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Background and purposeSelective voluntary motor control is an important factor influencing gross motor function, interjoint coordination, and the outcome of hamstring-lengthening surgery in spastic cerebral palsy. Using DTI, we investigated whether selective voluntary motor control would show strong correlations with WM motor tract microstructure and whether selective voluntary motor control is more sensitive to global WM impairment than gross motor function.Materials and methodsChildren with spastic bilateral cerebral palsy born preterm and typically developing children were recruited. The Selective Control Assessment of the Lower Extremity (SCALE) and Gross Motor Function Measure (GMFM) were assessed in participants with cerebral palsy. Participants underwent brain MR imaging to collect DWI data. Tract-Based Spatial Statistics was used to analyze the WM for between-group differences and correlations with SCALE and GMFM. ROI analyses compared motor regions.ResultsTwelve children with cerebral palsy (mean age, 11.5 years) and 12 typically developing children (mean age, 10.3 years) participated. Altered DTI outcomes were found throughout the whole brain for the cerebral palsy group. SCALE, developed to evaluate selective voluntary motor control in cerebral palsy, showed significant positive correlations with fractional anisotropy in more WM voxels throughout the whole brain and for motor regions, including the corticospinal tract and corpus callosum, compared with GMFM. A significant negative correlation between radial diffusivity and SCALE, but not GMFM, was found within the corpus callosum.ConclusionsSCALE was a more sensitive clinical correlate of motor and whole-brain WM tract impairment in children with spastic bilateral cerebral palsy, suggesting greater anisotropy and myelination in these regions for those with higher selective voluntary motor control.

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.

This study explored the relationship between the morphological characteristics of the first tarsometatarsal ligaments and fibularis longus (FL) and the severity of articular cartilage degeneration in the first tarsometatarsal joint. Sixty legs from 30 cadavers were examined. The plantar, dorsal, and medial first tarsometatarsal ligaments were classified by fiber bundle number, and their morphological characteristics (fiber bundle length, width, thickness) were measured. The FL was categorized by its continuity with the plantar first tarsometatarsal ligament (PTML): Type A, connection with the PTML only on the first metatarsal; Type B, connection along the entire PTML; and Type C, no connection with the PTML. The severity of articular cartilage degeneration was assessed in four stages. No significant differences in cartilage degeneration among ligament types were found. Negative correlations were observed between the fiber bundle width and thickness of the PTML and the severity of cartilage degeneration. FL was classified as Type A in 68%, Type B in 27%, and Type C in 5% of feet. The fiber bundle thickness of the PTML in Type B was greater than in other types. Our findings suggest that smaller fiber bundle width and thickness in the PTML may be associated with severe cartilage degeneration. The FL had continuity with the PTML in 95% of feet and could enhance the mechanical strength of the PTML in Type B feet., (© 2024 American Association of Clinical Anatomists and British Association of Clinical Anatomists.)

Yes-associated protein (YAP) is a mechanosensitive protein crucial for bone remodeling. Although research has identified pathways and components involved in YAP regulation, the precise mechanisms of its localization during Piezo1 activation or vibration remain unclear. Piezo1, a mechanosensitive ion channel, allows calcium ions to flow into cells upon activation. Recent studies suggest that combining Yoda1, a Piezo1 activator, with low-magnitude high-frequency (LMHF) vibration (>30 Hz, <1 g acceleration) enhances YAP nuclear translocation. This combination potentially improves the mechanoresponse and therapeutic efficacy of LMHF vibration in bone cells. This study aims to elucidate how Yoda1 and LMHF vibration regulate mechanosensitive structures and pathways, leading to YAP nuclear translocation in MLO-Y4 osteocyte like cells. We investigated the roles of the cytoskeleton and nuclear envelope (NE) in YAP activation under combined LMHF vibration and Yoda1 treatments. Additionally, we analyzed differentially expressed genes (DEGs) in MLO-Y4 cells subjected to these treatments and in Piezo1 knockdown MLO-Y4 cells exposed to vibration. Our findings indicated that increased YAP nuclear translocation with combined treatment may result from the distinct effects of Yoda1 and vibration. Specifically, Yoda1 influenced YAP through mechanisms involving actin and NE dynamics, while LMHF vibration may modulate YAP via the interleukin 6 (IL6)/signal transducer and activator of transcription 3 (STAT3) axis. This study provides new insights and potential therapeutic targets for osteocyte-related pathologies., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine the effects of hydrogen water on retinal blood flow (RBF) dysregulation in diabetes, we evaluated changes in RBF in response to flicker stimulation and systemic hyperoxia in diabetic mice., Methods: Twelve type 2 diabetic mice were divided into a group that received non-hydrogen water (n = 6, control group) and the other that received hydrogen-rich water (0.6-0.8 mM) (n = 6, HRW group) from six weeks of age. Body weight, blood glucose, intraocular pressure, and blood pressure were evaluated from eight to 14 weeks of age. RBF was measured in the vascular area of the optic disc as mean blur rate using laser speckle flowgraphy in the resting state and response to flicker stimulation and hyperoxia. We evaluated glial activation and oxidative stress based on immunofluorescence expression., Results: At 14 weeks, blood glucose level was significantly lower in the HRW group, though still elevated. RBF changes improved significantly in the HRW group compared with the control group from eight weeks of age and persisted throughout the study. Immunofluorescent expression of glial fibrillary acidic protein, particularly in the outer plexiform layer, was significantly decreased in the HRW group. Among oxidative stress markers, 3-nitrotyrosine was significantly suppressed in the HRW group., Conclusions: Hydrogen-rich water intake significantly improved RBF dysregulation in diabetic mice. Hydrogen may improve impaired neurovascular coupling function in diabetic mice by suppressing gliosis and oxidative stress in the retina., Translational Relevance: This study highlights the potential of oral intake of hydrogen-rich water to mitigate retinal dysfunction in diabetic mice.

Background: Using echocardiography to assess right ventricular (RV) function after cardioplegic arrest is challenging. Cardiac magnetic resonance (CMR) imaging is a superior alternative, with the feature tracking technique enabling quantitative assessment of myocardial deformation., Methods: This single-centre, prospective study from 2020 to 2022 assessed RV function in 42 patients who underwent open heart surgery with cardioplegic arrest. CMR data were collected preoperatively, one week postoperatively, and at follow-up (6-12 months after surgery), and assessed using the CMR feature tracking technique., Results: Postoperatively, there was no significant change in RV end-diastolic volume, but RV end-systolic volume significantly decreased, leading to a notable increase in RV ejection fraction. By follow-up, both RV end-diastolic and end-systolic volumes had significantly reduced compared with the preoperative values. Right ventricular longitudinal contractility decreased after surgery but recovered to the preoperative values by follow-up, while RV circumferential contractility improved postoperatively and remained superior to the preoperative levels at follow-up., Conclusion: On CMR imaging, significant changes in RV systolic motion were observed after cardioplegic arrest, with decreased longitudinal but increased circumferential contractility. At follow up, these changes had reverted to the preoperative patterns by the mid-term (6-12 months)., Competing Interests: Declarations of Interest There are no conflicts of interest to disclose., (Copyright © 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Micropatterning is reliable method for quantifying pluripotency of human-induced pluripotent stem cells (hiPSCs) that differentiate to form a spatial pattern of sorted, ordered and nonoverlapped three germ layers on the micropattern. In this study, we propose a deep learning method to quantify spatial patterning of the germ layers in the early differentiation stage of hiPSCs using micropattern images. We propose decoding and encoding U-net structures learning labelled Hoechst (DNA-stained) hiPSC regions with corresponding Hoechst and bright-field micropattern images to segment hiPSCs on Hoechst or bright-field images. We also propose a U-net structure to extract extraembryonic regions on a micropattern, and an algorithm to compares intensities of the fluorescence images staining respective germ-layer cells and extract their regions. The proposed method thus can quantify the pluripotency of a hiPSC line with spatial patterning including cell numbers, areas and distributions of germ-layer and extraembryonic cells on a micropattern, and reveal the formation process of hiPSCs and germ layers in the early differentiation stage by segmenting live-cell bright-field images. In our assay, the cell-number accuracy achieved 86% and 85%, and the cell region accuracy 89% and 81% for segmenting Hoechst and bright-field micropattern images, respectively. Applications to micropattern images of multiple hiPSC lines, micropattern sizes, groups of markers, living and fixed cells show the proposed method can be expected to be a useful protocol and tool to quantify pluripotency of a new hiPSC line before providing it to the scientific community., (© 2024 The Author(s). Journal of Microscopy published by John Wiley & Sons Ltd on behalf of Royal Microscopical Society.)

Background: The incidence of pancreatic cancer is on the rise, and its prognosis remains poor. Recent reports have established a link between the gut and oral microbiome and pancreatic cancer. However, the intricacies of this association within the Japanese population remain unclear. In this study, we investigated the gut and oral microbiomes of Japanese patients with pancreatic cancer, comparing them with those of healthy individuals., Methods: We recruited 30 patients with untreated pancreatic cancer and 18 healthy controls at Kyoto University Hospital (2018-2022). We performed a comprehensive 16S rRNA gene sequencing to analyze their gut and oral microbiomes., Results: Analysis revealed that the diversity of the gut and oral microbiomes of patients with pancreatic cancer was reduced compared to that of the healthy controls. Specifically, we observed an increase in the genus Streptococcus in both the gut and oral microbiomes and a significant decrease in several butyrate-producing bacteria in fecal samples. Moreover, bacteria such as Streptococcus mitis and Holdemanella biformis were present in pancreatic cancer tissues, suggesting that they might influence the carcinogenesis and progression of pancreatic cancer., Conclusions: The gut and oral microbiome differed between patients with pancreatic cancer and healthy controls, with a notable decrease in butyrate-producing bacteria in the gut microbiome of the patients. This suggests that there may be a distinct microbial signature associated with pancreatic cancer in the Japanese population. Further studies are required to elucidate the microbiome's causal role in this cancer and help develop prognostic markers or targeted therapies., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In the phase 3 EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 study, cemiplimab significantly improved overall survival (OS) versus chemotherapy for patients with recurrent or metastatic cervical cancer who progressed after first-line platinum-based chemotherapy. We present a post hoc subgroup analysis of patients enrolled in Japan., Methods: Patients were enrolled regardless of programmed cell death-ligand 1 status and randomized 1:1 to cemiplimab 350 mg intravenously every 3 weeks or investigator's choice  single-agent chemotherapy for up to 96 weeks. Primary endpoint was OS. Key secondary endpoints were progression-free survival (PFS) and objective response rate (ORR)., Results: Overall, 608 patients were randomized, of whom 56 (9.2%) were in Japan (cemiplimab, n = 29; chemotherapy, n = 27). The median (range) duration of follow-up was 13.6 (6.0-25.3) versus 18.2 (6.0-38.2) months for patients in Japan and for the overall population, respectively. Median OS (95% confidence interval [CI]) was 8.4 (7.0-not evaluable) and 9.4 (5.4-14.9) months for cemiplimab versus chemotherapy (hazard ratio [HR]: 0.86; 95% CI: 0.43-1.68). Median PFS (95% CI) was 4.0 (1.4-8.2) versus 3.7 (1.8-4.2) months with cemiplimab and chemotherapy (HR: 0.90; 95% CI: 0.50-1.61), respectively. ORR was 17.2% for cemiplimab and 7.4% for chemotherapy (odds ratio, 2.47; 95% CI, 0.44-13.99). Incidence of treatment-emergent adverse events at any grade was 79.3% for cemiplimab and 100% for chemotherapy. Grade ≥3 adverse events were 37.9% versus 66.7% with cemiplimab and chemotherapy, respectively., Discussion: While acknowledging limitations inherent to a small subgroup analysis, the HR of 0.86 observed in Japanese patients suggests an emerging survival benefit despite a 4.6-month shorter median duration of follow-up versus the overall study population., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: The suprapatellar bursa is located in the proximal deep layer of the patella and is thought to reduce tissue friction by changing from a single-membrane structure to a double-membrane structure during knee joint motion. However, the dynamics of the suprapatellar bursa have only been inferred from positional relationships, and the actual dynamics have not been confirmed., Methods: Dynamics of the suprapatellar bursa during knee joint motion were observed in eight knees of four Thiel-fixed cadavers and the angle at which the bursa begins to show a double membrane was revealed. The flexion angles of knee joints were measured when the double-membrane structure of the suprapatellar bursa began to appear during knee joint extension., Results: The suprapatellar bursa changes from a single membrane to a double-membrane structure at 91 ± 4° of flexion, when the knee joint is moved from a flexed position to an extended position., Conclusion: The suprapatellar bursa may be involved in limitations to knee joint range of motion and pain at an angle of approximately 90°. Further studies are needed to verify whether the same dynamics are observed in living subjects., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Introduction: Most infants born as small for gestational age (SGA) demonstrate catch up growth by 2-4 years, but some fail to do so. This failure is associated with several health risks, including neuropsychological development issues. However, data on the morphological characteristics of the brains of infants born as SGA without achieving catch up growth are lacking. This study aims to determine the structural aspects of the brains of children born as SGA without catch up growth., Methods: We conducted voxel- and surface-based morphometric analyses of 1.5-T T1-weighted brain images scanned from eight infants born as SGA who could not achieve catch up growth by 3 years and sixteen individuals with idiopathic short stature (ISS) to exclude body size effects. Growth hormone (GH) secretion stimulation tests were used to rule out GH deficiency in all SGA and ISS cases. The magnetic resonance imaging data were assessed using Levene's test for equality of variances and a two-tailed unpaired t -test for equality of means. The Benjamini-Hochberg procedure was used to apply discovery rate correction for multiple comparisons., Results: Morphometric analyses of both t -statical map and surface-based analyses using general linear multiple analysis determined decreased left insula thickness and volume in SGA without catch up growth compared with ISS., Conclusion: The brain scans of patients with SGA who lack catch up growth indicated distinct morphological disparities when compared to those with ISS. The discernible features of brain morphology observed in patients born as SGA without catch up growth may improve understanding of the association of SGA without catch up growth with both intellectual and psychological outcomes., 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 © 2024 Takatani, Shiohama, Takatani, Hattori, Yokota and Hamada.)

Repetitive passive movement (RPM) enhances reciprocal inhibition. RPM is more effective when performed rapidly and at wide joint angles. However, patients with limited joint range of motion may not receive the most effective RPM. Therefore, having an alternative method for performing RPM in patients who cannot perform actual exercise due to limited joint motion is necessary. This study investigated the effects of RPM on spinal excitability using a visual kinesthetic illusion. Participants included 17 healthy adults (7 women). Measurements were taken before, during, and immediately after the intervention. We established two intervention conditions: the control condition, in which participants focused their attention forward, and the illusion condition, in which participants watched a video about RPM. F-waves from the tibialis anterior and soleus muscles were measured, and F-wave persistence and F/M amplitude ratios were analyzed. Under the illusion condition, compared with the preintervention condition, the F/M amplitude ratio of the tibialis anterior increased by approximately 44% during the intervention ( p < 0.05), whereas the F-wave persistence of the soleus decreased by approximately 23% from the immediate start of the intervention ( p < 0.05). This study suggests that a visual kinesthetic illusion can increase the spinal excitability of the tibialis anterior, whereas reciprocal inhibition can decrease the spinal excitability of the soleus.

Background: The flexor-pronator muscles (FPM) and their common tendon (CT) are essential in protecting the medial ulnar collateral ligament against elbow valgus stress during pitching. This study aimed to investigate the effect of repetitive pitching on FPM strength and CT stiffness., Methods: Fifteen healthy males (mean age: 21.8 ± 1.3-years-old) with over 5 years of baseball experience performed a series of 100 full-effort fastball pitches. We measured grip and isolated digital flexion strength of the second, third, and fourth digits before and after the pitching task. The decline in muscle strength was determined using the rate of change in muscle strength after pitching relative to that before. CT stiffness was measured using a hand-held myotonometer device at rest and during grip motion at 50% maximum voluntary contraction. The increase in CT stiffness during grip motion relative to rest was calculated as the augmentation rate of CT stiffness. Statistical analyses were performed to compare the changes in grip strength, digital flexion strength, and CT stiffness due to pitching. Additionally, the reduction rate of muscle strength was compared among various strength variables. Correlation coefficients were used to evaluate the relationships between the augmentation rate of CT stiffness after pitching and the reduction rate in any muscle strength., Results: Grip and isolated digital flexion strengths decreased significantly after pitching (P < 0.01). The decline in muscle strength was significantly higher for all isolated digital strengths than that for grip strength (P < 0.05). CT stiffness was augmented with grip motion compared to that at rest pre- and post-pitching (P < 0.001). However, no change in CT stiffness due to pitching was observed, regardless of the grip motion (P > 0.05). Additionally, a lower augmentation rate of CT stiffness after pitching was moderately associated with the greater reduction rate of the second digital flexion strength (r = 0.607, P = 0.016) without other relationships., Conclusion: This study found reduced grip and digital flexion strength after pitching; with no change in CT stiffness. However, given the consequences of correlation analyses, individuals with a more prominent reduction in second digital flexion strength due to pitching were impaired in CT stiffness augmentation after pitching. Digital flexion strength represents the strength of the flexor digitorum superficial; therefore, this study suggests that forearm FPM, particularly the second digit of the flexor digitorum superficial, is an important factor for enhancing CT stiffness., (Copyright © 2024. Published by Elsevier Inc.)

Background: Naldemedine is an orally available peripherally acting μ-opioid receptor antagonist approved to treat opioid-induced constipation (OIC). It is contraindicated for patients with known or suspected gastrointestinal obstruction to protect against naldemedine-induced perforation. Here, we report a clinical case of suspected perforation of a diverticulum in the sigmoid colon associated with naldemedine., Case Presentation: The patient was a 65-year-old man with a history of oral cancer who had been prescribed oxycodone (20 mg/day) for cancer pain. On day 0, the patient started naldemedine 0.2 mg once daily before bedtime for OIC. The dose of oxycodone was increased for pain control up to 60 mg/day. On day 35 of naldemedine treatment, the patient developed fever and abdominal pain, and his frequency of defecation had decreased. Initial laboratory results showed a C-reactive protein (CRP) level of 28.5 mg/dL and white blood cell (WBC) count of 13,500/µL. On day 37, the patient still had tenderness in his lower abdomen. Abdominal computed tomography revealed free air in the abdominal cavity suggesting an intestinal perforation. A Hartmann procedure was performed. Histopathological findings showed numerous diverticula in the sigmoid colon, some of which were perforated., Conclusions: These results suggest that the effects of OIC may have compressed the intestinal tract, which was followed by naldemedine-activation of peristalsis, which led to the onset of intestinal perforation. In patients with pre-existing diverticular disease, we should monitor for increased WBC counts and CRP levels after the initiation of treatment with naldemedine, and consider performing appropriate tests early in the event of abdominal complaints., (© 2024. The Author(s).)

Purpose: Identification of the Adamkiewicz artery before aortic surgery is important for preventing postoperative complications due to spinal cord ischemia. The Adamkiewicz artery is difficult to identify due to its small diameter. Nitroglycerin has a vasodilatory effect and is used clinically to improve visualization of blood vessels on coronary computed tomography (CT) angiography. We investigated whether the vasodilatory effect of nitroglycerin could improve the ability to visualize the Adamkiewicz artery., Methods: We extracted 33 cases wherein contrast-enhanced CT images were taken before and after aortic aneurysm surgery. Nitroglycerin was administered for coronary artery evaluation on the preoperative CT. However, no nitroglycerin was administered before the postoperative CT. Aortic contrast-to-noise ratio, CT value, image noise, and diameter of the Adamkiewicz artery and anterior spinal artery were measured. The depiction of the Adamkiewicz artery was graded into four grades and evaluated. These measurements were performed by two independent reviewers., Results: In nitroglycerin-administered cases, the contrast-to-noise ratio and CT values were significantly higher (P < 0.001, P < 0.001, respectively); the Adamkiewicz artery and anterior spinal artery diameters were dilated (P = 0.005, P = 0.001, respectively). The Adamkiewicz artery score also improved significantly (P < 0.001). No significant difference was found in image noise., Conclusion: Nitroglycerin contributed to improving the Adamkiewicz artery's visualization., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: To date, there is limited evidence on the effects of bronchodilators on respiratory dynamics in chronic obstructive pulmonary disease (COPD). Dynamic chest radiography (DCR) is a novel radiographic modality that provides real-time, objective and quantifiable kinetic data, including changes in the lung area (Rs), tracheal diameter, diaphragmatic kinetics and pulmonary ventilation during respiration, at a lower radiation dose than that used by fluoroscopic or CT imaging. However, the therapeutic effect of dual bronchodilators on respiratory kinetics, such as chest wall dynamics and respiratory muscle function, has not yet been prospectively evaluated using DCR., Aim: This study aims to evaluate the effects of bronchodilator therapy on respiratory kinetics in patients with COPD using DCR., Methods and Analysis: This is an open-label, prospective, single-centre, non-controlled, comparative study. A total of 35 patients with COPD, aged 40-85 years, with a forced expiratory volume in the first second of 30-80%, will be enrolled. After a 2-4 weeks washout period, patients will receive tiotropium/olodaterol therapy for 6 weeks. Treatment effects will be evaluated based on DCR findings, pulmonary function test results and patient-related outcomes obtained before and after treatment. The primary endpoint is the change in Rs after therapy. The secondary endpoints include differences in other DCR parameters (diaphragmatic kinetics, tracheal diameter change and maximum pixel value change rate), pulmonary function test results and patient-related outcomes between pre-therapy and post-therapy values. All adverse events will be reported., Ethics and Dissemination: Ethical approval for this study was obtained from the Ethics Committee of Chiba University Hospital. The results of this trial will be published in a peer-reviewed journal., Trial Registration Number: jRCTs032210543., Competing Interests: Competing interests: KOno and KOka is currently employed full-time at KonicaMinolta.inc. None of the other authors declare any competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To investigate whether the addition of eltrombopag (EPAG) to rabbit anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) for newly diagnosed severe aplastic anemia (SAA) improves outcomes and affects the cumulative incidence of clonal evolution (CE), we conducted a multicenter retrospective analysis., Methods: Data were collected from 101 patients, aged 15 - 65 years, undergoing initial IST., Results: No significant imbalance in age, sex, or severity was observed between the EPAG (n = 20) and non-EPAG (n = 81) groups. The median duration of EPAG administration in EPAG group was 16.1 months (range: 0.6 - 41.1 months). Six months after the initiation of IST, the complete response (CR) rate significantly improved in the EPAG group (P < 0.01). The cumulative incidence of allogeneic stem cell transplantation (allo-SCT) at 2 years and the 2-year overall survival (OS) were not significantly different between the two groups (allo-SCT, P = 0.31; OS, P = 0.64). Grade 3-4 adverse events in the EPAG group and the cumulative incidence of CE (P = 0.96) showed no increase., Conclusion: In summary, IST showed significantly better initial efficacy in the EPAG group. Although the addition of EPAG did not reduce the need for allo-SCT, no increase was observed in the incidence of CE with long-term EPAG use., Competing Interests: The authors declare no direct competing financial interests., (Copyright 2024, Yokota et al.)

Purpose: Quantitative MRI techniques such as T2 mapping are useful in comprehensive evaluation of various pathologies of the knee joint yet require separate scans to conventional morphological measurements and long acquisition times. The recently introduced 3D MIXTURE (Multi-Interleaved X-prepared Turbo-Spin Echo with Intuitive Relaxometry) technique can obtain simultaneous morphologic and quantitative information of the knee joint. To compare MIXTURE with conventional methods and to identify differences in morphological and quantitative information., Methods: Phantom studies were conducted, and in vivo human scans were performed (20 patients) presented with knee arthralgia. MIXTURE is based on 3D TSE without and with T2 preparation modules in an interleaved manner for both morphology with PDW and fat suppressed T2W imaging as well as quantitative T2 mapping within one single scan. Image quality and lesion depiction were visually assessed and compared between MIXTURE and conventional 2D TSE by two experienced radiologists. Contrast-to-noise ratio was used to assess the adjacent tissue contrast in a quantitative way for both obtained PDW and fat suppressed T2W images. Quantitative T2 values were measured in phantom and from in vivo knee cartilage., Results: The overall diagnostic confidence and contrast-to-noise ratio were deemed comparable between MIXTURE and 2D TSE. While the chosen T2 preparation modules for MIXTURE rendered consistent T2 values comparing to the current standard, measured cartilage T2 values ranged from 26.1 to 50.7 ms, with significant difference between the lesion and normal areas (p < 0.05)., Conclusions: MIXTURE can help to provide high-resolution information for both anatomical and pathological assessment., 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 Elsevier B.V. All rights reserved.)

Objective Although patients with neuroimmunological disorders often need to be treated with glucocorticoids and are at risk of developing glucocorticoid-induced osteoporosis, no research has focused on the treatment of glucocorticoid-induced osteoporosis in such patients. Methods We compared the efficacy of denosumab and bisphosphonates in glucocorticoid-induced osteoporosis in neuroimmunological diseases. In 57 patients with neuroimmunological disorders treated with corticosteroids (34 with neuromyelitis optica spectrum disorders, 16 with myasthenia gravis, and 7 with others), we retrospectively studied the long-term effects of denosumab (n=23) and bisphosphonates (n=34) on spine and total hip bone mineral density (BMD) measured by dual energy X-ray absorptiometry. Results There were no significant differences in the age, lumbar spine BMD, or mean dose or duration of prednisolone administration at baseline between the denosumab and bisphosphonate groups. During the follow-up period of up to 6 years, the increase in the lumbar spine and total hip BMD was greater in the denosumab group than in the bisphosphonate group (p<0.01). Insufficient bone fractures were observed in 2 (9%) of the 23 patients in the denosumab group and in 2 (6%) of the 34 patients in the bisphosphonate group (not significant). Conclusion Denosumab is more effective than bisphosphonates in increasing the BMD of patients with neuroimmunological disorders receiving glucocorticoids.

Background: Immune checkpoint inhibitors (ICIs) are crucial in cancer treatment; however, they carry the risk of immune-related adverse events (irAEs), such as enteritis., Case Presentation: This study investigated the role of the gut microbiota during the onset and remission of irAE enteritis in a patient with stage IV melanoma undergoing anti-PD-1 and anti-CTLA-4 therapy. Following commencement of ICI treatment, the patient developed severe diarrhea and was diagnosed with grade 3 irAE enteritis. Steroid and probiotic treatments provided swift symptom relief and remission, as confirmed by reduced fecal calprotectin levels and gastrointestinal imaging. Microbiota diversity analysis conducted via 16S rRNA gene sequencing identified a decrease in Streptococcus prevalence with improvement in enteritis symptoms. Conversely, genera Fusobacterium, Faecalibacterium, Bacteroides, Prevotella, and Bifidobacterium showed increased representation after remission. These genera are associated with anti-inflammatory properties and fibrous substrate degradation, aiding gut health. Immunological assessment demonstrated fluctuations in cytokine expression and the modulation of costimulatory molecules, aligning with therapeutic interventions and microbiota alterations., Conclusions: Our findings indicate a significant correlation between gut microbiota and immune responses in irAE enteritis. This underscores the potential utility of microbiome profiling in predicting irAE occurrence and in providing treatment strategies, thereby promoting a more comprehensive approach to managing the adverse effects of ICIs., (© 2024. The Author(s).)

A 77-year-old man presented with progressive consciousness disturbance, presumably caused by a backward fall. Head computed tomography findings showed a large intracerebral hemorrhage in the left parietal lobe. Radiated fractures with an oval depression of the bilateral parietal bone crossing the midline were noted. Surgical evacuation of the hemorrhage was performed via a left-sided parietal craniotomy, during which fragments from the fracture with eggshell-like thinning were noted. Biparietal thinning is an uncommon condition noted in radiological findings of a symmetrical oval depression of bilateral parietal bones with reduced diploe thickness. Cases of traumatic brain injury in patients with biparietal thinning have rarely been reported. This condition should be recognized as a possible predisposing factor for traumatic brain injury., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To evaluate retinal blood flow (RBF) regulation in response to RBF stress in maturity-onset diabetes of the young type 3 (MODY3) pigs., Study Design: Case-control study., Methods: MODY3 pigs (diabetes mellitus [DM] group, n = 8) transfected with the human mutant hepatocyte nuclear factor-1⍺ and normal pigs of the same age (normal group, n = 8) were used as subjects. After confirming DM onset, the experiment was performed under inhalation anesthesia with isoflurane at 2 months of age before the cataract progressed. Ocular blood flow was assessed by calculating the optic papillary mean blur rate using laser speckle flowgraphy, modified for pig eye measurements. After baseline ocular blood flow measurements, flicker stimulation (12 Hz, 3 min) was applied, and ocular blood flow was measured over time., Results: Blood glucose was 81.8 ± 5.1 mg/dL in the normal group and 311.4 ± 23.1 mg/dL in the DM group (mean ± standard error). The percent change in ocular blood flow at 3 min after flicker stimulation was +31.0 ± 10.9% in the normal group and -6.6 ± 6.5% in the DM group compared to the preload value, and the difference was statistically significant (Mann-Whitney test, P = 0.015)., Conclusion: RBF response to flicker stimulation is reduced at 2 months of age in MODY3 pigs, suggesting that retinal neurovascular coupling is impaired from the early onset of DM., (© 2024. Japanese Ophthalmological Society.)

Objective: Vertebral artery (VA) injury poses a significant risk in cervical spine surgery, necessitating accurate preoperative assessment. This study aims to introduce and validate a novel approach that combines the Fast field echo that resembles a computed tomography using restricted echo spacing (FRACTURE) sequence with Time of Flight (TOF) Magnetic Resonance Angiography (MRA) for comprehensive evaluation of VA courses in the cervical spine., Materials and Methods: A total of eight healthy volunteers and two patients participated in this study. The FRACTURE sequence provided high-resolution bone images of the cervical spine, while TOF MRA offered non-invasive vascular imaging. Fusion images were created by merging FRACTURE and MRA modalities to simultaneously visualize cervical spine structures and VA courses. Board-certified orthopedic spine surgeons independently evaluated images to assess the visibility of anatomical characteristics of the VA course by Likert-scale., Results: The FRACTURE-MRA fusion images effectively depicted the extraosseous course of the VA at the craniovertebral junction, the intraosseous course of the VA at the craniovertebral junction, the VA entrance level to the transverse foramen, and the side-to-side asymmetry of bilateral VAs. Additionally, clinical cases demonstrated the utility of the proposed technique in identifying anomalies and guiding surgical interventions., Conclusions: The integration of the FRACTURE sequence and TOF MRA presents a promising methodology for the precise evaluation of VA courses in the cervical spine. This approach improves preoperative planning for cervical spine surgery with detailed anatomy and is a valuable alternative to conventional methods without contrast agents., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Anamorelin, a drug to treat cancer cachexia, binds to ghrelin receptors and improves body weight and appetite. In clinical trials in Japan, patients experienced a 10.7% frequency of stimulant conduction system depression as a severe side effect. Although rare, anamorelin sometimes causes fatal arrhythmias. Because patients with cancer cachexia are often underweight, data on the safety of anamorelin in obese patients are lacking. We report a case of QT interval prolongation after anamorelin administration to an obese patient with non-small cell lung cancer., Case Presentation: A female patient with a body mass index of 30 kg/m2 underwent immunotherapy for lung adenocarcinoma. She presented with severe weight loss, anorexia, and fatigue. She had no history of heart disease. On day 12, after administration of anamorelin 100 mg once daily, the patient developed nausea, diarrhea, and anorexia, which were considered cancer immunotherapy-induced immune-related adverse events, and she was admitted to the hospital. An electrocardiogram (ECG) on admission showed a QTc interval of 502 ms. On admission, her hepatic function was Child-Pugh class B, and anamorelin was discontinued the next day. On day 3 after anamorelin discontinuation, the QTc interval was prolonged by up to 557 ms, then decreased to 490 ms on day 6, and improved to 450 ms on day 16. Re-administration of anamorelin was avoided., Conclusions: When administering anamorelin to obese patients, we should be aware of the potential for stimulatory conduction system depression, as in underweight patients. Therefore, we should monitor patients by ECG from the early stages of anamorelin administration. Anamorelin is lipophilic, and its volume of distribution is increased in obese patients. Consequently, obese patients may continue to have QT interval prolongation after discontinuation of anamorelin, requiring long-term side-effect monitoring., (© 2024. The Author(s).)

Background: The skeletal system is a common site for metastasis from breast cancer. In our prior work, we developed induced tumor-suppressing cells (iTSCs) capable of secreting a set of tumor-suppressing proteins. In this study, we examined the possibility of identifying anticancer peptides (ACPs) from trypsin-digested protein fragments derived from iTSC proteomes., Methods: The efficacy of ACPs was examined using an MTT-based cell viability assay, a Scratch-based motility assay, an EdU-based proliferation assay, and a transwell invasion assay. To evaluate the mechanism of inhibitory action, a fluorescence resonance energy transfer (FRET)-based GTPase activity assay and a molecular docking analysis were conducted. The efficacy of ACPs was also tested using an ex vivo cancer tissue assay and a bone microenvironment assay., Results: Among the 12 ACP candidates, P18 (TDYMVGSYGPR) demonstrated the most effective anticancer activity. P18 was derived from Arhgdia, a Rho GDP dissociation inhibitor alpha, and exhibited inhibitory effects on the viability, migration, and invasion of breast cancer cells. It also hindered the GTPase activity of RhoA and Cdc42 and downregulated the expression of oncoproteins such as Snail and Src. The inhibitory impact of P18 was additive when it was combined with chemotherapeutic drugs such as Cisplatin and Taxol in both breast cancer cells and patient-derived tissues. P18 had no inhibitory effect on mesenchymal stem cells but suppressed the maturation of RANKL-stimulated osteoclasts and mitigated the bone loss associated with breast cancer. Furthermore, the P18 analog modified by N-terminal acetylation and C-terminal amidation (Ac-P18-NH2) exhibited stronger tumor-suppressor effects., Conclusions: This study introduced a unique methodology for selecting an effective ACP from the iTSC secretome. P18 holds promise for the treatment of breast cancer and the prevention of bone destruction by regulating GTPase signaling.

We assessed the short-term effects of switching from intravitreal aflibercept (IVA) to intravitreal faricimab (IVF) on ocular blood flow in patients with treatment-resistant diabetic macular edema (DME). The medical records of 15 patients with DME who had received IVA injection ≥ 3 months before were retrospectively reviewed. The best-corrected visual acuity, central macular thickness (CMT) on optical coherence tomography, and mean blur rate (MBR) of all disc areas on laser speckle flowgraphy were measured before, 1 week after, and 4 weeks after IVA and IVF, respectively. The changes in visual acuity showed no significant difference after switching from IVA to IVF (P = 0.732). The mean CMT decreased significantly during the follow-up period (both P < 0.001). MBR showed no significant difference during the follow-up period (P = 0.26). However, it decreased significantly 4 weeks after IVF (P = 0.01) compared with the baseline value, but not 4 weeks after IVA (P = 0.074). A significant association was observed between decreased MBR and decreased CMT in patients who received IVF (correlation coefficient: 0.501, P = 0.005) but not in those who received IVA (P = 0.735). Thus, IVF maintained ocular blood flow reduction, although no significant differences in visual acuity and CMT changes were observed compared to IVA., (© 2024. The Author(s).)

This study aimed to elucidate the relationship between joint structures of the first tarsometatarsal and articular facet degeneration. A total of 100 feet from 50 cadavers were examined. The articular facets of the first metatarsal and medial cuneiform were categorized into four types based on the superior and inferior facets' separation, and the formation of the inferior lateral facet on the lateral plantar prominence: Type I, a single facet with no separation or inferior lateral facet; Type II-a, two facets with separation but no inferior lateral facet; Type II-b, two facets, no separation, but with an inferior lateral facet; Type III, three facets with separation and an inferior lateral facet. When both bone types matched, they were defined as Type I, Type II-a, Type II-b, and Type III joints, respectively; unmatched types were classified as Unpair joints. The severity of articular cartilage degeneration on both bones was assessed using a 5-point scale. The degeneration grade was compared among joint types. Type III joints exhibited significantly milder articular cartilage degeneration in medial cuneiform compared to Type II-a, II-b, Unpair joints. The formation of inferior lateral facet and separation of the superior and inferior facets might be crucial for the joint's stability., (© 2024. The Author(s).)

Domains in a crystal, which have crystallographic uniformity and are geometrically segmented, typically arise from various phase transitions. The physical properties within individual domains are inherently the same as those in the homogeneous bulk. As a result, sufficiently large domains have little influence on the bulk properties. However, as the domains decrease in size to the nanoscale, for instance, due to multiple phase instabilities or spatial inhomogeneities, then the materials often acquire exceptional functionalities that are unattainable without these domains. This effect is exemplified by the ultrahigh dielectric and piezoelectric responses observed in ferroelectric oxides with nanoscale polar domains as well as in ferroelectric relaxors with polar nanoclusters. Here, we demonstrate that hashed nanoscale domains in an antiferroelectric material are also capable of boosting dielectric permittivity in an unconventional way. This discovery has been made in an antiferroelectric titanite-type oxide, CaTi(Si 1- x Ge x )O 5 , in which the permittivity significantly increases when the antiferroelectric order becomes short-range. Our transmission electron microscopy observations have clarified that polar regions simultaneously appear around antiphase boundaries in the antiferroelectric phase of CaTi(Si 1- x Ge x )O 5 . As the concentration of the antiphase boundary increases, the polar regions become denser and play a crucial role in boosting the permittivity. At the composition of x = 0.5, the value of the permittivity finally reaches double that in the bulk and shows excellent linearity, at least until an electric field of 500 kV/cm is applied. The present findings highlight the promise of domain engineering for boosting the permittivity in antiferroelectrics as a way to develop materials with excellent dielectric properties.

The shoulder joint has a high degree of freedom and an extremely complex and unstable kinematic mechanism. Coordinated contraction of the rotator cuff muscles that stop around the humeral head and the deltoid muscles and the extensibility of soft tissues, such as the joint capsule, labrum, and ligaments, contribute to shoulder-joint stability. Understanding the mechanics of shoulder-joint movement, including soft-tissue characteristics, is important for disease prevention and the development of a device for disease treatment. This study aimed to create a musculoskeletal shoulder model to represent the realistic behavior of joint movement and soft-tissue deformation as a dynamic simulation using a rigid-body model for bones and a soft-body model for soft tissues via a spring-damper-mass system. To reproduce the muscle-contraction properties of organisms, we used a muscle-expansion representation and Hill's mechanical muscle model. Shoulder motion, including the movement of the center of rotation in joints, was reproduced, and the strain in the joint capsule during dynamic shoulder movement was quantified. Furthermore, we investigated narrowing of the acromiohumeral distance in several situations to induce tissue damage due to rotator cuff impingement at the anterior-subacromial border during shoulder abduction. Given that the model can analyze exercises under disease conditions, such as muscle and tendon injuries and impingement syndrome, the proposed model is expected to help elucidate disease mechanisms and develop treatment guidelines., (© 2024. The Author(s), under exclusive licence to Japanese Association of Anatomists.)

Background: Patient-friendly audiovisual (AV) systems in head MRI examinations can potentially reduce patient anxiety and contrast-enhanced MRI (CE-MRI) adverse reactions to gadolinium., Purpose: To evaluate whether a patient-friendly AV system reduces the rate of adverse reactions to gadolinium-based contrast agents., Study Type: Retrospective., Population: Four thousand eight hundred thirty-two outpatients (2462 female) attending for clinical CE-MRI studies. (Gadoteridol: 1971, Meglumine gadoterate: 2733, Gadobutrol: 128.) FIELD STRENGTH/SEQUENCE: Routine CE-MRI of head and neck using a 1.5 T or 3 T scanner with or without a patient-friendly AV system., Assessment: One thousand one hundred fifty-nine patients were scanned on MRI machines equipped with patient-friendly AV systems (AV group) and 3673 on MRI machines without AV systems (control group). Adverse reaction rate and symptoms were reviewed by referring to the system database and electronic medical records and compared between the two groups. Adverse reactions were defined as physiological reactions, such as vomiting and allergic-like reactions, such as urticaria, occurring within 1 hour of contrast injection. We compare patient backgrounds, adverse reaction rate, adverse reactions symptoms and the severity between the two groups., Statistical Tests: Adverse reaction rate with and without a patient-friendly AV system were compared using Fisher's exact test. The relationship between patient-friendly AV systems and the occurrence of adverse reactions was evaluated with logistic regression. Statistical significance was set at P < 0.05., Results: Of the 4832 patients enrolled, 65 (1.35%) experienced adverse reactions. The most common adverse reactions in both groups were urticaria and pruritus. Adverse reaction rate was significantly lower in the AV group than in the control group (0.7% vs. 1.6%). No significant difference was observed in the severity (P = 1.000) of adverse reactions and symptoms (allergic-like reaction: P = 0.08, physiologic reaction: P = 1.000) between the two groups., Data Conclusion: The patient-friendly AV system significantly reduce adverse reaction occurrence to gadolinium-based contrast agents., Evidence Level: 4 TECHNICAL EFFICACY: Stage 1., (© 2023 International Society for Magnetic Resonance in Medicine.)

HER2 expression in breast cancer is evaluated to select patients for anti-HER2 therapy. With the advent of newly approved HER2-targeted drugs for low HER2 expression breast cancer, more solid evidence on the whole spectrum of HER2 expression is needed. In this study, we quantitatively assessed HER2 expression from the whole core by combining high-intensity phosphor-integrated dot (PID) immunostaining and whole slide imaging (WSI) analysis. Two types of staining were performed using a 170-core tissue microarray of invasive breast cancer. First, HER2 was stained by immunohistochemistry (IHC), and IHC scores were determined by two practicing pathologists according to the ASCO/CAP HER2 guideline. Second, HER2 was stained with PID, and tentative PID scores were determined by quantitative analysis. The results show that PID can numerically classify HER2 expression status into scores 3+, 2+, 1+, and 0. The HER2 value quantified by PID strongly correlated with the 3, 3'-diaminobenzidine (DAB) IHC score determined by pathologists (R2 = 0.93). PID IHC score 1+ cases included both DAB IHC score 1+ and 0 cases, and low HER2 expression cases appeared to be often evaluated as DAB IHC score 0. Therefore, digital image analysis by PID and WSI can help stratify HER2 IHC. It may also help classify low HER2 expression., Competing Interests: N.S. T.M. H.Y. and H.O. are employees of Konica Minolta, Inc. H.T. is a consultant for Konica Minolta, Inc., (Copyright: © 2024 Saito 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.)

Purpose: Differences in the contours created during magnetic resonance imaging-guided online adaptive radiotherapy (MRgOART) affect dose distribution. This study evaluated the interobserver error in delineating the organs at risk (OARs) in patients with pancreatic cancer treated with MRgOART. Moreover, we explored the effectiveness of drugs that could suppress peristalsis in restraining intra-fractional motion by evaluating OAR visualization in multiple patients., Methods: This study enrolled three patients who underwent MRgOART for pancreatic cancer. The study cohort was classified into three conditions based on the MRI sequence and butylscopolamine administration (Buscopan): 1, T2 imaging without butylscopolamine administration; 2, T2 imaging with butylscopolamine administration; and 3, multi-contrast imaging with butylscopolamine administration. Four blinded observers visualized the OARs (stomach, duodenum, small intestine, and large intestine) on MR images acquired during the initial and final MRgOART sessions. The contour was delineated on a slice area of ±2 cm surrounding the planning target volume. The dice similarity coefficient (DSC) was used to evaluate the contour. Moreover, the OARs were visualized on both MR images acquired before and after the contour delineation process during MRgOART to evaluate whether peristalsis could be suppressed. The DSC was calculated for each OAR., Results: Interobserver errors in the OARs (stomach, duodenum, small intestine, large intestine) for the three conditions were 0.636, 0.418, 0.676, and 0.806; 0.725, 0.635, 0.762, and 0.821; and 0.841, 0.677, 0.762, and 0.807, respectively. The DSC was higher in all conditions with butylscopolamine administration compared with those without it, except for the stomach in condition 2, as observed in the last session of MR image. The DSCs for OARs (stomach, duodenum, small intestine, large intestine) extracted before and after contouring were 0.86, 0.78, 0.88, and 0.87; 0.97, 0.94, 0.90, and 0.94; and 0.94, 0.86, 0.89, and 0.91 for conditions 1, 2, and 3, respectively., Conclusion: Butylscopolamine effectively reduced interobserver error and intra-fractional motion during the MRgOART treatment., Competing Interests: MT and KA received endowed chairs funded by Elekta K.K. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Kurokawa, Tsuneda, Abe, Ikeda, Kanazawa, Saito, Kodate, Harada, Yokota, Watanabe and Uno.)

The aim of this study was to clarify the effects of transcutaneous auricular vagus nerve stimulation (taVNS) to the left cymba concha on the pain perception using nociceptive withdrawal reflex (NWR), which is known to be associated with chronic pain, and to investigate whether there is a relationship between taVNS-induced suppression of the NWR and parasympathetic activation. We applied either 3.0 mA, 100 Hz taVNS for 120 s on the left cymba concha (taVNS condition) or the left earlobe (Sham condition) for 20 healthy adults. NWR threshold was measured before (Baseline), immediately after (Post 0), 10 min (Post 10) and 30 min after (Post 30) stimulation. The NWR threshold was obtained from biceps femoris muscle by applying electrical stimulation to the sural nerve. During taVNS, electrocardiogram was recorded, and changes in autonomic nervous activity measured by heart rate variability (HRV) were analyzed. We found that the NWR thresholds at Post 10 and Post 30 increased compared with baseline in the taVNS group (10 min after: p = .008, 30 min after: p = .008). In addition, increased parasympathetic activity by taVNS correlated with a greater increase in NWR threshold at Post 10 and Post 30 (Post 10: p = .003; Post 30: p = .001). The present results of this single-blinded study demonstrate the pain-suppressing effect of taVNS on NWR threshold and suggest that the degree of parasympathetic activation during taVNS may predict the pain-suppressing effect of taVNS after its application., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Magnetic resonance neurography requires varying imaging techniques based on the site of imaging and anticipated disease. In assessing the brachial and lumbosacral plexus, a three-dimensional (3D) spin echo method, such as 3D-short tau inversion recovery imaging, is frequently employed. It's beneficial to familiarize oneself with the imaging sequence and understand the appearance of normal images in advance. The imaging parameters used in our institute are provided below as a reference. When interpreting the images, pay close attention to nerve thickening, signal intensity changes, asymmetry between the left and right sides, and irregularities in nerve caliber. Efforts are underway to standardize qualitative assessments and quantify signals through technological advancements.

In this study, we developed a rigid-scope system that can perform hyperspectral imaging (HSI) between visible and 1600 nm wavelengths using a supercontinuum light source and an acousto-optic tunable filter to emit specific wavelengths. The system optical performance was verified, and the classification ability was investigated. Consequently, it was demonstrated that HSI (490-1600 nm) could be performed. In addition, seven different targets could be classified by the neural network with an accuracy of 99.6%, recall of 93.7%, and specificity of 99.1% when the wavelength range of over 1000 nm (OTN) was extracted from HSI data as train data.

Competing Interests: There are no conflicts of interest.