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Adequate levels of thyroid hormones (THs) in the fetal brain are vital for early neurodevelopment. Most of the TH in fetal brain is derived from circulating thyroxine (T4), which gets locally converted into the biologically active triiodothyronine (T3) by deiodinase enzymes. One of the major routes of TH into the brain is through the blood-cerebrospinal fluid barrier (BCSFB). The BCSFB is maintained by the choroid plexus (CP), which separates the blood from the cerebrospinal fluid (CSF). TH transport across the BCSFB is facilitated by TH transmembrane transporters (THTMTs) present in the CP. However, TH transport across the BCSFB is still poorly understood as there is a lack of human representative BCSFB models. Previously, a human choroid plexus papilloma cell line (HIBCPP) has been established, which exhibits certain key characteristics of the human CP. In this study, the suitability of the HIBCPP cell line as a human in vitro BCSFB model for TH transport was evaluated. For this, HIBCPP cells were grown on transwell inserts and the gene and protein expression of several THTMTs was assessed using qPCR and immunohistochemistry. Additionally, the transport of T4 across a HIBCPP monolayer was assessed using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), with a special focus on the role of transthyretin (TTR), a TH binding protein produced by the CP involved in TH transport across the BCSFB. Finally, inhibition studies were performed with various THTMT inhibitors, to conclude which THTMT drive TH transport across the BCSFB. Gene and protein expression data showed that several THTMTs were expressed in the HIBCPP model, however HIBCPP cells lacked key THTMTs, notably monocarboxylate transporter 8 (MCT8) and organic anion transporter polypeptide 1C1 (OATP1C1), known to be highly expressed in the human BCSFB. Moreover, TH transport across the HIBCPP model was low and addition of TTR did not increase this transport. Two TTR-binding chemicals, TBBPA and F21388, significantly decreased the transport of T4 across the HIBCPPs cells, suggesting a possible role of intracellular TTR in the transport of T4 across the BCSFB. The transport of TTR-T4 complex might be mediated through SR-B1, indicated by the decreased T4 transport after BLT-1 exposure. However, the poor expression of several important THTMTs, together with the low amount of TH transport, indicate that the HIBCPP cells lack key features that drive TH transport in the BCSFB. The HIBCPP cells could serve as a model to further study the mechanisms of TTR driven TH transport, but for the identification of THTMTs more in vivo accurate BCSFB models are necessary., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Opioids are known to induce delirium, and the incidence of delirium induced by individual opioids has been investigated. However, only a limited number of studies have examined the incidence of delirium induced by oral hydromorphone., Objective: To investigate whether differences exist in the incidence of delirium associated with oral morphine and oral hydromorphone during the initiation phase of treatment., Methods: The participants were opioid-naive inpatients with cancer who started oral morphine or oral hydromorphone at Shizuoka Cancer Center (in Shizuoka, Japan) between June 2017 and November 2020. The incidence of delirium in the first week of opioid use was compared between the 2 groups., Results: A total of 90 patients met the inclusion criteria, 27 who received oral hydromorphone and 63 who received oral morphine. The incidence rate of delirium in the oral hydromorphone group tended to be higher (19%, 5/27) than in the oral morphine group (8%, 5/63), although the difference was not statistically significant (odds ratio 0.4, 95% confidence interval, 0.1-1.4, p = 0.16 by the Fisher exact test). Propensity score matching was used to control for differences in patient background as confounders in the development of delirium, following which the incidence rate of delirium remained higher, but not significantly so, in the oral hydromorphone group (11%, 2/19) than in the oral morphine group (5%, 1/19) (odds ratio 0.5, 95% confidence interval 0.04-5.7, p > 0.99 by the Fisher exact test)., Conclusions: There was no statistically significant difference in the incidence of delirium between those who received morphine and those who received hydromorphone, which suggests that for opioid-naive inpatients with cancer, oral hydromorphone can be used in a manner similar to that for oral morphine., Competing Interests: Competing interests: None declared., (© 2025 Canadian Society of Healthcare-Systems Pharmacy | Société canadienne de pharmacie dans les réseaux de la santé.)

Background: The choroid plexus (ChP) is the secretory epithelial structure located in the brain ventricles. Choroid plexus tumors (CPTs) are rare neoplasms predominantly occurring in young patients with intensified malignancy in children. CPT treatment is hindered by insufficient knowledge of tumor pathology and the limited availability of valid models., Methods: Genomic and transcriptomic data from CPT patients were analyzed to identify the putative pathological pathway. Cellular and molecular techniques were employed to validate bioinformatic results in CPT patient samples. Pharmacologic inhibition of Wnt/β-catenin signaling was assessed in CPT cells. Cell-based assays of ChP cell lines were performed following CRISPR-Cas9-derived knockout and overexpression of Wnt/β-catenin pathway genes. A 3D CPT model was generated through CRISPR-Cas9-derived knockout of APC., Results: We discovered that Wnt/β-catenin signaling is activated in human CPTs, likely as a consequence of large-scale chromosomal instability events of the CPT genomes. We demonstrated that CPT-derived cells depend on autocrine Wnt/β-catenin signaling for survival. Constitutive Wnt/β-catenin pathway activation, either through knockout of the negative regulator APC or overexpression of the ligand WNT3A, induced tumorigenic properties in ChP 2D in vitro models. Increased activation of the Wnt/β-catenin pathway in ChP organoids, through treatment with a potent GSK3β inhibitor, reduced the differentiation of mature ChP epithelial cells. Remarkably, the depletion of APC was sufficient to induce the oncogenic transformation of ChP organoids., Conclusions: Our research identifies Wnt/β-catenin signaling as a critical driver of CPT tumorigenesis and provides the first 3D in vitro model for future pathological and therapeutic studies of CPT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: The integration of artificial intelligence (AI), particularly deep learning (DL), with optical coherence tomography (OCT) offers significant opportunities in the diagnosis and management of glaucoma. This article explores the application of various DL models in enhancing OCT capabilities and addresses the challenges associated with their clinical implementation., Methods: A review of articles utilizing DL models was conducted, including convolutional neural networks (CNNs), recurrent neural networks (RNNs), generative adversarial networks (GANs), autoencoders, and large language models (LLMs). Key developments and practical applications of these models in OCT image analysis were emphasized, particularly in the context of enhancing image quality, glaucoma diagnosis, and monitoring progression., Results: CNNs excel in segmenting retinal layers and detecting glaucomatous damage, whereas RNNs are effective in analyzing sequential OCT scans for disease progression. GANs enhance image quality and data augmentation, and autoencoders facilitate advanced feature extraction. LLMs show promise in integrating textual and visual data for comprehensive diagnostic assessments. Despite these advancements, challenges such as data availability, variability, potential biases, and the need for extensive validation persist., Conclusions: DL models are reshaping glaucoma management by enhancing OCT's diagnostic capabilities. However, the successful translation into clinical practice requires addressing major challenges related to data variability, biases, fairness, and model validation to ensure accurate and reliable patient care., Translational Relevance: This review bridges the gap between basic research and clinical care by demonstrating how AI, particularly DL models, can markedly enhance OCT's clinical utility in diagnosis, monitoring, and prediction, moving toward more individualized, personalized, and precise treatment strategies.

Patients with obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome sometimes present with distinct symptoms related to coexisting urogenital abnormalities. We present a case of refractory abscess formation in a blind-ended remnant ureter associated with ipsilateral renal agenesis. A 15-year-old patient with OHVIRA syndrome, who had a blind-ended remnant ureter, underwent obstructed hemivagina opening 18 months after menarche due to heavy genital bleeding and abdominal pain after the end of menstruation. Four years later, the patient presented with recurring fever and abdominal pain due to a refractory abscess in the ureter. Although the continuity between the ureter and the previously opened hemivagina was not identified, the same bacteria were detected in the abscess and vaginal discharge, indicating that an ascending bacterial infection of the vagina may cause refractory abscess formation in a blind-ended remnant ureter. Open ureterectomy with partial bladder resection was needed to resolve the symptoms., (© 2024 Japan Society of Obstetrics and Gynecology.)

Background: Continuous subcutaneous administration of injectable opioids is simple and effective; however, skin disorders may occur when high opioid dosages are used. Therefore, we investigated opioid injection drugs with a low risk of skin disorders., Methods: A retrospective study was conducted using the electronic medical records of patients prescribed 1% hydromorphone hydrochloride or 4% morphine hydrochloride with instructions for continuous subcutaneous administration at Shizuoka Cancer Center from January 2017 to December 2021. The primary endpoint was skin disorders incidence, and the two groups were compared using Cox proportional hazards model analyses and Fisher's exact test at 5% significance level. Patient background factors expected to influence skin disorders were also investigated, and multivariate logistic analysis of skin disorders incidence was performed., Results: The incidence of skin disorders in the hydromorphone hydrochloride and morphine hydrochloride groups were 3.7% (1/27 patients) and 28.1% (9/32 patients), respectively, showing a significant difference in two statistical analyses between the two groups (Cox proportional hazards model analyses HR: 0.09, 95% CI: 0.01-0.70, P = 0.022. Fisher's exact test OR: 0.10, 95% CI: 0.01-0.84, P = 0.016). In the multivariate analysis, the administration of hydromorphone hydrochloride (OR: 0.04, 95% CI: 0.003-0.48, P = 0.012) was also found to have a significant negative correlation with the occurrence of skin disorders. On the contrary, administration period ≥ 28 days (OR: 18.16, 95% CI: 2.22-148.60, P = 0.007) was a factor with a significant positive correlation., Conclusions: Subcutaneous 1% hydromorphone hydrochloride administration had a lower risk of skin disorders than 4% morphine hydrochloride injection. Moreover, prolonging the administration period increased the risk of developing skin disorders. This suggests that a 1% hydromorphone hydrochloride Injection is a good clinical decision for patients who are likely to have a longer administration period and require a higher dosage of injectable opioids., Trial Registration: Retrospectively registered., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethical Review Board of Shizuoka Cancer Center (approval number: J2021-174-2023-10-3) and conducted in compliance with the “Ethical Guidelines for Medical and Health Research Involving Human Subjects”. Information about study inclusion was posted on the hospital’s bulletin, and consent was obtained via the opt-out method. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Meningiomas are the most frequent brain tumors, typically benign and curable by surgery. However, some patients experience repeated recurrences from residual tumors. To address such cases, the development of novel therapeutic options is crucial. For this purpose, the availability of cell lines that possess the characteristics of benign meningiomas is essential. Here, we established a benign meningioma cell line under 3% O 2 hypoxic conditions without the induction of immortalization genes. This cell line, named TKB-MEN2, has been stably grown for over two years with more than 20 passages. There were no hotspot telomerase reverse transcriptase (TERT) promoter mutations or cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) homozygous deletions, which are genetic features typical of malignant meningiomas. Cultured under hypoxic conditions, this cell line showed fewer characteristics of cellular senescence, such as morphological changes, IL-6 secretion, and lower senescence-associated b-galactosidase activity, compared to the same cell line cultured under 20% O 2 conditions. This immortalized non-transgenic cell line appears to reflect the characteristics of a genuine benign meningioma, potentially allowing the identification of new therapeutic targets and the development of novel therapies for benign meningiomas., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no financial or other conflict of interest to this research and its publication. Ethical approval: This research was approved by the Ethical Review Committee of the University of Tsukuba Hospital (Approval No. H29-314). The patient provided informed consent and a written agreement to participate in this study. The animal experiment was approved by the University of Tsukuba Animal Experiment Ethics Committee (Approval No. 23–058). All animal experiments were conducted in accordance with the animal experimentation regulations of the University of Tsukuba., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Background: The reporting of adverse events in medical devices (MD) is a starting point of post-market surveillance and the most common source of initial safety signals. Because MD adverse events (AE) occur globally and involve high-profile international public health crises, international regulators implanted standard codes for MDAE reporting. This study aimed to assess the application of MDAE terminology and codes by providing examples of virtual events., Methods: An online survey was conducted among participants of the MD Training Program for Regulatory Authorities which provide International Medical Device Regulators Forum (IMDRF) adverse event terminology and codes, and six virtual MDAE cases., Results: All 29 of the 72 participants were regulators. In all cases, most participants selected the broad (level 1) codes rather than the detailed (level 2 or level 3) codes. While responders selected a variety of codes for all annexes in case 1, over 50% of responders selected the intended codes in case 6. The codes for cause investigation were chosen more frequently than other annexes for device problem, components, and health effect. No differences were observed in code selection amongst different stakeholders., Conclusions: We identified the diversification in terminology and code selection for reporting MDAEs., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Institutional Review Board (IRB) of Soonchunhyang University Bucheon Hospital (Approval no. SCHBC 2022–12-011). Informed consent from all subjects and/or their legal guardian(s) for publication of identifying information/images in an online open-access publication was waived by the IRB. All procedures were performed in accordance with the Declaration of Helsinki. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Techniques for triggering neural differentiation of embryonic and induced pluripotent stem cells into neural stem cells and neurons have been established. However, neural induction of mesenchymal stem cells, including dental pulp stem cells (DPSCs), has been assessed primarily based on neural-related gene regulation, and detailed studies into the characteristics and differentiation status of cells are lacking. Therefore, this study was aimed at evaluating the cellular components and differentiation pathways of neural lineage cells obtained via neural induction of human DPSCs. Human DPSCs were induced to neural cells in monolayer culture and examined for gene expression and mechanisms underlying differentiation using microarray-based ingenuity pathway analysis. In addition, the neural lineage cells were subjected to single-cell RNA sequencing (scRNA-seq) to classify cell populations based on gene expression profiles and to elucidate their differentiation pathways. Ingenuity pathway analysis revealed that genes exhibiting marked overexpression, post-neuronal induction, such as FABP7 and ZIC1, were associated with neurogenesis. Furthermore, in canonical pathway analysis, axon guidance signals demonstrated maximum activation. The scRNA-seq and cell type annotations revealed the presence of neural progenitor cells, astrocytes, neurons, and a small number of non-neural lineage cells. Moreover, trajectory and pseudotime analyses demonstrated that the neural progenitor cells initially engendered neurons, which subsequently differentiated into astrocytes. This result indicates that the aforementioned neural induction strategy generated neural stem/progenitor cells from DPSCs, which might differentiate and proliferate to constitute neural lineage cells. Therefore, neural induction of DPSCs may present an alternative approach to pluripotent stem cell-based therapeutic interventions for nervous system disorders., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

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

Aim: To present evidence- and consensus-based recommendations for the diagnosis abnormal uterine bleeding., Methods: A literature search for the diagnosis of abnormal uterine bleeding was systematically conducted in PubMed from its inception to May 2024 to identify meta-analyses, reviews, randomized controlled trials, and clinical trials, followed by an additional systematic search using keywords. Based on this evidence, an expert panel developed background, clinical, and future research questions., Results: Based on a systematic search and the collected evidence, we developed five background questions, three clinical questions, and one future research question, with recommendations and/or statements. Evidence and recommendations are provided for clinical questions. Additionally, we developed a flowchart for diagnosis showing the steps of the examinations to be performed., Conclusion: The flowchart and nine recommendations/statements specify an efficient diagnostic procedure to differentiate abnormal causative diseases of uterine bleeding optimized for actual Japanese situations., (© 2024 Japan Society of Obstetrics and Gynecology.)

Objective: The European Cardio-Oncology Guidelines recommend regular electrocardiography and troponin testing during immune checkpoint inhibitors (ICIs) treatment, but their efficacy for monitoring ICI treatment remains unclear. This study aimed to evaluate the effectiveness of a surveillance protocol for early detection of ICI-induced myocarditis., Methods: Between May 2014 and May 2024, patients who began treatment with ICIs at our hospital and developed ICI-induced myocarditis were included in this study. We created a straightforward management flowchart for myocarditis. The protocol was based on monitoring troponin T levels. We confirmed the efficacy of our surveillance protocol using a case series of ICI-induced myocarditis., Results: During the observation period, 3481 patients were newly started on ICIs at our hospital. Five patients were previously diagnosed with myocarditis, and five patients were diagnosed with myocarditis after the implementation of the surveillance protocol. The manual enabled the early detection of myocarditis, and the mortality rate for myocarditis at our hospital improved from 60% to 0%. The incidence of conduction system disorders significantly reduced from 100% to 0% ( P  < 0.01). After the surveillance protocol was initiated, there were no cases of myocarditis requiring immunosuppressive drugs beyond steroids., Conclusions: This study confirmed the relevance of a troponin-based surveillance protocol for the early detection of ICI-induced myocarditis. The implementation of the surveillance protocol reduced mortality from myocarditis and significantly reduced serious complications of conduction system disorders. Although this study is a small case series of patients who developed myocarditis, we confirm the effectiveness of surveillance for myocarditis., Competing Interests: Takuya Oyakawa received honoraria from Pfizer, Daiichi Sankyo, TOA EIYO, Novartis, AstraZeneca, and Bristol-Myers Squibb. Nao Muraoka has no conflict of interest. Kei Iida has no conflict of interest. Ayano Fujita has no conflict of interest. Yokoyama Koichi has no conflict of interest. Ishikawa Hiroshi has no conflict of interest. Haruyasu Murakami reports grants from Chugaipharma, AstraZeneca, Abbvie, Daiichi Sankyo, IQvia, and Taiho Pharmaceutical, Bayer, and received honoraria from Chugai pharma, Daiichi Sankyo, AtraZeneca, Takeda, Amgen, Ono Pharmaceutical, Bristol-Myers Squibb Japan, MSD, Pfizer, Novartis Lilly Japan, Taiho pharmaceutical, and Eisai, Nihonkayaku, as well as participation on a data safety monitoring board or advisory board, outside the submitted work., (© 2024 The Authors.)

Background/aim: Radiotherapy-induced malfunction of pacemakers and cardiac defibrillators has been reported, and corresponding guidelines have been developed in various countries. Although several studies have reported the effects of radiotherapy in patients with implantable left ventricular assist device (LVAD), its safety remains unclear. Herein, we report three cases of stereotactic ablative radiotherapy (SABR) using CyberKnife for early-stage lung cancer in patients with implantable LVAD., Case Report: Three patients in their 50s or 60s, including two women and one man, who had LVADs due to dilated or ischemic cardiomyopathy and performance status of 0 or 1, were diagnosed with stage IA2 lung cancer (cT1bN0M0) by imaging only. All three patients were deemed inoperable due to cardiac comorbidity and underwent SABR at the Osaka University Hospital. The total radiation dose was 42-52 Gy, administered in four fractions. All treatment plans were designed to keep the LVAD dose below 2 Gy. In all patients, SABR was completed without acute adverse events or LVAD malfunction. During the follow-up period of 3-29 months, no disease progression or chronic adverse events were observed in any of the patients., Conclusion: This case series indicated that SABR using CyberKnife is a safe treatment option for early-stage lung cancer in patients with LVAD by reducing the dose to the LVAD., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: To clarify the diagnostic process of the causative disease of abnormal uterine bleeding (AUB) in Japan according to the International Federation of Gynecology and Obstetrics AUB diagnostic system., Methods: Patients diagnosed with AUB were included in a nationwide survey of AUB conducted during any 2-week period between December 2019 and January 2020. The second survey included information on patient background, AUB symptoms, examinations for diagnosing AUB, the order in which they were performed, and the causative diseases of AUB., Results: Correspondence analysis showed an association between hormonal testing, hysterosalpingography, and magnetic resonance imaging (MRI) in patients with amenorrhea, and heavy menstrual bleeding was strongly correlated with various examinations, such as coagulation tests, pelvic MRI, and endometrial cytology or biopsy. The results also indicated that each AUB causative disease can be diagnosed based on a specific examination profile., Conclusion: We clarified the process of diagnosing the causative disease of AUB in our country and determined that it was mainly diagnosed by imaging and pathological examination in cases of structural disease. The high rate of AUB-E and the low rate of AUB-C are possibly associated with specific examination trends in Japan. The results of this study will be useful for the development of a standard protocol for AUB diagnosis in our country., (© 2024 The Author(s). Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology.)

Uterine fibroids (UFs), the most common tumors in women of reproductive age, are characterized by sex steroid-dependent growth and excessive deposition of extracellular matrix (ECM) surrounding UF smooth muscle cells. Women with symptomatic UFs experience heavy menstrual bleeding and consequent iron-deficiency anemia. They also have a risk of recurrent pregnancy loss, preterm birth, and cesarean delivery, indicating that UFs can negatively affect reproductive outcomes. Various types of immune cells, including innate and adaptive cells, are observed in UFs; however, the impact of these cells on the pathophysiology of UFs remains unclear. Inflammation may play important roles in the growth of UFs, and expression levels of proinflammatory and inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-10, TNF-α, and TGF-β, are upregulated in UFs. These cytokines play important roles in the interaction between growth factors and ECM that is regulated by the sex steroids estrogen and progesterone. Furthermore, proinflammatory mediators are upregulated in females with UFs, with higher expression levels in the endometrium with submucosal and intramural UFs than in the endometrium without UFs, indicating that these proinflammatory cytokines may impair endometrial receptivity, leading to implantation failure in in vitro fertilization programs. Hormonal treatments using gonadotropin releasing hormone analogs and the selective progesterone receptor modulator ulipristal acetate significantly shrink UFs and improve UF-related symptoms. These compounds can regulate local inflammation in UFs and adjacent myometrium. Controlling and improving local inflammation caused by UFs may represent a novel therapeutic strategy for UFs and potentially improve reproductive outcomes in women with symptomatic UFs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Hiroshi Ishikawa reports financial support was provided by Japan Society for the Promotion of Science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Hypoxic-ischemic (HI) insult in infants induces brain injury and results in motor coordination impairments associated with cerebral palsy; however, preventive measures for HI brain injury in preterm infants remain unclear. We investigated the impact of progesterone (P4) in a rat HI insult model that mimics HI brain injury in preterm infants., Methods: Neonatal male rats with their right common carotid artery coagulated were exposed to a 1-h hypoxia (6% oxygen) on postnatal day (PND) 3. P4 (0.2 mg) was subcutaneously administered daily from PND4-12. Motor coordination function and muscular strength were evaluated on PND50 using rotarod and grip strength tests, respectively. Brain histology was evaluated via immunohistochemistry using anti-NeuN, anti-Olig2, and anti-IbaI antibodies on PND15 and PND50., Results: In male rats, P4 significantly improved the latency-to-fall off on the rotarod test in the insult rats to the levels of the sham-operation rats. Neither the insult nor P4 administration impacted the grip strength results. No significant differences were observed in the number of neurons, oligodendrocyte progenitor cells (OPCs), and microglia in the motor and somatosensory area of the cortex between the insult and insult followed by P4-administered rats on PND50. The number of OPCs in the corpus callosum was significantly increased in the ipsilateral side compared with the contralateral side of the insult in the P4-administered rats, indicating that P4 facilitates recruitment of OPCs to the corpus callosum. HI insult accelerated neuronal differentiation in rats on PND15, which was abrogated in the P4-administerd group, suggesting that P4 suppresses transient neuronal differentiation caused by the insult., Conclusion: P4 administration restored motor coordination impairments caused by postnatal HI insult in male rats. The insult timing corresponds to that of human preterm infants, indicating P4's potential for protecting HI brain injury in preterm male infants., Competing Interests: Declaration of competing interest All authors have nothing to disclose., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Purpose: This study aims to investigate the prevalence of artifacts in optical coherence tomography (OCT) images with acceptable signal strength and evaluate the performance of supervised deep learning models in improving OCT image quality assessment., Methods: We conducted a retrospective study on 4555 OCT images from 546 patients, with each image having an acceptable signal strength (≥6). A comprehensive analysis of prevalent OCT artifacts was performed, and five pretrained convolutional neural network models were trained and tested to infer images based on quality., Results: Our results showed a high prevalence of artifacts in OCT images with acceptable signal strength. Approximately 21% of images were labeled as nonacceptable quality. The EfficientNetV2 model demonstrated superior performance in classifying OCT image quality, achieving an area under the receiver operating characteristic curve of 0.950 ± 0.007 and an area under the precision recall curve of 0.985 ± 0.002., Conclusions: The findings highlight the limitations of relying solely on signal strength for OCT image quality assessment and the potential of deep learning models in accurately classifying image quality., Translational Relevance: Application of the deep learning-based OCT image quality assessment models may improve the OCT image data quality for both clinical applications and research.

The human polyomavirus JCPyV is an opportunistic pathogen that infects greater than 60% of the world's population. The virus establishes a persistent and asymptomatic infection in the urogenital system but can cause a fatal demyelinating disease in immunosuppressed or immunomodulated patients following invasion of the CNS. The mechanisms responsible for JCPyV invasion into CNS tissues are not known but direct invasion from the blood to the cerebral spinal fluid via the choroid plexus has been hypothesized. To study the potential of the choroid plexus as a site of neuroinvasion, we used an adult human choroid plexus epithelial cell line to model the blood-cerebrospinal fluid (B-CSF) barrier in a transwell system. We found that these cells formed a highly restrictive barrier to virus penetration either as free virus or as virus associated with extracellular vesicles (EVJC+). The restriction was not absolute and small amounts of virus or EVJC+ penetrated and were able to establish foci of infection in primary astrocytes. Disruption of the barrier with capsaicin did not increase virus or EVJC+ penetration leading us to hypothesize that virus and EVJC+ were highly cell-associated and crossed the barrier by an active process. An inhibitor of macropinocytosis increased virus penetration from the basolateral (blood side) to the apical side (CSF side). In contrast, inhibitors of clathrin and raft dependent transcytosis reduced virus transport from the basolateral to the apical side of the barrier. None of the drugs inhibited apical to basolateral transport suggesting directionality. Pretreatment with cyclosporin A, an inhibitor of P-gp, MRP2 and BCRP multidrug resistance transporters, restored viral penetration in cells treated with raft and clathrin dependent transcytosis inhibitors. Because choroid plexus epithelial cells are known to be susceptible to JCPyV infection both in vitro and in vivo we also examined the release of infectious virus from the barrier. We found that virus was preferentially released from the cells into the apical (CSF) chamber. These data show clearly that there are two mechanisms of penetration, direct transcytosis which is capable of seeding the CSF with small amounts of virus, and infection followed by directional release of infectious virions into the CSF compartment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 O’Hara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: We report on the 1-year outcomes of fetuses who underwent thoracoamniotic shunting (TAS) with a double-basket catheter for fetal hydrothorax (FHT) using a national post-marketing surveillance registry., Methods: This surveillance study was conducted for cases enrolled between 2011 and 2019. Preoperative, operative, and postoperative findings and outcomes had to be reported through the national surveillance website., Results: Forty-three institutes enrolled 295 patients. In 60 patients, associated abnormalities were diagnosed after birth. Among the 235 patients with isolated hydrothorax, the survival rate at 1 year of age was 70.5%. Among these patients, 89% did not require oxygen or other respiratory support. The 1-year survival rate in complicated cases was 27%. Trisomy 21 was the most common associated problem (40%). Catheter associated problems, including dislocation (25%), obstruction (24%), and preterm rupture of the membranes (6%) were observed, but there were no severe maternal complications. TAS before 29.5 weeks of gestation (odds ratio [OR] 0.16) and skin edema and ascites (OR 0.06) were risk factors for death at one year, whereas appropriate shunt location for >28 days (OR 4.2) was a protective factor., Conclusion: We report a favorable survival rate in fetuses with isolated FHT treated with this double-basket catheter., (© 2024 John Wiley & Sons Ltd.)

Purpose: To establish generalizable pointwise spatial relationship between structure and function through occlusion analysis of a deep-learning (DL) model for predicting the visual field (VF) sensitivities from 3-dimensional (3D) OCT scan., Design: Retrospective cross-sectional study., Participants: A total of 2151 eyes from 1129 patients., Methods: A DL model was trained to predict 52 VF sensitivities of 24-2 standard automated perimetry from 3D spectral-domain OCT images of the optic nerve head (ONH) with 12 915 OCT-VF pairs. Using occlusion analysis, the contribution of each individual cube covering a 240 × 240 × 31.25 μm region of the ONH to the model's prediction was systematically evaluated for each OCT-VF pair in a separate test set that consisted of 996 OCT-VF pairs. After simple translation (shifting in x- and y-axes to match the ONH center), group t-statistic maps were derived to visualize statistically significant ONH regions for each VF test point within a group. This analysis allowed for understanding the importance of each super voxel (240 × 240 × 31.25 μm covering the entire 4.32 × 4.32 × 1.125 mm ONH cube) in predicting VF test points for specific patient groups., Main Outcome Measures: The region at the ONH corresponding to each VF test point and the effect of the former on the latter., Results: The test set was divided to 2 groups, the healthy-to-early-glaucoma group (792 OCT-VF pairs, VF mean deviation [MD]: -1.32 ± 1.90 decibels [dB]) and the moderate-to-advanced-glaucoma group (204 OCT-VF pairs, VF MD: -17.93 ± 7.68 dB). Two-dimensional group t-statistic maps (x, y projection) were generated for both groups, assigning related ONH regions to visual field test points. The identified influential structural locations for VF sensitivity prediction at each test point aligned well with existing knowledge and understanding of structure-function spatial relationships., Conclusions: This study successfully visualized the global trend of point-by-point spatial relationships between OCT-based structure and VF-based function without the need for prior knowledge or segmentation of OCTs. The revealed spatial correlations were consistent with previously published mappings. This presents possibilities of learning from trained machine learning models without applying any prior knowledge, potentially robust, and free from bias., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Background: We often encounter preterm infants with Down syndrome (DS) who die in the neonatal intensive care unit (NICU). In this study, we examined survival until NICU discharge and assessed the developmental prognosis of preterm infants with DS., Methods: We retrospectively reviewed 416 infants with DS hospitalized during the past 27 years at our NICU., Results: Death occurred in 8/20 (40%) infants at <32 weeks' gestation, 11/23 (48%) at 32-33 weeks, 9/99 (9%) at 34-36 weeks, and 9/274 (3%) at >36 weeks. In total, 84% of infants who died and 25% of those who survived had a non-reassuring fetal status (p < 0.001). Sex, small-for-gestational-age status, and postnatal transport were not associated with death. The main causes of death were bronchopulmonary dysplasia in 4/8 (50%) infants at <32 weeks' gestation, transient abnormal myelopoiesis in 11/20 (55%) and lymphatic dysplasia in 6/20 (30%) at 32-36 weeks, and varied causes at >36 weeks. Among survivors born at <34 weeks' gestation, 6/19 (32%) aged >2 years had moderate or severe cerebral palsy., Conclusions: These data on the high mortality and morbidity of preterm infants with DS may be useful for patient treatment and parent counseling in NICUs treating critically ill infants., Impact: Most infants with Down syndrome born at <34 weeks' gestation are born by cesarean section because of the non-reassuring fetal status. The mortality rate before discharge for infants with Down syndrome born at <34 weeks' gestation was 40%, and 30% of survivors developed moderate or severe cerebral palsy. The risk of death due to bronchopulmonary dysplasia and pulmonary hypertension was high in very preterm infants with Down syndrome despite the absence of chorioamnionitis. Infants with Down syndrome were born 1-2 weeks earlier than unaffected controls., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Purpose: To determine whether peripapillary atrophy (PPA) area is an indicator of glaucomatous structural and functional damage and progression., Methods: In this retrospective longitudinal analysis from ongoing prospective study we qualified 71 eyes (50 subjects) with glaucoma. All subjects had a comprehensive ophthalmic examination, visual field (VF), and spectral-domain optical coherence tomography (OCT) testing in at least three visits. PPA was manually delineated on en face OCT optic nerve head scans, while observing the corresponding cross-sectional images, as the hyper-reflective area contiguous with the optic disc., Results: The mean follow-up duration was 4.4 ± 1.4 years with an average of 6.8 ± 2.2 visits. At baseline, PPA area was significantly associated only with VF's mean deviation (MD; P = 0.041), visual field index (VFI; P = 0.041), superior ganglion cell inner plexiform layer (GCIPL; P = 0.011), and disc area (P = 0.011). Longitudinally, PPA area was negatively and significantly associated with MD (P = 0.015), VFI (P = 0.035), GCIPL (P = 0.009), superior GCIPL (P = 0.034), and disc area (P = 0.007, positive association)., Conclusions: Longitudinal change in PPA area is an indicator of glaucomatous structural and functional progression but PPA area at baseline cannot predict future progression., Translational Relevance: Longitudinal changes in peripapillary atrophy area measured by OCT can be an indicator of structural and functional glaucoma progression.

Previous studies have shown that interpregnancy weight fluctuations impact perinatal outcomes. In order to examine this in Japanese women, we analyzed the data of 2,861 women in their first and second pregnancies who delivered singletons between 2000 and 2022. We compared the second pregnancy perinatal outcomes of women whose interpregnancy body mass index (BMI) change was -1 to 1 unit with those of women whose BMI change was < -1 or ≥ 1 unit. An interpregnancy BMI change ≥ 1 unit was associated with an increased risk of developing gestational diabetes mellitus (adjusted odds ratio [aOR], 1.51; 95% confidence interval [CI], 1.18-1.95) and delivering a large for gestational age neonate (aOR, 1.67; 95% CI, 1.15-2.42) but a decreased risk of preterm birth (aOR, 0.66; 95% CI, 0.46-0.95). An interpregnancy BMI change < -1 unit was associated with a decreased risk of developing gestational diabetes mellitus (aOR, 0.51; 95% CI, 0.31-0.85). In a subgroup analysis of three groups divided according to prepregnancy BMI, interpregnancy BMI changes ≥ 1 unit in women with a BMI of < 18.5 kg/m2 before their first pregnancy were associated with a remarkable risk reduction of developing preterm birth (aOR, 0.30; 95% CI, 0.11-0.81). Interpregnancy BMI changes < -1 unit in women with a BMI of ≥ 25 kg/m2 before their first pregnancy were associated with a remarkable risk reduction of developing gestational diabetes mellitus (aOR, 0.33; 95% CI, 0.12-0.88). Weight gain during interpregnancy period was related to an increased risk of gestational diabetes mellitus and delivery of a large-for-gestational-age neonate, whereas weight loss was related to a decreased risk of developing gestational diabetes mellitus. These results indicate the importance of interpregnancy weight control as part of preconception care; therefore, women considering additional pregnancies should be educated on the importance of maintaining a healthy weight., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yamamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aim: To identify the symptoms and relevant factors associated with acute adrenal insufficiency of early-onset Sheehan syndrome., Methods: We retrospectively reviewed the charts of 125 women admitted to our intensive care unit because of postpartum hemorrhage between January 2011 and December 2021. Three women developed acute adrenal insufficiency. We investigated the total blood loss, shock status, consciousness level upon arrival, and intensive care provided to the women. We also analyzed the symptoms and laboratory data that led to the diagnosis of acute adrenal insufficiency. Continuous variables were presented by median (minimum-maximum)., Results: The medians and ranges of age, total blood loss, and shock index [heart rate/systolic blood pressure] on admission were 33.1 (17.2-45.3) years, 3351 (595-20 260) g, and 0.94 (0.55-2.94), respectively. Seven women were older than 40 years, 28 experienced >5000 g blood loss, 17 had shock index >1.5, 27 had impaired consciousness upon arrival, and 15 underwent hysterectomy. Women who developed acute adrenal insufficiency were <40 years old and had a bleeding volume of over 5000 g, impaired consciousness upon arrival, and had undergone hysterectomy. They had experienced lactation failure, presented with hyponatremia-related symptoms on postpartum days 8-9, experienced general malaise, headache, and impaired consciousness, and showed severe hyponatremia., Conclusions: Massive postpartum hemorrhage over 5000 g, impaired consciousness upon arrival, and hysterectomy as a hemostatic measure were relevant factors associated with acute adrenal insufficiency of early-onset Sheehan syndrome. Hyponatremia-related symptoms occurring after lactation failure are indicative of the onset of acute adrenal insufficiency., (© 2023 Japan Society of Obstetrics and Gynecology.)

Background: Endometriosis-related pain encompassing dysmenorrhea, dyspareunia, and chronic pelvic pain, reduces the quality of life in premenopausal women. Although treatment options for endometriosis alleviate this pain, approximately one-third of women still experience pain even after receiving treatment, indicating the need for novel approaches to pain relief in those women. The Angel Touch device (AT-04) is a portable magnetic fields irradiation device that incorporates a combination of mixed alternative magnetic fields at 2 kHz and 83.3 MHz. A phase III trial confirmed the efficacy and safety of AT-02, a prototype of AT-04, for pain relief in patients with fibromyalgia., Methods: This is a phase III, multicenter, prospective, randomized, sham device-controlled, double-blind, parallel study. The participants will be premenopausal women aged > 18 years who have endometriosis-related pain with at least moderate severity. Considering dropouts, 50 participants have been deemed appropriate. Eligible women will be centrally registered, and the data center will randomly allocate them in a 1:1 ratio to the intervention and control groups. Women in the intervention group will receive electromagnetic wave irradiation generated by AT-04 and those who in the control group will wear a sham device for 16 weeks, and both groups will wear AT-04 for another 4 weeks. The primary outcome measure is the change in the Numeric Rating Scale score at 16 weeks compared with the baseline. Secondary outcome measures are efficacy for pelvic pain including dysmenorrhea and non-menstrual pain, and chronic pelvic pain not related to menstruation, dysmenorrhea, and dyspareunia, and improvement of quality of life during the study period. Safety will be evaluated by device defects and the frequency of adverse events. The study protocol has been approved by the Clinical Study Review Board of Chiba University Hospital, Chiba, Japan, and will be conducted in accordance with the principles of the Declaration of Helsinki and the Japanese Clinical Trials Act and relevant notifications., Discussion: This study aims to develop a novel method of managing endometriosis-related pain. The AT-04 is an ultralow-invasive device that can be used without inhibiting ovulation, suggesting potential benefits to women of reproductive-age. Trial registration number Japan Registry of Clinical Trials (jRCTs032230278)., (© 2024. The Author(s).)

Lacticaseibacillus paracasei strain Shirota (LcS) modulates psychological homeostasis via the gut-brain axis. To explore the possible efficacy of LcS for improving daytime performance, we conducted a double-blind, randomized, crossover, placebo-controlled study of 12 healthy office workers with sleep complaints. The participants received fermented milk containing viable LcS (daily intake of 1 × 10 11 colony-forming units) and non-fermented placebo milk, each for a 4-week period. In the last week of each period, the participants underwent assessments of their subjective mood and measurements of physiological state indicators via an electroencephalogram (EEG) and heart rate variability in the morning and afternoon. The attention score in the afternoon as assessed by the visual analog scale was higher in the LcS intake period than in the placebo intake period ( p = 0.041). Theta power on EEG measured at rest or during an auditory oddball task in the afternoon was significantly lower in the LcS period than in the placebo period ( p = 0.025 and 0.009, respectively). The change rate of theta power was associated with the change in attention score. Treatment-associated changes were also observed in heart rate and the sympathetic nerve activity index. These results indicate that LcS has possible efficacy for improving daytime performance, supported by observations of the related physiological state indicators.

Background: Although abdominal or hysteroscopic metroplasty for septate uterus is considered to reduce pregnancy loss and increase the take-home baby (THB) rate in women with a history of recurrent pregnancy loss, there exists an inherent risk of impaired fertility. This study aimed to clarify the reproductive outcomes of women with septate uterus who underwent abdominal and hysteroscopic metroplasty in a single center., Methods: This retrospective observational study enrolled 27 women who underwent metroplasty between 2007 and 2019. The analysis included women with septate uterus [European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) type U2)] or septate-bicornuate uterus (ESHRE/ESGE type U3b) who underwent either abdominal or hysteroscopic metroplasty. Women who did not have an immediate desire to conceive were excluded from the analysis. As a rule, we recommended pregnancy without surgery for women who had not experienced repeated pregnancy loss. Abdominal metroplasty (ABM) was performed using the modified Tompkins' method and hysteroscopic metroplasty was performed using hysteroscopic transcervical resection of the septum [transcervical metroplasty (TCM)]. The conception ratio was calculated as the number of women who achieved ≥ 1 conception/total number of women, the pregnancy loss ratio was calculated as the number of women who experienced ≥ 1 pregnancy loss/the number of women who conceived, and the THB ratio was calculated as the number of women who achieved ≥ 1 THB/total number of women., Results: Seventeen women underwent ABM and 10 women underwent TCM. Thirty-three conceptions and 26 babies were taken home after surgery. ABM did not change the ≥ 1 conception ratio (76% vs. 83% before and after surgery, respectively; RR = 1.08, p = 0.80). Meanwhile, ABM decreased the ≥ 1 pregnancy loss ratio (100% vs. 36%, RR = 0.36, p < 0.001) and increased the ≥ 1 THB ratio (12% vs. 71%, RR = 6.00, p < 0.01). Similarly, TCM did not change the ≥ 1 conception ratio, decreased the ≥ 1 pregnancy loss ratio, and increased the ≥ 1 THB ratio., Conclusions: Both abdominal and hysteroscopic metroplasty for septate uterus increased the THB rate by preventing pregnancy loss without affecting the chance of pregnancy., Trial Registration: Not applicable., (© 2023. The Author(s).)

Objective: To clarify the reproductive outcomes of women who underwent abdominal repair surgery for cesarean scar defect (CSD)., Study Design: This is a retrospective observational study performed in a tertiary center. We retrospectively reviewed 20 women who underwent abdominal repair between 2007 and 2021. The indication for the repair was a minimal residual myometrial thickness (RMT) of ≦3.0 mm. We investigated surgical complications, changes in minimal RMT before and three-months after the repair, and reproductive outcomes., Results: The median age at the time of repair was 36 years (27-40), with a median body mass index of 21.0 (17.7-28.7) and a median of 1 prior cesarean section (1-5). Twelve women reported secondary infertility, while eight women were concerned about the potential risk of uterine rupture in future pregnancies due to thin RMT. Additionally, one woman had a co-existing vesicouterine fistula, two had abscess and hematoma formation at the precedent cesarean section, and three showed remarkable dehiscence of the defect. The median minimal RMT significantly increased to 5.05 mm (range; 2.5-14.2 mm) after the repair. Seven women had a total of eight live births, with a median duration from the repair to a live-birth pregnancy of 11.5 months (range; 4-20 months). No surgical complications occurred during the repair, and there were no instances of uterine rupture in subsequent pregnancies. However, one woman who became pregnant with twins following double blastocyst transfer required a cesarean section at 25 weeks of pregnancy due to bulging towards the bladder side of the repaired CSD., Conclusion: Abdominal repair for CSD is feasible in women with thin RMT who experience secondary infertility. Twin pregnancies can promote thinning of the CSD repair site, potentially increasing the risk of uterine rupture., 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 B.V. All rights reserved.)

Background: As a consequence of SARS-CoV-2 infection various neurocognitive and neuropsychiatric symptoms can appear, which may persist for several months post infection. However, cell type-specific routes of brain infection and underlying mechanisms resulting in neuroglial dysfunction are not well understood., Methods: Here, we investigated the susceptibility of cells constituting the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus (ChP) to SARS-CoV-2 infection using human induced pluripotent stem cell (hiPSC)-derived cellular models and a ChP papilloma-derived epithelial cell line as well as ChP tissue from COVID-19 patients, respectively., Results: We noted a differential infectibility of hiPSC-derived brain microvascular endothelial cells (BMECs) depending on the differentiation method. Extended endothelial culture method (EECM)-BMECs characterized by a complete set of endothelial markers, good barrier properties and a mature immune phenotype were refractory to SARS-CoV-2 infection and did not exhibit an activated phenotype after prolonged SARS-CoV-2 inoculation. In contrast, defined medium method (DMM)-BMECs, characterized by a mixed endothelial and epithelial phenotype and excellent barrier properties were productively infected by SARS-CoV-2 in an ACE2-dependent manner. hiPSC-derived brain pericyte-like cells (BPLCs) lacking ACE2 expression were not susceptible to SARS-CoV-2 infection. Furthermore, the human choroid plexus papilloma-derived epithelial cell line HIBCPP, modeling the BCSFB was productively infected by SARS-CoV-2 preferentially from the basolateral side, facing the blood compartment. Assessment of ChP tissue from COVID-19 patients by RNA in situ hybridization revealed SARS-CoV-2 transcripts in ChP epithelial and ChP stromal cells., Conclusions: Our study shows that the BCSFB of the ChP rather than the BBB is susceptible to direct SARS-CoV-2 infection. Thus, neuropsychiatric symptoms because of COVID-19 may rather be associated with dysfunction of the BCSFB than the BBB. Future studies should consider a role of the ChP in underlying neuropsychiatric symptoms following SARS-CoV-2 infection., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Abstract: Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized by accumulation of abundant extracellular matrix (ECM) and sex steroid-dependent growth. Women with symptomatic UFs have reduced quality of life and decreased labor productivity. Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs. They are gain-of-function mutations and are more frequently observed in Black women and commonly observed even in small UFs. MED12 mutation-positive UFs (MED12-UFs) often develop multiple rather than solitary and have distinct gene expression profiles, DNA methylomes, transcriptomes, and proteomes. Gene expressions related to ECM organization and collagen-rich ECM components are upregulated, and impaired Mediator kinase activity and dysregulation of Wnt/β-catenin signaling are identified in MED12-UFs. Clinically, the UF shrinking effect of gonadotropin-releasing hormone agonists and ulipristal acetate is dependent on the MED12 mutation status. Understanding of characteristics of MED12-UFs and functions of MED12 mutations for UF tumorigenesis may elucidate the pathophysiology of UFs, leading to the development of new therapeutic options in women with symptomatic UFs.

Purpose: To review eyes with peripapillary and macular retinoschisis without a visible optic pit or advanced glaucomatous optic atrophy, or No Optic Pit Retinoschisis (NOPIR)., Design: Retrospective multicenter case series., Subjects: The study included 11 eyes of 11 patients., Methods: Retrospective study of eyes with macular retinoschisis without a visible optic pit, advanced optic nerve head cupping, or macular leakage on fluorescein angiography., Main Outcome Measures: Visual acuity (VA), retinoschisis resolution, months to resolution, and recurrence of retinoschisis RESULTS: The mean age was 68.1 ± 17.6 years, mean intraocular pressure was 17.4 ± 3.8 mmHg, and the mean spherical equivalent refractive error was -3.1 ± 2.9 diopters. No subject had pathologic myopia. Seven subjects were treated for glaucoma, and 9 subjects had nerve fiber layer defects on OCT. All eyes had retinoschisis in the outer nuclear layer (ONL) in the nasal macula and extending to the edge of the optic disc, and 8 subjects had fovea-involving retinoschisis. Three nonfoveal and 4 fovea-involved eyes were observed, and 4 fovea-involved eyes with vision loss underwent surgery. Surgery involved preoperative juxtapapillary laser followed by vitrectomy and membrane and internal limiting membrane peeling with intraocular gas and face-down position. The mean baseline VA was significantly worse in the surgery group than that in the observation group (P = 0.020). Retinoschisis resolved and vision improved in all surgical cases. The mean resolution time for the surgery group was 2.75 ± 0.96 months, which was shorter than that for the observation group (28.0 ± 21.2 months; P = 0.014). No eye developed recurrence of the retinoschisis after surgery., Conclusions: Peripapillary and macular retinoschisis can develop in eyes without a visible optic pit or advanced glaucomatous cupping. Eyes without foveal involvement and those with foveal involvement but only mild decrease in vision can be observed for spontaneous resolution. If there is persistent foveal involvement with vision loss, surgery can improve vision by resolving the macular retinoschisis. Surgery for fovea-involved macular retinoschisis without a visible optic pit resulted in faster anatomic resolution and better vision recovery., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The success of cell transplantation therapy for ischemic stroke is hindered by the low cell survival rate in poststroke brain, due in part to high free radical production and ensuing oxidative stress. We have developed redox nanoparticles to eliminate reactive oxygen species. In this study, we tested the protective efficacy of these redox nanoparticles in cell culture and a mouse model of ischemic stroke. Induced human dental pulp stem cells were subjected to oxygen-glucose deprivation and reoxygenation to recapitulate ischemia and reperfusion in the penumbra surrounding a cerebral infarct. Cell viability using WST-8 assay, apoptosis using TUNEL, free radicals using MitoSOX, and inflammatory cytokines using ELISA kit were measured in the presence and absence of redox nanoparticles after oxygen-glucose deprivation and reoxygenation. The scavenging activity of redox nanoparticles against reactive oxygen species was detected by electron spin resonance. Moreover, induced cells were transplanted intracerebrally into to the distal middle cerebral artery occlusion model with and without redox nanoparticles, and the survival rate measured. Cell viability was enhanced, while apoptosis, free radical generation, and inflammatory cytokine expression levels were reduced in cultures with redox nanoparticles. Further, reduced redox nanoparticles were detected in the cytoplasm, indicating free radical scavenging. Addition of redox nanoparticles also improved the survival rate of transplanted cells after 6 weeks in vivo. These redox nanoparticles may increase the applicability and success of induced stem cell therapy for ischemic stroke patents by promoting long-term survival., (© 2023. The Author(s) under exclusive licence to Japan Human Cell Society.)

Purpose: The presence of imbalanced datasets in medical applications can negatively affect deep learning methods. This study aims to investigate how the performance of convolutional neural networks (CNNs) for glaucoma diagnosis can be improved by addressing imbalanced learning issues through utilizing glaucoma suspect samples, which are often excluded from studies because they are a mixture of healthy and preperimetric glaucomatous eyes, in a semi-supervised learning approach., Methods: A baseline 3D CNN was developed and trained on a real-world glaucoma dataset, which is naturally imbalanced (like many other real-world medical datasets). Then, three methods, including reweighting samples, data resampling to form balanced batches, and semi-supervised learning on glaucoma suspect data were applied to practically assess their impacts on the performances of the trained methods., Results: The proposed method achieved a mean accuracy of 95.24%, an F1 score of 97.42%, and an area under the curve of receiver operating characteristic (AUC ROC) of 95.64%, whereas the corresponding results for the traditional supervised training using weighted cross-entropy loss were 92.88%, 96.12%, and 92.72%, respectively. The obtained results show statistically significant improvements in all metrics., Conclusions: Exploiting glaucoma suspect eyes in a semi-supervised learning method coupled with resampling can improve glaucoma diagnosis performance by mitigating imbalanced learning issues., Translational Relevance: Clinical imbalanced datasets may negatively affect medical applications of deep learning. Utilizing data with uncertain diagnosis, such as glaucoma suspects, through a combination of semi-supervised learning and class-imbalanced learning strategies can partially address the problems of having limited data and learning on imbalanced datasets.

Aim: To evaluate whether an acute vulvar ulcer that developed after the COVID-19 vaccine administration is an adverse effect of the vaccine., Methods: This is a descriptive study of two cases that we observed in addition to cases that have been reported in the literature. We searched for case reports in the PubMed. The consistency of clinical manifestations among cases and the association between ulceration and vaccination were assessed., Results: Fourteen female patients were identified, including 12 patients from 8 literatures published in 2021 and 2022 and 2 patients from our cases. Of the 14 patients, 11 had received the BNT162b2 vaccine, 2 had received the ChAdOx1 nCoV-19 vaccine, and one had received the mRNA-1273 vaccine. The patient's ages were 16.9 ± 5.0 (mean ± SD) years. Postvaccination, the disease progressed in the following sequence (time interval from vaccination): fever and other systemic inflammatory reactions (0.9 ± 0.4 days), development of vulvar ulcers (2.4 ± 1.2 days), and resolution of the ulcer (16.9 ± 7.4 days). The ulcers eventually healed in all cases, except one where the prognosis was not noted. For two-dose vaccine recipients, more patients developed the ulcer after the full vaccination (the second or third doses) compared with after the first dose: n = 10 and n = 2, respectively., Conclusion: The acute vulvar ulcer was closely associated with COVID-19 vaccination in terms of temporality and vaccine doses, supporting the notion that a vulvar ulcer is an adverse event of the COVID-19 vaccines., (© 2023 Japan Society of Obstetrics and Gynecology.)

Background: Congenital diaphragmatic hernia (CDH) is associated with high neonatal mortality. We performed this study to test the hypothesis that left ventricular (LV) and right ventricular (RV) volumes assessed by three-dimensional echocardiography may be associated with mortality in CDH., Methods: This study was a single-center retrospective cohort study involving 35 infants with CDH. RV and LV end-diastolic volume (RVEDV and LVEDV, respectively) were measured by three-dimensional echocardiography and were corrected by birth body weight (BBW) on day 1. RVEDV/BBW, LVEDV/BBW, and LVEDV/RVEDV were compared between CDH survivors and non-survivors. Receiver-operating characteristic curve analysis was performed to assess the predictive ability for mortality of the echocardiographic parameters., Results: Comparing CDH non-survivors (n = 6) with survivors (n = 29), respectively, RVEDV/BBW was significantly larger (2.54 ± 0.33 vs 1.86 ± 0.35 ml/kg; P < 0.01), LVEDV/BBW was significantly smaller (0.86 ± 0.21 vs 1.22 ± 0.33 ml/kg; P < 0.001), and LVEDV/RVEDV was significantly lower (0.34 ± 0.06 vs 0.66 ± 0.18; P < 0.001). The area under the curve for LVEDV/RVEDV was the largest (0.98)., Conclusions: Three-dimensional echocardiographic volume imbalance between the RV and LV was remarkable in CDH non-survivors. The LVEDV/RVEDV ratio may be associated with mortality in CDH., Impact: Mortality with congenital diaphragmatic hernia (CDH) is high, and evaluating left and right ventricular structures and functions may be helpful in assessing the prognosis. Three-dimensional (3D) echocardiography indicated that the left ventricular end-diastolic volume/right ventricular end-diastolic volume ratio within 24 h after birth was associated with mortality in CDH infants. The usefulness of this ratio should be validated in prospective multicenter studies involving larger numbers of patients., (© 2023. The Author(s).)

Purpose: To evaluate disease progression using static perimetry (SP) in patients with USH2A-related retinal degeneration, including Usher syndrome type 2 (USH2) and nonsyndromic autosomal recessive retinitis pigmentosa., Design: Prospective, observational cohort study., Methods: A total of 102 patients with biallelic disease-causing sequence variants in USH2A with baseline best-corrected visual acuity (BCVA) letter score ≥54 were recruited from 16 clinical sites in Europe and North America. SP, BCVA, full-field stimulus thresholds, spectral domain optical coherence tomography macular scans, and fundus-guided mesopic microperimetry were performed at baseline and annually. The main outcome measures were total hill of vision (V TOT ), hill of vision in the central 30° (V 30 ), V TOT minus V 30 (V PERIPH ), and mean sensitivity., Results: The average decline (95% CI) was 2.05 (1.40, 2.70) decibel-steradian (dB-sr)/y for V TOT , 0.48 (0.32, 0.65) dB-sr/y for V 30 , 1.53 (0.97, 2.08) dB-sr/y for V PERIPH , and 0.55 (0.40, 0.71) dB/y for mean sensitivity. Average percentage decline per year was 8.3 (5.5, 11.1) for V TOT , 5.2 (3.0, 7.4) for V 30 , 16.0 (9.5, 22.0) for V PERIPH , and 5.1 (3.5, 6.7) for mean sensitivity. Changes from baseline to year 2 in all SP measures were highly correlated (r's ranging from 0.52 [V 30 vs V PERIPH ] to 0.98 [V TOT vs V PERIPH ])., Conclusions: Quantitative measures of SP declined significantly over 2 years in USH2A-related retinal degeneration. The annual percentage rate of change was greatest for V TOT and V PERIPH , whereas V 30 and mean sensitivity changed least, reflecting earlier and more severe peripheral degeneration compared with central loss., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The structural changes measured by optical coherence tomography (OCT) are related to functional changes in visual fields (VFs). This study aims to accurately assess the structure-function relationship and overcome the challenges brought by the minimal measurable level (floor effect) of segmentation-dependent OCT measurements commonly used in prior studies., Methods: We developed a deep learning model to estimate the functional performance directly from three-dimensional (3D) OCT volumes and compared it to the model trained with segmentation-dependent two-dimensional (2D) OCT thickness maps. Moreover, we proposed a gradient loss to utilize the spatial information of VFs., Results: Our 3D model was significantly better than the 2D model both globally and pointwise regarding both mean absolute error (MAE = 3.11 + 3.54 vs. 3.47 ± 3.75 dB, P < 0.001) and Pearson's correlation coefficient (0.80 vs. 0.75, P < 0.001). On a subset of test data with floor effects, the 3D model showed less influence from floor effects than the 2D model (MAE = 5.24 ± 3.99 vs. 6.34 ± 4.58 dB, P < 0.001, and correlation 0.83 vs. 0.74, P < 0.001). The gradient loss improved the estimation error for low-sensitivity values. Furthermore, our 3D model outperformed all prior studies., Conclusions: By providing a better quantitative model to encapsulate the structure-function relationship more accurately, our method may help deriving VF test surrogates., Translational Relevance: DL-based VF surrogates not only benefit patients by reducing the testing time of VFs but also allow clinicians to make clinical judgments without the inherent limitations of VFs.

The choroid plexus (ChP) has been suggested as an alternative central nervous system (CNS) entry site for CCR6 + Th17 cells during the initiation of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). To advance our understanding of the importance of the ChP in orchestrating CNS immune cell entry during neuroinflammation, we here directly compared the accumulation of CD45 + immune cell subsets in the ChP, the brain and spinal cord at different stages of EAE by flow cytometry. We found that the ChP harbors high numbers of CD45 int resident innate but also of CD45 hi adaptive immune cell subsets including CCR6 + Th17 cells. With the exception to tissue-resident myeloid cells and B cells, numbers of CD45 + immune cells and specifically of CD4 + T cells increased in the ChP prior to EAE onset and remained elevated while declining in brain and spinal cord during chronic disease. Increased numbers of ChP immune cells preceded their increase in the cerebrospinal fluid (CSF). Th17 but also other CD4 + effector T-cell subsets could migrate from the basolateral to the apical side of the blood-cerebrospinal fluid barrier (BCSFB) in vitro, however, diapedesis of effector Th cells including that of Th17 cells did not require interaction of CCR6 with BCSFB derived CCL20. Our data underscore the important role of the ChP as CNS immune cell entry site in the context of autoimmune neuroinflammation., (© 2023. The Author(s).)

Objectives: We aimed to clarify the accuracy of pregnant women's knowledge and understanding regarding infectious disease screening in early pregnancy and clarify the roles that should be played by health care providers in promoting the health of pregnant women and their children., Methods: A cross-sectional questionnaire survey was conducted in 25 hospitals across Japan from May 2018 to September 2019. We compared the agreement rates regarding screening results for hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, human T-cell leukemia virus-1 (HTLV-1), and cervical cytology in the medical records and understanding of their results by pregnant women. We then investigated whether participants had knowledge regarding the risk of mother-to child transmission in these diseases and factors associated with their knowledge., Results: We enrolled 2,838 respondents in this study. The rates of agreement for HBV and cervical cancer screening related to human papillomavirus infection were "substantial," those for syphilis was "moderate," and those for HCV and HTLV-1 were "fair," according to the Kappa coefficient. The rate of knowledge regarding mother-to-child transmission of syphilis was highest (37.0%); this rate for the other items was approximately 30%. Increased knowledge was associated with higher educational level and higher annual income., Conclusions for Practice: Pregnant women in Japan had generally good levels of understanding regarding their results in early-pregnancy infectious disease screening. However, they had insufficient knowledge regarding mother-to-child transmission of these diseases. Health care providers should raise awareness in infectious disease prevention among pregnant women and the general public, providing appropriate measures and implementing effective perinatal checkups and follow-ups for infectious diseases., (© 2023. The Author(s).)

Background: Retinal oxygen saturation (sO 2 ) provides essential information about the eye's response to pathological changes that can result in vision loss. Visible-light optical coherence tomography (vis-OCT) is a noninvasive tool that has the potential to measure retinal sO 2 in a clinical setting. However, its reliability is currently limited by unwanted signals referred to as spectral contaminants (SCs), and a comprehensive strategy to isolate true oxygen-dependent signals from SCs in vis-OCT is lacking., Methods: We develop an adaptive spectroscopic vis-OCT (ADS-vis-OCT) technique that can adaptively remove SCs and accurately measure sO 2 under the unique conditions of each vessel. We also validate the accuracy of ADS-vis-OCT using ex vivo blood phantoms and assess its repeatability in the retina of healthy volunteers., Results: In ex vivo blood phantoms, ADS-vis-OCT agrees with a blood gas machine with only a 1% bias in samples with sO 2 ranging from 0% to 100%. In the human retina, the root mean squared error between sO 2 values in major arteries measured by ADS-vis-OCT and a pulse oximeter is 2.1% across 18 research participants. Additionally, the standard deviations of repeated ADS-vis-OCT measurements of sO 2 values in smaller arteries and veins are 2.5% and 2.3%, respectively. Non-adaptive methods do not achieve comparable repeatabilities from healthy volunteers., Conclusions: ADS-vis-OCT effectively removes SCs from human images, yielding accurate and repeatable sO 2 measurements in retinal arteries and veins with varying diameters. This work could have important implications for the clinical use of vis-OCT to manage eye diseases., (© 2023. The Author(s).)

Purpose: Lamina cribrosa (LC) deformation is hypothesized to play a major role in glaucoma pathogenesis. The purpose of this study was to determine in vivo how varying intraocular pressure (IOP) under fixed intracranial pressure (ICP), and vice versa, deforms the pore paths throughout the LC volume., Methods: Spectral-domain optical coherence tomography scans of the optic nerve head were acquired from healthy adult rhesus monkeys under different pressures. IOP and ICP were controlled with gravity-based perfusion systems into the anterior chamber and lateral ventricle, respectively. IOP and ICP were modulated from baseline to high (19-30 mmHg) and highest (35-50 mmHg) levels while maintaining a fixed ICP of 8 to 12 mmHg and IOP of 15 mmHg, respectively. After three-dimensional registration and segmentation, the paths of pores visible in all settings were tracked based on their geometric centroids. Pore path tortuosity was defined as the measured distance divided by the minimal distance between the most anterior and posterior centroids., Results: The median pore tortuosity at baseline varied among the eyes (range, 1.16-1.68). For the IOP effect under fixed ICP (six eyes, five animals), two eyes showed statistically significant increased tortuosity and one showed a decrease (P < 0.05, mixed-effects model). No significant change was detected in three eyes. When modulating ICP under fixed IOP (five eyes, four animals), a similar response pattern was detected., Conclusions: Baseline pore tortuosity and the response to acute pressure increase vary substantially across eyes., Translational Relevance: LC pore path tortuosity could be associated with glaucoma susceptibility.

The choroid plexus (CP) is part of the blood-cerebrospinal fluid barrier (BCSFB) and was recently described as an important component of the circadian clock system. It is the principal source of cerebrospinal fluid (CSF) and responsible for the synthesis and secretion of various neuroprotective peptides including those involved in amyloid-β (Aβ) transport/degradation, contributing to Aβ homeostasis. Inadequate Aβ metabolic clearance and transport across the BCSFB have been associated with circadian dysfunctions in Alzheimer's disease (AD) patients. To investigate whether AD pathology influences Aβ scavengers circadian expression, we collected CP at different time points from an AD mouse model (APP/PS1) (female and male animals, aged 6- and 12-months-old) and analyzed their mRNA expression by Real-time RT-PCR. Only angiotensin-converting enzyme (Ace) expression in 6-month-old female wild-type mice and transthyretin (Ttr) expression in 12-month-old female wild-type mice presented significant rhythmicity. The circadian rhythmicity of Ace and Ttr, prompt us to analyze the involvement of circadian rhythm in Aβ uptake. A human CP papilloma (HIBCPP) cell line was incubated with Aβ-488 and uptake was evaluated at different time points using flow cytometry. Aβ uptake displayed circadian rhythmicity. Our results suggest that AD might affect Aβ scavengers rhythmicity and that Aβ clearance is a rhythmic process possibly regulated by the rhythmic expression of Aβ scavengers., (© 2022 Wiley Periodicals LLC.)

The Gram-negative bacterium Neisseria meningitidis , which causes meningitis in humans, has been demonstrated to manipulate or alter host signalling pathways during infection of the central nervous system (CNS). However, these complex signalling networks are not completely understood. We investigate the phosphoproteome of an in vitro model of the blood-cerebrospinal fluid barrier (BCSFB) based on human epithelial choroid plexus (CP) papilloma (HIBCPP) cells during infection with the N. meningitidis serogroup B strain MC58 in presence and absence of the bacterial capsule. Interestingly, our data demonstrates a stronger impact on the phosphoproteome of the cells by the capsule-deficient mutant of MC58. Using enrichment analyses, potential pathways, molecular processes, biological processes, cellular components and kinases were determined to be regulated as a consequence of N. meningitidis infection of the BCSFB. Our data highlight a variety of protein regulations that are altered during infection of CP epithelial cells with N. meningitidis, with the regulation of several pathways and molecular events only being detected after infection with the capsule-deficient mutant. Mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD038560., 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 Herold, Denzer, Muranyi, Stump-Guthier, Ishikawa, Schroten and Schwerk.)

Purpose: Chemotherapy-induced neutropenia (CIN) is a dose-limiting factor for cytotoxic chemotherapy, but recently, it was suggested that CIN contributes to prolonged survival. In this study, we examined the association between severe CIN and survival and determined whether CIN affected survival in patients with extensive-stage small cell lung cancer (ES-SCLC)., Methods: The medical records from 214 patients with ES-SCLC treated with etoposide or irinotecan in combination with cisplatin (EP/IP) between 2012 and 2016 were collected and retrospectively analyzed. Landmark analysis was performed at the end of cycle 4, and the relationship between severe CIN and survival was determined by a log-rank test. In addition, a multivariate analysis using the COX proportional hazard model was performed to identify independent predictive factors. The Landmark analysis included 102 patients in the IP group and 47 patients in the EP group., Results: No significant difference was found between grades 0-3 and grade 4 neutropenia and overall survival (OS) in the EP group (P = 0.57). Contrariwise, for the IP patients, the median OS was 444 days for grades 0-3 and 633 days for grade 4 neutropenia, which was significantly longer for patients who developed grade 4 neutropenia (P = 0.03). Multivariate analysis adjusted for potential factors revealed that the development of grade 4 CIN was identified as a significant predictor of longer OS (hazard ratio [HR], 0.50; 95% confidence interval (CI), 0.28-0.87, P = 0.015)., Conclusion: The results indicated that the development of severe CIN with IP therapy is associated with prolonged OS., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A multiscale extension for the well-known block matching and 4D filtering (BM4D) method is proposed by analyzing and extending the wavelet subbands denoising method in such a way that the proposed method avoids directly denoising detail subbands, which considerably simplifies the computations and makes the multiscale processing feasible in 3D. To this end, we first derive the multiscale construction method in 2D and propose multiscale extensions for three 2D natural image denoising methods. Then, the derivation is extended to 3D by proposing mixed multiscale BM4D (mmBM4D) for optical coherence tomography (OCT) image denoising. We tested mmBM4D on three public OCT datasets captured by various imaging devices. The experiments revealed that mmBM4D significantly outperforms its original counterpart and performs on par with the state-of-the-art OCT denoising methods. In terms of peak-signal-to-noise-ratio (PSNR), mmBM4D surpasses the original BM4D by more than 0.68 decibels over the first dataset. In the second and third datasets, significant improvements in the mean to standard deviation ratio, contrast to noise ratio, and equivalent number of looks were achieved. Furthermore, on the downstream task of retinal layer segmentation, the layer quality preservation of the compared OCT denoising methods is evaluated., 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. Published by Elsevier Ltd.)

Purpose: To evaluate changes in monkey optic nerve head (ONH) morphology under acutely controlled intraocular pressure (IOP) and intracranial pressure (ICP)., Methods: Seven ONHs from six monkeys were imaged via optical coherence tomography while IOP and ICP were maintained at one of 16 conditions. These conditions were defined by 4 levels for each pressure: low, baseline, high and very high. Images were processed to determine scleral canal area, aspect ratio, and planarity and anterior lamina cribrosa (ALC) shape index and curvature. Linear mixed effect models were utilized to investigate the effects of IOP, ICP and their interactions on ONH morphological features. The IOP-ICP interaction model was compared with one based on translaminar pressure difference (TLPD)., Results: We observed complex, eye-specific, non-linear patterns of ONH morphological changes with changes in IOP and ICP. For all ONH morphological features, linear mixed effects models demonstrated significant interactions between IOP and ICP that were unaccounted for by TLPD. Interactions indicate that the effects of IOP and ICP depend on the other pressure. The IOP-ICP interaction model was a higher quality predictor of ONH features than a TLPD model., Conclusions: In vivo modulation of IOP and ICP causes nonlinear and non-monotonic changes in monkey ONH morphology that depend on both pressures and is not accounted for by a simplistic TLPD. These results support and extend prior findings., Translational Relevance: A better understanding of ICP's influence on the effects of IOP can help inform the highly variable presentations of glaucoma and effective treatment strategies., Competing Interests: Proprietary Interest: J.S. Schuman receives royalties for intellectual property licensed by Massachusetts Institute of Technology to Zeiss. All other authors: Nothing to disclose