides favorable survival outcomes in patients with advanced UC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The efficacy, safety, and liver toxicity of enfortumab vedotin (EV) for elderly advanced urothelial carcinoma (UC) patients and patients with a poor performance status (PS) are unclear., Patients and Methods: We retrospectively analyzed the efficacy, safety, and liver toxicity of EV in elderly patients and patients with a poor PS between December 2021 and August 2023., Results: Sixty-two patients (≥75 years old, n=22; PS≥2, n=10) were enrolled. Patients with PS≥2 had significantly lower albumin levels than those with PS<2 (p=0.023). The objective response and disease control rates did not differ significantly between patients <75 and ≥75 years old (p=0.598 and p=0.769, respectively) or between those with PS<2 and PS≥2 (p>0.99 and p=0.178, respectively). Progression-free survival (PFS) and overall survival (OS) were not significantly different in patients <75 years and ≥75 years (p=0984, 0.368). A significant difference in PFS (p=0.047) but not OS (p=0.086) was observed between the PS<2 and PS≥2 groups. The rates of any-grade and severe (grade ≥3) adverse events did not differ significantly between patients <75 and ≥75 years (p=0.471, p=0.136) or between PS<2 and PS≥2 groups (p>0.99, 0.99). Aspartate aminotransferase (AST) levels significantly increased, but alanine aminotransferase levels did not, following EV treatment (p<0.001). Multivariate analyses revealed that the albumin level was an independent prognostic factor (hazard ratio=0.159; p<0.001)., Conclusion: EV demonstrated similar efficacy and safety in elderly and younger patients with advanced UC. In patients with a poor PS, although the safety was similar, survival was significantly worse in terms of PFS, while the AST levels were significantly elevated., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The subtype of urothelial carcinoma (SUC) has been known to possess morphological diversity for histologic subtype or divergent differentiation. However, the efficacy of avelumab against SUC remains unclear. Therefore, the effect of the treatment as well as the survival results of avelumab monotherapy were evaluated as a first-line therapeutic maintenance in patients with advanced SUC., Methods: A retrospective analysis was conducted on consecutive patients from the Uro-Oncology Group in Kyushu study population with advanced lower and upper urinary tract cancer who underwent avelumab maintenance therapy without progression after first-line platinum-based chemotherapy. Patients with pure urothelial carcinoma (PUC) and SUC were comparatively analyzed based on objective response rate (ORR), disease control rate, progression-free survival (PFS), and overall survival (OS)., Results: Out of 49 recorded patients, 38 and 11 had PUC and SUC, respectively. The most common subtype element was glandular differentiation (n=5), followed by squamous differentiation (n=3), micropapillary (n=1), and plasmacytoid subtypes (n=1). The SUC and PUC groups had comparable ORR (0% vs. 2.6%, P>0.99) and disease control rates (54.5% vs. 44.7%, P=0.73). These patient groups also showed no significant difference in PFS (median 3.9 vs. 3.1 months, P=0.33) or OS (median 16.7 vs. 22.1 months, P=0.47)., Conclusions: The response of SUC and PUC to avelumab was comparable in patients with advanced lower and upper urinary tract cancer, indicating that avelumab maintenance therapy is also effective for SUC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-53/coif). The authors have no conflicts of interest to declare., (2024 Translational Andrology and Urology. All rights reserved.)

Nanophthalmos, characterized by an abnormally small ocular globe, presents significant challenges in the management of strabismus due to its unique anatomical constraints. This detailed case report highlights the intricacies and outcomes of strabismus surgery in a patient with nanophthalmos, providing valuable insights into the surgical considerations and adaptations required for this rare condition. The subject of this case, a young girl diagnosed with esotropia and high hyperopia, underwent unilateral medial rectus muscle recession in an attempt to correct her esotropia. Despite the careful surgical approach and postoperative management, a two-year follow-up revealed a limited response to the intervention, with improvements in visual acuity but continued presence of esotropia and lack of stereopsis development. This case sheds light on several key considerations in the surgical treatment of strabismus in nanophthalmos patients, including the potential for reduced surgical effectiveness due to the small globe size, the importance of accurate preoperative assessment, and the challenges in predicting surgical outcomes. Additionally, it discusses the implications of these findings for future surgical planning, the potential need for revision surgeries, and the broader research context, emphasizing the necessity for a deeper understanding of the biomechanical and anatomical particularities of nanophthalmos in the context of strabismus surgery. The report concludes with recommendations for improving surgical strategies and patient outcomes, advocating for more comprehensive studies and a tailored approach to treating strabismus in individuals with nanophthalmos., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Negishi et al.)

Background/aim: The clinical outcomes associated with cutaneous toxicity and changes in the renal function of patients receiving enfortumab vedotin (EV) for advanced urothelial carcinoma (UC) is unclear., Patients and Methods: We retrospectively analyzed the relationship between clinical outcomes and EV-related cutaneous toxicity, and the influence on the renal function in 58 patients with advanced UC who received EV after the failure of platinum-based chemotherapy and immune checkpoint inhibitors from December 2021 to July 2023., Results: There were no differences in the overall response and disease control rates between patients with any grade of EV-related cutaneous toxicity and without (p=0.605 and p>0.99, respectively) nor of grade ≥3 (p>0.99 and p=0.173, respectively). Progression-free survival was not significantly associated with EV-related cutaneous toxicity of any grade (5.4 vs. 5.6 months, p=0.557) nor of grade ≥3 (2.7 vs. 5.6 months, p=0.053). Overall survival was not significantly associated with EV-related cutaneous toxicity of any grade (11.8 vs. 8.9 months, p=0.389), nor of grade ≥3 (4.6 vs. 11.4 months, p=0.168). The incidence of EV-related cutaneous toxicity of any grade was significantly higher in patients with any grade of ICI-related cutaneous toxicity (88.9% vs. 36.7%, p=0.008). There was no significant difference in the serum creatinine levels after EV treatment (p=0.211). Divided into two groups according to their renal function, using a serum creatinine cut-off of 2 mg/dl, there were no significant changes after EV treatment in either group (p=0.187 and p=0.938)., Conclusion: EV-related cutaneous toxicity did not affect clinical outcomes, although it occurred in patients who experienced immune checkpoint inhibitor-related cutaneous toxicity. EV did not affect renal function., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: In Japan, radiologists perform qualitative visual classification to define four categories of mammary gland density. However, an objective estimation of mammary gland density is necessary. To address this, we developed an automatic classification software using image similarity., Methods: We prepared 741 cases of mediolateral oblique images (MLO) for evaluation, and they were diagnosed as normal among the mammography images taken at our hospital. Image matching was performed using the evaluation images and an image database for breast density determination. In this study, the image similarity used zero normalized cross-correlation (ZNCC) as an index. In addition, if the breast thickness is less than 30 mm and each breast density category ZNNC has the same value, the category is evaluated on the fat side. We compared the results of qualitative visual classification and automatic classification methods to assess consistency., Results: The agreement with the subjective breast composition classification was 78.5%, and the weighted kappa coefficient was 0.98. One mismatched case was evaluated on the higher density side with the same ZNCC value between categories and a breast thickness greater than 30 mm., Conclusion: Image similarity provides an excellent estimation of quantification of breast density. This system could contribute to improving the efficiency of the mammography screening system.

We investigated the reduction in patient radiation exposure dose during percutaneous coronary intervention (PCI) by stent enhancement processing. We examined the effects of dose reduction based on the image quality of stent enhancement processing using a purpose-built dynamic phantom. We evaluated the image contrast (IC) of the stent in stent-enhanced images (SVref), digital angiography (DA), and stent-enhanced images with a 20%, 40%, and 60% lower imaging doses (SV20, SV40, and SV60). We visually evaluated graininess and stent shape using the mean opinion score (MOS) and retrospectively evaluated the acquisition duration of stent enhancement in PCI cases; finally, we estimated the decrease in patient radiation exposure due to stent enhancement. The image contrast of SVref at phantom thicknesses of 20 cm was 51.25 ± 3.82, while the image contrast of DA was significantly reduced at 14.90 ± 1.57 (p < 0.05). We observed a significant decrease in the MOS of graininess in SV60 and MOS of stent shape in DA (p < 0.05). Furthermore, the average imaging duration for stent enhancement using PCI was 22.65 ± 7.43 s, and the maximum imaging duration was 68.07 s. We hypothesize that patient radiation exposure dose can be reduced by up to 60.17 mGy by lowering the imaging dose during the stent enhancement process. Stent enhancement processing improves the visibility of stent images, and can reduce radiation exposure by approximately 40% during confirmation imaging of stents. Our study contributes to the reduction of radiation exposure dose for operators and patients in PCI., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Background: At present, eradication regimens for non-Helicobacter pylori Helicobacter (NHPH) have not been established yet. We investigated effectiveness of the standard triple-drug combination therapy for Helicobacter pylori eradication and of a proton pump inhibitor (PPI) monotherapy in eradication of NHPH., Methods: Subjects were the patients who were diagnosed with NHPH-infected gastritis based on microscopic findings, helical-shaped organisms obviously larger than Helicobacter pylori, in the gastric mucosal specimens using Giemsa staining at Kenwakai Hospital between November 2010 and September 2021, whose NHPH species were identified by polymerase chain reaction (PCR) analysis of urease genes in endoscopically-biopsied samples, and who consented to NHPH eradication with either the triple-drug combination therapy for one week or a PPI monotherapy for six months. Six months after the completion of eradication, its result was determined with esophagogastroduodenoscopy, microscopic examination, and PCR analysis. In cases of unsuccessful eradication, a second eradication with the other therapy was suggested to the patient., Results: PCR analysis detected NHPH in 38 patients: 36 as Helicobacter suis and two as Helicobacter heilmannii/Helicobacter ailurogastricus. Fourteen Helicobacter suis-infected and one Helicobacter heilmannii/Helicobacter ailurogastricus-infected patients requested eradication therapy. The triple-drug combination therapy succeeded in four of five patients, while the PPI monotherapy succeeded in five of 10 patients. Three of five patients who had been unsuccessful with the latter therapy requested the triple-drug combination therapy as the second eradication and all three were successful. In total, the triple-drug combination therapy succeeded in seven out of eight (87.5%) attempted cases, while the PPI monotherapy in five out of 10 (50%) attempted cases., Conclusions: In NHPH eradication, the triple-drug combination therapy was considered to be effective to some extent and to become the first-line therapy. While, although less successful, PPI monotherapy appeared to be a potentially promising option particularly for patients with allergy or resistance to antibiotics. Effectiveness of PPI monotherapy may be attributed to hyperacid environment preference of Helicobacter suis and PPI's acid-suppressive effect. Additionally, male predominance in NHPH-infected gastritis patients may be explained by gender difference in gastric acid secretory capacity. However, further evidence needs to be accumulated., Study Registration: This study was approved by the Research Ethics Committee of Kenwakai Hospital (No. 2,017,024)., (© 2024. The Author(s).)

Background: Cancer therapeutics-related cardiac dysfunction (CTRCD) is a well-recognised complication of cancer treatment. Treatment of CTRCD involves cardioprotective therapy (CPT) which can lead to a recovery of CTRCD with normalisation of the left ventricular ejection fraction (LVEF). As a result, there are potentially millions of cancer survivors with recovered CTRCD on CPT. Cardioprotective therapy can be associated with an undesirable long-term pill burden, financial costs, and side effects. Cancer survivorship is anticipated to increase significantly by the end of this decade. To date, there is no evidence of the safety of stopping CPT in this setting. This study seeks to evaluate the hypothesis that ceasing cardioprotective medication is a feasible and safe option without significant impact on LVEF in low-risk patients who have recovered from CTRCD., Methods and Analysis: We will perform a multicentre prospective open-label randomised controlled trial with blinded endpoint (PROBE) of supervised CPT cessation compared to continuing CPT (control). The primary study end point is the change in LVEF by cardiac magnetic resonance imaging at 6 months of enrolment between the two groups. Secondary end points include changes in quality-of-life questionnaires, other cardiac imaging parameters, and recurrence of heart failure., Conclusion: Cessation Of Pharmacotherapy In Recovered Chemotherapy-induced cardioToxicity (COP-RCT) is one of the first studies currently underway to evaluate the safety of ceasing CPT in recovered CTRCD. The results will inform clinical practice in this evidence-free zone., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose, (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background/aim: The association between clinical outcomes and posttreatment changes in the neutrophil-to-lymphocyte ratio (NLR) and neutrophil-to-eosinophil ratio (NER) in patients receiving avelumab maintenance therapy for advanced urothelial carcinoma (UC) is unclear., Patients and Methods: We retrospectively analyzed data from advanced UC patients who received avelumab and had not progressed with first-line platinum-based chemotherapy. The association between the changes in NLR and NER from pretreatment to week 6 of avelumab treatment and therapeutic efficacy was evaluated., Results: Thirty-two patients were enrolled in this study (male, n=25; female, n=7; median age, 71 years). At six weeks, 19 patients (59.4%) had a decreased NLR and 18 patients (56.3%) had a decreased NER. When the change in NER from pretreatment to six weeks was compared, there was a significant decrease in responders (without progressive disease) (p=0.008); however, there was no significant decrease in non-responders (progressive disease) (p=0.855). The NLR showed no significant change in either group (p=0.099, 0.358). When patients were compared according to the change in the NLR at six weeks, progression-free survival (PFS) and overall survival (OS) did not differ between the decreased NLR and increased NLR groups (p=0.116, 0.256). When patients were compared according to the change in the NER, the decreased and increased groups showed significant differences in PFS and OS (p<0.001, 0.030)., Conclusion: In the present real-world study, the responders showed a significantly decreased NER at six weeks. This was associated with improved PFS and OS in patients with advanced UC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The characteristic endoscopic findings of non-Helicobacter pylori Helicobacter (NHPH) gastritis, including white marbled appearance and crack-like mucosa, have been reported. However, these findings can also manifest in H. pylori (HP)-infected gastritis. This study compared NHPH gastritis and mild atrophic HP gastritis to identify features that may enhance NHPH diagnosis., Materials and Methods: A total of 2087 patients underwent upper gastrointestinal endoscopy and were histologically evaluated by multiple gastric mucosal biopsies according to the updated Sydney System (USS) at Shinshu University Hospital between 2005 and 2023. Among them, nine patients were classified into the NHPH group and 134 patients with HP infection and mild atrophy were classified into the HP group for retrospective comparisons of endoscopic findings and clinicopathological characteristics., Results: All nine patients in the NHPH group (eight males [89%], median ± standard deviation [SD] age: 49 ± 13.0 years) were infected with H. suis. The 134 patients in the HP group contained 70 men (52%) and had a median ± SD age of 35 ± 19.9 years. Endoscopic findings were statistically comparable for white marbled appearance (three patients [33%] in the NHPH group and 37 patients [31%] in the HP group) and crack-like mucosa (three patients [33%] and 27 patients [20%], respectively). Diffuse redness was significantly less frequent in the NHPH group (one patient [14%] vs. 97 patients [72%], p < 0.001). White marbled appearance or crack-like mucosa without diffuse redness was significantly more common in the NHPH group (56% vs. 13%, p = 0.004), with a sensitivity and specificity of 56% and 87%, respectively. Mean USS neutrophil infiltration and Helicobacter density scores were significantly higher in the HP group (both p < 0.01), which might have influenced the endoscopic findings of diffuse redness., Conclusions: When endoscopic findings of white marbled appearance or cracked-like mucosa are present, evaluation for diffuse redness may contribute to a more accurate diagnosis of NHPH gastritis., (© 2024 John Wiley & Sons Ltd.)

Objectives: Krüppel-like factor (KLF)5, which is overexpressed in carcinomas such as oral cancer, inhibits epidermal differentiation. KLF5 induces dedifferentiation of carcinoma cells, which effectuates carcinoma progression; nevertheless, the regulatory mechanism affecting the transcription of the KLF5 gene remains ambiguous., Methods: Transcriptional activity of the KLF5 silencer, specifically the 425-bp region (425-region), was examined using reporter assays. An additional analysis was conducted to assess the impact of the minimal essential region (MER) of KLF5 on its basal expression. The affinity of cAMP responsive element binding protein 1 (CREB1) for three potential CREB1-binding sites in the 425-region was analyzed using DNA pull-down and quantitative chromatin immunoprecipitation assays. Reporter assays employing a human oral squamous carcinoma cell line, HSC2, transfected with small interfering RNA or complementary DNA for CREB1, were performed to investigate the effect of CREB1 binding sites on MER activity., Results: The 425-region exhibited no transcriptional activity and suppressed MER transcriptional activity. This region encodes three putative CREB1-binding sites, and CREB1 demonstrated equal binding affinity for all three sites. The deletion of each of these binding sites reduced CREB1 precipitation and enhanced MER activity. Endogenous CREB1 knockdown and overexpression elevated and reduced MER activity, respectively, at the intact sites. Conversely, site deletion hampered and improved MER activity upon CREB1 knockdown and overexpression, respectively., Conclusions: Suppression of KLF5 basal expression via CREB1 binding to the 425-region requires all three CREB1-binding sites to remain intact in oral carcinoma cells. Consequently, deletion of the CREB1-binding site relieves suppression of KLF5 basal expression., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to report., (Copyright © 2023 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)

Background: Non-Helicobacter pylori Helicobacter (NHPH) is rarely detected in duodenal mucosa due to its preference for slightly acidic environments. Here, we report four cases of NHPH-infected gastritis with duodenal spiral bacilli, potentially NHPH, indicating the possibility of duodenal mucosal infection., Case Presentation: In every case, gastric mucosa showed endoscopic findings characteristic of NHPH-infected gastritis, and a mucosal biopsy was taken from the duodenal bulb; spiral bacilli were identified under microscopy using Giemsa staining. Case 1, a 46-year-old man, had diffuse spotty redness, mucosal edema, and multiple tiny erosions in the duodenal bulb, along with larger erosions in the second portion of the duodenum upon endoscopic examination. Histopathologically, moderate infiltration of mononuclear cells and neutrophils in the lamina propria and gastric epithelial metaplasia were observed. Case 2, a 54-year-old man, showed an elevated lesion, 1 cm in diameter, with multiple red spots and a few tiny erosions in the duodenal bulb. Histopathologically, mild inflammatory cell infiltration and gastric epithelial metaplasia were observed. In Case 3, a 52-year-old man, endoscopy revealed a flat elevated lesion, 7 mm in diameter, with multiple red spots and a few tiny erosions in the anterior wall of the duodenal bulb. Histopathologically, we observed moderate inflammatory cell infiltration in the gastric antrum and gastric epithelial metaplasia in the duodenal bulb. Case 4, a 40-year-old man, showed mild spotty redness in the duodenal bulb. Histopathologically, mild mononucleocyte infiltration and gastric epithelial metaplasia were observed. A single spiral bacillus was observed in Case 4 by microscopy. In all but Case 2, Helicobacter suis was identified in the gastric juice by polymerase chain reaction analysis., Conclusions: Spiral bacilli resembling NHPH may infect the duodenal mucosa, particularly the bulb, causing inflammation. Gastric contents entering the duodenum may reduce the intraduodenal pH, promoting NHPH survival and proliferation., (© 2024 John Wiley & Sons Ltd.)

Anthracycline therapy (ANT) is associated with cancer therapy-related cardiac dysfunction. Coronary flow velocity reserve (CFVR) has shown prognostic utility in non-cancer cohorts, but no data have been obtained in a cardio-oncology setting. We investigated the acute effect of ANT on CFVR in breast cancer patients. A total of 12 female breast cancer patients undergoing ANT had pre- and post-ANT CFVR assessment. A significant decline in CFVR occurred (baseline: 2.66 ± 0.41 vs post-ANT: 2.47 ± 0.37, P  = 0.016). This prospective study is the first to identify ANT-related coronary physiology changes in humans. Further studies are required to determine their clinical significance., (© 2024 The Authors.)

Subtype of urothelial carcinoma (SUC), defined here as urothelial carcinoma with any histologic subtype or divergent differentiation, is a clinically aggressive disease. However, the efficacy of enfortumab vedotin (EV) against SUC remains unclear. Hence, this study aimed to assess the oncological outcomes of patients with SUC treated with EV for metastatic disease. We retrospectively evaluated consecutive patients with advanced lower and upper urinary tract cancer who received EV after platinum-based chemotherapy and immune checkpoint blockade therapy at six institutions. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with SUC. We identified 44 and 18 patients with PUC and SUC, respectively. Squamous differentiation was the most common subtype element, followed by glandular differentiation and sarcomatoid subtype. Although patients with SUC had a comparable ORR to those with PUC, the duration of response for SUC was short. Patients with SUC had poorer PFS than those with PUC; however, no significant difference was observed in OS. Multivariate analysis revealed that SUC was significantly associated with shorter PFS. Although the response of metastatic SUC to EV was similar to that of PUC, SUC showed faster progression than PUC.

Objectives: Diallyl disulfide (DADS) is a natural organosulfur compound found in garlic and related plants with various pharmacologic effects. However, whether DADS improves obesity-induced insulin resistance (IR) and its underlying mechanisms remain unclear. The aim of this study was to investigate the effects of DADS on systemic IR in high-fat diet-induced obese mice., Methods: To induce obesity, 8-wk-old male C57BL/6J mice were fed a high-fat diet (60% fat/kcal). The mice were assigned to three weight-matched groups: control (CON, n = 8), low-dose DADS (DADS-L, n = 8), and high-dose DADS (DADS-H, n = 9). The treated mice were orally administered DADS (25 or 100 mg/kg) 5 d/wk for 8 wk. At 15 wk of age, an intraperitoneal glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed. Twenty-four hours after the final administration of DADS, epididymal fat and the liver were sampled after a 5-h fast., Results: DADS administration significantly attenuated body and fat weight gains during the experimental period. Additionally, systemic IR, as evaluated by ITT, was significantly improved by DADS administration in a dose-dependent manner. High-dose DADS administration significantly decreased liver triacylglycerol levels. Moreover, high-dose DADS administration decreased the c-Jun N-terminal kinase (JNK) phosphorylation and significantly increased heat shock protein 72 expression in the liver., Conclusions: The results of this study suggested that DADS administration alleviated systemic IR in obese mice. This may be associated with decreased hepatic fat accumulation and a heat shock protein 72-mediated decrease in JNK activity in the liver., 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 © 2023 Elsevier Inc. All rights reserved.)

Salmonella enterica subsp. enterica serovar Typhimurium has recently emerged worldwide as a producer of extended-spectrum β-lactamase (ESBL). However, drug-resistant clinical isolates are rare in Japan. The common types of ESBLs found are the CTX-M-type β-lactamases, including novel β-lactamases such as CTX-M-64. CTX-M-64 has a chimeric structure comprising a combination of the CTX-M-1 and CTX-M-9 groups. In 2017, S. Typhimurium was isolated from stool, blood, and urine cultures of an 82-year-old man. Herein, we describe the discovery of a clinical isolate of S. Typhimurium in Japan. Antimicrobial susceptibility testing revealed that the isolate was resistant to third- and fourth-generation cephalosporins, including ceftazidime and monobactam. The minimum inhibitory concentrations of ceftazidime and ceftriaxone were restored by administration of clavulanic acid. Whole-genome sequencing analysis revealed that the isolate harbored the bla CTX-M-64 gene on an IncHI2/IncHI2A-type plasmid, with an assembly length of 174,477 bp. The genetic structure of the region surrounding the bla CTX-M-64 gene, ISKpn26-ΔISEcp1-bla CTX-M-64 -orf477, was shared only with the chromosome sequence of S. Typhimurium detected in food-producing chickens in Guangdong, China. Although rare, S. Typhimurium can induce bloodstream infections and produce ESBL. To our knowledge, this is the first report of a CTX-M-64-producing Enterobacterales clinical isolate of domestic origin in Japan.

Background/aim: The organ-specific therapeutic effects of avelumab for the maintenance treatment of advanced urothelial carcinoma (UC) are unclear., Patients and Methods: Patients who received avelumab for advanced UC that had not progressed with first-line platinum-based chemotherapy and who had measurable disease were retrospectively analyzed. The organ-specific response was evaluated, and progression-free survival (PFS) and overall survival (OS) were estimated., Results: We analyzed 42 patients (male, n=31; median age, 72 years). The overall response rate [complete response (CR)+ partial response (PR)] and disease control rate (CR+PR+stable disease) were 2.4% and 47.6%, respectively. In total, 27, 11, 8 and 5 patients had measurable lymph node [organ-specific response rate (OSRR) 7.4%, organ-specific disease control rate (OSDCR) 59.3%], lung (OSRR 18.2%, OSDCR 36.4%), primary tumor organ (OSRR 0%, OSDCR 100%) and liver (OSRR 0%, OSDCR 100%) disease, respectively. The median PFS and OS was 3.8 months and 20.2 months, respectively. Regarding organ-specific PFS, a log-rank test confirmed significant differences between patients with and without primary tumor organ disease (p=0.009) and patients with and without liver metastasis (p=0.015). Regarding organ-specific OS, a log-rank test revealed no significant differences between patients with and without metastatic disease for all organs (lung: p=0.835; lymph node: p=0.914; bone: p=0.257; primary tumor: p=0.057; liver: p=0.893)., Conclusion: In patients receiving avelumab maintenance therapy, no significant differences in OS were observed between patients with and without metastasis to any organ, including the primary organ, although metastases and the primary tumor organ disease showed different responses., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Recently, mammography systems equipped with digital breast tomosynthesis (DBT) have become widely used in Japan. Therefore, it is urgently necessary to establish a quality control method for DBTs. So far, we have been studying acceptance tests for DBTs with reference to EUREF. In 2020, IEC 61223-3-6 was published, which provides not only acceptance tests but also constancy test methods. Therefore, we conducted data collection using DBTs sold in Japan and examined the feasibility of conducting constancy tests. Although there were some items that were difficult to implement in each device, we were able to confirm quality control items that could be implemented in many devices. In addition, we were able to confirm routine tests that enable rapid evaluation. Based on these results, we have developed a "Digital Breast Tomosynthesis Quality Control Manual". In this paper, we report an overview of the manual and the results of routine tests.

The average glandular dose (AGD) is very important in the quality control of mammography. The AGD calculation requires measurements of half-value layer (HVL) and entrance surface air karma (ESAK). The HVL is measured by the Al-attenuation method using a non-energy-dependent ionization dosimeter. As the Al-attenuation method performs measurements using a succession of added filters, it requires lots of X-ray exposure and measurement time. In recent years, measuring instruments that can measure tube voltage, irradiation time, exposure dose, HVL, and other factors, at the same time, using one shot of X-rays have been developed. In this study, measurement of the AGD using multiparameter X-ray measuring instrument about rhodium (Rh) and tungsten (W) anode X-ray tubes. A comparative study was performed using standard ionization dosimeters. The error in measurements was as follows: HVL 5.8%, ESAK 3.3%, and AGD 2.9%. The AGD measurement using a multiparameter X-ray measuring instrument is simple and can significantly reduce the measurement time while maintaining accuracy.

Purpose: To describe clinical presentations of acquired comitant esotropia and digital device use in children, adolescents, and young adults without neurological problems., Study Design: Multicenter prospective observational study., Methods: Patients with acquired comitant esotropia, without intracranial diseases aged 5-35 years at the time of visit, who were seen at pre-registered facilities within 1 year of onset were enrolled. The duration from the onset of symptoms and the time of digital device usage approximately 1 month before onset and their lifestyles were surveyed. Visual acuity, cycloplegic refraction, and strabismus angles were measured. Data were analyzed in three age groups (Child: 5-12 years, Adolescent: 13-18 years, and Young adult: 19-35 years)., Results: Between November 2019 and December 2021, 218 patients were enrolled from 55 facilities, and 194 patients (including 62 children, 69 adolescents, and 63 young adults) were analyzed. The child group spent the least amount of time using digital devices (children: 159; adolescents: 210; young adults: 267 min/work day, p < 0.05; (mean time in the same order below) 229, 338, 314 min/holiday, p < 0.05) and had the largest strabismus angle (mean strabismus angle at near: 30, 22, 18 PD, p < 0.01; at far: 28, 26, 21 PD, p<0.05)., Conclusion: The clinical features of acquired comitant esotropia and hand-held digital device usage differed between children aged ≤ 12 years and older patients. This report gives the current clinical characteristics of young patients with acquired esotropia and digital device usage., (© 2023. Japanese Ophthalmological Society.)

Background/aim: The association of clinical outcomes with posttreatment persistent changes in eosinophils and other white blood cell (WBC) subtypes in patients with advanced urothelial cancer (UC) treated with pembrolizumab after the failure of platinum-based chemotherapy is unclear., Patients and Methods: We retrospectively analyzed 87 patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy. The changes in WBC subtypes from pretreatment were evaluated three and six weeks after pembrolizumab administration. The association between the changes in the WBC subtypes and clinical outcomes was then evaluated using the Kaplan-Meier method and a Cox regression model., Results: Among WBC subtypes, significant changes in the absolute (AEC) and relative eosinophil count (REC) and the neutrophil-to-eosinophil ratio (NER) were observed at three and six weeks compared with pretreatment (p<0.001). Multivariable Cox regression analyses revealed that a persistent decrease in AEC and REC and a persistent increase in NER were associated with poor overall survival., Conclusion: Persistent increase in AEC and REC and decrease in NER in the early phase after pembrolizumab may be significant early predictive markers of improved clinical outcomes in patients with advanced UC receiving pembrolizumab., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In human walking, whole-body angular momentum (WBAM) about the body centre-of-mass is reportedly maintained in a small range throughout a gait cycle by the intersegmental cancellation of angular momentum. However, the WBAM is certainly not zero, which indicates that external moments applied from the ground due to ground reaction forces (GRFs) and vertical free moments (VFMs) counteract the WBAM. This study provides a complete dataset of the WBAM, each segmental angular momentum, and the external moments due to GRFs and VFMs during human walking. This is done to test whether (1) the three components of the WBAM are cancelled by coordinated intersegmental movements, and whether (2) the external moments due to GRFs and VFMs contribute only minimally to WBAM regulation throughout a gait cycle. This study demonstrates that WBAM is regulated in a small range not only by the segment-to-segment cancellation, but also largely through contributions by the GRFs. The magnitude of VFM is significantly smaller than the peak vertical moment generated by the GRFs; however, in the single-support phase during walking, the VFM is possibly critical for coping with the change in the vertical WBAM due to force perturbations and arm or trunk movements., (© 2023. The Author(s).)

In human bipedal walking, the plantar surface of the foot is in contact with the floor surface, so that a vertical free moment (VFM), a torque about a vertical axis acting at the centre-of-pressure due to friction between the foot and the ground, is generated and applied to the foot. The present study investigated the functional significance of the VFM in the mechanics and evolution of human bipedal walking by analysing kinematics and kinetics of human walking when the VFM is selectively eliminated using point-contact shoes. When the VFM was selectively eliminated during walking, the thorax and pelvis axially rotated in-phase, as opposed to normal out-of-phase rotation. The amplitudes of the axial rotation also significantly increased, indicating that the VFM greatly contributes to stable and efficient bipedal walking. However, such changes in the trunk movement occurred only when arm swing was restricted, suggesting that the VFM is critical only when arm swing is restrained. Therefore, the human plantigrade foot capable of generating large VFM is possibly adaptive for bipedal walking with carrying food, corroborating with the so-called provisioning hypothesis that food carrying in the early hominins is a selective pressure for the evolution of human bipedalism., (© 2023. The Author(s).)

Evidence is accumulating that ultraviolet A (UVA) plays an important role in photo-carcinogenesis. However, the types of DNA damage involved in the resulting mutations remain unclear. Previously, using Drosophila, we found that UVA from light-emitting diode (LED-UVA) induces double-strand breaks in DNA through oxidative damage in an oxidative damage-sensitive (urate-null) strain. Recently, it was proposed that cyclobutane pyrimidine dimers (CPDs), which also are induced by UVA irradiation, might play a significant role in the induction of mutations. In the present study, we investigated whether reactive oxygen species (ROS) and CPDs are produced in larval bodies following LED-UVA irradiation. In addition, we assessed the somatic cell mutation rate in urate-null Drosophila induced by monochromatic UVA irradiation. The production of ROS through LED-UVA irradiation was markedly higher in the urate-null strain than in the wild-type Drosophila. CPDs were detected in the DNA of both of UVA- and UVB-irradiated larvae. The level of CPDs was unexpectedly higher in the wild-type strain than in urate-null flies following UVA irradiation, whereas this parameter was expectedly similar between the urate-null and wild-type Drosophila following UVB irradiation. The somatic cell mutation rate induced by UVA irradiation was higher in the urate-null strain than in the wild-type strain. These results suggest that mutations induced by UVA-specific pathways occur through ROS production, rather than via CPD formation., Competing Interests: Conflicts of interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Apoptotic cell death is an important survival system for multicellular organisms because it removes damaged cells. Mutation is also a survival method for dealing with damaged cells in multicellular and also unicellular organisms, when DNA lesions are not removed. However, to the best of our knowledge, no reports have comprehensively explored the direct relationship between apoptosis and somatic cell mutations induced by various mutagenic factors., Results: Mutation was examined by the wing-spot test, which is used to detect somatic cell mutations, including chromosomal recombination. Apoptosis was observed in the wing discs by acridine orange staining in situ. After treatment with chemical mutagens, ultraviolet light (UV), and X-ray, both the apoptotic frequency and mutagenic activity increased in a dose-dependent manner at non-toxic doses. When we used DNA repair-deficient Drosophila strains, the correlation coefficient of the relationship between apoptosis and mutagenicity, differed from that of the wild-type. To explore how apoptosis affects the behavior of mutated cells, we determined the spot size, i.e., the number of mutated cells in a spot. In parallel with an increase in apoptosis, the spot size increased with MNU or X-ray treatment dose-dependently; however, this increase was not seen with UV irradiation. In addition, BrdU incorporation, an indicator of cell proliferation, in the wing discs was suppressed at 6 h, with peak at 12 h post-treatment with X-ray, and that it started to increase again at 24 h; however, this was not seen with UV irradiation., Conclusion: Damage-induced apoptosis and mutation might be coordinated with each other, and the frequency of apoptosis and mutagenicity are balanced depending on the type of DNA damage. From the data of the spot size and BrdU incorporation, it is possible that mutated cells replace apoptotic cells due to their high frequency of cell division, resulting in enlargement of the spot size after MNU or X-ray treatment. We consider that the induction of mutation, apoptosis, and/or cell growth varies in multi-cellular organisms depending on the type of the mutagens, and that their balance and coordination have an important function to counter DNA damage for the survival of the organism., (© 2023. The Author(s).)

Methylmercury (MeHg), a global environmental pollutant, could seriously damage the central nervous system (CNS) and cause neurological disorders such as cerebellar symptoms. Although numerous studies have revealed detailed toxicity mechanisms of MeHg in neurons, toxicity in astrocytes is barely known. Here, we tried to shed light on the toxicity mechanisms of MeHg exposure in cultured normal rat cerebellar astrocytes (NRA), focusing on the involvement of reactive oxygen species (ROS) in MeHg toxicity by assessing the effects of major antioxidants Trolox, a free-radical scavenger, N-acetyl-L-cysteine (NAC), a potent thiol-containing antioxidant, and glutathione (GSH), an endogenous thiol-containing antioxidant. Exposure to MeHg at just approximately 2 µM for 96 h increased cell viability, which was accompanied by the increase in intracellular ROS level and at ≥ 5 µM induced significant cell death and lowered ROS level. Trolox and NAC suppressed 2 µM MeHg-induced increases in cell viability and ROS level corresponding to control, although GSH with 2 µM MeHg induced significant cell death and ROS increase. On the contrary, against 4 µM MeHg-induced cell loss and ROS decrease, NAC inhibited both cell loss and ROS decrease, Trolox inhibited cell loss and further enhanced ROS decrease, and GSH moderately inhibited cell loss and increased ROS level above the control level. MeHg-induced oxidative stress was suggested by increases in the protein expression levels of heme oxygenase-1 (HO-1), Hsp70, and Nrf2, except for the decrease in SOD-1 and no change in catalase. Furthermore, MeHg exposure dose-dependently induced increases in the phosphorylation of MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK) and phosphorylation and/or expression levels of transcription factors (CREB, c-Jun, and c-Fos) in NRA. NAC successfully suppressed 2 µM MeHg-induced alterations in all of the above-mentioned MeHg-responsive factors, whereas Trolox suppressed some MeHg-responsive factors but failed to suppress MeHg-induced increases in the protein expression levels of HO-1 and Hsp70 and increase in p38MAPK phosphorylation. Protein expression analyses in NRA exposed to 2 µM MeHg and GSH were excluded because of devastating cell death. These results suggested that MeHg could induce aberrant NRA activation, and ROS must be substantially involved in the toxicity mechanism of MeHg in NRA; however, other factors should be assumed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takayuki Negishi reports financial support was provided by Government of Japan Ministry of Education Culture Sports Science and Technology. Takayuki Negishi reports financial support was provided by Japan Society for the Promotion of Science., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Global longitudinal strain (GLS) can predict cancer therapeutics-related cardiac dysfunction and guide initiation of cardioprotection (CPT)., Objectives: In this study, the authors sought to determine whether echocardiography GLS-guided CPT provides less cardiac dysfunction in survivors of potentially cardiotoxic chemotherapy, compared with usual care at 3 years., Methods: In this international multicenter prospective randomized controlled trial, patients were enrolled from 28 international sites. All patients treated with anthracyclines with another risk factor for heart failure were randomly allocated to GLS-guided (>12% relative reduction in GLS) or ejection fraction (EF)-guided (>10% absolute reduction of EF to <55%) CPT. The primary end point was the change in 3-dimensional (3D) EF (ΔEF) from baseline to 3 years., Results: Among 331 patients enrolled, 255 (77%, age 54 ± 12 years, 95% women) completed 3-year follow-up (123 in the EF-guided group and 132 in the GLS-guided group). Most had breast cancer (n = 236; 93%), and anthracycline followed by trastuzumab was the most common chemotherapy regimen (84%). Although 67 (26%) had hypertension and 32 (13%) had diabetes mellitus, left ventricular function was normal at baseline (EF: 59% ± 6%, GLS: 20.7% ± 2.3%). CPT was administered in 18 patients (14.6%) in the EF-guided group and 41 (31%) in the GLS-guided group (P = 0.03). Most patients showed recovery in EF and GLS after chemotherapy; 3-year ΔEF was -0.03% ± 7.9% in the EF-guided group and -0.02% ± 6.5% in the GLS-guided (P = 0.99) group; respective 3-year EFs were 58% ± 6% and 59% ± 5% (P = 0.06). At 3 years, 17 patients (5%) had cancer therapeutics-related cardiac dysfunction (11 in the EF-guided group and 6 in the GLS guided group; P = 0.16); 1 patient in each group was admitted for heart failure., Conclusions: Among patients taking potentially cardiotoxic chemotherapy for cancer, the 3-year data showed improvement of LV dysfunction compared with 1 year, with no difference in ΔEF between GLS- and EF-guided CPT. (Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes [SUCCOUR]; ACTRN12614000341628)., Competing Interests: Funding Support and Author Disclosures This study was supported in part by a project grant (1119955) from the National Health and Medical Research Council, Canberra, Australia, and an unrestricted grant from General Electric Healthcare, Horten, Norway. At the CHU de Québec site, the study was funded by the Fondation du CHU de Québec. Dr Marwick is supported by an investigator grant (2008129) from the National Health and Medical Research Council, Canberra, Australia. Dr Thavendiranathan is supported by a Canadian Institutes of Health Research New Investigator Award (147814), an Ontario Early Research Award, and a Canada Research Chair in Cardio-oncology. Dr K. Negishi is supported by a fellowship (award reference no. 101868) from the National Heart Foundation of Australia. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Rotavirus (RV) is a leading cause of gastroenteritis in children. In Japan, Rotarix (RV1; GlaxoSmithKline), which is a monovalent vaccine derived from human RV (G1P[8]), has been introduced since November 2011, and RotaTeq (RV5; MSD) which is an pentavalent, human-bovine mono-reassortant vaccine (G1, G2, G3, G4, and P1A[8]), has been introduced since July 2012. Long-term follow-up on vaccine efficacy and RV genotypical change should be carried out in order to control RV infection. The RV gastroenteritis (RVGE) outbreak occurred during the 2018/2019 season in Aichi prefecture, Japan. Therefore, the molecular epidemiology of RV among three different groups of RVGE, which were outpatients who received RV1, those who received RV5, and those without vaccination, was explored. Clinical features of RVGE patients were compared among the three patient groups. Children less than 15 years of age with gastroenteritis who visited any of seven pediatric practices between January and June 2019 were enrolled in the study. G, P, and E genotypes were determined by direct sequencing of reverse transcription-polymerase chain reaction products amplified from stool samples. Among 110 patients, there were 27, 28, and 55 in the RV1-vaccinated, RV5-vaccinated, and unvaccinated groups, respectively. The most frequent genotype was G8P[8] (92/110 patients, 83.6%). Genotype distributions did not significantly differ among the three patient groups ( P  = .125). Mean Vesikari score was significantly lower among RV1-vaccinated (7.1) and RV5-vaccinated patients (6.4) than among unvaccinated patients (10.2) ( P  < .001). Even in RVGE patients treated in an outpatient clinic, RV vaccine reduced the severity of the disease in this cohort.

The Japan Network for Research and Information on Medical Exposures (J-RIME) established the diagnostic reference level (DRL) and is advancing optimization of radiation protection. We believe that the difference in the imaging dose between facilities may be due to the fact that automatic exposure control (AEC) adjustment is not unified among manufacturers. The consistency of AEC is specified in JIS 4751-2-54, but it is not applicable to digital X-ray imaging systems because it is for optical density of analog X-ray imaging systems. This article evaluates the consistency of AEC in digital X-ray imaging systems. The AEC consistency was compared with the AEC-estimated dose from the air kerma (K AEC ) using the phosphor-based imaging plate placed at the back of the AEC detector. We measured the AEC tube voltage and subject thickness characteristics (tracking) of four types of digital X-ray imaging systems at three facilities. In the test of tube voltage characteristics, the average K AEC values at all tube voltages were 2.37±0.04  µGy for A system, 7.30±1.44  µGy for B system, 3.53±0.13  µGy for C system, and 5.70±0.18  µGy for D system. The relative errors were +2.6 to -1.8% for A system, +25.3 to -22.6% for B system, +5.2 to -1.4% for C system, and +2.5 to -4.4% for D system. In the subject thickness characteristics test, the average K AEC values for all Al thicknesses were 2.34±0.02  µGy for A system, 5.95±0.23  µGy for B system, 4.25±1.12  µGy for C system, and 5.03±1.27  µGy for D system. The relative errors were +1.0 to -0.9% for A system, +4.1 to -5.0% for B system, +40.5 to -28.1% for C system, and +19.7 to -42.9% for D system.

Introduction: Metastases from renal cell carcinoma develop in various organs. However, the breadth of discrepancy in response to immune checkpoint inhibitors across tumor sites within the same individual remains unclear., Patients and Methods: We reviewed 50 patients with metastatic renal cell carcinoma who had target lesions at multiple sites and received nivolumab monotherapy (n = 36) or nivolumab plus ipilimumab (n = 14). When the best overall response in tumor burden increased at one site but decreased at other sites, the response was defined as a dissociated response. The response was evaluated according to the Response Evaluation Criteria in Solid Tumors 1.1, and patients who met the definition of dissociated response were categorized as dissociated response. The rate of dissociated response and prognosis were evaluated., Results: Eight of 36 (22%) and 4 of 14 (29%) patients treated with nivolumab and nivolumab plus ipilimumab were categorized as having dissociated response, respectively. The median overall survival of the patients treated with nivolumab was 20.2 months for those with a partial response, 6.8 months for those with stable disease, and 13.2 months for those with progressive disease, while dissociated response was not reached. There was no significant difference in the median overall survival between patients categorized as having progressive disease and those with dissociates response (P = 0.224)., Conclusion: A certain proportion of patients with metastatic renal cell carcinoma show dissociated response when treated with immune checkpoint inhibitors. The prognosis of patients with dissociated response and progressive disease was not shown to be significantly different., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic inflammation is considered as an etiology of obesity and type 2 diabetes. Brown adipose tissue (BAT) of obese animals shows increased inflammation. Regular exercise has anti-inflammatory effects; however, the effects of exercise training on BAT inflammation in obese animals remain unclear. Thus, this study aimed to investigate the effects of exercise training on inflammation-related signaling in the BAT of obese and diabetic rats. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an obese/diabetic rodent model, were randomly divided into either sedentary ( n  = 11) or exercise training ( n  = 8) groups. Long-Evans Tokushima Otsuka (LETO; n  = 9) rats were used as the nondiabetic sedentary controls. Exercise training using a treadmill was conducted 4 days per week for 20 weeks, starting at 5 weeks old. As a result, exercise training attenuated the phosphorylation levels of p65 and mitogen-activated protein kinases in the BAT of OLETF rats, concurrently with the improvement of obesity and systemic glucose tolerance. Moreover, exercise training decreased oxidative stress and increased the antioxidant and anti-inflammatory protein levels in the BAT. Conversely, exercise training did not alter the expression levels of uncoupling protein-1 and oxidative phosphorylation-related proteins in the BAT, which were lower in the OLETF rats than the LETO rats. In conclusion, our data suggest that exercise training prevents the activation of inflammatory signaling in the BAT of obese/diabetic rats., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

To determine the course of treatment while considering the patients' desires, we examined trends regarding patients' perception and expectations over the course of cancer pharmacotherapy. We retrospectively reviewed interview sheets filled in by patients with advanced urogenital cancers when they started a new pharmacotherapy regimen between 2014 and 2020. The responses to the following questions were analyzed: 1) How did your doctor explain the treatment objectives?; 2) Are you willing to receive treatment?; and 3) When the standard treatment becomes difficult to continue, would you like to try another treatment even if it may cause severe side effects? A total of 277 patients answered the interview sheet. The percentage of patients who accurately perceived the treatment objectives among patients receiving 1st, 2nd, and 3rd line regimens was 67%, 79%, and 93%, respectively. The percentage significantly improved over the course of pharmacotherapy (p = 0.0057). The percentage of patients who indicated that they were willing to receive treatment in 1st, 2nd, and 3rd line regimens was 80%, 83%, and 86%, respectively. The percentage of patients who indicated that they wanted to try another treatment when the standard treatment became difficult to continue in 1st, 2nd, and 3rd line regimens was 56%, 64%, and 59%, respectively. The percentage of patients who accurately perceived the objective of pharmacotherapy increased over the course of pharmacotherapy. The rate of patients who were willing to receive treatment and try other treatments when the standard treatment became too difficult to continue remained consistently high., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Satou 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.)

PlexinA1 (PlxnA1) is a transmembrane receptor for semaphorins (Semas), a large family of axonal guidance cues vital during neural development. PlxnA1 is expressed in embryonic interneurons, and PlxnA1 deletion in mice leads to less interneurons in the developing cortex. In addition, PlxnA1 has been identified as a schizophrenia susceptibility gene. In our previous study, PlxnA1 knockout (KO) mice under a BALB/cAJ genetic background exhibited significantly increased self-grooming and reduced prepulse inhibition, a reliable phenotype for investigating the neurobiology of schizophrenia. However, the mechanism underlying the abnormal behavior of PlxnA1 KO mice remains unclear. We first confirmed PlxnA1 mRNA expression in parvalbumin-expressing interneurons (PV cells) in the medial prefrontal cortex (mPFC) of adult mice. Immunohistochemical analysis (IHC) showed significantly decreased densities of both GABAergic neurons and PV cells in the mPFC of PlxnA1 KO mice compared with wild type mice (WT). PV cells were found to express molecule interacting with CasL 1 (MICAL1), an effector involved in Sema-Plxn signaling for axon guidance, suggesting MICAL1 and PlxnA1 co-expression in PV cells. Furthermore, IHC analysis of 8-oxo-dG, an oxidative stress marker, revealed significantly increased oxidative stress in PlxnA1 -deficient PV cells compared with WT. Thus, increased oxidative stress and decreased PV cell density in the mPFC may determine the onset of PlxnA1 KO mice's abnormal behavior. Accordingly, deficient PlxnA1-mediated signaling may increase oxidative stress in PV cells, thereby disrupting PV-cell networks in the mPFC and causing abnormal behavior related to neuropsychiatric diseases., Competing Interests: None., (© 2022 The Authors.)

Background: To evaluate the eosinophil changes, efficacy and safety of pembrolizumab treatment in advanced urothelial carcinoma patients of older age and those with a poor performance status (PS)., Materials and Methods: Consecutive patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy between January 2018 and June 2021 were retrospectively examined., Results: 105 patients (median age, 72 years), 71.4% of whom were men, were enrolled. Patients of ≥75 years of age were considered to be older patients (n=40), and patients with PS ≥2 were considered to have a poor PS (n=10). The objective response and disease control rates were 42.5% and 52.5%, respectively, in older patients and 0% and 10.0%, respectively, in patients with a poor PS. Overall survival (OS) in the older and younger groups did not differ to a statistically significant extent. However, a poor PS was significantly associated with poor survival. Safety analyses demonstrated no significant difference in the occurrence of any immune-related adverse events (irAEs), including grade ≥3, between the older and younger groups. However, a poor PS was significantly associated with the low occurrence of any irAEs. The change of the eosinophil count, the increase of the relative eosinophil count (REC) and the decrease of the neutrophil-to-eosinophil ratio (NER) did not differ to a statistically significant extent between the older and younger groups, but showed significant differences between the poor and good PS (PS 0-1) groups., Conclusion: Pembrolizumab for advanced UC demonstrated similar changes in the eosinophil count, efficacy and toxicity in both older and younger patients. In patients with a poor PS, although toxicity was significantly lower, survival was significantly worse, and neither an increase in REC nor a decrease in NER were observed, but these values showed significant changes in patients with a good PS., Competing Interests: The authors declare that they have no conflict of interest for this study., (© 2022 Furubayashi et al.)

Introduction: Although variant urothelial carcinoma (VUC, defined here as urothelial carcinoma with any histological variant) is a clinically aggressive disease, the efficacy of pembrolizumab against VUC is not well characterized. This study assessed the therapeutic response and survival outcomes in patients with advanced VUC treated with pembrolizumab for unresectable recurrent or metastatic disease., Patients and Methods: We retrospectively evaluated 103 patients with advanced bladder and upper urinary tract cancer who received pembrolizumab after failure of platinum-based chemotherapy at 6 institutions between January 2018 and June 2021. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with VUC., Results: We identified 81 and 22 patients with PUC and VUC, respectively. Squamous differentiation (n = 14) was the most common variant element, followed by glandular differentiation (n = 3) and micropapillary variant (n = 3). Baseline characteristics were comparable between the groups. Patients with VUC showed significantly better ORR (59.1% vs. 29.6%, P = .014) and comparable DCR (68.2% vs. 49.4%, P = .150) compared to those with PUC. There were no significant differences between the PUC and VUC groups with respect to PFS (median 5.0 months vs. 10.4 months, P = .222) or OS (median 13.5 months vs. 23.8 months, P = .497)., Conclusion: Response of VUC to pembrolizumab was not inferior to that of PUC in patients with advanced-stage bladder and upper urinary tract cancer., (Copyright © 2022. Published by Elsevier Inc.)

Competing Interests: Toshio Uraoka has received lecture fees from Olympus Co.