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Purpose of this study is to evaluate patient characteristics, treatments and outcomes in bone metastasis radiotherapy practice. Patients for whom radiotherapy for bone metastasis was planned at 26 institutions in Japan between December 2020 and March 2021 were consecutively registered in this prospective, observational study. Study measures included patient characteristics, pain relief, skeletal-related events (SREs), overall survival and incidence of radiation-related adverse events. Pain was evaluated using a numerical rating scale (NRS) from 0 to 10. Irradiated dose was analyzed by the biologically effective dose (BED) assuming α/β = 10. Overall, 232 patients were registered; 224 patients and 302 lesions were fully analyzed. Eastern Cooperative Oncology Group Performance Status was 0/1/2/3/4 in 23%/38%/22%/13%/4%; 59% of patients had spinal metastases and 84% had painful lesions (NRS ≥ 2). BED was <20 Gy (in 27%), 20-30 Gy (24%), 30-40 Gy (36%) and ≥ 40 Gy (13%); 9% of patients were treated by stereotactic body radiotherapy. Grade 3 adverse events occurred in 4% and no grade 4-5 toxicity was reported. Pain relief was achieved in 52% at 2 months. BED is not related to pain relief. The cumulative incidence of SREs was 6.5% (95% confidence interval (CI) 3.1-9.9) at 6 months; no factors were significantly associated with SREs. With spinal lesions, 18% of patients were not ambulatory at baseline and 50% of evaluable patients in this group could walk at 2 months. The 6-month overall survival rate was 70.2% (95% CI 64.2-76.9%). In conclusion, we report real-world details of radiotherapy in bone metastasis., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Diagnosis improvement requires physician-nurse collaboration. This study explored nurses' concerns regarding physicians' diagnoses and how they were communicated to physicians. This cross-sectional study, employing a web-based questionnaire, included nurses registered on Japan's largest online media site from June 26, 2023, to July 31, 2023. The survey inquired whether participants felt concerned about a physician's diagnosis within a month, if they communicated their concerns once they arose, and, if not, their reasons. The reasons for not being investigated were also examined. The nurses' frequency of feeling concerned about a physician's diagnosis and the barriers to communicating these concerns to the physician were evaluated. Overall, 430 nurses answered the survey (female, 349 [81.2%]; median age, 45 [35-51] years; median years of experience, 19 [12-25]). Of the nurses, 61.2% experienced concerns about a physician's diagnosis within the past month; 52.5% felt concerned but did not communicate this to the physician. The most common reasons for not communicating included concern about the physician's pride, being ignored when communicating, and the nurse not believing that a diagnosis should be made. Our results highlight the need to foster psychologically safe workplaces for nurses and create educational programs encouraging nurse involvement in diagnosis., (© 2024. The Author(s).)

Vocal communication plays a crucial role in the social interactions of primates, particularly in survival and social organization. Humans have developed a unique and advanced vocal communication strategy in the form of language. To study the evolution of human language, it is necessary to investigate the neural mechanisms underlying vocal processing in humans, as well as to understand how brain mechanisms have evolved by comparing them with those in nonhuman primates. Herein, we developed a method to noninvasively measure the electroencephalography (EEG) of awake nonhuman primates. This recording method allows for long-term studies without harming the animals, and, importantly, allows us to directly compare nonhuman primate EEG data with human data, providing insights into the evolution of human language. In the current study, we used the scalp EEG recording method to investigate brain activity in response to species-specific vocalizations in marmosets. This study provides novel insights by using scalp EEG to capture widespread neural representations in marmosets during vocal perception, filling gaps in existing knowledge.

We sought to identify potential evidence-practice gaps in palliative radiotherapy using quality indicators (QIs), previously developed using a modified Delphi method. Seven QIs were used to assess the quality of radiotherapy for bone metastases (BoM) and brain metastases (BrM). Compliance rate was calculated as the percentage of patients for whom recommended medical care was conducted. Random effects models were used to estimate the pooled compliance rates. Of the 39 invited radiation oncologists, 29 (74%) from 29 centers participated in the survey; 13 (45%) were academic and 16 (55%) were non-academic hospitals. For the QIs, except for BoM-4, the pooled compliance rates were higher than 80%; however, for at least some of the centers, the compliance rate was lower than these pooled rates. For BoM-4 regarding steroid use concurrent with radiotherapy for malignant spinal cord compression, the pooled compliance rate was as low as 32%. For BoM-1 regarding the choice of radiation schedule, the compliance rate was higher in academic hospitals than in non-academic hospitals (P = 0.021). For BrM-3 regarding the initiation of radiotherapy without delay, the compliance rate was lower in academic hospitals than in non-academic hospitals (P = 0.016). In conclusion, overall, compliance rates were high; however, for many QIs, practice remains to be improved in at least some centers. Steroids are infrequently used concurrently with radiotherapy for malignant spinal cord compression., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Boron neutron capture therapy (BNCT) is a unique radiotherapy of selectively eradicating tumor cells using boron compounds (e.g., 4-borono-L-phenylalanine [BPA]) that are heterogeneously taken up at the cellular level. Such heterogenicity potentially reduces the curative efficiency. However, the effects of temporospatial heterogenicity on cell killing remain unclear. With the technical combination of radiation track detector and biophysical simulations, this study revealed the cell cycle-dependent heterogenicity of BPA uptake and subsequent biological effects of BNCT on HeLa cells expressing fluorescent ubiquitination-based cell cycle indicators, as well as the modification effects of polyvinyl alcohol (PVA). The results showed that the BPA concentration in the S/G 2 /M phase was higher than that in the G 1 /S phase and that PVA enhances the biological effects both by improving the uptake and by canceling the heterogenicity. These findings might contribute to a maximization of therapeutic efficacy when BNCT is combined with PVA and/or cell cycle-specific anticancer agents., (© 2024. The Author(s).)

Objective: In Japan, perioperative prophylaxis of pulmonary embolism (PE) in gynecologic cancer patients with preoperative asymptomatic venous thromboembolism (VTE) has not been well established yet. The GOTIC-VTE trial was a prospective, multi-center, single-arm clinical trial to investigate the prevention of postoperative symptomatic PE onset by seamless anticoagulant therapy from the preoperative period to 4 weeks after surgery instead of using intermittent pneumatic compression., Methods: Anticoagulant therapy was started immediately after asymptomatic VTE diagnosis and stopped preoperatively according to the rules of each institution. Unfractionated heparin administration was resumed within 12 hours postoperatively, and this was followed by the switch to low-molecular-weight heparin and subsequently, edoxaban; this cycle was continued for 28 days. Primary outcome was the occurrence of symptomatic PE in 28 days postoperatively. Secondary outcomes were the incidence of VTE-related events in 28 days and 6 months postoperatively and protocol-related adverse events., Results: Between February 2018 and September 2020, 99 patients were enrolled; of these, 82 patients were assessed as the full analysis set, including 58 for ovarian cancer, fallopian tube, or peritoneal cancer; 21 for endometrial cancer; and 3 for cervical cancer. No symptomatic PE was observed within 28 days postoperatively; two patients had bleeding events (major bleeding and clinically relevant nonmajor bleeding) and three had grade 3 adverse events (increased alanine transaminase, aspartate aminotransferase, or gamma-glutamyl transferase)., Conclusion: The multifaceted perioperative management for gynecologic malignancies with asymptomatic VTE effectively prevented postoperative symptomatic PE., Trial Registration: JRCT Identifier: jRCTs031180124., Competing Interests: YT, TS, and HF received honoraria from Daiichi Sankyo. KY received a research grant from Daiichi Sankyo. KH received honoraria and a research grant from Daiichi Sankyo. KF received honoraria from Daiichi Sankyo for consultation., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Retained placenta (RP) adversely affects postpartum productivity and reproduction in dairy cattle. Thus, methods to predict the occurrence of RP before calving would be desirable. Herein, we assessed whether vaginal temperature measurements (which have already been applied to detect calving) could be used to predict the occurrence of RP in cattle. A vaginal temperature recording device was inserted into the vagina of 49 pregnant Holstein-Friesian heifers (n = 16) and cows (n = 33); this device recorded the vaginal temperature every 5 min until the device dropped out at calving. Serum was collected 10 days before the expected calving date. The time points of calving and placental expulsion were identified via video recordings. We further calculated calving duration (temperature decrease to calving) and placenta expulsion time (PE time = calving to placenta expulsion). The PE times were divided into four categories (0-4 h, 4-8 h, 8-12 h, and RP at >12 h), while subsequent analysis revealed that an extension of the PE time dependent on the shortening of the calving duration (P < 0.05). The vaginal temperature patterns also differed in a PE time-dependent manner, and cows with RP did not show any re-elevation of vaginal temperature. Serum analyses indicated an energy deficiency in RP cattle. These results suggest that RP may be detected early as a specific change in the vaginal temperature associated with reproductive hormone secretion.

Most Pacific salmon species grow in the ocean, return to their native rivers to reproduce, and then die (semelparous type). However, rainbow trout survive after spawning and reproduce repeatedly until the end of their lives (iteroparous type). Little is known about how germline stem cells behave during gametogenesis in the two types of Pacific salmon. In this study, we show that all germline stem cells disappear after the first gametogenesis in Chinook and Kokanee salmon, whereas germline stem cells are maintained in rainbow trout. However, the germline stem cells of Chinook and Kokanee salmon transplanted into rainbow trout survive even after their spawning seasons and supply salmon gametes for multiple years. These results indicate that the behavior of the germline stem cells is mainly regulated by the somatic environment.

Background: Empathy with patients improves clinical outcomes. Although previous studies have shown no significant differences in empathy levels between physicians and nurses, investigations have not considered differences in cultural backgrounds and related factors of healthcare providers at the individual level., Objective: This study compares empathy between physicians and nurses in Japan and identifies relevant factors that contribute to these differences., Design: A cross-sectional survey design was used in the study. The online survey was conducted using the Nikkei Medical Online website., Participants: A total of 5441 physicians and 965 nurses in Japan who were registered as members of Nikkei Medical Online were included., Main Measures: Empathy was measured by the Jefferson Scale of Empathy (JSE)., Key Results: Cronbach's α was 0.89. The mean JSE score for Japanese physicians was significantly lower at 100.05 (SD = 15.75) than the mean score of 110.63 (SD = 12.25) for nurses (p<0.001). In related factors, higher age (increasing by one year) (+0.29; 95% CI 0.25 to 0.32; p<0.001), self-identified female gender (+5.45; 95% CI 4.40 to 6.49; p<0.001), having children (+1.20; 95% CI 0.30 to 2.10; p=0.009), and working at a hospital with 20-99 beds (+1.73; 95% CI 0.03 to 3.43; p=0.046) were significantly associated with higher scores, whereas those whose mother is a physician (-6.65; 95% CI -8.82 to -4.47; p<0.001) and father is a nurse (-9.53; 95% CI -16.54 to -2.52; p=0.008) or co-medical professional (-3.85; 95% CI -5.49 to -2.21; p<0.001) were significantly associated with lower scores., Conclusions: Physicians had significantly lower scores on the JSE than nurses in Japan. Higher age, self-identified female gender, having children, working at a small hospital, having a mother who is a physician, and having a father who is a nurse or co-medical professional were factors associated with the level of empathy., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Two-dimensional (2D) clinical gait analysis systems are more affordable and portable than contemporary three-dimensional (3D) clinical models. Using the Vicon 3D motion capture system as the standard, we evaluated the internal statistics of the Imasen and open-source OpenPose gait measurement systems, both designed for 2D input, to validate their output based on the similarity of results and the legitimacy of their inner statistical processes. We measured time factors, distance factors, and joint angles of the hip and knee joints in the sagittal plane while varying speeds and gaits during level walking in three in-person walking experiments under normal, maximum-speed, and tandem scenarios. The intraclass correlation coefficients of the 2D models were greater than 0.769 for all gait parameters compared with those of Vicon, except for some knee joint angles. The relative agreement was excellent for the time-distance gait parameter and moderate-to-excellent for each gait motion contraction range, except for hip joint angles. The time-distance gait parameter was high for Cronbach's alpha coefficients of 0.899-0.993 but low for 0.298-0.971. Correlation coefficients were greater than 0.571 for time-distance gait parameters but lower for joint angle parameters, particularly hip joint angles. Our study elucidates areas in which to improve 2D models for their widespread clinical application.

Background: Cognitive impairment, a core feature of schizophrenia, is associated with poor outcomes. Pharmacotherapy and psychosocial treatment, when used alone, have inadequate effect sizes for cognitive impairment, leading to recent interest in combination interventions. A previous study examined the additive effect of cognitive remediation on lurasidone in patients with schizophrenia, which was negative. Although improvement in cognitive function was suggested for lurasidone, it was inconclusive because there was no antipsychotic control in the study. To clarify whether lurasidone has a meaningful impact on cognitive function in combination with cognitive remediation, we use paliperidone as a control antipsychotic in this study. We hypothesize that combination with lurasidone will improve cognitive and social function to a greater extent than paliperidone., Methods: The valuable interaction with cognitive remediation and optimal antipsychotics for recovery in schizophrenia study is a multicenter, interventional, open-label, rater-blind, randomized comparison study, comparing the effect of lurasidone plus cognitive remediation with that of paliperidone plus cognitive remediation in patients with schizophrenia. The Neuropsychological Educational Approach to Remediation (NEAR) is used for cognitive remediation. Eligible patients will be randomized 1:1 to receive lurasidone or paliperidone combined with NEAR (6 weeks antipsychotic alone followed by 24 weeks combination antipsychotic plus NEAR). The primary endpoint is the change from baseline in the tablet-based Brief Assessment of Cognition in Schizophrenia composite T-score at the end of the NEAR combination treatment period. Secondary endpoints will include change from baseline in social function, schizophrenia symptoms, and quality of life at the end of the NEAR combination treatment period. Furthermore, change from baseline to the end of the pharmacotherapy period and change from the end of the pharmacotherapy period to the end of the NEAR combination treatment period will be assessed for all endpoints. Safety will also be evaluated., Discussion: Achievement of adequate cognitive function is central to supporting social function, which is a key treatment goal for patients with schizophrenia. We think this study will fill in the gaps of the previous study and provide useful information regarding treatment decisions for patients with schizophrenia., Clinical Trial Registration: Japan Registry of Clinical Trials ID, jRCTs031200338., Competing Interests: RK received honoraria from Sumitomo Pharma Co., Ltd. SaI received honoraria from Nippon Boehringer Ingelheim Co., Ltd., Lundbeck Japan K.K., Sumitomo Pharma Co., Ltd., and Takeda Pharmaceutical Co., Ltd. HO received research funding from Otsuka Pharmaceutical Co., Ltd.; and is the director of Japan Society of Clinical Trials and Research and The Japanese Association of Pharmaceutical Medicine. MO received honoraria from Pfizer Japan Inc., AstraZeneca K.K., and EP-SOGO Co., Ltd. ST and YN are employees of Sumitomo Pharma Co., Ltd. KN received honoraria from Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corp., Takeda Pharmaceutical Co., Ltd., Lundbeck Japan K.K., Viatris Inc., Eisai Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Mochida Pharmaceutical Co., Ltd.; support for transportation to attend meetings from Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corp., Takeda Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Mochida Pharmaceutical Co., Ltd.; and his institution received grants from Shionogi & Co., Ltd., Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corp., Nippon Boehringer Ingelheim Co., Ltd., and Mochida Pharmaceutical Co., Ltd. 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 Kubota, Ikezawa, Oi, Oba, Izumi, Tsuno, Adachi, Miwa, Toya, Nishizato, Haga, Iwane and Nakagome.)

Introduction: Since the SARS-CoV-2 Omicron variant became dominant, assessing COVID-19 vaccine effectiveness (VE) against severe disease using hospitalization as an outcome became more challenging due to incidental infections via admission screening and variable admission criteria, resulting in a wide range of estimates. To address this, the World Health Organization (WHO) guidance recommends the use of outcomes that are more specific to severe pneumonia such as oxygen use and mechanical ventilation., Methods: A case-control study was conducted in 24 hospitals in Japan for the Delta-dominant period (August-November 2021; "Delta") and early Omicron (BA.1/BA.2)-dominant period (January-June 2022; "Omicron"). Detailed chart review/interviews were conducted in January-May 2023. VE was measured using various outcomes including disease requiring oxygen therapy, disease requiring invasive mechanical ventilation (IMV), death, outcome restricting to "true" severe COVID-19 (where oxygen requirement is due to COVID-19 rather than another condition(s)), and progression from oxygen use to IMV or death among COVID-19 patients., Results: The analysis included 2125 individuals with respiratory failure (1608 cases [75.7%]; 99.2% of vaccinees received mRNA vaccines). During Delta, 2 doses provided high protection for up to 6 months (oxygen requirement: 95.2% [95% CI:88.7-98.0%] [restricted to "true" severe COVID-19: 95.5% {89.3-98.1%}]; IMV: 99.6% [97.3-99.9%]; fatal: 98.6% [92.3-99.7%]). During Omicron, 3 doses provided high protection for up to 6 months (oxygen requirement: 85.5% [68.8-93.3%] ["true" severe COVID-19: 88.1% {73.6-94.7%}]; IMV: 97.9% [85.9-99.7%]; fatal: 99.6% [95.2-99.97]). There was a trend towards higher VE for more severe and specific outcomes., Conclusion: Multiple outcomes pointed towards high protection of 2 doses during Delta and 3 doses during Omicron. These results demonstrate the importance of using severe and specific outcomes to accurately measure VE against severe COVID-19, as recommended in WHO guidance in settings of intense transmission as seen during Omicron., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takeshi Arashiro is an unpaid consultant for the World Health Organization. The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The centrosome is involved in cytoplasmic microtubule organization during interphase and in mitotic spindle assembly during cell division. Centrosome amplification (abnormal proliferation of centrosome number) has been observed in several types of cancer and in precancerous conditions. Therefore, it is important to elucidate the mechanism of centrosome amplification in order to understand the early stage of carcinogenesis. Primary cells could be used to better understand the early stage of carcinogenesis rather than immortalized cells, which tend to have various genetic and epigenetic changes. Previously, we demonstrated that a poly(ADP-ribose) polymerase (PARP) inhibitor, 3-aminobenzamide (3AB), which is known to be nontoxic and nonmutagenic, could induce centrosome amplification and chromosomal aneuploidy in CHO-K1 cells. In this study, we compared primary mouse embryonic fibroblasts (MEF) and immortalized MEF using 3AB. Although centrosome amplification was induced with 3AB treatment in immortalized MEF, a more potent PARP inhibitor, AG14361, was required for primary MEF. However, after centrosome amplification, neither 3AB in immortalized MEF nor AG14361 in primary MEF caused chromosomal aneuploidy, suggesting that further genetic and/or epigenetic change(s) are required to exhibit aneuploidy. The DNA-damaging agents doxorubicin and γ-irradiation can cause cancer and centrosome amplification in experimental animals. Although doxorubicin and γ-irradiation induced centrosome amplification and led to decreased p27Kip protein levels in immortalized MEF and primary MEF, the phosphorylation ratio of nucleophosmin (Thr199) increased in immortalized MEF, whereas it decreased in primary MEF. These results suggest that there exists a yet unidentified pathway, different from the nucleophosmin phosphorylation pathway, which can cause centrosome amplification in primary MEF.

Purpose of Study: A physician's ability to empathize is crucial for patient health outcomes, and this differs according to speciality, personal characteristics, and environmental factors. This study aimed to examine the empathy levels among physicians based on their specialities and to identify the influencing factors., Study Design: A nationwide, online, cross-sectional survey was conducted using the Nikkei Business Publication online physician member homepage. Participants were 5441 physicians in Japan registered as members of Nikkei Medical Online across 20 specialities. We used the Jefferson Scale of Empathy (JSE) to measure the physicians' empathy levels. Cronbach's alpha was 0.84., Results: The mean JSE score was 100.05, SD = 15.75. Multivariate analyses showed that the highest JSE scores were for general medicine [+5.58, 95% confidence interval (CI) 2.60-8.56], general surgery (+3.63, 95% CI 0.97-6.28), psychiatry (+3.47, 95% CI 1.76-5.17), and paediatrics (+1.92, 95% CI 0.11-3.73). Factors associated with higher JSE scores were being female (+5.86, 95% CI 4.68-7.04), managers (+1.11, 95% CI 0.16-2.07), working in a small hospital (+2.19, 95% CI 0.23-4.15), and with children (+3.32, 95% CI 2.29-4.36)., Conclusions: A significant decrease in the empathy levels was found when the parent of the participant was also a medical provider. Being a general medicine physician or a female physician in a high position who has children was positively and significantly correlated with high empathy levels., (© The Author(s) 2023. Published by Oxford University Press on behalf of Postgraduate Medical Journal. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To identify factors significantly associated with quality of life (QOL) and determine if these associations are strong enough to predict certain aspects of QOL without measuring them., Methods: We conducted an exploratory secondary analysis of baseline data of 224 patients (enrolled between December 2020 and March 2021) from a previously published prospective observational study on radiotherapy for bone metastases at 26 centres. Using univariable linear regression, we assessed the association between patient/treatment factors and QOL scale scores as measured by the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 15-Palliative (QLQ-C15-PAL) and the EORTC QOL Questionnaire Bone Metastases module (QLQ-BM22)., Results: Age and sex were not significantly associated with QOL. Worse performance status, higher pain scores, and opioid and single-fraction use were significantly associated with most QOL scales; these four factors were associated with worse global QOL, worse functioning status, and more severe symptoms. The coefficients of determination for most QOL scales were less than 0.2, indicating that most of the variability in QOL scores was not explained by any of the explanatory variables., Conclusion: Performance status, pain intensity, and opioid and single-fraction use were significantly associated with most QOL scales. However, the associations were not strong enough to estimate QOL., Advances in Knowledge: To date, the association between treatment factors and QOL in patients with bone metastases has not been fully studied. We identified the factors that were significantly associated with QOL and found that these associations were not strong enough to predict QOL., Competing Interests: Competing interestsKei Ito was a member of the advisory board and has received honorariums from Varian Medical Systems K. K.

Common marmosets usually give birth to twins and form a social group consisting of a breeding couple and pairs of same-aged siblings. The twins may engage in the first agonistic fights between them, twin-fights (TFs), during adolescence. This study investigated the TFs based on records accumulated in our captive colony over 12 years to elucidate the proximate causations that trigger the TFs. We aimed to determine whether the TF onset mainly depended on internal events (such as the onset of puberty) as previously suggested or external events (such as the birth of the younger siblings and the behavioral change of the group members). Although both events usually occur simultaneously, the birth control method (i.e., manipulation of ovulation and interbirth-intervals by prostaglandin administration to females) could temporally separate these events. A comparison of the onset day and occurrence rate with or without the birth control procedure revealed that TFs were triggered by a combination of internal and external events, that is, external events were the predominant triggers of TF, under the influence of internal events. The timing of TF onset was significantly delayed when the birth of the younger siblings was delayed and the twins grew older under the birth-controlled condition, suggesting that the birth of younger siblings and related behavioral changes of group members, as well as twins' developmental maturation, could trigger TF. Higher TF rates between same-sex twins were consistent with previous studies, reflecting the characteristics of same-sex directed aggression in callitrichines., (© 2023 The Authors. American Journal of Primatology published by Wiley Periodicals LLC.)

Non-clinical toxicology is a major cause of drug candidate attrition during development. In particular, drug-induced seizures are the most common finding in central nervous system (CNS) toxicity. Current safety pharmacology tests for assessing CNS functions are often inadequate in detecting seizure-inducing compounds early in drug development, leading to significant delays. This paper presents an in vitro seizure liability assay using voltage-sensitive dye (VSD) imaging techniques in hippocampal brain slices, offering a powerful alternative to traditional electrophysiological methods. Hippocampal slices were isolated from mice, and VSD optical responses evoked by stimulating the Schaffer collateral pathway were recorded and analyzed in the stratum radiatum (SR) and stratum pyramidale (SP). VSDs allow for the comprehensive visualization of neuronal action potentials and postsynaptic potentials on a millisecond timescale. By employing this approach, we investigated the in vitro drug-induced seizure liability of representative pro-convulsant compounds. Picrotoxin (PiTX; 1-100 μM), gabazine (GZ; 0.1-10 μM), and 4-aminopyridine (4AP; 10-100 μM) exhibited seizure-like responses in the hippocampus, but pilocarpine hydrochloride (Pilo; 10-100 μM) did not. Our findings demonstrate the potential of VSD-based assays in identifying seizurogenic compounds during early drug discovery, thereby reducing delays in drug development and providing insights into the mechanisms underlying seizure induction and the associated risks of pro-convulsant compounds., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Utsumi, Taketoshi, Miwa, Tominaga and Tominaga.)

This paper describes contextualized medication event extraction for automatically identifying medication change events with their contexts from clinical notes. The striding named entity recognition (NER) model extracts medication name spans from an input text sequence using a sliding-window approach. Specifically, the striding NER model separates the input sequence into a set of overlapping subsequences of 512 tokens with 128 tokens of stride, processing each subsequence using a large pre-trained language model and aggregating the outputs from the subsequences. The event and context classification has been done with multi-turn question-answering (QA) and span-based models. The span-based model classifies the span of each medication name using the span representation of the language model. In the QA model, event classification is augmented with questions in classifying the change events of each medication name and the context of the change events, while the model architecture is a classification style that is the same as the span-based model. We evaluated our extraction system on the n2c2 2022 Track 1 dataset, which is annotated for medication extraction (ME), event classification (EC), and context classification (CC) from clinical notes. Our system is a pipeline of the striding NER model for ME and the ensemble of the span-based and QA-based models for EC and CC. Our system achieved a combined F-score of 66.47% for the end-to-end contextualized medication event extraction (Release 1), which is the highest score among the participants of the n2c2 2022 Track 1., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Motivation: Entity linking is the task of linking entity mentions to the database entries corresponding to the entity mentions. Entity linking enables the treatment of superficially different but semantically identical mentions as the same entity. Since millions of concepts are listed in biomedical databases, selecting the correct database entry for each targeted entity is challenging. Simple string matching between the word and each synonym in biomedical databases is insufficient to handle a wide variety of variants of biomedical entities appearing in the biomedical literature. Recent progress in neural approaches is promising for entity linking. Still, existing neural methods require sufficient data, which is difficult to prepare in biomedical entity linking that deals with millions of biomedical concepts. Therefore, we need to develop a new neural method to train entity-linking models over the sparse training data covering a very limited part of the biomedical concepts., Results: We have devised a pure neural model that classifies biomedical entity mentions into millions of biomedical concepts. The classifier employs (1) the layer overwriting that breaks through the performance ceiling during training, (2) training data augmentation using database entries that compensate for the problem of insufficient training data, and (3) the cosine similarity-based loss function that helps distinguish the millions of biomedical concepts. Our system using the proposed classifier was ranked first in the official run of the National NLP Clinical Challenges (n2c2) 2019 Track 3, which targeted linking medical/clinical entity mentions to 434,056 Concept Unique Identifier (CUI) entries. We also applied our system to the MedMentions dataset, which has 3.2M candidate concepts. Experimental results confirmed the same advantages of our proposed method. We further evaluated our system on the NLM-CHEM corpus with 350K candidate concepts, and our system achieved a new state-of-the-art performance on the corpus., Availability: https://github.com/tti-coin/bio-linking Contact:makoto.miwa@toyota-ti.ac.jp., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: The role of serum fibroblast growth factor 23 (FGF23) level in early neonatal period on the diagnosis of X-linked hypophosphatemic rickets (XLH) remains unclear., Case Presentation: Two female patients from the first pedigree had an affected mother, and the other female from the second pedigree had an affected father. In all three cases, FGF23 levels were high in cord blood and peripheral blood at day 4-5. Additionally, the FGF23 levels considerably increased from birth to day 4-5. We identified a PHEX pathogenic variant and initiated treatment during infancy in each case., Conclusions: In neonates with a parent diagnosed as PHEX -associated XLH, FGF23 in cord blood and peripheral blood at day 4-5 may be useful markers for predicting the presence of XLH., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: Uterine carcinosarcoma (UCS), a subtype of endometrial carcinoma, is a rare and aggressive cancer with a poor prognosis. High clinical efficacy of trastuzumab deruxtecan (T-DXd) in HER2-expressing UCS was recently reported in a phase II trial (STATICE trial). We performed a co-clinical study of T-DXd using patient-derived xenograft (PDX) models of participants in the STATICE trial., Experimental Design: Tumor specimens were resected during primary surgery or biopsied at recurrence from patients with UCS and transplanted into immunodeficient mice. Seven UCS-PDXs from six patients were established and HER2, estrogen receptor (ER), and p53 expression in PDX and the original tumor was assessed. Drug efficacy tests were performed using six of the seven PDXs. Of the six UCS-PDXs tested, two were derived from patients enrolled in the STATICE trial., Results: The histopathological characteristics of the six PDXs were well-conserved from the original tumors. HER2 expression was 1+ in all PDXs, and ER and p53 expression was almost similar to that in the original tumors. Remarkable tumor shrinkage after T-DXd administration was observed in four of the six PDXs (67%), comparable with the response rate (70%) of HER2 1+ patients in the STATICE trial. Two patients enrolled in the STATICE trial showed partial response as the best response, and the clinical effect was well-replicated with marked tumor shrinkage., Conclusions: We successfully performed a co-clinical study of T-DXd in HER2-expressing UCS, along with the STATICE trial. Our PDX models can predict clinical efficacy and serve as an effective preclinical evaluation platform., (©2023 American Association for Cancer Research.)

Salinity stress can greatly reduce seed production because plants are especially sensitive to salt during their reproductive stage. Here, we show that the sodium ion transporter AtHKT1;1 is specifically expressed around the phloem and xylem of the stamen in Arabidopsis thaliana to prevent a marked decrease in seed production caused by salt stress. The stamens of AtHKT1;1 mutant under salt stress overaccumulate Na + , limiting their elongation and resulting in male sterility. Specifically restricting AtHKT1;1 expression to the phloem leads to a 1.5-fold increase in the seed yield upon sodium ion stress. Expanding phloem expression of AtHKT1;1 throughout the entire plant is a promising strategy for increasing plant productivity under salinity stress.

The splendid alfonsino Beryx splendens is a commercially important deep-sea fish in East Asian countries. Because the wild stock of this species has been declining, there is an urgent need to develop aquaculture systems. In the present study, we investigated the long-chain polyunsaturated fatty acid (LC-PUFA) requirements of B. splendens, which are known as essential dietary components in many carnivorous marine fish species. The fatty acid profiles of the muscles, liver, and stomach contents of B. splendens suggested that it acquires substantial levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from its natural diet. The functional characterization of a fatty acid desaturase (Fads2) and three elongases (Elovl5, Elovl4a, and Elovl4b) from B. splendens confirmed their enzymatic capabilities in LC-PUFA biosynthesis. Fads2 showed Δ6 and Δ8 bifunctional desaturase activities. Elovl5 showed preferential elongase activities toward C 18 and C 20 PUFA substrates, whereas Elovl4a and Elovl4b showed activities toward various C 18-22 substrates. Given that Fads2 showed no Δ5 desaturase activity and no other fads-like sequence was found in the B. splendens genome, EPA and arachidonic acid cannot be synthesized from C 18 precursors; hence, they can be categorized as dietary essential fatty acids in B. splendens. EPA can be converted into DHA in B. splendens via the so-called Sprecher pathway. However, given that fads2 is only expressed in the brain, it is unlikely that the capacity of B. splendens to biosynthesize DHA from EPA can fulfill its physiological requirements. These results will be useful to researchers developing B. splendens aquaculture methods., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Three randomized controlled trials have resulted in extremely extensive application of the strategy of using neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) for patients with advanced epithelial ovarian cancer in Japan. This study aimed to evaluate the status and effectiveness of treatment strategies using NAC followed by IDS in Japanese clinical practice., Patients and Methods: We conducted a multi-institutional observational study of 940 women with Federation of Gynecology and Obstetrics (FIGO) stages III-IV epithelial ovarian cancer treated at one of nine centers between 2010 and 2015. Progression-free survival (PFS) and overall survival (OS) were compared between 486 propensity-score matched participants who underwent NAC followed by IDS and primary debulking surgery (PDS) followed by adjuvant chemotherapy., Results: Patients with FIGO stage IIIC receiving NAC had a shorter OS (median OS: 48.1 vs. 68.2 months, hazard ratio [HR]: 1.34; 95% confidence interval [CI] 0.99-1.82, p = 0.06) but not PFS (median PFS: 19.7 vs. 19.4 months, HR: 1.02; 95% CI: 0.80-1.31, p = 0.88). However, patients with FIGO stage IV receiving NAC and PDS had comparable PFS (median PFS: 16.6 vs. 14.7 months, HR: 1.07 95% CI: 0.74-1.53, p = 0.73) and OS (median PFS: 45.2 vs. 35.7 months, HR: 0.98; 95% CI: 0.65-1.47, p = 0.93)., Conclusions: NAC followed by IDS did not improve survival. In patients with FIGO stage IIIC, NAC may be associated with a shorter OS., (© 2023. The Author(s).)

Background: Histological analysis has revealed the need for new treatment techniques for epithelial ovarian cancer. Immune checkpoint inhibitors may be a new therapeutic strategy for ovarian clear cell carcinoma (OCCC). Lymphocyte-activation gene 3 (LAG-3), an immune checkpoint, is a poor prognostic factor and a new therapeutic target for several malignancies. In this study, we demonstrated the correlation between LAG-3 expression and the clinicopathological features of OCCC. We evaluated LAG-3 expression in tumor-infiltrating lymphocytes (TILs) via immunohistochemical analysis using tissue microarrays containing surgically resected specimens from 171 patients with OCCC., Results: The number of LAG-3-positive cases was 48 (28.1%), whereas the number of LAG-3-negative cases was 123 (71.9%). LAG-3 expression significantly increased in patients with advanced stages (P = 0.036) and recurrence (P = 0.012); however, its expression did not correlate with age (P = 0.613), residual tumor (P = 0.156), or death (P = 0.086). Using the Kaplan - Meier method, LAG-3 expression was found to be correlated with poor overall survival (P = 0.020) and progression-free survival (P = 0.019). Multivariate analysis revealed LAG-3 expression (hazard ratio [HR] = 1.86; 95% confidence interval [CI], 1.00 - 3.44, P = 0.049) and residual tumor (HR = 9.71; 95% CI, 5.13 - 18.52, P < 0.001) as independent prognostic factors., Conclusion: Our study demonstrated that LAG-3 expression in patients with OCCC may be a useful biomarker for the prognosis of OCCC and could serve as a new therapeutic target., (© 2023. The Author(s).)

Automatic extraction of patient medication histories from free-text clinical notes can increase the amount of relevant information to clinicians for developing treatment plans. In addition to detecting medication events, clinical text mining systems must also be able to predict event context, such as negation, uncertainty, and time of occurrence, in order to construct accurate patient timelines. Towards this goal, we introduce Levitated Context Markers (LCMs), a novel transformer-based model for contextualized event extraction. LCMs are an adaptation of levitated markers -originally developed for relation extraction- that allow pretrained transformer models to utilize global input representations while also focusing on event-related subspans using a sparse attention mechanism. In addition to outperforming a strong baseline model on the Contextualized Medication Event Dataset, we show that LCMs' sparse attention can provide interpretable predictions by detecting relevant context cues in an unsupervised manner., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Reintubation is not an uncommon occurrence following extubation and discontinuation of mechanical ventilation. In COVID-19 patients, the proportion of reintubation may be higher than that of non-COVID-19 patients. Furthermore, COVID-19 patients may have a higher risk for developing laryngotracheal stenosis, along with a higher proportion of reintubation than in non-COVID-19 patients. Our understanding of the proportion of reintubation in COVID-19 patients is limited in Japan. Additionally, the reasons for reintubation have not been adequately examined in previous studies outside of Japan. Thus, the present study aimed to describe the proportion and causes of reintubation among COVID-19 patients in Japan., Methods: This was a multicenter observational study that included 64 participating centers across Japan. This study included mechanically ventilated COVID-19 patients who were discharged between April 1, 2020 and September 30, 2020. The outcomes examined were the proportion and causes of reintubation., Results: A total of 373 patients were eligible for inclusion in the current analysis. The median age of patients was 64 years and 80.4% were male. Reintubation was required for 35 patients (9.4%) and the most common causes for reintubation were respiratory failure (71.4%; n = 25) and laryngotracheal stenosis (8.6%; n = 3)., Conclusions: The proportion of reintubation among COVID-19 patients in Japan was relatively low. Respiratory failure was the most common cause for reintubation. Reintubation due to laryngotracheal stenosis accounted for only a small fraction of all reintubated COVID-19 patients in Japan., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive chronic fibrosing interstitial lung disease with causes that have remained unclear to date. Development of effective treatments will require elucidation of the detailed pathogenetic mechanisms of IPF at both the molecular and cellular levels. With a biomedical corpus that includes IPF-related entities and events, text-mining systems can efficiently extract such mechanism-related information from huge amounts of literature on the disease. A novel corpus consisting of 150 abstracts with 9297 entities intended for training a text-mining system was constructed to clarify IPF-related pathogenetic mechanisms. For this corpus, entity information was annotated, as were relation and event information. To construct IPF-related networks, we also conducted entity normalization with IDs assigned to entities. Thereby, we extracted the same entities, which are expressed differently. Moreover, IPF-related events have been defined in this corpus, in contrast to existing corpora. This corpus will be useful to extract IPF-related information from scientific texts. Because many entities and events are related to lung diseases, this freely available corpus can also be used to extract information related to other lung diseases such as lung cancer and interstitial pneumonia caused by COVID-19., (© 2023. The Author(s).)

Background: Cholangiocarcinoma (CCA) is an intractable cancer, and its incidence in northeastern Thailand is the highest worldwide. Infection with the liver fluke Opisthorchis viverrini (OV) has been associated with CCA risk. However, animal experiments have suggested that OV alone does not induce CCA, but its combination with a chemical carcinogen like nitrosamine can cause experimentally induced CCA in hamsters. Therefore, in humans, other environmental and genetic factors may also be involved., Aim: To examine relations between risk for CCA and genetic polymorphisms in carcinogen-metabolizing and inflammation-related genes., Methods: This hospital-based case-control study enrolled 95 case-control pairs matched by age (± 5 years) and sex. We examined relations between risk for CCA and genetic polymorphisms in carcinogen-metabolizing and inflammation-related genes, serum anti-OV, alcohol consumption, and smoking. Polymorphisms of CYP2E1 , IL-6 (-174 and -634), IL-10 (-819), and NF-κB (-94) and their co-occurrence with polymorphisms in the drug-metabolizing enzyme gene GSTT1 or GSTM1 were also analyzed., Results: Although CCA risk was not significantly associated with any single polymorphism, persons with the GSTT1 wild-type and CYP2E1 c1/c2 + c2/c2 genotype had an increased risk (OR = 3.33, 95%CI: 1.23-9.00) as compared with persons having the GSTT1 wild-type and CYP2E1 c1/c1 wild genotype. The presence of anti-OV in serum was associated with a 7- to 11-fold increased risk, and smoking level was related to an OR of 1.5-1.8 in multivariable analyses adjusted for each of the seven genetic polymorphisms., Conclusion: In addition to infection with OV, gene-gene interactions may be considered as one of the risk factors for CCA development., Competing Interests: Conflict-of-interest statement: All authors declare that they have no competing interests., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose: The aim of this study was to understand the income and employment status of patients at the start of and during follow-up after palliative radiation therapy for bone metastasis., Methods and Materials: From December 2020 to March 2021, a prospective multi-institutional observational study was conducted to investigate income and employment of patients at the start of administration of radiation therapy for bone metastasis and at 2 and 6 months after treatment. Of 333 patients referred to radiation therapy for bone metastasis, 101 were not registered, mainly because of their poor general condition, and another 8 were excluded from the follow-up analysis owing to ineligibility., Results: In 224 patients analyzed, 108 had retired for reasons unrelated to cancer, 43 had retired for reasons related to cancer, 31 were taking leave, and 2 had lost their jobs at the time of registration. The number of patients who were in the working group was 40 (30 with no change in income and 10 with decreased income) at registration, 35 at 2 months, and 24 at 6 months. Younger patients ( P  = 0), patients with better performance status ( P  = 0), patients who were ambulatory ( P  = .008), and patients with lower scores on a numerical rating scale of pain ( P  = 0) were significantly more likely to be in the working group at registration. There were 9 patients who experienced improvements in their working status or income at least once in the follow-up after radiation therapy., Conclusions: The majority of patients with bone metastasis were not working at the start of or after radiation therapy, but the number of patients who were working was not negligible. Radiation oncologists should be aware of the working status of patients and provide appropriate support for each patient. The benefit of radiation therapy to support patients continuing their work and returning to work should be investigated further in prospective studies., (© 2023 The Authors.)

Neuroprotection is one of the hot topics in medicine. Alzheimer's disease, amyotrophic lateral sclerosis, retinal pigment epithelial (RPE) degeneration, and axonal degeneration have been studied for the involvement of NAD depletion. Localized NAD + depletion could lead to overactivation and crowding of local NAD + salvage pathways. It has been stated that NAD + depletion caused by PARPs and PAR cycling has been related to metabolic diseases and cancer. Additionally, it is now acknowledged that SARM1 dependent NAD + depletion causes axon degeneration. New targeted therapeutics, such as SARM1 inhibitors, and NAD + salvage drugs will help alleviate the dysfunctions affecting cell life and death in neurodegeneration as well as in metabolic diseases and cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Motivation: Most of the conventional deep neural network-based methods for drug-drug interaction (DDI) extraction consider only context information around drug mentions in the text. However, human experts use heterogeneous background knowledge about drugs to comprehend pharmaceutical papers and extract relationships between drugs. Therefore, we propose a novel method that simultaneously considers various heterogeneous information for DDI extraction from the literature., Results: We first construct drug representations by conducting the link prediction task on a heterogeneous pharmaceutical knowledge graph (KG) dataset. We then effectively combine the text information of input sentences in the corpus and the information on drugs in the heterogeneous KG (HKG) dataset. Finally, we evaluate our DDI extraction method on the DDIExtraction-2013 shared task dataset. In the experiment, integrating heterogeneous drug information significantly improves the DDI extraction performance, and we achieved an F-score of 85.40%, which results in state-of-the-art performance. We evaluated our method on the DrugProt dataset and improved the performance significantly, achieving an F-score of 77.9%. Further analysis showed that each type of node in the HKG contributes to the performance improvement of DDI extraction, indicating the importance of considering multiple pieces of information., Availability and Implementation: Our code is available at https://github.com/tticoin/HKG-DDIE.git., (© The Author(s) 2022. Published by Oxford University Press.)

PolyADP-ribosylation is a posttranslational modification of proteins that results from enzymatic synthesis of poly(ADP-ribose) with NAD + as the substrate. A unique characteristic of polyADP-ribosylation is that the poly(ADP-ribose) chain can have 200 or more ADP-ribose residues in branched patterns, and the presence and variety of these chains can have substantive effects on protein function. To understand how polyADP-ribosylation affects biological processes, it is important to know the physiological level of poly(ADP-ribose) in cells. Under normal cell physiological conditions and in the absence of any exogenous DNA damaging agents, we found that the concentration of poly(ADP-ribose) in HeLa cells is approximately 0.04 pmol (25 pg)/10 6 cells, as measured with a double-antibody sandwich, enzyme-linked immunosorbent assay protocol that avoids artificial activation of PARP1 during cell lysis. Notably, this system demonstrated that the poly(ADP-ribose) level peaks in S phase and that the average cellular turnover of a single poly(ADP-ribose) is less than 40 s., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

We aimed to identify the threshold for P0.1 in a breath-by-breath manner measured by the Hamilton C6 on quasi-occlusion for high respiratory drive and inspiratory effort. In this prospective observational study, we analyzed the relationships between airway P0.1 on quasi-occlusion and esophageal pressure (esophageal P0.1 and esophageal pressure swing). We also conducted a linear regression analysis and derived the threshold of airway P0.1 on quasi-occlusion for high respiratory drive and inspiratory effort. We found that airway P0.1 measured on quasi-occlusion had a strong positive correlation with esophageal P0.1 measured on quasi-occlusion and esophageal pressure swing, respectively. Additionally, the P0.1 threshold for high respiratory drive and inspiratory effort were calculated at approximately 1.0 cmH 2 O from the regression equations. Our calculations suggest a lower threshold of airway P0.1 measured by the Hamilton C6 on quasi-occlusion than that which has been previously reported., (© 2022. The Author(s).)

Standard plastic scintillating fiber cannot detect low-energy β-rays as the cladding prevents them from reaching the fiber core. We developed an outer-layer scintillating (OLS) fiber with a plastic scintillator on the outermost layer for low-energy β-ray detection. The concept of fiber construction is presented. The fundamental optical properties of the OLS fiber, such as the emission spectrum, attenuation length, and scintillation decay time, were evaluated. Here, Ni-63 with a maximum energy of 67.0 keV was used as a low-energy β-emitting nuclide. Simulation studies on the interaction between low-energy electrons emitted from Ni-63 and a single fiber were performed prior to actual measurements. The data showed that Ni-63 can be measured using silicon photomultiplier photosensors in a coincidence mode. The OLS fiber was effective for low-energy β-ray detection.

We report the discovery of two compounds, TKD150 and TKD152, that promote the aggregation of α-synuclein (aSN) using a real-time quaking-induced conversion (RT-QuIC) assay to detect abnormal aSN. By utilizing a Pd-catalyzed C-H arylation of benzoxazole with iodoarenes and implementing a planar conformation to the design, we successfully identified TKD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PA86, the two identified compounds were able to promote aggregation of aSN at twice the rate. Application of TKD150 and TKD152 to the RT-QuIC assay will shorten the inherent lag time and may allow wider use of this assay in clinical settings for the diagnosis of α-synucleinopathy-related diseases., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

Protein targets of polyADP-ribosylation undergo covalent modification with high-molecular-weight, branched poly(ADP-ribose) (PAR) of lengths up to 200 or more ADP-ribose residues derived from NAD + . PAR polymerase 1 (PARP1) is the most abundant and well-characterized enzyme involved in PAR biosynthesis. Extensive studies have been carried out to determine how polyADP-ribosylation (PARylation) regulates cell proliferation during cell cycle, with conflicting conclusions. Since significant activation of PARP1 occurs during cell lysis in vitro, we changed the standard method for cell lysis, and using our sensitive ELISA system, quantified without addition of a PAR glycohydrolase inhibitor and clarified that the PAR level is significantly higher in S phase than that in G1. Under normal condition in the absence of exogenous DNA-damaging agent, PAR turns over with a half-life of <40 s; consistent with significant decrease of NAD + levels in S phase, which is rescued by PARP inhibitors, in line with the observed rapid turnover of PAR. PARP inhibitors delayed cell cycle in S phase and decreased cell proliferation. Our results underscore the importance of a suitable assay system to measure rapid PAR chain dynamics in living cells and aid our understanding of the function of PARylation during the cell cycle., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Auditory steady-state responses (ASSRs) are basic neural responses used to probe the ability of auditory circuits to produce synchronous activity to repetitive external stimulation. Reduced ASSR has been observed in patients with schizophrenia, especially at 40 Hz. Although ASSR is a translatable biomarker with a potential both in animal models and patients with schizophrenia, little is known about the features of ASSR in monkeys. Herein, we recorded the ASSR from humans, rhesus monkeys, and marmosets using the same method to directly compare the characteristics of ASSRs among the species. We used auditory trains on a wide range of frequencies to investigate the suitable frequency for ASSRs induction, because monkeys usually use stimulus frequency ranges different from humans for vocalization. We found that monkeys and marmosets also show auditory event-related potentials and phase-locking activity in gamma-frequency trains, although the optimal frequency with the best synchronization differed among these species. These results suggest that the ASSR could be a useful translational, cross-species biomarker to examine the generation of gamma-band synchronization in nonhuman primate models of schizophrenia., (© 2022. The Author(s).)

Background: Nested and overlapping events are particularly frequent and informative structures in biomedical event extraction. However, state-of-the-art neural models either neglect those structures during learning or use syntactic features and external tools to detect them. To overcome these limitations, this paper presents and compares two neural models: a novel EXhaustive Neural Network (EXNN) and a Search-Based Neural Network (SBNN) for detection of nested and overlapping events., Results: We evaluate the proposed models as an event detection component in isolation and within a pipeline setting. Evaluation in several annotated biomedical event extraction datasets shows that both EXNN and SBNN achieve higher performance in detecting nested and overlapping events, compared to the state-of-the-art model Turku Event Extraction System (TEES)., Conclusions: The experimental results reveal that both EXNN and SBNN are effective for biomedical event extraction. Furthermore, results on a pipeline setting indicate that our models improve detection of events compared to models that use either gold or predicted named entities., (© 2022. The Author(s).)

In germ cell transplantation experiments, the use of sterile recipients that do not produce their own gametes is an important prerequisite. Triploidization and dnd gene knockdown (KD) methods have been widely used to produce sterile fish. However, triploidization does not produce complete sterility in some fish species, and gene KD is labor and time intensive since it requires microinjection into individual fertilized eggs. To overcome these problems, in this study, we generated homozygous mutants of the dead end (dnd) gene in rainbow trout (Oncorhynchus mykiss) using the clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system, analyzed their reproductive capacity, and evaluated their suitability as recipients for germ cell transplantation. By crossing F1 heterozygous mutants produced from founders subjected to genome editing, an F2 generation consisting of approximately 1/4 homozygous knockout mutants (dnd KO) was obtained. The dnd KO hatchlings retained the same number of primordial germ cells (PGCs) as the wild-type (WT) individuals, after which the number gradually decreased. At 1 year of age, germ cells were completely absent in all analyzed individuals. To evaluate the dnd KO individuals as recipients for germ cell transplantation, germ cells prepared from donor individuals were transplanted into the abdominal cavity of dnd KO hatchlings. These cells migrated to the recipient gonads, where they initiated gametogenesis. The mature recipient individuals produced only donor-derived sperm and eggs in equivalent numbers to WT rainbow trout. These results indicate that dnd KO rainbow trout are suitable recipient candidates possessing a high capacity to nurse donor-derived germ cells., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cancer cells are known to have chromosomal number abnormalities (aneuploidy), a hallmark of malignant tumors. Cancer cells also have an increased number of centrosomes (centrosome amplification). Paradoxically, cancer therapies, including γ-irradiation and some anticancer drugs, are carcinogenic and can induce centrosome amplification and chromosomal aneuploidy. Thus, the processes of carcinogenesis and killing cancer cells might have some mechanisms in common. Previously, we found that the inhibitors of polyADP-ribosylation, a post-translational modification of proteins, caused centrosome amplification. However, the mechanism of action of the inhibitors of polyADP-ribosylation is not fully understood. In this study, we found that an inhibitor of polyADP-ribosylation, 3-aminobenzamide, caused centrosome amplification, as well as aneuploidy of chromosomes in CHO-K1 cells. Moreover, inhibitors of polyADP-ribosylation inhibited AKT phosphorylation, and inhibitors of AKT phosphorylation inhibited polyADP-ribosylation, suggesting the involvement of polyADP-ribosylation in the PI3K/Akt/mTOR signaling pathway for controlling cell proliferation. Our data suggest a possibility for developing drugs that induce centrosome amplification and aneuploidy for therapeutic applications to clinical cancer.

The coronavirus disease (COVID-19) pandemic has aggravated anxiety and depression worldwide, particularly in patients with chronic illnesses and mental disorders. Using validated questionnaires, in this paper, we examine the psychological effects of the pandemic in Japan in detail. The General Mental Health Scale (GHQ), the State-Trait Anxiety Inventory (STAI), and the Center for Epidemiologic Studies Depression Scale (CES-D) were used to assess mental health, state and trait anxiety, and depression, respectively. The survey was completed during the patients' first visits to the clinic of Psychosomatic Internal Medicine from November 2018 to April 2021. The Mann-Whitney U test was used to compare data from 226 participants before and during the COVID-19 pandemic. The GHQ total, GHQ subscales of "social dysfunction" and "anxiety and dysphoria", and state anxiety scores were significantly higher during than before the pandemic. The GHQ total, some GHQ subscales, and state anxiety scores were significantly higher among male than female participants during the pandemic. The GHQ total, some GHQ subscales, CES-D, and state anxiety scores in those aged 10-39 years were significantly higher. Thus, the COVID-19 pandemic may have caused mental health changes in many individuals based on their gender, age, and with time.

Background: Administration of poly (ADP-ribose) polymerase (PARP) inhibitors after achieving a response to platinum-containing drugs significantly prolonged relapse-free survival compared to placebo administration. PARP inhibitors have been used in clinical practice. However, patients with platinum-resistant relapsed ovarian cancer still have a poor prognosis and there is an unmet need. The purpose of this study was to examine the clinical significance of metabolic genes and focal adhesion kinase (FAK) activity in advanced ovarian high-grade serous carcinoma (HGSC)., Methods: The RNA sequencing (RNA-seq) data and clinical data of HGSC patients were obtained from the Genomic Data Commons (GDC) Data Portal and analysed ( https://portal.gdc.cancer.gov/ ). In addition, tumour tissue was sampled by laparotomy or screening laparoscopy prior to treatment initiation from patients diagnosed with stage IIIC ovarian cancer (International Federation of Gynecology and Obstetrics (FIGO) classification, 2014) at the Saitama Medical University International Medical Center, and among the patients diagnosed with HGSC, 16 cases of available cryopreserved specimens were included in this study. The present study was reviewed and approved by the Institutional Review Board of Saitama Medical University International Medical Center (Saitama, Japan). Among the 6307 variable genes detected in both The Cancer Genome Atlas-Ovarian (TCGA-OV) data and clinical specimen data, 35 genes related to metabolism and FAK activity were applied. RNA-seq data were analysed using the Subio Platform (Subio Inc, Japan). JMP 15 (SAS, USA) was used for statistical analysis and various types of machine learning. The Kaplan-Meier method was used for survival analysis, and the Wilcoxon test was used to analyse significant differences. P < 0.05 was considered significant., Results: In the TCGA-OV data, patients with stage IIIC with a residual tumour diameter of 1-10 mm were selected for K means clustering and classified into groups with significant prognostic correlations (p = 0.0444). These groups were significantly associated with platinum sensitivity/resistance in clinical cases (χ 2 test, p = 0.0408) and showed significant relationships with progression-free survival (p = 0.0307)., Conclusion: In the TCGA-OV data, 2 groups classified by clustering focusing on metabolism-related genes and FAK activity were shown to be associated with platinum resistance and a poor prognosis., (© 2022. The Author(s).)

Summary: Large-scale pre-trained language models (PLMs) have advanced state-of-the-art (SOTA) performance on various biomedical text mining tasks. The power of such PLMs can be combined with the advantages of deep generative models. These are examples of these combinations. However, they are trained only on general domain text, and biomedical models are still missing. In this work, we describe BioVAE, the first large-scale pre-trained latent variable language model for the biomedical domain, which uses the OPTIMUS framework to train on large volumes of biomedical text. The model shows SOTA performance on several biomedical text mining tasks when compared to existing publicly available biomedical PLMs. In addition, our model can generate more accurate biomedical sentences than the original OPTIMUS output., Availability and Implementation: Our source code and pre-trained models are freely available: https://github.com/aistairc/BioVAE., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press.)

Immunoglobulin A (IgA) in saliva, mostly consisting of secretory IgA, plays an important role in the mucosal immune mechanism. This study evaluated changes in salivary IgA and Immunoglobulin G (IgG) concentrations in Japanese Black cows (n = 16) during calving. Individual saliva samples were collected -2, 0, and 2 weeks postpartum. Immunoglobulin concentrations differed significantly among weeks (P < 0.05), but the effect of parity and week × parity was insignificant. Salivary IgA concentrations decreased drastically (P < 0.05) after calving compared with those at -2 weeks postpartum and remained low until 2 weeks postpartum. The salivary IgG concentrations decreased gradually during peripartum and differed at -2 and 2 weeks postpartum (P < 0.05). Considering the immunoglobulin concentrations at -2 weeks postpartum as the reference standard for 100%, the rates of decrease in IgA concentrations (36.7 ± 6.9%) were significantly lower (P < 0.05) than those of IgG (70.3 ± 10.1%) at calving day. To our knowledge, this is the first report indicating that salivary IgA concentrations decreased drastically after calving in Japanese Black cows. Further studies monitoring the secretory functions of IgA in the salivary gland are essential for understanding maternal immunity in cattle., (© 2022 Japanese Society of Animal Science.)

In cow herd management, inadequate embryo implantation leads to pregnancy loss and causes severe economic losses. Thus, it is crucial to understand the molecular mechanisms underlying endometrial receptivity and subsequent embryo implantation. Transmembrane glycocalyx mucin 1 (MUC1) has a large and highly glycosylated extracellular domain known to inhibit embryo implantation via steric hindrance. The role of MUC1 in the bovine endometrium remains to be explored. Herein, we used simple but reliable in vivo and in vitro experiments to investigate the expression and regulation of MUC1 in the bovine endometrium. MUC1 gene expression was analyzed in endometrial epithelial cells collected by the cytobrush technique using reverse transcription-quantitative polymerase chain reaction. MUC1 protein expression was evaluated by immunohistochemical analysis of endometrial samples collected from slaughtered cows. We used an in vitro cell culture model to study the regulation of MUC1 expression by treating cells with sex steroidal hormones or co-culturing cells with a blastocyst. The results revealed that MUC1 was expressed and localized to the apical surface of luminal epithelial cells in the bovine endometrium. MUC1 expression disappeared during the luteal phase of the estrous cycle and during pregnancy. 17β-estradiol induced MUC1 expression, whereas progesterone inhibited its increase and co-culturing with blastocysts did not affect the expression. A long postpartum interval is a known risk factor for reduced fertility, and MUC1 expression was higher in this compromised condition. Our results demonstrated the MUC1 regulation by steroid hormones in bovine endometrium for embryo implantation, and we observed a negative correlation between MUC1 expression and fertility.

Purpose: A quality indicator (QI) is a valuable tool to evaluate the quality of health care systems. In palliative radiation oncology, only a few related QIs have been developed to date. In this study, we sought to develop and pilot test QIs that assess the quality of care in palliative radiation therapy., Methods and Materials: A modified Delphi method was used to establish consensus with an expert panel. The panel consisted of 8 radiation oncologists who have expertise in palliative radiation oncology and 1 expert on Delphi methodology. Online panel meetings and e-mail surveys were conducted to develop QIs on palliative radiation therapy for bone and brain metastases. Feasibility of measurement was assessed though pilot surveys that were conducted by radiation oncologists at 5 facilities., Results: After 3 online meetings and 2 e-mail surveys, we developed 4 QIs on bone metastases and 3 QIs on brain metastases. Two email surveys and 2 pilot surveys confirmed the validity of QIs and the feasibility of measurement, respectively., Conclusions: We developed valid and feasible QIs on palliative radiation therapy for bone and brain metastases. Our work may contribute to reduce the evidence-practice gaps in palliative radiation oncology., (© 2021 The Author(s).)

Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD + ; it has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To the best of our knowledge, selective inhibitors for LDHB have not yet been reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD + . As a result, we identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. This compound exhibited uncompetitive LDHB inhibition (EC 50  = 42 nM). X-ray crystallography revealed that AXKO-0046 bound to the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerisation interface of the two dimers is critical for the enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism., (© 2021. The Author(s).)