Search

Stable radicals have attracted increasing attention in recent years because of their unique electronic and optical characteristics. Aminoxyl radicals are one of the most widely studied stable radicals to date, but their applications in opto-functional materials have yet to be explored in detail. Our group previously reported the boron complexes of aminoxyl radicals exhibit near-infrared (NIR) absorption. In this work, an aminoxyl radical without boron-complexation was synthesized to elucidate the effects of boron coordination on the properties of the aminoxyl radicals. The results of electron spin resonance spectroscopy, ultraviolet-visible-NIR absorption measurements, and density functional theory calculations indicated that boron complexation facilitated spin delocalization over the radical π-frameworks. Furthermore, a π-extended aminoxyl radical-boron complex exhibited a significant wavelength-shift to longer wavelengths in the NIR-II absorption region, thereby reflecting its larger π-conjugated radical skeleton.

Background: This study aimed to describe and compare therapeutic approaches for horses with acute diarrhea in different geographic regions worldwide., Methods: Clinical information was retrospectively collected from diarrheic horses presented to participating institutions between 2016 and 2020, including fluid therapy on admission, antimicrobial drugs, probiotics, anti-endotoxic medications, anti-inflammatory drugs, gastroprotectants, digital cryotherapy, and toxin-binding agents. Seasonal and geographic differences were investigated., Results: 1438 horses from 26 participating hospitals from 5 continents were included. On admission, 65% (926/1419) of horses were administered a fluid bolus. Antimicrobial drugs were administered to 55% (792/1419) within the first 24 hours of admission, with penicillin and gentamicin being the most used combination (25%, 198/792). Horses with leukopenia (OR: 2.264, 95%CI: 1.754 to 2.921; P<0.001) or meeting systemic inflammatory response syndrome criteria (OR: 2.542, 95%CI: 1.919 to 3.368; P<0.001) had higher odds of being administered antimicrobial drugs. Other treatments administered included probiotics (15%, 215/1438), polymyxin B (13%; 187/1438), pentoxifylline (8%; 118/1438), gastroprotectants (44%; 626/1419), digital cryotherapy (34%; 489/1435), plasma transfusion (13%; 182/1410) and toxin-binding agents (36%; 515/1438)., Limitations: Due to the retrospective nature of the study, the rationale for treatment decisions was unavailable, and associations with survival could not be evaluated., Conclusions: Treatments varied between hospitals from different geographic regions. Prospective clinical trials are required to evaluate the effects of various treatments on survival., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gomez 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.)

Salbutamol is a short-acting and selective beta-2 adrenergic agonist. Inhaled (IH) administration of salbutamol is widely used to control lower respiratory tract disease in horses. Here, we estimated the pharmacokinetic parameters of salbutamol after a single intravenous (IV) or IH administration in six horses, and we statistically analysed the detection times with various dosing regimens. Plasma and urine concentrations of salbutamol were measured by liquid chromatography-tandem mass spectrometry, and data were modelled by using a nonlinear mixed effect model followed by Monte Carlo simulation (MCS). With IH salbutamol, the maximum plasma concentration was 0.12 ± 0.06 ng/mL at 0.29 ± 0.17 h after administration. Typical values were, for clearance, 1.53 L/kg/h; distribution volume at steady state, 5.43 L/kg; terminal half-life, 6.06 h; IH bioavailability, 19.0%; and urine to plasma ratio, 2057. Statistically estimated 95th percentile detection times in the urine at levels below the international screening limit (0.5 ng/mL) proposed by the International Federation of Horseracing Authorities, as simulated in 5000 horses by MCS, were 44 h after 1.6 μg/kg q 24 and 54 h after 1.6 μg/kg q 4 h over a 3-day IH administration period., (© 2024 John Wiley & Sons Ltd.)

Introduction: Recalibration of body ownership perception occurs through an integration among multiple modalities. A recent study has shown that respiratory rhythm also causes the recalibration of ownership perception. However, the risk factors influencing the recalibration of ownership perception caused by vision-respiratory interaction remain unclear. In this study, focusing on aging and Parkinson's disease (PD), we examined the effects of those risk factors on the recalibration., Methods: By applying the rubber hand illusion (RHI), which temporarily alters ownership perception, and using a device that synchronizes the respiratory rhythm with the movement of a mannequin hand, we measured a change in ownership perception in RHI training by vision-respiratory interaction. The changed ownership was compared among the elderly healthy, PD, and young healthy groups., Results: The results showed no difference in the changed ownership between the elderly healthy and PD groups, while the two groups decreased the change in the ownership perception compared to the young healthy group., Discussion: The finding suggests that aging, not PD, related to the recalibration of ownership perception by vision-respiratory interaction. An anomaly in body perception due to aging may be associated with a mechanism in which respiratory rhythm affects the adaptation of body representations., Competing Interests: Author MN was employed by Dentsu Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shoji, Honma, Masaoka, Nakayama, Kosuge, Kosuge, Uchida, Sakakura, Matsui, Ito, Nohara, Watanabe, Kanemoto, Kasai, Kuroda, Yano, Murakami and Izumizaki.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) remain a major global health challenge, with aerosol transmission being the primary route of spread. The use of antivirals as medical countermeasures to control SARS-CoV-2 transmission and spread is promising but remains to be clarified. The current study established and used an in vivo hamster aerosol transmission model system to evaluate the efficacy of the protease inhibitor ensitrelvir to prevent the spread of SARS-CoV-2. Male Index Syrian hamsters were intranasally infected with SARS-CoV-2, paired with naïve Contact hamsters, and co-housed for 12 h under conditions to allow for only aerosol transmission. The Index hamsters were treated three times with ensitrelvir starting 8 h post infection, or the Contact hamsters were treated once with ensitrelvir 12 h prior to co-housing. Viral infection and transmission were monitored by evaluating nasal lavage fluid, lung tissues, and body and lung weights. Post-infection administration of ensitrelvir to Index hamsters suppressed virus shedding in a dose-dependent manner. Pre-exposure administration of 750 mg/kg ensitrelvir to naïve Contact hamsters also protected against aerosol SARS-CoV-2 infection in a dose-dependent manner. Furthermore, pre-exposure treatment of 750 mg/kg ensitrelvir supressed body weight loss and lung weight increase of aerosol infected hamsters compared to vehicle-treated hamsters. These findings suggest that ensitrelvir may prevent SARS-CoV-2 spread when administered to infected patients and may prevent or limit SARS-CoV-2 infection when prophylactically administered to non-infected individuals. Both approaches may help protect at-risk individuals, such as family members living with SARS-CoV-2-infected patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare the following competing financial interest(s): (1) Shionogi & Co., Ltd. has applied for a patent on ensitrelvir(2) Masaaki Nakashima, Haruaki Nobori, Takayuki Kuroda, Alice Shimba, Satoshi Miyagawa, Akane Hayashi, Kazumi Matsumoto, Mei Yoshida, Kaoru Baba, Teruhisa Kato, and Keita Fukao are employees of Shionogi & Co., Ltd. and its subsidiary company, Shionogi TechnoAdvance Research Co., Ltd.(3) Some of the authors are shareholders in Shionogi & Co., Ltd., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The presence of residual undifferentiated pluripotent stem cells (PSCs) in PSC-derived cell therapy products (CTPs) is a major safety issue for their clinical application, due to the potential risk of PSC-derived tumor formation. An international multidisciplinary multisite study to evaluate a droplet digital PCR (ddPCR) approach to detect residual undifferentiated PSCs in PSC-derived CTPs was conducted as part of the Health and Environmental Sciences Institute Cell Therapy-TRAcking, Circulation & Safety Technical Committee. To evaluate the use of ddPCR in quantifying residual iPSCs in a cell sample, different quantities of induced pluripotent stem cells (iPSCs) were spiked into a background of iPSC-derived cardiomyocytes (CMs) to mimic different concentrations of residual iPSCs. A one step reverse transcription ddPCR (RT-ddPCR) was performed to measure mRNA levels of several iPSC-specific markers and to evaluate the assay performance (precision, sensitivity, and specificity) between and within laboratories. The RT-ddPCR assay variability was initially assessed by measuring the same RNA samples across all participating facilities. Subsequently, each facility independently conducted the entire process, incorporating the spiking step, to discern the parameters influencing potential variability. Our results show that a RT-ddPCR assay targeting ESRG, LINC00678, and LIN28A genes offers a highly sensitive and robust detection of impurities of iPSC-derived CMs and that the main contribution to variability between laboratories is the iPSC-spiking procedure, and not the RT-ddPCR. The RT-ddPCR assay would be generally applicable for tumorigenicity evaluation of PSC-derived CTPs with appropriate marker genes suitable for each CTP., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Over 200 health information exchanges (HIEs) are currently operational in Japan. The most common feature of HIEs is remote on-demand viewing or searching of aggregated patient health data from multiple institutions. However, the usage of this feature by individual users and institutions remains unknown., Objective: This study aims to understand usage of the on-demand patient data viewing feature of large-scale HIEs by individual health care workers and institutions in Japan., Methods: We conducted audit log analyses of large-scale HIEs. The research subjects were HIEs connected to over 100 institutions and with over 10,000 patients. Each health care worker's profile and audit log data for HIEs were collected. We conducted four types of analyses on the extracted audit log. First, we calculated the ratio of the number of days of active HIE use for each hospital-affiliated doctor account. Second, we calculated cumulative monthly usage days of HIEs by each institution in financial year (FY) 2021/22. Third, we calculated each facility type's monthly active institution ratio in FY2021/22. Fourth, we compared the monthly active institution ratio by medical institution for each HIE and the proportion of cumulative usage days by user type for each HIE., Results: We identified 24 HIEs as candidates for data collection and we analyzed data from 7 HIEs. Among hospital doctors, 93.5% (7326/7833) had never used HIEs during the available period in FY2021/22, while 19 doctors used them at least 30% of days. The median (IQR) monthly active institution ratios were 0.482 (0.470-0.487) for hospitals, 0.243 (0.230-0.247) for medical clinics, and 0.030 (0.024-0.048) for dental clinics. In 51.9% (1781/3434) of hospitals, the cumulative monthly usage days of HIEs was 0, while in 26.8% (921/3434) of hospitals, it was between 1 and 10, and in 3% (103/3434) of hospitals, it was 100 or more. The median (IQR) monthly active institution ratio in medical institutions was 0.511 (0.487-0.529) for the most used HIE and 0.109 (0.0927-0.117) for the least used. The proportion of cumulative usage days of HIE by user type was complex for each HIE, and no consistent trends could be discerned., Conclusions: In the large-scale HIEs surveyed in this study, the overall usage of the on-demand patient data viewing feature was low, consistent with past official reports. User-level analyses of audit logs revealed large disparities in the number of days of HIE use among health care workers and institutions. There were also large disparities in HIE use by facility type or HIE; the percentage of cumulative HIE usage days by user type also differed by HIE. This study indicates the need for further research into why there are large disparities in demand for HIEs in Japan as well as the need to design comprehensive audit logs that can be matched with other official datasets., (© Jun Suzumoto, Yukiko Mori, Tomohiro Kuroda. Originally published in JMIR Medical Informatics (https://medinform.jmir.org).)

Porcine organs and human induced pluripotent stem cell (iPSC)-derived organoids as alternative organs for human transplantation have garnered attention, but both face technical challenges. Interspecies chimeric organ production using human iPSCs shows promise in overcoming these challenges. Our group successfully generated chimeric renal organoids using human iPSC-derived nephron progenitor cells (NPCs) and fetal mouse kidneys. However, the current technology is limited to rodents. Therefore, this study focused on producing human-pig chimeric renal organoids, as pigs are the most promising species for xenotransplantation. Modification of existing culture systems enables continuous renal development in both species, resulting in the successful creation of human-pig chimeric renal organoids. Moreover, this method can be applied to generate humanized xenogeneic kidneys for future clinical applications. This study provides evidence that optimizing culture conditions enables the early-stage kidney development beyond species barriers, thus laying the foundation for accelerating research on humanized xenogeneic kidney fabrication for clinical purposes., (© 2024. The Author(s).)

Introduction: Quinidine (QND) sulfate is an effective treatment for atrial fibrillation (AF) in horses, and several dosage regimens have been proposed to address its wide variability in response and potential adverse effects. The purpose of this study was to analyze the variability in plasma quinidine concentrations using population pharmacokinetics to determine an effective and safe dosage regimen for Thoroughbred horses., Methods: Six healthy Thoroughbred horses were treated with 20 mg/kg quinidine sulfate dihydrate (16.58 mg/kg QND base) administered PO or 5 mg/kg quinidine hydrochloride monohydrate (4.28 mg/kg QND base) administered IV (single administration), and blood samples were taken regularly. Four healthy horses were treated with 20 mg/kg quinidine sulfate dihydrate administered twice (every 6 h) via PO route. For the other 19 Thoroughbred racehorses that developed AF, blood samples were taken during quinidine therapy. Quinidine concentrations were measured in all plasma samples using liquid chromatography with tandem mass spectrometry, and the data from 29 horses were modeled using a nonlinear mixed-effects model, followed by Monte Carlo simulations (MCS)., Results: The median quinidine concentration for successful sinus rhythm conversion was 2.0 μg/mL (range: 0.5-2.7 μg/mL) in AF horses, while a median concentration of 3.8 μg/mL (range: 1.6-5.1 μg/mL) showed adverse effects. MCS predicted that plasma quinidine concentrations for quinidine sulfate dihydrate PO administration (loading dose: 30 mg/kg, maintenance dose: 6.5 mg/kg q 2 h) reached 1.4, 2.0 and 2.7 μg/mL in 90, 50 and 10% of the horse populations, respectively. Increasing the loading dose to 45 mg/kg and the maintenance dose to 9 mg/kg q 2 h, the plasma concentrations achieved were 1.9, 2.8, and 3.8 μg/mL in 90, 50, and 10% of horse populations, respectively., Discussion: Using simulations, different empirical dosing regimens were proposed to achieve plasma quinidine concentrations immediately or progressively, representing a tradeoff between optimizing therapeutic effects and minimizing adverse effects. A combination of these dosing regimens is recommended to gradually increase the therapeutic concentration levels of quinidine for safe and effective treatment of AF in racehorses., Competing Interests: TK, YM, CK, YT, YE, KI, HI, HM, NT, TN, and MO were employed by Japan Racing Association. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kuroda, Minamijima, Kinman, Takahashi, Ebisuda, Inoue, Ishikawa, Mita, Tamura, Nukada, Toutain and Ohta.)

Backgroud Aims: Regenerative therapies employing cell therapy products (CTPs) have attracted considerable attention. Biodistribution (BD) evaluation of CTPs is mainly performed to clarify the cell survival time, engraftment, and distribution site. This evaluation is crucial for predicting the efficacy and safety profiles of clinical studies based on non-clinical BD study outcomes. However, no internationally unified method has been established for assessing cell BD after administration. Here, we aimed to standardize the BD assay method used for CTPs, conducting the following evaluations using the same protocol across multiple study facilities: (1) in vitro validation of quantitative polymerase chain reaction (qPCR) and droplet digital PCR (ddPCR) analyses using the primate-specific Alu gene, and (2) in vivo BD studies after the intravenous administration of human mesenchymal stem cells (hMSCs) to immunodeficient mice, commonly used in non-clinical tumorigenicity studies., Methods: Quality control samples were prepared and analyzed by adding a fixed number of human-derived cells to several mouse tissues. The respective quantitative performances of the qPCR and ddPCR methods were compared for accuracy and precision. hMSCs were intravenously administered to immunodeficient mice, and tissues were collected at 1, 4, and 24 h after administration., Results: Both methods demonstrated an accuracy (relative error) generally within ±50% and a precision (coefficient of variation) generally less than 50%. While differences in calibration curve ranges were observed between qPCR and ddPCR, no significant differences in quantification were found among the assay facilities. The BD of hMSCs in mice was evaluated at seven facilities (qPCR at three facilities; ddPCR at four facilities), revealing similar tissue distribution profiles in all facilities, with the lungs showing the highest cell distribution among the tissues tested., Conclusions: Quantitative evaluation of qPCR and ddPCR using Alu sequences was conducted, demonstrating that the test method can be adapted for BD evaluation., Competing Interests: Declarations of competing interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article except for YY, who is an employee of Bio-Rad Laboratories., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The virus obtained from a swab sample ID: S66 in Hiroshima was reported to have a single T-base insertion in the ORF8 coding region. However, no T insertion was observed when we determined the genomic sequence using another method. We then extracted RNA from the S66 swab sample and sequenced the insertion site using the Sanger method. The resulting waveform was disrupted beyond the insertion site, suggesting the presence of a mixed population of viruses with different sequences. Through plasmid cloning of RT-PCR amplification fragments and virus cloning by limiting dilution, along with TIDE analysis to determine the ratio of components from the Sanger sequencing waveform, it was confirmed that the sample contained a mixture of viruses with varying numbers of T-base insertions. The virus with one T insertion (T1+) was predominant in 70-75 % of the genomes, and genomes with T0, T2+, T3+, T4+, and T5+ were also detected. No T-base insertion mutations were observed in the ORF8 region in three other SARS-CoV-2 samples. In the S66 sample, a C27911T point mutation near the insertion site in the ORF8 region resulted in a sequence of seven or more consecutive T bases, which was the cause of the T-base insertion. When the cloned S66 virus (T1+) was passaged in cultured cells, there was a tendency for viruses with more insertion bases to become dominant with successive generations, suggesting that the T-base insertion was due to polymerase stuttering. The insertion of T bases resulted in synthesis of deletion mutants of the ORF8 protein, but no significant change was observed in the proliferation of the viruses in cultured cells. A search of the GenBank database using NCBI BLAST for viruses similar to S66 with T-base insertion mutations revealed hundreds of viruses widely distributed on the molecular phylogenetic tree. These base insertion viruses were thought to have occasionally arisen during the virus infection process. This study suggests one mechanism of insertion mutations in SARS-CoV-2, and it is important to consider the emergence of future mutant strains., 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. Published by Elsevier B.V.)

Surgical-site infections (SSIs) at implant sites in horses are sometimes difficult to control with systemic antimicrobials. Because one of the likely reasons is insufficient antimicrobial concentrations, there is a need to increase these concentrations in and around the infected tissue. Marbofloxacin (MAR)-encapsulated microparticles (MAR-MPs) made of biodegradable poly (lactic-co-glycolic) acid are capable of sustained release in vitro. We examined the concentration of MAR in the subcutaneous tissue fluid at sites where MAR-MPs had been administered. On day 0, six 3- × 4-cm subcutaneous pockets were created in the neck of each of six Thoroughbred horses under sedation and local anesthesia. MAR-MPs containing 50 mg of MAR were added to each pocket, which was then sutured. On days 1, 2, 3, 4, and 7, subcutaneous tissue fluid from one pocket per horse was collected and analyzed by LC-MS/MS. From days 1 to 7, the median MAR concentration in the subcutaneous tissue fluid ranged from 17.7 (4.89-125.6) to 33.05 (15.1-71.6) µg/mL. The median concentrations in the subcutaneous tissue fluid exceeded the MIC 90 (the minimum inhibitory concentration that would inhibit the growth of 90 % of the tested bacterial isolates) of MAR for clinical isolates reported previously. The area of swelling at the site of administration was significantly larger on days 1 to 4 than just after administration (P < 0.05). MAR-MPs could be useful for controlling SSIs that require high antimicrobial concentrations for extended periods when they are used with strategies that reduce side effects., Competing Interests: Declaration of competing interest The authors declare no competing interests. None of us has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024. Published by Elsevier Inc.)

Pancreatic neuroendocrine tumors (PanNETs) are generally hypervascular and readily detectable on imaging tests. However, hypovascular PanNETs are clinically problematic, requiring multiple imaging tests and tissue analyses to differentiate them from pancreatic ductal cancers. A 41 year-old man presented with Whipple's triad; 72 h fasting test followed by glucagon challenge test suggested insulinoma. However, contrast-enhanced computed tomography image showed a 17 mm tumor with poor enhancement and unclear borders in the tail of the pancreas . Abdominal magnetic resonance imaging and contrast-enhanced endoscopic ultrasonography (EUS) indicated cystic degeneration and necrosis at the same site; EUS-guided fine-needle aspiration cytology indicated a PanNET Grade 1 tumor. Although the imaging was inconclusive, diazoxide treatment ameliorated the hypoglycemia-related symptoms and insulinoma was deemed likely; following tail pancreatectomy and splenectomy, the symptoms disappeared. Pathological examination revealed a tumor positive for insulin and classed as PanNET Grade 1 according to the 2019 WHO classification. The microvessel density (MVD) of the tumor was found to be as low as 3.9%, which may partly account for the inconclusive images. The present case was difficult to diagnose preoperatively due to hypovascularity on imaging because of reduced MVD. It is clinically important to evaluate MVD in cases of hypovascular PanNETs by multiple preoperative imaging studies to differentiate them from pancreatic cancers and to validate the findings by postoperative pathological analysis., Competing Interests: Conflicts of interestDY has received consulting/lecture fees from Novo Nordisk Pharma Ltd., Nippon Boehringer Ingelheim, Eli Lilly Japan K.K., and Kyowa Kirin Co., Ltd. DY also received grants from Arkray Inc., Novo Nordisk Pharma Ltd., Nippon Boehringer Ingelheim, Taisho Pharmaceutical Co. Ltd., and Terumo Corporation. YH has received lecture fees from Sumitomo Pharma Co. Ltd. RI, MS, TK, SO, SK, YL, YT, KT, MM, TH, TM, TK, TK, and TM declare that they have no conflict of interest. All authors declare that they have no competing interests relevant to this study., (© The Japan Diabetes Society 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.)

Background: Several cases of autoimmune disease onset after treatment for Cushing's syndrome have been reported., Case Presentation: Herein, we report a case of myasthenia gravis crisis in a 51-year-old woman 2 months after adrenalectomy for adrenal Cushing's syndrome accompanied by takotsubo cardiomyopathy. The resolution of excessive endogenous cortisol after adrenalectomy may have triggered the onset of previously latent myasthenia gravis., Conclusions: Observing the similarities in symptoms between myasthenia gravis and adrenal crisis, which can sometimes be challenging to differentiate, is essential. Moreover, the presence of takotsubo cardiomyopathy as a non-motor manifestation of myasthenic crisis must be noted., (© 2024. The Author(s).)

Background: Breast metastasis from small cell neuroendocrine carcinoma (SNEC) is very rare. In the present report, we describe a case of a female patient who was initially diagnosed with triple negative primary bilateral breast cancer, but during systemic examination, the diagnosis was bilateral breast metastasis from SNEC., Case Presentation: A 62-year-old woman with no history of smoking presented to the Department of General Medicine with left-sided chest pain, and computed tomography revealed masses in both breasts and left pleural thickening that was further confirmed by mammography and ultrasound of the breasts. A needle biopsy was performed, and triple negative primary bilateral breast cancer was diagnosed. Because progastrin-releasing peptide (ProGRP) 37,300 pg/ml (normal range, 0-81.0 pg/ml) and neuron-specific enolase 35.0 ng/ml (normal range, 0-16.3 ng/ml) levels were elevated, thoracoscopic biopsy was performed, and SNEC was diagnosed. Pathological examinations showed that the bilateral breast masses were also positive for immunohistochemical staining of chromogranin A, synaptophysin, and CD56, leading to a diagnosis of bilateral breast metastasis of neuroendocrine tumor., Conclusion: Although very rare, the possibility of breast metastasis should be considered when malignancy is suspected in other organs., (© 2024. The Author(s).)

Organic matter in the Martian sediments may provide a key to understanding the prebiotic chemistry and habitability of early Mars. The Curiosity rover has measured highly variable and 13 C-depleted carbon isotopic values in early Martian organic matter whose origin is uncertain. One hypothesis suggests the deposition of simple organic molecules generated from 13 C-depleted CO derived from CO 2 photochemical reduction in the atmosphere. Here, we present a coupled photochemistry-climate evolution model incorporating carbon isotope fractionation processes induced by CO 2 photolysis, carbon escape, and volcanic outgassing in an early Martian atmosphere of 0.5-2 bar, composed mainly of CO 2 , CO, and H 2 to track the evolution of the carbon isotopic composition of C-bearing species. The calculated carbon isotopic ratio in formaldehyde (H 2 CO) can be highly depleted in 13 C due to CO 2 -photolysis-induced fractionation and is variable with changes in atmospheric CO/CO 2 ratio, surface pressure, albedo, and H 2 outgassing rate. Conversely, CO 2 becomes enriched in 13 C, as estimated from the carbonates preserved in ALH84001 meteorite. Complex organic matter formed by the polymerization of such H 2 CO could explain the strong depletion in 13 C observed in the Martian organic matter. Mixing with other sources of organic matter would account for its unique variable carbon isotopic values., (© 2024. The Author(s).)

Background: Hereditary angioedema (HAE), a rare genetic disease, induces acute attacks of swelling in various regions of the body. Its prevalence is estimated to be 1 in 50,000 people, with no reported bias among different ethnic groups. However, considering the estimated prevalence, the number of patients in Japan diagnosed with HAE remains approximately 1 in 250,000, which means that only 20% of potential HAE cases are identified., Objective: This study aimed to develop an artificial intelligence (AI) model that can detect patients with suspected HAE using medical history data (medical claims, prescriptions, and electronic medical records [EMRs]) in the United States. We also aimed to validate the detection performance of the model for HAE cases using the Japanese dataset., Methods: The HAE patient and control groups were identified using the US claims and EMR datasets. We analyzed the characteristics of the diagnostic history of patients with HAE and developed an AI model to predict the probability of HAE based on a generalized linear model and bootstrap method. The model was then applied to the EMR data of the Kyoto University Hospital to verify its applicability to the Japanese dataset., Results: Precision and sensitivity were measured to validate the model performance. Using the comprehensive US dataset, the precision score was 2% in the initial model development step. Our model can screen out suspected patients, where 1 in 50 of these patients have HAE. In addition, in the validation step with Japanese EMR data, the precision score was 23.6%, which exceeded our expectations. We achieved a sensitivity score of 61.5% for the US dataset and 37.6% for the validation exercise using data from a single Japanese hospital. Overall, our model could predict patients with typical HAE symptoms., Conclusions: This study indicates that our AI model can detect HAE in patients with typical symptoms and is effective in Japanese data. However, further prospective clinical studies are required to investigate whether this model can be used to diagnose HAE., (©Kouhei Yamashita, Yuji Nomoto, Tomoya Hirose, Akira Yutani, Akira Okada, Nayu Watanabe, Ken Suzuki, Munenori Senzaki, Tomohiro Kuroda. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 13.09.2024.)

Background: Selective biliary cannulation in endoscopic retrograde cholangiopancreatography can be challenging due to factors like papillary morphology. Various patterns indicate cannulation difficulty, but the combinations causing difficulty and the optimal cannulation method for each scenario are unclear., Aims: This study aimed to identify cannulation difficulty patterns and develop a predictive scoring system for selecting the appropriate cannulation method., Methods: We retrospectively compared 776 patients with naïve papilla, dividing them into conventional contrast cannulation (N = 510) and salvage technique (N = 266) groups. The salvage group included patients using pancreatic duct guidewire placement and/or wire-guided cannulation due to difficulties with the contrast method. Papillary morphology (Haraldsson's classification), periampullary diverticulum (PAD), and scope operability were analyzed using multiple regression to identify risk factors for cannulation difficulties. Factors were scored based on hazard ratios to access combinations causing difficulties., Results: The salvage group had more older patients and higher frequencies of type 2 (small), type 3 (protruding or pendulous), type 4 (creased or ridged) papillae, PAD, and poor scope operability. Significant risk factors in the multivariate analysis included type 2 [odds ratio (OR) 6.88], type 3 (OR 7.74), type 4 (OR 4.06) papillae, PAD (OR 2.26), and poor scope operability (OR 4.03). Pattern recognition scores were significantly higher in the salvage group (1.31 vs. 3.43, P < 0.0001)., Conclusions: Type 2-4 papillae, PAD, and poor scope operability are significant risk factors for cannulation difficulty. Pattern recognition scores based on these factors can predict cannulation difficulty and aid in selecting between conventional and salvage methods., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Resurgence can be defined as increases in previously reinforced and subsequently extinguished target responding when conditions for an alternative response worsen. Worsening of alternative conditions, such as extinction, has been linked to relapse of clinically relevant behavior. Preclinical researchers have evaluated whether punishing target responses while differentially reinforcing an alternative response could reduce resurgence when conditions are worsened with extinction, with mixed results. In the present investigation, we systematically replicated this line of research with human participants recruited via crowdsourcing, using response cost as punishment. During Phase 1, we reinforced target responses with 100 points per delivery, exchangeable for money. During Phase 2, we reinforced alternative responses, discontinued point reinforcement for target responses, and parametrically manipulated across groups the magnitude of point loss (1, 100, 320, or 1,000 points) contingent on target responses. During Phase 3, we tested for resurgence by extinguishing target and alternative responses. Added punishment systematically decreased target responding during Phase 2 but did not influence resurgence during Phase 3. With a meta-analysis, we compared our findings with existing research examining a range of punishers and species. The results of the meta-analysis comport with the present findings, suggesting that the inclusion of punishment reduces target responding during DRA but, overall, has no systematic effects on resurgence., (© 2024 Society for the Experimental Analysis of Behavior.)

Background: Evidence regarding chemosensitivity to different therapeutic regimens in epithelial ovarian cancer (EOC) remains limited. This study aimed to investigate EOC implementation in daily clinical practice and reveal favorable regimens for EOC among Japanese patients., Methods: We retrospectively collected clinical data of patients newly diagnosed with EOC from 2012 to 2021 at our affiliated institutions. We evaluated overall survival (OS) and progression-free survival (PFS) of conventional paclitaxel plus carboplatin (TC) vs. dose-dense TC (ddTC) according to the eligibility of GOG262 and JGOG3016 and those with bevacizumab (BEV) vs. without BEV based on GOG218. Further, we evaluated OS and PFS of ddTC and ddTC + BEV to TC + BEV among patients with stage III/IV., Results: The ddTC group (n = 402) demonstrated longer PFS and OS than the TC group (n = 165) (adjusted hazard ratios [aHRs] [95% confidential intervals (CIs)]: 0.69 [0.55-0.88] and 0.67 [0.50-0.90], respectively). The group with BEV (n = 158) demonstrated a longer PFS than those without BEV (n = 296) (0.74 [0.57-0.95]), but not for OS (0.84 [0.60-1.17]). The ddTC and ddTC + BEV groups (n = 259 and 117) demonstrated no statistically significant differences in PFS and OS than the TC + BEV group (n = 75) (1.09 [0.79-1.50] and 0.74 [0.52-1.08] for PFS and 0.89 [0.59-1.34] and 0.73 [0.50-1.05] for OS, respectively)., Conclusion: Our study may indicate ddTC, BEV, and their combination regimen as the promising first-line chemotherapy option among Japanese patients with advanced EOC., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

The association of renal function with fracture incidence during teriparatide or alendronate treatment in elderly Japanese women was examined. Fracture incidence differed by fracture type, renal function, and treatment protocol. The results provide important information on pharmacotherapy in clinical practice for osteoporosis., Purpose: Incidence rate of morphometric vertebral fracture was lower under treatment with once-weekly teriparatide (TPTD) followed by alendronate (ALN) than under treatment with ALN throughout the study among elderly Japanese women at high fracture risk in JOINT-05. This is an exploratory subgroup analysis according to chronic kidney disease (CKD) status at baseline., Methods: Participants received sequential therapy with TPTD for 72 weeks, followed by ALN for 48 weeks (TPTD-ALN group, N = 483) or ALN monotherapy for 120 weeks (ALN group, N = 496). Baseline CKD status was classified by the estimated glomerular filtration rate (eGFR) and categorized as: CKD 1/2 (eGFR ≥ 60 mL/min/1.73 m 2 ), CKD 3a (eGFR 45-59 mL/min/1.73 m 2 ), or CKD 3b/4 (eGFR < 45 mL/min/1.73 m 2 ). Incidences of vertebral fractures including morphometric fractures, non-vertebral fractures, and all fractures were evaluated during follow-up., Results: Baseline characteristics were not different between treatment groups. Higher stages of CKD were associated with age and number of prevalent vertebral fracture. In CKD 1/2 patients (N = 556 with 90 incidents of morphometric vertebral fracture), the incidence of vertebral fractures was lower in the TPTD-ALN group than in the ALN group (p = 0.01). In CKD 3b/4 patients (N = 112 with 10 incidents of non-vertebral fracture), the incidence of non-vertebral fractures was lower in the ALN group than in the TPTD-ALN group, although the number of fractures was small. In the ALN group, the incidences of vertebral fractures, non-vertebral fractures, and all fractures remained constant across CKD stages., Conclusion: This exploratory analysis showed that fracture incidence on ALN was constant regardless of renal function. It also suggested that the incidence of vertebral fractures on TPTD-ALN was lower than ALN monotherapy in CKD 1/2 patients. These results provide important information for drug selection in the clinical practice of osteoporosis., Competing Interests: Declarations. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Declaration of Helsinki and its later amendments or comparable ethical standards. Conflicts of interest: Y. Takeuchi has received consulting fees, speaking fees, and/or honoraria from Amgen Inc., Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Mochida Pharma Co., Ltd., and Teijin Pharma Ltd. S. Tanaka has received lecture fees from the Research Institute of Healthcare Data Science. He has received consultation fees and outsourcing fees from Eli Lilly and Company, Welby, Daiichi Sankyo Company, Limited, Janssen Pharmaceutical K.K., Satt, and the Public Health Research Foundation. He has received research grants from the Japan Agency for Medical Research and Development, the Japanese Ministry of Health Labor and Welfare, the Japanese Ministry of Education, Science, and Technology, and Novo Nordisk. He engaged in a research project of the Japan Agency for Medical Research and Development. H. Hagino received lecture fees or grants outside the submitted work from Amgen Inc., Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mochida Pharma Co., Ltd., Teijin Pharma Ltd., and UCB Japan Co., Ltd. S. Soen has received consulting fees, speaking fees, and/or honoraria from Amgen Inc., Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan Co., Ltd., Mochida Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Teijin Pharma Ltd., and UCB Japan Co., Ltd. T. Kuroda and S. Mori declare no competing interests., (© 2024. The Author(s).)

Context: Cultural adaptation is essential for optimizing programs centered around autonomy, such as the Serious Illness Care Program (SICP), especially for populations valuing family-involved decision-making., Objectives: We aimed to evaluate the feasibility and efficacy of a culturally adapted SICP-based nurse-physician collaborative Advance Care Planning (ACP) intervention tailored for patients with advanced cancer who prefer family-involved decision-making., Methods: Oncology nurses, extensively trained and closely collaborating with physicians, conducted structured discussions with patients in the intervention group. The culturally adapted SICP-based ACP intervention was supplemented with trust-building, family involvement, and understanding of patient values. Primary inclusion criteria included patients within six weeks of initiating first-line palliative chemotherapy. Primary endpoints were achieving a 70% completion rate and assessing spiritual well-being (FACIT-Sp) at six months. Secondary endpoints included anxiety (GAD-7), depression (PHQ-9), quality of life (QOL) (CoQoLo), and ACP progress (ACP Engagement Scale) at the same interval., Results: Forty-one patients (67.2%) completed the six-month follow-up, falling short of the targeted completion rate. The least-squares mean change from baseline in spiritual well-being at six months was 3.00 in the intervention group and -2.22 in the standard care group (difference, 5.22 points; 95% confidence interval, 1.38-9.06; P = 0.009). Similar superiority of the intervention was observed in QOL and ACP progress., Conclusion: Despite not meeting the targeted completion rate, the intervention group demonstrated enhanced spiritual well-being, QOL, and ACP progress. Our findings suggest revisions to the intervention manual to improve feasibility and to progress to an efficacy-focused randomized controlled trial., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: A less-invasive left atrial assist device (LAADx) is a novel and implantable, extracardiac blood pump concept, intended for the treatment of diastolic heart failure, represented by heart failure with preserved ejection fraction., Methods: A mixed-flow pump was used as the working LAADx model. Its performance was evaluated at 3 speeds, using an in vitro pulsatile mock circulatory loop, with a pneumatic pump that can simulate diastolic heart failure conditions by adjusting the diastolic drive pressure. The LAADx model was implanted in 4 healthy calves. The pump's inflow and outflow cannulas were inserted into the left atrium (LA) and left ventricle (LV), respectively, without cardiopulmonary bypass. The LAADx was operated at 3 speeds, and diastolic heart failure-like conditions were induced by inflating a balloon, inserted into the LV., Results: With the in vitro study, diastolic heart failure-like conditions were successfully induced, exhibiting decreased cardiac output and aortic pressure as well as increased mean LA pressure both mitigated with the LAADx support. With regard to the in vivo study, simulated diastolic heart failure conditions showed a decrease in aortic pressure and an increase in LA pressure and LV end-diastolic pressure, which were again mitigated by the LAADx. Echocardiography showed good positioning of the outflow cannula and neither cardiac dysfunction nor mitral interference was observed., Conclusions: Initial in vitro and in vivo results confirmed that the LAADx model, a device concept driven by creating an extracardiac route from the LA to LV, has the potential to mitigate high LA pressure and improve LV filling of heart failure with preserved ejection fraction pathology., Competing Interests: Drs Fukamachi and Karimov, and Mr Kuban are coinventors of the LAADx, an extracardiac left atrial assist device. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handing or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)

Background: One of the disadvantages of medical documentation in Electronic Medical Record (EMR) systems is that records tend to be redundant by "copying and pasting", a writing style to duplicate and revise previous records. In this study, we analyzed the similarity between records to identify the factors affecting the writing style of clinical notes., Method: We analyzed 98,038 records of 4,149 patients from two years in the Department of Obstetricians and Gynecology at Kyoto University Hospital, Japan. We observed the correlation between the distribution of the record similarity and string amounts, as well as the disease codes and ratios of outpatient visit., Results: The patient group with high record similarity and large number of strings was the group with reproductive medicine, followed by the group of malignant tumor follow-up or Women's Healthcare., Discussion: In reproductive medicine, physicians have a demand for an overarching evaluation, and in follow-up malignancies or in Women's Healthcare, they have a demand to check for subtle differences from the last time. These facts along with our data insist that the writing style in EMR systems is related to the patient's status., Conclusion: We declared that the writing style in EMR systems is affected by the patient's status. The writing style of duplicating and revising is preferred (1) when there is a clinical demand for an overarching evaluation, and (2) when there is a clinical demand to check for subtle differences from the last time.

Patient perception involves a patient's thoughts and beliefs regarding their health status. It is also associated with medical compliance and outcomes. However, discrepancies often arise between patient perception and physicians' documentation within the medical records, resulting in misunderstanding and suboptimal doctor-patient communication. In this study, we assessed the efficacy of generative artificial intelligence (AI) in comparing the content of patient perception as recorded in patient questionnaires and physicians' records of the Department of Breast Surgery. We evaluated the precision and recall of the generative AI by comparison with human-created ground truth. Our results demonstrated the high performance of the generative AI in comprehending and contrasting symptoms and the entire content recorded differently by patients and physicians, with F1 scores ranging from 0.77 to 0.97. These results highlight the potential contribution of a generative AI to deeper mutual comprehension in healthcare scenarios.

Lao PDR's Ministry of Health has problem with fragmented data, lack of standardization, and inability to interoperate hinder child health data collection. Electronic health information exchange (HIE) could improve data quality and shared child health records (SCHR). In this study we developed the SCHR by interoperating with existing healthcare systems. The FHIR IPS standards were customized based on data elements. 14 experts from the technical working group (TWG) had determined the minimum dataset for data transactions and system testing was analyzed on the HAPI FHIR server. Used FHIR IPS standards for interoperability within Client Registry (CR-DHIS2), Electronic Immunization Record (EIR-DHIS2) and Electronic Medical Record (EMR) works well for data transactions. The initial result of the SCHR could be able to provide a real target child and to monitor full vaccination. However, prior to the actual deployment of the system, it is necessary to validate it and guarantee the confidentiality and safety of the data.

For better collaboration among radiologists, the interpretation workload should be evaluated, considering the difference in difficulty for interpreting each case. However, objective evaluation of difficulty is challenging. This study proposes a multimodal classifier of structural and textual data to predict difficulty based on order information and patient data without using images. The classifier showed performance with a specificity of 0.9 and an accuracy of 0.7.

Despite the perceived advantages of health information exchange (HIE), their utilization has been stagnant, and a detailed survey at the regional level is needed to address this issue. We conducted interviews with operators of HIEs in operation in Japan as a pilot study and found that subjective descriptions by healthcare professionals contained in clinical notes are frequently referenced in HIEs. Currently, however, only a limited number of medical institutions in Japan disclose subjective descriptions. In this study, we aim to clarify the factors that influence whether or not to disclose subjective descriptions through an interview survey. Although the final results are yet to be determined, it is anticipated that the non-disclosing medical institutions will show negative aspects of disclosure, such as privacy concerns and misuse of information. Addressing the concerns raised in this study is important for the future dissemination of HIE.

Objective: To clarify the anti-inflammatory effect of platelet lysate (PL) on equine persistent synovitis by using a model of synovitis induced by monoiodoacetic acid (MIA)., Methods: Nonseptic synovitis was induced by administering MIA into both antebrachiocarpal joints of 6 clinically healthy horses on day 0. On days 23, 30, and 37, carpal circumference measurement and synovial fluid collection for assays (leucocytes, LDH, tumor necrosis factor-α, and TGF-β1) were performed, after which PL was injected into 1 antebrachiocarpal joint and saline into the contralateral joint. Synovium and synovial fluid were obtained on day 44 for histological analysis and quantification of inflammation-related genes (matrix metalloproteinase-13, a disintegrin and metalloproteinase with thrombospondin motifs 4, receptor activator of nuclear factor κ-Β ligand, and collagen type I α2 chain) and the abovementioned proteins., Results: The LDH level on day 44 was significantly lower in the PL-injected joint than in the saline-treated one. However, no significant differences were found in the other indices quantified, including osteoclast counts on the synovium., Conclusions: Multiple IA administration of PL does not exert anti-inflammatory effects on the equine persistent synovitis induced by MIA., Clinical Relevance: Intra-articular PL administration did not alter many inflammatory biomarkers, suggesting that PL does not have a direct anti-inflammatory effect. However, the reduction in synovial LDH levels suggests that PL promoted joint tissue repair and may consequently alleviate inflammation at the site of administration.

Introduction: To identify predictors of discontinuing treatment with teriparatide (TPTD) and alendronate (ALN), data from a randomized, controlled trial (JOINT-05) involving postmenopausal Japanese women at high risk of fracture were re-analyzed., Materials and Methods: Participants received sequential therapy with once-weekly TPTD for 72 weeks followed by ALN for 48 weeks (TPTD-ALN group) or monotherapy with ALN for 120 weeks (ALN group). Background data including comorbidities, fracture prevalence, cognitive function, quality of life, activities of daily living, bone metabolism parameters, and nutrient intake were collected. The endpoints were 3 types of discontinuations by the reason: a poor compliance, adverse events (AEs), or any reason including those unrelated to AEs or poor compliance. Odds ratios (ORs) of baseline predictors of discontinuation were evaluated by single or multiple regression analysis., Results: A total of 234 (49.0%) patients in the TPTD-ALN group and 167 (34.2%) patients in the ALN group discontinued. In the TPTD-ALN group, a lower serum calcium level was a significant predictor of compliance-related discontinuation. Serum 25-hydroxyvitamin D levels were lower in patients with lower serum calcium levels than with higher serum calcium levels. In the ALN group, poor cognitive function was significantly associated with compliance-related discontinuation, and higher body mass index and alcohol intake were predictors of AE-related discontinuation. Predictors of discontinuation were drug-specific. Lower serum calcium levels and poor cognitive function were predictors of discontinuing once-weekly TPTD and ALN, respectively., Conclusion: When starting TPTD and ALN treatment, careful attention to patients with lower serum calcium levels and poor cognitive function, respectively, may be needed for better treatment continuity., (© 2024. The Author(s).)

Purpose: Surgical procedures for anorectoplasty for anorectal malformations (ARMs), particularly rectourethral fistula (RUF), depend on the institution. We investigated the diagnosis and treatment of RUF in male patients with ARMs in Japan using a questionnaire survey., Methods: An online survey inquiring about the diagnosis and treatment (diagnostic modalities, surgical approaches, fistula dissection devices, and fistula closure techniques) of each type of ARM in male patients was conducted among institutional members of the Japanese Study Group of Anorectal Anomalies. Fisher's exact test was used to compare surgical methods between posterior sagittal anorectoplasty (PSARP) and laparoscopy-assisted anorectoplasty (LAARP)., Results: Sixty-one institutions (100%) completed the survey. LAARP was the preferred approach for high-type ARM (75.4%). PSARP was preferred for intermediate-type ARM (59.0%). Monopolar devices were most commonly used (72.1%) for RUF dissection. Blunt dissection was more frequent in the PSARP group (PSARP vs. LAARP: 55.6 vs. 20.0%, p < 0.005). Cystoscopy/urethroscopy to confirm the extent of dissection was used more frequently in the LAARP group (70.0% vs. 25.0%, p < 0.005). Clips and staplers were used more frequently in the LAARP group (p < 0.05)., Conclusion: Distinct fistula management strategies for PSARP and LAARP were revealed. Further studies are needed to investigate the postoperative outcomes associated with these practices., (© 2024. The Author(s).)

Background and Aim: Rapidly aging societies have become a major issue worldwide including Japan. This study aimed to elucidate relative changes in the characteristics of inpatients in Japan related to this issue., Methods: A total of 23 835 Japanese inpatients treated from 2010 to 2021 were enrolled (2010-2013, period I; 2014-2017, period II; 2018-2021, period III). Changes in clinical features were retrospectively analyzed based on ICD-10 diagnosis data., Results: The percentage of patients aged over 75 years increased over time (period I, 38.0%; II, 39.5%, III, 41.4%). Emergency admissions comprised 27.5% of all in period I, which increased to 43.2% in period II and again to 44.5% in period III (P < 0.001). In period I, gastrointestinal disease, liver disease, pancreatic-biliary disease, and other disease types were noted in 47.4%, 29.5%, 19.2%, and 3.9%, respectively, while those values were 44.0%, 18.0%, 33.9%, and 4.1%, respectively, in period III (P < 0.001). The frequency of liver disease decreased by approximately 0.6-fold from periods I to III, while that of biliary-pancreatic disease increased by approximately 1.8-fold during that time. Both percentage and actual numbers of patients with biliary-pancreatic disease increased during the examined periods. Analysis of changes in the proportion of organs affected by malignancy during periods I, II, and III showed a marked increase in cases of biliary-pancreatic malignancy (11.6%, 19.5%, 26.6%, respectively) (P < 0.001)., Conclusion: In association with the rapidly aging Japanese society, there has been an increasing frequency of biliary-pancreatic disease cases requiring hospitalization for treatment in the west Japan region of Shikoku., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The potential value of hypervascularity detected with power Doppler ultrasonography (PDU) within equine superficial digital flexor tendon (SDFT) as a prognostic factor of SDFT injury is not clear. The purpose of this study was to test the hypothesis that hypervascularity within SDFT is one of the risk factors for subsequent severe SDFT injury and to evaluate the prognostic value. A prospective cohort study of 97 Thoroughbred racehorses without any clinical signs of SDFT injury was conducted. Six variables of age, body weight, sex, the cross-sectional area of SDFT, PDU signal within SDFT and experience of steeplechase were assessed for the possibility of risk factors of subsequent SDFT injury in follow-up period of 1 year. Multivariable logistic regression analyses were used for assessment of the odds ratios (ORs) and 95 % confidence intervals (CIs) of SDFT injury. Multivariable logistic regression analysis revealed that the PDU signal within SDFT was a risk factor for the development of SDFT injury in follow-up period (P = 0.017). The adjusted OR of SDFT injury was significantly higher in PDU positive group than in PDU negative group (OR 3.17, 95 % CIs 1.20-8.35). Although further studies are required, these results would be useful for early detection and/or prevention of development for clinical severe SDFT injury., Competing Interests: Declaration of Competing Interest None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The damage that may be caused to the operating table and patients under general anaesthesia when a large earthquake occurs is unclear. We aimed to evaluate the movement and damage to operating tables and patients under general anaesthesia during an earthquake., Methods: An operating table with a manikin resembling a patient on it was placed on a shaking table, and seismic waves were input into the shaking table. The effects of seismic waves were evaluated by altering surgical positions (supine and head-down positions), operating tables, flooring material, seismic waves, and output. We observed the movement of the operating table and measured the acceleration of the operating table and manikin head., Results: Under 90% output of long-period seismic waves, the operating table with the supine manikin was overturned. Under experimental conditions that did not cause rocking, shaking such as tilting of the operating table caused stronger acceleration in the manikin's head than in the operating table. There was no clear relationship between operating table rocking and maximum acceleration as a result of programmed seismic waves. In long-period earthquakes, rocking and overturning occurred >60 s after the onset of shaking, whereas in direct earthquakes, rocking occurred within 10 s., Conclusions: An earthquake could cause strong acceleration of the patient's head under general anaesthesia, and operating tables may overturn or shake violently. Regarding patient safety, further measures to prevent overturning should be considered., Competing Interests: The authors declare that they have no conflicts of interest., (© 2024 The Authors.)

Atypical femoral fracture (AFF) is generally a rare complication of long-term use of bisphosphonate (BP); glucocorticoid (GC) use and Asian race are also risk factors. Femoral localized periosteal thickening (LPT, also termed "beaking") of the lateral cortex often precedes AFF. This cohort study investigated the incidence of LPT and AFF and their clinical courses over 10 yr in patients with autoimmune inflammatory rheumatic diseases (AIRDs) treated with BP and GC. The study population consisted of 121 patients with AIRDs taking BP and GC. LPT was screened by X-ray, and the LPT shape was evaluated. Prednisolone (PSL) dose was 10 (8-12) mg/d at enrollment and 9 (6-10) mg/d at the last observation. LPT was evident in 10 patients at enrollment and increased linearly to 31 patients (26%) at the last observation. AFF occurred in 9 femurs of 5 patients with LPT. All patients with AFF had bilateral LPT, and the prevalence of pointed type and LPT height were higher in the AFF-positive group than in the AFF-negative group. AFF occurred before BP discontinuation in 2 patients, 1 yr after BP discontinuation in 1, after BP discontinuation followed by 7 yr of alfacalcidol use in 1, and after switching from alfacalcidol to denosumab in 1. The prevalence rates of AFF and LPT associated with long-term BP use with concomitant use of GC (mostly PSL ≥ 6 mg/d) in Japanese patients with AIRD increased over time. The selection of long-term osteoporosis treatment for LPT-positive patients is difficult in some cases., Competing Interests: H.S. received lecture fee from Asahi Kasei Pharma, Daiichi Sankyo Company and Astellas pharma Inc. N.K., Y.K., E.H., A.W., Y.N., D.K., T.N., Y.W., J.J.K., T.K., M.N., N.E., and I.N. declare that they have no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Background: Ultrasound-guided percutaneous cryoablation (PCA) for early-stage breast cancer (ESBC) can be performed under local anesthesia in an outpatient clinic. This study continues a pilot stage to examine local control, safety, patient quality of life (QoL), satisfaction and cosmetic outcomes of cryoablation for ESBC., Methods: PCA was performed under local anesthesia for patients with primary ESBC, followed by radiation and endocrine therapies. Oncologic outcomes were examined by imaging (mammography, ultrasound, MRI) at baseline and 1, 6, 12, 24, 36, and 60 months post-cryoablation. EQ-VAS, EQ-5D-5L, subjective satisfaction and Moiré topography were used to measure health-related QoL outcomes., Results: Eighteen patients, mean aged 59.0 ± 9.0 years, mean tumor size 9.8 ± 2.3 mm, ER + , PR + (17/18), HER2-, Ki67 < 20% (15/18), underwent PCA and were followed for a mean of 44.3 months. No serious adverse events were reported, and no patients had local recurrence or distant metastasis in the 5-year follow-up. Cosmetic outcomes, satisfaction level, and QoL all improved post-cryoablation. Five-year average reduction rates of the cryolesion long, short, and depth diameters, on US, were 61.3%, 42.3%, and 22.8%, respectively, compared to the 86.2% volume reduction rate on MRI. The correlation coefficient between MRI and US measurement criteria was highest for the long diameter. During follow-up, calcification of the treated area was observed in 13/18 cases., Conclusion: Cryoablation for ESBC is an effective and safe procedure with excellent cosmetic outcomes and improved QoL. This study contributes to the growing evidence supporting cryoablation as a potential standard treatment for ESBC, given compliance to pre-defined patient selection criteria., (© 2024. The Author(s).)

Introduction: MEASURE2 (Multisite Evaluation Study on Analytical Methods for Non-clinical Safety Assessment of HUman-derived REgenerative Medical Products 2) is a Japanese experimental public-private partnership initiative that aims to standardize testing methods for tumorigenicity evaluation of human pluripotent stem cell (hPSC)-derived cell therapy products (CTPs). MEASURE2 organized multisite studies to optimize the methodology of the highly efficient culture (HEC) assay, a sensitive culture-based in vitro assay for detecting residual undifferentiated hPSCs in CTPs., Methods: In these multisite studies, 1) the efficiency of colony formation by human induced pluripotent stem cells (hiPSCs) under two different culture conditions and 2) the sorting efficiency of microbeads conjugated to various anti-hPSC markers during hiPSC enrichment were evaluated using samples in which hiPSCs were spiked into hiPSC-derived mesenchymal stem cells., Results: The efficiency of colony formation was significantly higher under culture conditions with the combination of Chroman 1, Emricasan, Polyamines, and Trans-ISRIB (CEPT) than with Y-27632, which is widely used for the survival of hPSCs. Between-laboratory variance was also smaller under the condition with CEPT than with Y-27632. The sorting efficiency of microbeads conjugated with the anti-Tra-1-60 antibody was sufficiently higher (>80%) than those of the other various microbeads investigated., Conclusions: Results of these multisite studies are expected to contribute to improvements in the sensitivity and robustness of the HEC assay, as well as to the future standardization of the tumorigenicity risk assessment of hPSC-derived CTPs., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s).)

Background: Multiple studies have examined the impact of deferral on the motivation of prospective blood donors, proposing various policies and strategies to support individuals who undergo this experience. However, existing information and communications technology systems focused on blood donation have not yet integrated these ideas or provided options to assist with the deferral experience., Objective: This study aims to propose an initial gamified design aimed at mitigating the impact of the deferral experience by addressing the drivers of awareness and knowledge, interaction and validation, and motivation. Additionally, the study explores the feasibility of implementing such a system for potential users., Methods: We conducted a literature review focusing on the dynamics of motivation and intention related to blood donation, as well as the deferral situation and its impact on citizens. Through this review, we identified weak donor identity, lack of knowledge, and reduced motivation as key factors requiring support from appropriate interventions. These factors were then defined as our key drivers. Taking these into account, we proposed a gamification approach that incorporates concepts from the MDA framework. The aim is to stimulate the aforementioned drivers and expand the concept of contribution and identity in blood donation. For a preliminary evaluation, we designed a prototype to collect feedback on usability, usefulness, and interest regarding a potential implementation of our proposed gamification approach., Results: Among the participants, a total of 11 citizens interacted with the app and provided feedback through our survey. They indicated that interacting with the app was relatively easy, with an average score of 4.13 out of 5 when considering the 11 tasks of interaction. The SUS results yielded a final average score of 70.91 from the participants' answers. Positive responses were received when participants were asked about liking the concept of the app (3.82), being likely to download it (3.55), and being likely to recommend it to others (3.64). Participants expressed positivity about the implementation of the design but also highlighted current shortcomings and suggested possible improvements in both functionality and usability., Conclusions: Although deferral is a common issue in blood donation, there is a missed opportunity in existing ICT services regarding how to effectively handle such experiences. Our proposed design and implementation seem to have captured the interest of prospective users due to its perceived positive usefulness and potential. However, further confirmation is needed. Improving the design of activities that currently rely heavily on extrinsic motivation elements and integrating more social components to create an enhanced activity loop for intrinsic motivation could further increase the value of the proposed project. Future research could involve conducting a more specialized and longitudinal design evaluation with a larger sample size., (©Roberto Espinoza Chamorro, Luciano H O Santos, Yukiko Mori, Chang Liu, Goshiro Yamamoto, Tomohiro Kuroda. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 14.06.2024.)

Background: The subjective visual vertical (SVV) test can evaluate otolith function and spatial awareness and is performed in dedicated vertigo centers using specialized equipment; however, it is not otherwise widely used because of the specific equipment and space requirements. An SVV test smartphone app was developed to easily perform assessments in outpatient facilities., Objective: This study aimed to verify whether the SVV test smartphone app with commercially available virtual reality goggles can be used in a clinical setting., Methods: The reference range was calculated for 15 healthy participants. We included 14 adult patients with unilateral vestibular neuritis, sudden sensorineural hearing loss with vertigo, and Meniere disease and investigated the correlation between the SVV test results and vestibular evoked myogenic potential (VEMP) results., Results: The SVV reference range of healthy participants for the sitting front-facing position was small, ranging from -2.6º to 2.3º. Among the 14 patients, 6 (43%) exceeded the reference range for healthy participants. The SVV of patients with vestibular neuritis and sudden sensorineural hearing loss tended to deviate to the affected side. A total of 9 (64%) had abnormal cervical VEMP (cVEMP) values and 6 (43%) had abnormal ocular VEMP (oVEMP) values. No significant difference was found between the presence or absence of abnormal SVV values and the presence or absence of abnormal cVEMP and oVEMP values; however, the odds ratios (ORs) suggested a higher likelihood of abnormal SVV values among those with abnormal cVEMP and oVEMP responses (OR 2.40, 95% CI 0.18-32.88; P>.99; and OR 2, 95% CI 0.90-4.45; P=.46, respectively)., Conclusions: The SVV app can be used anywhere and in a short period while reducing directional bias by using virtual reality goggles, thus making it highly versatile and useful as a practical otolith dysfunction screening tool., (©Akiko Umibe, Hiroaki Fushiki, Reiko Tsunoda, Tatsuaki Kuroda, Kazuhiro Kuroda, Yasuhiro Tanaka. Originally published in JMIR Formative Research (https://formative.jmir.org), 04.06.2024.)

Aim: Frailty is defined as extreme vulnerability, a syndrome that exposes the individual to a higher risk of disability. While risk factors for frailty have been gradually uncovered, the full identification of biochemical factors and co-morbidities influencing frailty remains incomplete., Methods: Cross-sectional and longitudinal analyses were performed to elucidate the risk factors for the prevalence and progression of frailty. The study included 1035 Japanese female outpatients. At baseline, biochemical markers were measured. Co-morbidities included diabetes mellitus, dyslipidemia, hypertension, vertebral osteoarthritis, and osteoporosis. Frailty levels were assessed using frailty scores ranging from 0 to 5. Prevalence of frailty was judged by a score of 3 or above, and progression was judged by an increase in the frailty score during the observation period. Multiple regression analysis was used for the cross-sectional analysis, and the Cox hazard model was used for the longitudinal analysis., Results: Of the 1035 selected participants, 212 were diagnosed with frailty. Advanced age and log IL-6 and branched-chain amino acids (BCAA) levels were significant independent risk factors for frailty. Subjects were followed for 7.7 ± 5.9 years and progression was observed in 130 subjects. Older age, the absence of hyperlipidemia, the presence of osteoporosis, and lower frailty scores were identified as significant risk factors for frailty progression., Conclusions: Inflammatory and nutritional markers exhibited significant associations with the current frailty status, whereas co-morbidities such as osteoporosis or hyperlipidemia emerged as independent risk or protective factors of future frailty progression. Geriatr Gerontol Int 2024; 24: 523-528., (© 2024 Japan Geriatrics Society.)

Background/aim: Unresectable recurrence after curative treatments for hepatocellular carcinoma (HCC) is a life-limited event. Although the IMbrave050 trial (IM050) showed a favorable reduction in recurrence with adjuvant immune-combination chemotherapy, inclusion criteria of the radiofrequency ablation (RFA) group were lower risk than that of the resection group. This study aimed to elucidate the clinical features of patients treated with RFA, which really need adjuvant-chemotherapy., Methods: From 2000 to 2022, 528 patients with Child-Pugh A and HCC within the Milan criteria (MC), who met the IM050 criteria for RFA and undergone resection or RFA, were enrolled (71 years, HCV:HBV:HBV/HCV:alcohol:others = 337:44:5:53:89, multi-tumor = 138, RFA:resection = 309:219). Unresectable recurrence was defined as beyond the MC. Risk factors for recurrence beyond the MC were retrospectively evaluated., Results: Multivariate Cox-hazard analysis showed HCV-positive (HR 1.49), AFP-L3 > 10% (HR 1.75), and DCP > 100 mAU/mL (HR1.80) as significant prognostic factors for recurrence beyond the MC (each P < 0.05). Summing of positive factors (1 point for each) was used for scoring (AD-ON score), which showed increased positive rates for micro-hepatic vein invasion (score 0:1:2:3 = 0%:1.1%:6.6%:15.8%), micro-portal vein invasion (0:1:2:3 = 2.0%:12.1%:14.1%:31.6%), and poor differentiation (0:1:2:3 = 6.0%:6.7%:15.3%:15.8%) in the resection group associated with a greater score (each P < 0.01). In patients treated with RFA, those with greater AD-ON scores showed shorter time to recurrence beyond the MC, recurrence-free time, and overall survival (score 0:1:2:3 = no-estimation:97:66:23 months, 35:27:20:12 months, and 91:82:67:52 months, respectively, each P < 0.05)., Conclusion: HCC patients treated by RFA and with a high AD-ON score (≧2) should be considered for aggressive adjuvant-chemotherapy to prolong the period of recurrence beyond the MC., (© 2024. Japanese Society of Gastroenterology.)

Oxaliplatin, a platinum-based anticancer drug, is associated with peripheral neuropathy (oxaliplatin-induced peripheral neuropathy, OIPN), which can lead to worsening of quality of life and treatment interruption. The endothelial glycocalyx, a fragile carbohydrate-rich layer covering the luminal surface of endothelial cells, acts as an endothelial gatekeeper and has been suggested to protect nerves, astrocytes, and other cells from toxins and substances released from the capillary vessels. Mechanisms underlying OIPN and the role of the glycocalyx remain unclear. This study aimed to define changes in the three-dimensional ultrastructure of capillary endothelial glycocalyx near nerve fibers in the hind paws of mice with OIPN. The mouse model of OPIN revealed disruption of the endothelial glycocalyx in the peripheral nerve compartment, accompanied by vascular permeability, edema, and damage to the peripheral nerves. To investigate the potential treatment interventions, nafamostat mesilate, a glycocalyx protective agent was used in tumor-bearing male mice. Nafamostat mesilate suppressed mechanical allodynia associated with neuropathy. It also prevented intra-epidermal nerve fiber loss and improved vascular permeability in the peripheral paws. The disruption of endothelial glycocalyx in the capillaries that lie within peripheral nerve bundles is a novel finding in OPIN. Furthermore, these findings point toward the potential of a new treatment strategy targeting endothelial glycocalyx to prevent vascular injury as an effective treatment of neuropathy as well as of many other diseases. PERSPECTIVE: OIPN damages the endothelial glycocalyx in the peripheral capillaries, increasing vascular permeability. In order to prevent OIPN, this work offers a novel therapy approach that targets endothelial glycocalyx., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Aim: Branched-chain amino acids (BCAAs) have been shown to exert beneficial effects on muscle and bone metabolism; however, no studies to date have investigated whether BCAAs have beneficial effects on bone fractures. Herein, we aim to prospectively investigate the relationship between serum BCAA concentrations and the occurrence of vertebral fractures (VFs) in Japanese women., Methods: During the observation period (7.5 ± 6.1 years), 188 of 983 participants experienced VF. Kaplan-Meier analyses were conducted to examine time-dependent variations in the vertebral compression fracture occurrence rate. Patients were stratified into quartiles based on serum BCAA concentration for this analysis., Results: The analysis results indicated that the group with the lowest BCAA level developed VFs significantly earlier and with a higher frequency than the other groups (P < 0.001). A Cox proportional hazards model showed that BCAA concentration was a significant risk factor for incident fracture, even after adjusting for possible confounding factors. A series of multiple regression analyses were performed to identify factors related to serum BCAA concentration, with the results identifying levels of glycated hemoglobin (P < 0.001), adiponectin (P < 0.001), and NOx (P = 0.011) as significant factors associated with serum BCAA., Conclusions: Overall, the present study revealed that a lower serum BCAA level was an independent risk factor for incident VF in postmenopausal women. Geriatr Gerontol Int 2024; 24: 603-608., (© 2024 Japan Geriatrics Society.)

Purpose: Survival rates of patients with high-risk neuroblastoma are unacceptable. A time-intensified treatment strategy with delayed local treatment to control systemic diseases has been developed in Japan. We conducted a nationwide, prospective, single-arm clinical trial with delayed local treatment. This study evaluated the safety and efficacy of delayed surgery to increase treatment intensity., Patients and Methods: Seventy-five patients with high-risk neuroblastoma were enrolled in this study between May 2011 and September 2015. Delayed local treatment consisted of five courses of induction chemotherapy (cisplatin, pirarubicin, vincristine, and cyclophosphamide) and myeloablative high-dose chemotherapy (melphalan, etoposide, and carboplatin), followed by local tumor extirpation with surgery and irradiation. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), response rate, adverse events, and surgical complications., Results: Seventy-five patients were enrolled, and 64 were evaluable (stage 3, n = 8; stage 4, n = 56). The estimated 3-year PFS and OS rates (95% confidence interval [CI]) were 44.4% [31.8%-56.3%] and 80.7% [68.5%-88.5%], resspectively. The response rate of INRC after completion of the treatment protocol was 66% (42/64; 95% CI: 53%-77%; 23 CR [complete response], 10 VGPR [very good partial response], and nine PR [partial response]). None of the patients died during the protocol treatment or within 30 days of completion. Grade 4 adverse effects, excluding hematological adverse effects, occurred in 48% of patients [31/64; 95% CI: 36%-61%]. Major Surgical complications were observed in 25% of patients [13/51; 95% CI: 14%-40%]., Conclusion: This study indicates that delayed local treatment is feasible and shows promising efficacy, suggesting that this treatment should be considered further in a comparative study of high-risk neuroblastoma., (© 2024 Wiley Periodicals LLC.)

The extraction of data that contribute to regulatory approval from real-world data (RWD) is difficult because of the lack of a standardized data format and extraction methodology. Additionally, when real-world evidence (RWE) is used as an external control group, the similarity between internal and external control data is not evaluated. To investigate the data extraction methodology for the external control data of rare molecular subtypes, we have initiated the "REALISE" study. In this study, we aim to elucidate the "relevance" and "reliability" of RWD/RWE necessary for regulatory approval. As most databases are not designed for regulatory use in the creation phase, we will investigate retrospective methodologies to ensure RWD/RWE reliability. This study will compare the "relevance" and "reliability" of the ARCAD global database, SCRUM-Japan Registry, SCRUM-Japan observational study, and Flatiron Health RWD, and statistically analyze the differences and similarities among the four databases. We will also examine the methodology for extracting sufficiently relevant data from the SCRUM-Japan observational study. Additionally, if the reliability of the RWD/RWE does not reach the required level for regulatory approval, we will examine the methodologies to ensure the "reliability" of the SCRUM-Japan observational study for regulatory approval. The obtained results will be submitted to the "Consultation for Development of Registry" in the Pharmaceuticals and Medical Devices Agency, and we will discuss the standard methodology. The procedures and findings identified in the REALISE study will be organized from the perspectives of "database construction," "data analysis," and "outcome evaluation" and will be issued as "the draft guidelines.", Competing Interests: Disclosure Hideaki Bando reports research funding from Ono Pharmaceutical and honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly in Japan. Yasutoshi Sakamoto reports no conflict of interests. Toshihiro Misumi reports honoraria from Chugai, AstraZeneca, and Miyarisan. Yuriko Takeda reports no conflict of interests. Yoshiaki Nakamura reports honoraria from Chugai Pharmaceutical, Merck Biopharma, and Guardant Health AMEA and research grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Guardant Health, Genomedia, Daiichi Sankyo, Seagen, and Roche Diagnostics. Kazuya Mizuguchi and Yoshihiro Aoyagi reports no conflict of interests. Takayuki Yoshino reports honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, and MSD and research funding from Taiho Pharmaceutical, Ono Pharmaceutical, Chugai Pharmaceutical, Amgen, Parexel International, MSD, Daiichi Sankyo, Pfizer, Genomedia, Sysmex, Nihon Boehringer Ingelheim, and Sanofi. Atsushi Ohtsu reports research funding from BMS and honoraria from Chugai and Ono Pharmaceutical., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A population pharmacokinetic (PopPK) analysis was conducted using data from 215 Japanese administered oral sirolimus (tablet and granule) including healthy subjects and patients with intractable vascular anomalies and other diseases. The analysis included neonates, infants, and adults, and identified covariates that influence sirolimus pharmacokinetics (PK). The final model was used to predict sirolimus trough concentrations for various dosing regimens and covariates of interest. The results showed that sirolimus trough concentrations were predicted to increase with higher levels of hemoglobin, and that the granule formulation had a 1.23-fold higher exposure than the tablet formulation. Coadministration of CYP3A4 inducers was found to decrease trough concentrations by 54 %. The PK simulations showed that administration of the granule formulation at doses of 0.02, 0.04, 0.06, and 0.08 mg/kg/day in ages <3 months, 3 to <6 months, 6 to <12 months, and ≥1 year, respectively, resulted in >70 % target attainment within the therapeutic trough concentration range (5-15 ng/mL). In conclusion, incorporation of time-varying covariates (body weight and age) into the PopPK model appropriately predicted sirolimus concentrations in Japanese subjects from infants to adult sub-populations. This PopPK model would therefore be able to provide a reference for clinical individualization of sirolimus dosing., (Copyright © 2024. Published by Elsevier Ltd.)