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Mariko Jitsumori,1,* Shinya Matsuzaki,1,* Masayuki Endo,1 Takeya Hara,1 Takuji Tomimatsu,1 Satoko Matsuzaki,2 Tatsuya Miyake,1 Tsuyoshi Takiuchi,1 Aiko Kakigano,1 Kazuya Mimura,1 Eiji Kobayashi,1 Yutaka Ueda,1 Tadashi Kimura1 1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan; 2Department of Obstetrics and Gynecology, Otemae Hospital, Osaka, Japan*These authors contributed equally to this workCorrespondence: Shinya Matsuzaki; Aiko KakiganoDepartment of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, JapanTel +81-6-6879-3355Fax +81-6-6879-3359Email zacky@gyne.med.osaka-u.ac.jp; ai-kaki@gyne.med.osaka-u.ac.jpBackground: Uterine artery embolization (UAE) is used to treat severe postpartum hemorrhage (PPH). According to a few studies, UAE for PPH was associated with preterm birth, fetal growth restriction (FGR), and placenta accreta spectrum (PAS) in subsequent pregnancies. These previous studies, however, lacked controls, and to the best of our knowledge, no systematic literature reviews have been conducted thus far. We report the results of our retrospective case–control study of pregnancies after UAE at a single center and include a literature review to evaluate the risk of PAS in pregnancies after UAE.Methods: We retrospectively reviewed data from deliveries at our hospital between January 2012 and October 2017. We divided the delivery data into cases with previous UAEs performed for PPH (the post-UAE group) and those without UAEs (the non-UAE group, which included women without previous PPH). We defined PAS as cases in which hysterectomy was performed and pathological examination confirmed the diagnosis. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs).Results: We used data from 3155 patients in this study, of whom 16 patients had undergone UAE (post-UAE group) and 3139 had not (non-UAE group). We found no differences between the groups in terms of frequency of preterm births (12.5% versus 14.2%, respectively; OR, 0.863; 95% CI, 0.218 to 3.414; P = 0.84) or FGR (6.2% versus 10.0%, respectively; OR, 0.602; 95% CI, 0.104 to 3.584; P = 0.61). However, cases of PAS were significantly more common in the post-UAE group (37.5%) than in the non-UAE group (1.2%; OR, 50.303; 95% CI, 17.38 to 145.592; P < 0.01).Conclusion: Our results suggest that previous UAE is a significant risk factor for PAS.Keywords: placenta accreta, placenta accreta spectrum, uterine artery embolization, postpartum hemorrhage, obstetric outcomes

Mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits an immune-active tumor microenvironment (TME) compared to MMR proficient (pMMR)/microsatellite stable/Epstein-Barr virus-negative [EBV (-)] GC. The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered a key regulator of immune cell activation in the TME. However, its significance in regulating the immune-active TME in dMMR/MSI-H GC remains unclear. Here, we demonstrated that tumor cell-intrinsic cGAS-STING was highly expressed in dMMR GC compared to pMMR/EBV (-) GC. The expression of tumor cell-intrinsic STING was significantly and positively associated with the number of CD8 + tumor-infiltrating lymphocytes in GC. Analysis of TCGA datasets revealed that the expression of interferon-stimulated genes and STING downstream T-cell attracting chemokines was significantly higher in MSI-H GC compared to other subtypes of GC with EBV (-). These results suggest that tumor cell-intrinsic STING signaling plays a key role in activating immune cells in the dMMR/MSI-H GC TME and might serve as a novel biomarker predicting the efficacy of immunotherapy for GC treatment., (© 2024. The Author(s).)

Background: The preservation period afforded by cold storage of cells is short. However, the use of rare gases for cold storage as a means of extending the period of preservation would be highly beneficial., Objective: To examine the effect of temperature on the protective effect of cold storage of cells using pressurized dissolution of xenon gas, with particular focus on the inhibition of substance transport by viscosity., Methods: Human dermal fibroblast monolayers incubated in a culture dish for 48 h were used as a test sample, with culture medium used as a preservation solution. Samples were placed into a pressure-resistant vessel, which was pressurized with xenon gas at 0 or 0.5 MPa, and cells were stored at 0 to 5 °C for 18 h. Cell activity was evaluated by tetrazolium salt assay. The viscosity of the medium under pressurization at each storage temperature was estimated., Results: The maximum protective effect against cell damage of cold storage with pressurized dissolution of xenon gas was observed at 4 °C. An increase in estimated viscosity by pressurization was correlated with increased cell activity at 4 °C., Conclusion: Analysis of the temperature dependence of the protective effect against cell damage of cold storage with pressurized dissolution of xenon gas revealed that the most effective temperature is 4 °C. The data also suggest that increased viscosity due to pressurization plays a role in the protective effect.

Nonhuman primates (NHPs) exhibit complex and diverse behavior that typifies advanced cognitive function and social communication, but quantitative and systematical measure of this natural nonverbal processing has been a technical challenge. Specifically, a method is required to automatically segment time series of behavior into elemental motion motifs, much like finding meaningful words in character strings. Here, we propose a solution called SyntacticMotionParser (SMP), a general-purpose unsupervised behavior parsing algorithm using a nonparametric Bayesian model. Using three-dimensional posture-tracking data from NHPs, SMP automatically outputs an optimized sequence of latent motion motifs classified into the most likely number of states. When applied to behavioral datasets from common marmosets and rhesus monkeys, SMP outperformed conventional posture-clustering models and detected a set of behavioral ethograms from publicly available data. SMP also quantified and visualized the behavioral effects of chemogenetic neural manipulations. SMP thus has the potential to dramatically improve our understanding of natural NHP behavior in a variety of contexts., (© 2024. The Author(s).)

Purpose: To evaluate short-term outcomes of intravitreal injection of aflibercept 8 mg for neovascular age-related macular degeneration (nAMD)., Study Design: Retrospective, interventional case series., Methods: We retrospectively studied 35 eyes of 34 consecutive patients with nAMD, assessing best-corrected visual acuity (BCVA), foveal thickness (FT), and central choroidal thickness (CCT) before and 4 weeks after the initial intravitreal dose of aflibercept 8 mg. The rate of achieving a dry macula and the incidence of intraocular inflammation (IOI) at week 4 were also determined., Results: BCVA showed significant improvement, with significant reductions in FT and CCT 4 weeks after the initial injection of aflibercept 8 mg (all P < 0.01), with a dry macula being achieved in 20 eyes (57.1%). However, 3 eyes (8.6%) developed non-infectious IOI associated with retinal vasculitis, an adverse event not reported previously. The IOI in these eyes was relatively mild and treated with a posterior subtenon injection of triamcinolone acetonide with or without betamethasone eye drops, resulting in amelioration of IOI without any visual loss., Conclusions: Intravitreal aflibercept 8 mg appears to be effective for improving visual acuity and ameliorating exudative changes in eyes with nAMD. However, special attention should be given to the potential development of IOI associated with retinal vasculitis., (© 2024. The Author(s).)

The fungus Wickerhamiella pararugosa (Candida pararugosa) has been detected in various human organs but has rarely caused bloodstream infections. This report presents a case of central venous catheter-related bloodstream infection (CRBSI) of W. pararugosa in an adult. A female patient in her 80s was admitted to our facility for intestinal obstruction caused by colorectal cancer. The patient's ability to consume food was hindered, necessitating the insertion of a central venous catheter (CVC) into the internal jugular vein. On day 3 after admission, the patient developed a fever, prompting blood and CVC tip cultures to be performed. On day 5, yeast-like fungi were discovered in the blood cultures, and fosfluconazole (fluconazole [FLCZ] pro-drug) treatment was initiated. On day 8, yeast-like fungi were identified in both the blood and CVC tip cultures, leading to a diagnosis of CRBSI. The fungus was identified as W. pararugosa through biochemical and genetic characterization. This finding justified the use of micafungin (MCFG) for combination therapy. On day 17, the minimum inhibitory concentrations (MIC) for FLCZ and MCFG were 4-8 and 0.06 μg/mL, respectively. Accordingly, the treatment was changed to monotherapy with MCFG. After a 21-day treatment regimen, the patient was discharged on day 31. We present a case of CRBSI caused by W. pararugosa in an adult with intestinal obstruction. The notable increase in the MIC of FLCZ necessitated monotherapy with MCFG, which resulted in successful recovery of the patient., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Primates must adapt to changing environments by optimizing their behavior to make beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which two male macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task's rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate dissociable contributions of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates., (© 2024. The Author(s).)

While N -heterocyclic carbenes (NHCs) have recently been shown to be effective ligands for gold nanoclusters, very few examples of heterometallic clusters incorporating nongroup 11 metals are known. We present herein an Au-Pt NHC cluster featuring a crown-shaped [Au 8 Pt(NHC) 8 ] 2+ core, produced in high yield without the need for chromatographic purification. The method was largely independent of the substitution pattern of the NHC backbone; however, bulky wingtip groups were needed for clean conversion to the Au 8 Pt cluster. Clusters were characterized using single crystal X-ray diffraction, multinuclear nuclear magnetic resonance, electrospray ionization mass spectroscopy, and ultraviolet-visible spectroscopy, and electrochemical features of the cluster are also presented. A detailed analysis of the in-progress reaction mixture by ESI-MS supports the direct involvement of Au-H species as intermediates in cluster formation. These studies further demonstrate that NHC wingtip sterics play a key part in determining the nature of the initial cluster species, providing critical information for the generation of new NHC-stabilized nanoclusters.

Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of the serotonin 5-HT 4 receptor (5-HT 4 R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT 4 R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT 4 R in the dCDh. We then examined the effects of a specific 5-HT 4 R antagonist infused into the dCDh. Blockade of 5-HT 4 R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT 4 R blockade because saline controls showed no such effect. The results demonstrate that 5-HT 4 Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT 4 R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms., (© 2024. The Author(s).)

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18 F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18 F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development., Competing Interests: Declaration of interests M.O., M.-R.Z., and M. Higuchi filed a patent on compounds related to the present report (2019-034997, PCT/JP2020/002607)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Activating antibody-dependent cellular cytotoxicity (ADCC) by targeting claudin-18 isoform 2 (CLDN18.2) using zolbetuximab, a monoclonal antibody against CLDN18.2, has been considered a promising novel therapeutic strategy for gastric cancer (GC). However, the impact of CLDN18.2 expression on natural killer (NK) cells and monocytes/macrophages-crucial effector cells of ADCC-in GC has not been fully investigated. In the present study, we assessed the impact of CLDN18.2 expression on clinical outcomes, molecular features, and the frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, in GC by analyzing our own GC cohorts. The expression of CLDN18.2 did not significantly impact clinical outcomes of GC patients, while it was significantly and positively associated with Epstein-Barr virus (EBV) status and PD-L1 expression. The frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, were comparable between CLDN18.2-positive and CLDN18.2-negative GCs. Importantly, both CLDN18.2 expression and the number of tumor-infiltrating NK cells were significantly higher in EBV-associated GC compared to other molecular subtypes. Our findings support the effectiveness of zolbetuximab in CLDN18.2-positive GC, and offer a novel insight into the treatment of this cancer type, highlighting its potential effectiveness for CLDN18.2-positive/EBV-associated GC., (© 2024. The Author(s).)

Background: We previously showed that total tumor resection enhances metastatic growth in a syngeneic metastatic mouse model of neuroblastoma. In this study, we further investigated which surgical factors contributed most to metastatic growth., Methods: Tumor cells derived from MYCN transgenic mice were subcutaneously injected into wild-type mice. Mice were randomly assigned to receive partial resection (PR group), subcutaneous implantation of a sponge (Sp group), or observation (Obs group). The lymph node metastasis volume and the frequency of lung metastasis were compared 14 days after assignment by measuring C-reactive protein (CRP) and interleukin-6 (IL-6) levels., Results: The lymph node metastasis volume in the Sp group was larger than in the Obs group (148.4 [standard deviation {SD}: 209.5] vs. 10.2 [SD 12.8] mm 3 ). The frequency of lung metastasis was greater in the Sp group than in the PR group (11.9 [SD 12.2] vs. 6.6 [SD 4.0] counts/slide). The CRP level in the Sp group was higher than in the PR group (2.3 [SD 0.5] vs. 1.5 [SD 0.4] μg/mL), and the IL-6 level in the Sp group was higher than in the PR or Obs groups (28.4 [SD 34.5] vs. 12.4 [SD 19.0] vs. 5.4 [SD 8.1] pg/mL)., Conclusion: Metastatic growth may be enhanced by systemic inflammation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Visual object memory is a fundamental element of various cognitive abilities, and the underlying neural mechanisms have been extensively examined especially in the anterior temporal cortex of primates. However, both macroscopic large-scale functional network in which this region is embedded and microscopic neuron-level dynamics of top-down regulation it receives for object memory remains elusive. Here, we identified the orbitofrontal node as a critical partner of the anterior temporal node for object memory by combining whole-brain functional imaging during rest and a short-term object memory task in male macaques. Focal chemogenetic silencing of the identified orbitofrontal node downregulated both the local orbitofrontal and remote anterior temporal nodes during the task, in association with deteriorated mnemonic, but not perceptual, performance. Furthermore, imaging-guided neuronal recordings in the same monkeys during the same task causally revealed that orbitofrontal top-down modulation enhanced stimulus-selective mnemonic signal in individual anterior temporal neurons while leaving bottom-up perceptual signal unchanged. Furthermore, similar activity difference was also observed between correct and mnemonic error trials before silencing, suggesting its behavioral relevance. These multifaceted but convergent results provide a multiscale causal understanding of dynamic top-down regulation of the anterior temporal cortex along the ventral fronto-temporal network underpinning short-term object memory in primates., (© 2024. The Author(s).)

Severe cases of hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome requiring plasma exchange or dialysis should be differentiated from other thrombotic microangiopathy (TMA) and treated appropriately. To evaluate the prevalence and clinical characteristics of such cases in Japan, a questionnaire-based survey was conducted among obstetricians who are members of the Perinatal Research Network Group in Japan. There were a total of 335 cases of HELLP syndrome over a 3-year period in the 48 facilities that responded to the survey. Four patients required plasma exchange or dialysis, of which two were diagnosed with atypical hemolytic uremic syndrome and two with TMA secondary to systemic lupus erythematosus. Although such severe HELLP syndrome is rare, identifying the clinical features and making accurate differential diagnosis are critical for optimal clinical outcomes for mothers and neonates., (© 2024 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

The biomarker-oriented chemo-immunotherapy is useful and promising in the development of new anticancer agents, since the responders can be enriched by selecting patients with biomarkers. Compared to colorectal and lung cancers, the development of biomarker-driven molecular-targeted therapeutics for gastric cancers has been straggled. However, several new biomarkers in gastric cancers have been discovered and clinical trials in enrichment design with certain biomarkers have been conducted. Therefore, there are currently several treatment options to treat gastric cancer patients based on individual biomarker-oriented strategies. In the present review, we describe the useful biomarkers in gastric cancer, with focusing on HER2, PD-L1, and Claudin18.2, in relation to their clinical significance and associated targeted agents., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)