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This article discusses the use of transvaginal SlowflowHD imaging technology to examine the development of embryonic and fetal hearts in the first trimester of pregnancy. The study found that by the 11th week of gestation, all major structures of the heart had developed. The article also mentions previous studies that used older technology to visualize cardiac structures, but the quality of the images was poor. The authors conclude that transvaginal SlowflowHD imaging provides a high-resolution and sensitive method for assessing cardiac structures in early pregnancy. The use of SlowflowHD has the potential to diagnose congenital heart anomalies and provide valuable diagnostic information on various heart conditions. However, it cannot determine flow direction and velocity, and further research is needed to explore its potential role in early fetal cardiac diagnosis. [Extracted from the article]

Background: Interleukin (IL)-23 is involved in the pathogenesis of ulcerative colitis (UC). A genome-wide significant association between IL23R p.G149R (rs76418789) and UC was previously identified in Japan and Korea. This case-control study aims to examine this association within the Japanese population., Methods: The study included 384 cases diagnosed with UC within the past 4 years and 661 control subjects. Adjustment was made for sex, age, and smoking., Results: The frequency of the AA genotype of rs76418789 was 0.0 % in cases and 0.5 % in control subjects. In comparison to study subjects with the GG genotype of rs76418789, those with the GA or AA genotype had a significantly reduced risk of UC, with an adjusted odds ratio of 0.67 (95 % confidence interval: 0.44-0.999). A significant multiplicative interaction was observed between rs76418789 and having ever smoked influencing UC (p for interaction = 0.03). A significant positive association was found between having ever smoked and UC in individuals with at least one A allele, while no such positive relationship was observed in those with the GG genotype., Conclusion: IL23R SNP rs76418789 showed a significant association with UC. This study provides new evidence regarding the interaction between rs76418789 and smoking in relation to UC., 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 Ltd. All rights reserved.)

Context: Estimated remnant cholesterol (Rem-C) level, a risk factor for cardiovascular disease (CVD), is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosed via ultrasonography. However, the relationship between accurate serum Rem-C level measurements and histological findings of MASLD remains unclear., Objective: We aimed to elucidate the relationship between accurately measured serum Rem-C levels and histological findings of MASLD., Design: Cross-sectional single-center observational study., Methods: We assessed 222 patients (94 men and 128 women; age 20-80) who were diagnosed with MASLD via liver biopsy with available medical history, physical examination, and biochemical measurement data. Serum ester-type cholesterol and free cholesterol contents in the remnant lipoproteins were measured using an enzymatic method., Results: Serum Rem-C levels were significantly higher in patients with NAFLD activity score (NAS) 5-8, ＞66% steatosis grade, lobular inflammation with ≥5 foci, and many cells/prominent ballooning cells (a contiguous patch of hepatocytes showing prominent ballooning injury) than in patients with NAS 1-4, <33% steatosis grade, lobular inflammation with <2 foci, and few ballooning cells (several scattered balloon cells), respectively. While univariate analysis revealed no significant association between Rem-C levels and advanced fibrosis, a significant association between Rem-C levels and NAS was evident. This relationship remained significant in multivariate analysis adjusted for confounders. Furthermore, in the analysis by sex, these relationships were significant for men but not for women., Conclusion: High serum Rem-C levels were associated with high NAS, but not with fibrosis stage, particularly in men. Controlling serum Rem-C level may improve MASLD activity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. 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. See the journal About page for additional terms.)

Ribosome profiling, which is based on deep sequencing of ribosome footprints, has served as a powerful tool for elucidating the regulatory mechanism of protein synthesis. However, the current method has substantial issues: contamination by rRNAs and the lack of appropriate methods to measure ribosome numbers in transcripts. Here, we overcome these hurdles through the development of "Ribo-FilterOut", which is based on the separation of footprints from ribosome subunits by ultrafiltration, and "Ribo-Calibration", which relies on external spike-ins of stoichiometrically defined mRNA-ribosome complexes. A combination of these approaches estimates the number of ribosomes on a transcript, the translation initiation rate, and the overall number of translation events before its decay, all in a genome-wide manner. Moreover, our method reveals the allocation of ribosomes under heat shock stress, during aging, and across cell types. Our strategy of modified ribosome profiling measures kinetic and stoichiometric parameters of cellular translation across the transcriptome., (© 2024. The Author(s).)

We visualize antiferromagnetic domains in a representative quasi-one-dimensional S=1/2 quantum antiferromagnet, BaCu&#95;{2}Si&#95;{2}O&#95;{7}, using nonreciprocal directional dichroism, which differentiates the optical absorption of a pair of antiferromagnetic domains. Opposite antiferromagnetic domains, each about submillimeter in size, are found to coexist in a single-crystal specimen, and the domain walls run predominantly along the spin chains. We also demonstrate that the domain walls can be moved by an applied electric field through a magnetoelectric coupling and that the direction of the domain walls is maintained during the motion. We explain the domain wall anisotropy by the quasi-one-dimensional nature of the exchange interactions. This Letter will contribute to the understanding of the domain physics of quasi-one-dimensional quantum antiferromagnets.

Objective: Distal radius fractures (DRFs) with dorsal malunion increase the risk of osteoarthritis (OA), although the cause of post-DRF OA is yet to be elucidated. To clarify the abnormal effects of a post-DRF dorsal radius deformity, we evaluated the bone density (BD) and stress-distribution patterns of the articular surface in dorsally malunited DRFs., Design: In 36 cases of dorsally malunited DRFs following extra-articular fractures, we generated three-dimensional computerized models of the malunited distal radius from computed tomography data and extracted the subchondral bones of the radiocarpal joint (RCJ) and distal radioulnar joint (DRUJ). Both BD and stress distribution in the subchondral bones were quantitatively evaluated by comparing the affected and normal sides. Correlations of alterations in high-BD distribution and deformation angles were analyzed., Results: The center of high-BD distribution from the center of the RCJ in the volar(-)-dorsal(+) direction was dorsal (0.56 ± 0.72 mm) on the affected side compared with the normal side (-0.15 ± 0.63 mm) [95% CI: 0.43, 1.00, P < 0.0001]. The maximum stress distribution was also dorsal on the affected side (2.34 ± 3.52 mm) compared with the normal side (-2.49 ± 1.62 mm) [95% CI: 0.89, 1.79, P < 0.0001]. The alterations in BD and stress distribution correlated with the dorsiflexion and radial deviation angles. In the DRUJ, there was no significant difference in BD between the affected and normal sides., Conclusions: In dorsally malunited DRFs, the alignment change of the RCJ resulted in high BD-concentration areas and stress distribution on the dorsal side of the radius, which may constitute a precursor for OA., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Nocturia is a common symptom of lower urinary tract syndrome (LUTS). In previous studies, a close association between LUTS and colorectal inflammation has been reported. However, evidence regarding the association between nighttime urinary frequency and ulcerative colitis (UC) is limited. Herein, we investigated the association between nighttime urinary frequency and clinical outcomes of UC., Methods: We surveyed 287 Japanese patients with UC. A self-administered questionnaire was used to collect the information on the variables studied. Patients were divided into three groups based on nighttime urinary frequency: (1) no voids, (2) one void, and (3) two or more voids. The assessment of clinical outcomes was based on mucosal healing (MH) and clinical remission (CR). The association between nighttime urinary frequency and prevalence of MH and CR was evaluated using multivariate logistic regression analyses., Results: The prevalence of one nighttime frequency and two or more nighttime frequency in this cohort was 35.5% and 26.8%, respectively. The percentage of MH and CR was 24.7% and 59.2%, respectively. Two or more nighttime frequency (adjusted odds ratio [OR]: 0.31, 95% confidence interval [CI]: 0.13-0.73) was independently and inversely associated with MH. In nonelderly patients (<70 years) and patients in CR, an association between two or more nighttime frequency and MH remained significant (non-elderly: adjusted OR: 0.27, 95% CI: 0.09-0.72 and only CR: adjusted OR: 0.34, 95% CI: 0.12-0.90)., Conclusion: Nighttime urinary frequency was independently and inversely associated with MH in Japanese patients with UC. Nighttime urinary frequency may serve as a complementary physical sign of MH in patients with UC., (© 2024 Wiley Periodicals LLC.)

Transcription factors (TFs) form homo- or hetero-dimeric DNA binding complexes along with associated co-regulators that can have transcriptional repressor or activator functions. Defining the specific composition of the complexes is therefore key to understanding their biological role. Here, we utilized bimolecular fluorescence complementation (BiFC) to visualize the formation of defined TF dimers and associated co-regulators derived from the activator protein-1 (AP-1) and myocyte enhancer factor 2 (MEF2) families. Firstly, BiFC signals were observed in cells co-expressing TFs tagged with complimentary combinations of the split fluorescent protein, demonstrating the engineered formation of defined dimer complexes. Next, we applied this approach and determined that defined AP-1 dimers localized at discrete sub-nuclear locations. Subsequently, a combination of BiFC coupled with GFP binding peptide (GBP)-nanotrap allowed observation of protein-protein interactions between a co-regulator, HDAC4, and defined BiFC-MEF2 engineered dimers. To determine transactivation properties of defined TF dimers in a cellular system, the Gal4-DNA binding domain fused to GBP was utilized to assess the transcriptional properties of the BiFC-TF dimers using a generically applicable Gal4/UAS luciferase reporter gene assay system. Here, we report efficacy of a BiFC/GBP-nanobody approach that allows engineering, visualization, and functional analysis of defined TF dimers., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A 49-year-old man underwent an open cholecystectomy for advanced gallbladder cancer in 2021. Three months after surgery, the patient underwent an additional resection, which showed no malignant findings, but 12 months after surgery, contrast-enhanced CT and MRI showed a new mass lesion in segment 8 of the liver, and the patient was diagnosed with postoperative hepatic metastatic recurrence of gallbladder cancer. After referral to our institution, he received 1 course of gemcitabine+cisplatin(GC)therapy and 8 courses of gemcitabine+cisplatin+durvalumab(GCD)therapy. Contrast- enhanced CT and MRI showed that the metastases had shrunk, and PET scan showed no FDG accumulation. Two months after completion of chemotherapy, there was no evidence of metastatic enlargement and new metastasis including distant metastasis, and the patient was referred to our department. Since curative resection was expected, a laparoscopic partial hepatectomy of segment 8 of the liver was performed. Pathological diagnosis revealed no residual tumor. If the metastases could be well controlled by systemic chemotherapy, hepatectomy for hepatic metastases of biliary tract cancer could be a treatment option.

Brentuximab vedotin (BV), a conjugate of anti-CD30 antibody and monomethyl auristatin E, has emerged as a promising treatment option for refractory CD30+ mycosis fungoides (MF) and primary cutaneous anaplastic large-cell lymphoma (pcALCL). BV has been shown to be safe and effective in treating Hodgkin's lymphoma and peripheral T-cell lymphoma. This multicenter, prospective, single-arm phase I/II study evaluated the efficacy of BV in Japanese patients with CD30+ cutaneous lymphomas, namely CD30+ cutaneous T-cell lymphoma. Participants were divided into two groups: those with CD30+ MF or pcALCL (cohort 1, n = 13) and those with CD30+ lymphoproliferative disorders other than those in cohort 1 (cohort 2, n = 3). The studied population included the full analysis set (FAS), modified FAS (mFAS), and safety analysis set (SAF). These sets were identified in cohorts 1 and 1 + 2 and labeled FAS1 and FAS2, mFAS1 and mFAS2, and SAF1 and SAF2, respectively. Each treatment cycle lasted 3 weeks, and BV was continued for up to 16 cycles after the third cycle based on treatment response. The primary endpoint was the 4-month objective response rate (ORR4) determined by the Independent Review Forum (IRF). ORR4 was 69.2% for FAS1 and 62.5% for FAS2 (P < 0.0001). Secondary endpoints of ORR, assessed using the global response score (53.8% in FAS1) and modified severity-weighted assessment tool (62.5% in FAS1), using the IRF, provided results comparable to the primary findings. The incidence of ≥grade 3 adverse events (≥15%) in SAF1 was peripheral neuropathy in three patients (23%) and fever and eosinophilia in two patients (15%). In conclusion, BV showed favorable efficacy, tolerability, and safety profile in Japanese patients with relapsed or refractory CD30+ primary cutaneous T-cell lymphoma. The trial was registered with University Hospital Medical Information Network Clinical Trials Registry, Japan (protocol ID: UMIN000034205)., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

TGF-β is an immunosuppressive cytokine and plays a key role in progression of cancer by inducing immunosuppression in tumor microenvironment. Therefore, inhibition of TGF-β signaling pathway may provide a potential therapeutic intervention in treating cancers. Herein, we report the discovery of a series of novel thiazole derivatives as potent inhibitors of ALK5, a serine-threonine kinase which is responsible for TGF-β signal transduction. Compound 29b was identified as a potent inhibitor of ALK5 with an IC 50 value of 3.7 nM with an excellent kinase selectivity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masaaki Sawa is a Chief Scientific Officer of Carna Biosciences, Inc. and owns stocks of Carna Biosciences, Inc. Kazuhito Naka receives research funding from Carna Biosciences, Inc. All the other authors were full time employees of Carna Biosciences, Inc. and have no competing/conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Three-dimensional (3D) capacity for remodelling in cubitus varus deformity (CVD) after paediatric supracondylar humeral fractures (PSHFs) remains unelucidated. This study investigated remodelling patterns after PSHFs by examining 3D deformity distribution over time after injury., Methods: Computed tomography (CT) data of 86 patients with CVD after PSHFs were analysed. The 3D deformity angles in the sagittal, coronal, and axial directions were assessed and correlated with the duration between the age at injury and CT evaluation. For the subgroup analysis, we performed the same correlation analysis in a younger (< 8 years old) and an older group (≥ 8 years old); we categorized the duration into early (< 2 years), middle (≥ 2 to < 5 years), and late periods (≥ 5 years) and compared the deformity angles of each direction among the three groups., Results: Sagittal deformity showed a moderate correlation with the duration of deformity (r = -0.54; P < 0.001), while coronal and axial deformities showed a negligible correlation. Sagittal deformity showed moderate correlations with the duration in the younger group (r = -0.62; P < 0.001) and weak correlations in the older group (r = -0.37; P = 0.091). In the sagittal direction, the deformity angle in the early period was significantly larger than those in the mid and late periods (P < 0.001). However, there were no significant differences among the three groups in the coronal and axial directions., Conclusion: Sagittal deformities in CVDs are capable of remodelling, especially in the early period and at a younger age, whereas coronal and axial deformities are less likely to undergo remodelling., (© 2024. The Author(s).)

Systemic sclerosis (SSc) is a collagen disease with immune abnormalities, vasculopathy, and fibrosis. Ca blockers and prostaglandins are used to treat peripheral circulatory disturbances. Chronic limb-threatening ischemia (CLTI) is a disease characterized by extremity ulcers, necrosis, and pain due to limb ischemia. Since only a few patients present with coexistence of CLTI and SSc, the treatment outcomes of revascularization in these cases are unknown. In this study, we evaluated the clinical characteristics and treatment outcomes of seven patients with CLTI and SSc, and 35 patients with uncomplicated CLTI who were hospitalized from 2012 to 2022. A higher proportion of patients with uncomplicated CLTI had diabetes and male. There were no significant differences in the age at which ischemic ulceration occurred, other comorbidities, or in treatments, including antimicrobial agents, revascularization and amputation, improvement of pain, and the survival time from ulcer onset between the two subgroups. EVT or amputation was performed in six or two of the seven patients with CLTI and SSc, respectively. Among those who underwent EVT, 33% (2/6) achieved epithelialization and 67% (4/6) experienced pain relief. These results suggest that the revascularization in cases with CLTI and SSc should consider factors such as infection and general condition, since revascularization improve the pain of these patients., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Sodium ions and protons regulate various fundamental processes at the cell and tissue levels across all biological kingdoms. It is therefore pivotal for bioelectronic devices, such as biosensors and biotransducers, to control the transport of these ions through biological membranes. Our study explores the regulation of proton and sodium concentrations by integrating an Na + -type ATP synthase, a glucose dehydrogenase (GDH), and a urease into a multienzyme logic system. This system is designed to operate using various chemical control input signals, while the output current corresponds to the local change in proton or sodium concentrations. Therein, a H + and Na + biotransducer was integrated to fulfill the roles of signal transducers for the monitoring and simultaneous control of Na + and H + levels, respectively. To increase the proton concentration at the output, we utilized GDH driven by the inputs of glucose and nicotinamide adenine dinucleotide (NAD + ), while recorded the signal change from the biotransducer, together acting as an AND enzyme logic gate. On the contrary, we introduced urease enzyme which hydrolyzed urea to control the decrease in proton concentration, serving as a NOT gate and reset. By integrating these two enzyme logic gates we formed a simple multienzyme logic system for the control of proton concentrations. Furthermore, we also demonstrate a more complex, Na + -type ATP synthase-urease multienzyme logic system, controlled by the two different inputs of ADP and urea. By monitoring the voltage of the peak current as the output signal, this logic system acts as an AND enzyme logic gate. This study explores how multienzyme logic systems can modulate biologically important ion concentrations, opening the door toward advanced biological on-demand control of a variety of bioelectronic enzyme-based devices, such as biosensors and biotransducers.

Aim: Senescent cells, inducing a senescence-associated secretory phenotype (SASP), lead to chronic inflammation in hard-to-heal wound tissue. However, eliminating senescent cells may impede normal wound healing due to their important role in the wound healing mechanism. Accordingly, we focused on wound exudates in hard-to-heal wounds, which contain many inflammation biomarkers consistent with SASP. Therefore, we hypothesized that senescent cells might be present in the exudates and induce chronic inflammation. This study investigated the relationship between gene expression associated with cellular senescence in exudates from pressure injuries and wound healing status., Methods: This retrospective cohort study involved patients treated by a pressure injury team. We collected viable cells from wound dressings and analyzed gene expression. Pearson's correlation coefficient was calculated between cellular senescence and SASP expression. The relationship between the gene expression of cellular senescence and the wound area reduction rate by the following week was examined using a mixed-effects model., Results: CDKN1A-related to cellular senescence-was expressed in 96.3 % of 54 samples, and CDKN1A expression and SASPs positively correlated (PLAU: r = 0.68 and TNF: r = 0.34). Low CDKN1A expression was statistically associated with a large wound area reduction rate (β = 0.83, p < 0.01)., Conclusions: Gene expression of both cellular senescence and SASP factor in wound dressings suggests the presence of cellular senescence. Senescent cells in wound dressings could be associated with delayed wound healing in the following week., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Compartment syndrome commonly occurs in patients with forearm and lower leg fractures. Compartment syndromes of the gluteal and thigh muscles are less common. It is imperative that compartment syndrome be diagnosed and treated with fasciotomy as soon as possible. However, there are few reports on the diagnosis and treatment strategies for compartment syndromes that occur simultaneously in multiple anatomical regions or in the ipsilateral gluteal region and thigh., Case Presentation: We report on a 76-year-old man who was obliquely crushed under a tree extending from the right forearm to the left groin. He was brought to our emergency room, where he was diagnosed with compartment syndrome of the right forearm and left lower leg and crush syndrome. Emergency fasciotomy was performed. On the day after admission, swelling and tightness of the left gluteal thigh became apparent, and intracompartmental pressures were elevated, which led to an additional diagnosis of these compartment syndromes. A fasciotomy was performed, the gluteal skin incision was made according to the Kocher-Langenbeck approach (one of the posterior approaches for hip fractures), and the thigh was approached by extending the incision laterally. This surgical approach enabled the decompression of the compartments through a single incision and allowed for easier wound treatment and closure., Conclusion: This case highlights the diagnosis and treatment of compartment syndrome in four anatomical regions. Extension of the Kocher-Langenbeck approach to the lateral thigh can be a useful surgical approach for ipsilateral gluteal and thigh compartment syndrome., (© 2024. The Author(s).)

Purpose: Prophylactic drains reported to be useful to treat postoperative bile leakage (POBL) and reduce re-intervention after hepatectomy. However, prophylactic drains should remove in the early postoperative period. This study aimed to assess the association between postoperative complications and the drain-fluid data on postoperative day (POD) 1., Methods: Medical records of 530 patients who underwent hepatectomy were retrospectively reviewed. We evaluated the drain-fluid data on POD 1, such as bilirubin (BIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and drain discharge volume. These variables were compared between patients with and without postoperative complications such as POBL and abdominal abscess not due to POBL., Results: POBL was found in 44 patients (8.3%), PHLF was in 51 patients (9.6%), and abdominal abscess not due to POBL was in 21 patients (4.0%). Regarding POBL, drain-fluid BIL concentration and drain discharge volume was higher in the POBL group (p < 0.001 and p < 0.001, respectively). However, drain-fluid AST, ALT, and ALP concentrations were not different between two groups. As to the abdominal abscess not due to POBL, all drain-fluid data were not significantly different. Multivariate analysis for predicting POBL showed that the drain-fluid BIL concentration ≥ 2.68 mg/dL was an independent predictor (p < 0.001). In the subgroup analyses according to the type of hepatectomy, the drain-fluid BIL concentration was an independent predictor for POBL after both non-anatomical and anatomical hepatectomy., Conclusion: The drain-fluid BIL concentration on POD 1 is useful in predicting POBL after hepatectomy., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although viruses subvert innate immune pathways for their replication, there is evidence they can also co-opt anti-viral responses for their benefit. The ubiquitous human pathogen, Herpes Simplex Virus-1 (HSV-1), encodes a protein (UL12.5) that induces the release of mitochondrial nucleic acid into the cytosol, which activates immune sensing pathways and reduces productive replication in non-neuronal cells. HSV-1 establishes latency in neurons and can reactivate to cause disease. We found that UL12.5 is required for HSV-1 reactivation in neurons and acts to directly promote viral lytic gene expression during initial exit from latency. Further, the direct activation of innate immune sensing pathways triggered HSV reactivation and compensated for a lack of UL12.5. Finally, we found that the induction of HSV-1 lytic genes during reactivation required intact RNA and DNA sensing pathways, demonstrating that HSV-1 can both respond to and active antiviral nucleic acid sensing pathways to reactivate from a latent infection.

The complete loss of finger extension leads to significant inconvenience in daily life and often requires surgical treatment. Despite some disadvantages, the Boyes method, which uses the flexor digitorum superficialis tendon, is commonly performed for complete extensor rupture. We report the case of a 73-year-old woman living alone diagnosed with a subcutaneous rupture of all extensor tendons from the index to the little finger. The favourable range of motion of her wrist allowed us to perform extensor tenodesis. Additionally, the patient had a dislocated thumb interphalangeal (IP) joint, enabling us to use the extensor pollicis longus tendon for tendon transfer in combination with thumb IP joint fusion. The patient demonstrated favourable finger range-of-motion outcomes at the 6-month postoperative assessment. The case shows that extensor pollicis longus tendon transfer and tenodesis may be a viable treatment option for patients with complete extensor rupture accompanied by thumb IP joint deformity and normal wrist range of motion., (© Japan College of Rheumatology 2024. Published by Oxford University Press. 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.)

Mixed reality (MR) technologies have a high potential to enhance obstacle negotiation training beyond the capabilities of existing physical systems. Despite such potential, the feasibility of using MR for obstacle negotiation on typical training treadmill systems and its effects on obstacle negotiation performance remains largely unknown. This research bridges this gap by developing an MR obstacle negotiation training system deployed on a treadmill, and implementing two MR systems with a video see-through (VST) and an optical see-through (OST) Head Mounted Displays (HMDs). We investigated the obstacle negotiation performance with virtual and real obstacles. The main outcomes show that the VST MR system significantly changed the parameters of the leading foot in cases of Box obstacle (approximately 22 cm to 30 cm for stepping over 7cm-box), which we believe was mainly attributed to the latency difference between the HMDs. In the condition of OST MR HMD, users tended to not lift their trailing foot for virtual obstacles (approximately 30 cm to 25 cm for stepping over 7cm-box). Our findings indicate that the low-latency visual contact with the world and the user's body is a critical factor for visuo-motor integration to elicit obstacle negotiation.

Background and Aim: Recently, noninvasive fecal markers have been used as indicators of intestinal inflammation in patients with inflammatory bowel disease (IBD). We conducted a clinical validation study to measure fecal calprotectin (Cp), lactoferrin (Lf), and hemoglobin (Hb) levels using an all-in-one kit in patients with IBD and colorectal tumors and aimed to clarify the utility of these fecal markers., Methods: In this study, 104 patients were analyzed, including 25 patients with ulcerative colitis (UC), 20 with Crohn's disease (CD), 48 with colorectal tumors, and 13 healthy controls (HC). Of the 48 patients with colorectal tumors, 14 had invasive cancer. We validated the utility of fecal Cp, Lf, and Hb levels by simultaneously measuring fecal markers in patients with IBD and colorectal tumors., Results: Fecal Cp and Lf had almost equivalent abilities in detecting clinical remission in patients with UC; however, fecal Cp was slightly superior to Lf. Regarding colorectal tumors, fecal Cp and Lf levels tended to be higher in patients with adenomas and colorectal cancer than in HCs. Although fecal Hb alone had the best sensitivity and specificity for detecting colorectal cancer, it had relatively low sensitivity for detecting advanced neoplasms and colorectal cancer., Conclusion: Fecal Cp and Lf can be used as almost equivalent biomarkers to assess the clinical activity in patients with UC. Fecal Hb is the most useful marker for screening colorectal cancer; however, adding fecal Cp and Lf may compensate for the low sensitivity of detecting for advanced colorectal tumors based on Hb alone., (© 2024 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Sclerosing mesenteritis (SM) is a rare disorder that involves the mesenteric adipose tissue with chronic fibrosing inflammation. Few reports mention the natural history of severe SM cases. Here, we report a severe and relapsing SM case in which a long-term natural history could be followed. The patient had undergone surgery for small bowel stenosis of unknown cause 10 years earlier. He had stopped visiting the hospital at his discretion. He was admitted to the hospital 10 years later due to recurrent symptoms, and a close examination revealed multiple small intestinal strictures; thus, surgery was performed again. The pathological results revealed that the patient had SM, corticosteroid administration dramatically improved his symptoms, and he has maintained remission for a long time., (© 2024. Japanese Society of Gastroenterology.)

In contrast to intracellular gene transfer, the direct delivery of expressed proteins is a significantly challenging yet essential technique for elucidating cellular functions, including protein complex structure, liquid-liquid phase separation, therapeutic applications, and reprogramming. In this study, we developed a hybrid nanotube (HyNT) stamp system that physically inserts the HyNTs into adhesive cells, enabling the injection of target molecules through HyNT ducts. This system demonstrates the capability to deliver multiple proteins, such as lactate oxidase (LOx) and ubiquitin (UQ), to approximately 1.8 × 10 7 adhesive cells with a delivery efficiency of 89.9% and a viability of 97.1%. The delivery of LOx enzyme into HeLa cancer cells induced cell death, while enzyme-delivered healthy cells remained viable. Furthermore, our stamp system can deliver an isotope-labeled UQ into adhesive cells for detection by nuclear magnetic resonance (NMR).

The success rate of flap tissue reconstruction has increased in recent years owing to advancements in microsurgical techniques. However, complications, such as necrosis, are still more prevalent in diabetic patients compared to non-diabetic individuals, presenting an ongoing challenge. To address this issue, many previous studies have examined vascular anastomoses dilation and stability, primarily concerning surgical techniques or drugs. In contrast, in the present study, we focused on microvascular damage of the peripheral microvessels in patients with diabetes mellitus and the preventative impact of nafamostat mesylate. Herein, we aimed to investigate the effects of hyperglycemia on glycocalyx (GCX) levels in mice with type 2 diabetes. We examined the endothelial GCX (eGCX) in skin flap tissue of 9-12-week-old type 2 diabetic mice (db/db mice) using a perforator skin flap and explored treatment with nafamostat mesylate. The growth rates were compared after 1 week. Heterotype (db/+) mice were used as the control group. Morphological examination of postoperative tissues was performed at 1, 3, 5, and 7 days post-surgery. In addition, db/db mice were treated with 30 mg/kg/day of nafamostat mesylate daily and were evaluated on postoperative day 7. Seven days after surgery, all db/db mice showed significant partial flap necrosis. Temporal observation of the skin flaps revealed a stasis-like discoloration and necrosis starting from the contralateral side of the remaining perforating branch. The control group did not exhibit flap necrosis, and the flap remained intact. In the quantitative assessment of endothelial glycans using lectins, intensity scoring showed that the eGCX in the db/db group was significantly thinner than that in the db/+ group. These results were consistent with the scanning electron microscopy findings. In contrast, treatment with nafamostat mesylate significantly improved the flap engraftment rate and suppressed eGCX injury. In conclusion, treatment with nafamostat mesylate improves the disrupted eGCX structure of skin flap tissue in db/db mice, potentially ameliorating the impaired capillary-to-venous return in the skin flap tissue., 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.)

Objectives: To assess embryonic genital tubercle using transvaginal three-dimensional (3D) ultrasound at 8-10+6 weeks of gestation., Methods: One-hundred and two transvaginal 3D ultrasound scans were performed for first-trimester dating at 8-10+6 weeks of gestation. The genital tubercle angle (GTA) and genital tubercle length (GTL) were measured with a mid-sagittal view of the embryo using the 3D ultrasound multiplanar mode. Intra- and inter-observer agreements regarding GTA and GTL were also assessed with Bland-Altman plots and intra- and inter-correlation coefficients., Results: There were no significant differences in GTA between male and female embryos at 8, 9, 10 weeks, or 8-10+6 weeks of gestation, respectively. There were also no significant differences in GTL between male and female embryos at 8, 9, 10 weeks, or 8-10+6 weeks of gestation, respectively. However, GTL increased linearly with advancing gestation (r=0.8276, p<0.00001). Mean GTL (SD) values at 8, 9, and 10 weeks were 0.833 mm (0.274), 1.623 mm (0.262), and 2.152 mm (0.420), respectively (p<0.001). Intra- and inter-reproducibilities of GTA and GTL were excellent. The intra- and inter-correlation coefficients of GTA and GTL were 0.964 and 0.995, and 0.996 and 0.9933, respectively., Conclusions: The genital tubercle could be identified using transvaginal 3D ultrasound at 8-10+6 weeks of gestation. However, sex differentiation could not be performed at this age. The genital tubercle linearly developed with advancing gestation during the mid-first trimester of pregnancy., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

We herein report a case in which diazoxide was effective in treating reactive hypoglycemia caused by late dumping syndrome in a patient with end-stage renal disease (ESRD). A 50-year-old man with ESRD and a history of gastrectomy underwent hemodialysis. Although he was administered voglibose to treat recurrent reactive hypoglycemia caused by late dumping syndrome, he had difficulty continuing treatment because of gastrointestinal side effects. When he began diazoxide treatment, the reactive hypoglycemia improved. The dose was gradually increased with no apparent side effects, and the hypoglycemic attacks disappeared one year after the start of treatment.

Background: The rectal and vaginal walls are typically sutured if severe perineal lacerations with rectal mucosal damage occur during vaginal delivery. In case of anal incontinence after the repair, re-suturing of the anal sphincter muscle is standard procedure. However, this procedure may not result in sufficient improvement of function., Case Presentation: A 41-year-old woman underwent suture repair of the vaginal and rectal walls for fourth-degree perineal laceration at delivery. She was referred to our department after complaining of flatus and fecal incontinence. Her Wexner score was 15 points. Examination revealed decreased anal tonus and weak contractions on the ventral side. We diagnosed anal incontinence due to sphincter dysfunction after repair of a perineal laceration at delivery. We subsequently performed sphincter re-suturing with perineoplasty to restructure the perineal body by suturing the fascia located lateral to the perineal body and running in a ventral-dorsal direction, which filled the space between the anus and vagina and increased anal tonus. One month after surgery, the symptoms of anal incontinence disappeared (the Wexner score lowered to 0 points), and the anorectal manometry values increased compared to the preoperative values. According to recent reports on the anatomy of the female perineal region, bulbospongiosus muscle in women does not move toward the midline to attach to the perineal body, as has been previously believed. Instead, it attaches to the ipsilateral surface of the external anal sphincter. We consider the fascia lateral to the perineal body to be the fascia of the bulbospongiosus muscle., Conclusions: In a case of postpartum anal incontinence due to sphincter dysfunction after repair of severe perineal laceration, perineoplasty with re-suturing an anal sphincter muscle resulted in improvement in anal sphincter function. Compared to conventional simple suture repair of the rectal wall only, this surgical technique may improve sphincter function to a greater degree., (© 2024. The Author(s).)

Background: Training physiotherapists require substantial experience and a lengthy period of time to achieve proficiency. However, establishing an objective method for quantifying the degree of force applied during treatment remains elusive, making training difficult., Objectives: This study aims to clarify the difference in the degree of force application between novice and expert physiotherapists using muscle deformation sensors and to assist in teaching., Methods: A muscle deformation sensor array was utilized to capture the muscle bulging (muscle deformation), and the degree of force was visualized. The experiment involved two types of physiotherapy: upper and lower extremity exercises. Subsequently, the muscle deformation value and standard deviations of the muscle deformation data obtained were compared., Results: Significant differences between novices and experts were observed in forearm muscle deformation values and standard deviations across both types of physiotherapies (p<0.05). Additionally, a distinction was observed in the left lower limb flexor muscles during upper extremity exercise (p<0.05)., Conclusion: The results of this survey showed notable differences in the degree of force application between novices and experts, as demonstrated by our findings. Moreover, these implications extend beyond physiotherapy to sports, hobbies, and the teaching of traditional skills., Competing Interests: Patents in muscle deformation sensors (FirstVR), (Copyright © 2024, Shimabukuro et al.)

For the study of biological effects of direct current (DC) and extremely low frequency (ELF) electric fields, we have quantitatively analyzed red blood cell (RBC) movement in whole blood. Considering the inhomogeneous distribution of electric fields in vivo, five different electric field distributions were generated under a microscope. For theoretical analyses, we assumed electrophoresis and dielectrophoresis as basic motive forces and obtained the spatial distribution of blood cell velocity. The RBC velocity was measured using video image analysis. The spatial dependence of the velocity showed good agreement with that predicted by theoretical analysis. This result suggests the validity of the theoretical model based on electrophoresis and dielectrophoresis for the study of ELF electric field exposure to inhomogeneous animal and human bodies. Next, using the same measurement system, we attempted to find the electric field strength at which these effects occur. The threshold values were found to be 0.40 and 1.6 kV/m, respectively, for DC and AC electric field exposures. Furthermore, we investigated the reproducibility of the field effects in more realistic conditions of human exposure. The RBCs in microchannels were exposed to the electric field generated in capacitive coupling using electrodes separated by an air gap. Even in the new condition, similar effects were observed, which also verified the validity of the analysis described above. These results will provide useful information for the safety assessment of field exposure and for the future biomedical applications of electric fields to manipulate RBCs in vivo., (© 2023 The Authors. Bioelectromagnetics published by Wiley Periodicals LLC on behalf of Bioelectromagnetics Society.)

We performed a literature search to identify the details of patients with right ventricular outflow tract obstruction caused by an aneurysm of the ventricular membranous septum in a perimembranous ventricular septal defect. Thirty-one cases with a median age of 29 years (range, 1-69 years) were studied. A right ventricle-pulmonary artery systolic pressure gradient ranged from 35 to 107 mm Hg (mean 69 mm Hg). An interventricular shunt was absent in eight patients: two children and six adults. It is necessary to monitor the size of an aneurysm of the ventricular membranous septum, whether or not an interventricular shunt is present., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Socioeconomic status is a risk factor for poor disease prognosis. No studies of patients with ulcerative colitis (UC) have investigated the association between socioeconomic status and erectile dysfunction (ED), although UC is independently positively associated with ED. Therefore, the purpose of this survey to evaluate this issue in Japanese patients with UC. The study enrolled 165 patients with UC. Education status (low, middle, high) and household income (low, middle, high) were classified in three groups using self-administered surveys. The information regarding the Sexual Health Inventory for Men (SHIM) was obtained using self-administered questionnaires. The definition of mild to moderate or severe ED and severe ED was SHIM score <17 and SHIM score <8, respectively. The prevalence of mild to moderate or severe ED and severe ED was 64.9% and 47.9%, respectively. In crude analysis, household income was inversely associated with mild to moderate or severe ED and severe ED. After adjustment for age, current drinking, current smoking, exercise habit, body mass index, mucosal healing, and duration of UC, high household income was independently and inversely associated with mild to moderate or severe ED (adjusted odds ratio [OR] 0.23, 95% confidence interval [CI] [0.05, 0.93], p for trend = .038) and severe ED (adjusted OR 0.26, 95% CI [0.07, 0.85], p for trend = .024). In contrast, no association between education status and ED was found. In conclusion, household income was independently and inversely associated with ED in Japanese UC patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Although fetal growth restriction (FGR) is associated with an increased risk of cesarean delivery during induced labor, there is limited evidence to guide labor management. This study aimed to investigate the prognosis of induced labor in pregnancies with suspected FGR and whether oxytocin discontinuation during the active phase of labor affects maternal and neonatal outcomes., Study Design: This retrospective cohort study investigated singleton pregnancies with vertex presentation and indications for labor induction owing to FGR after 34.0 weeks of gestation at Osaka University Hospital. From January 2010 to December 2013, women were conventionally managed, and oxytocin was continued until delivery unless there was an indication for discontinuation (conventional management group). From January 2013 to December 2020, oxytocin was routinely discontinued, or the dose was reduced at the beginning of the active phase of labor (oxytocin discontinuation group)., Results: A total of 161 women (conventional management group, n  = 74; oxytocin discontinuation group, n  = 87) were included. After the active phase of induced labor, the total incidence of cesarean delivery was very low (3.1%), and the duration was short (173 ± 145 minutes). Oxytocin discontinuation was associated with lower cesarean delivery (1.1 vs. 5.4%; p  = 0.12) and uterine tachysystole (9.8 vs. 23.0%; p  = 0.08) rates and longer duration of the second stage of labor (mean: 56.5 ± 90 vs. 34.2 ± 45 minutes; p  = 0.08) than conventional management; however, the difference was not significant. The other maternal and neonatal outcomes, including postpartum hemorrhage, did not also significantly differ between them., Conclusion: After the active phase of induced labor for suspected FGR, the risk of cesarean delivery is low, and the high incidence of uterine tachysystole and rapid labor progression should be considered cautiously. Oxytocin can be safely discontinued during the active phase of labor in women undergoing labor induction for FGR without an increased risk of cesarean delivery or other unfavorable outcomes., Key Points: · The cesarean delivery rate was low after the active phase.. · The labor progress after the active phase was rapid.. · Oxytocin can be safely discontinued during the active phase.., Competing Interests: None declared., (Thieme. All rights reserved.)

Backgruound: Poor lifestyle habits may worsen nonalcoholic fatty liver disease (NAFLD), with progression to nonalcoholic steatohepatitis (NASH) and cirrhosis. This study investigated the association between glycemic control status and hepatic histological findings to elucidate the effect of glycemic control on NAFLD., Methods: This observational study included 331 patients diagnosed with NAFLD by liver biopsy. Effects of the glycemic control status on histological findings of NAFLD were evaluated by comparing the following four glycemic status groups defined by the glycosylated hemoglobin (HbA1c) level at the time of NAFLD diagnosis: ≤5.4%, 5.5%-6.4%, 6.5%-7.4%, and ≥7.5%., Results: Compared with the lowest HbA1c group (≤5.4%), the higher HbA1c groups (5.5%-6.4%, 6.5%-7.4%, and ≥7.5%) were associated with advanced liver fibrosis and high NAFLD activity score (NAS). On multivariate analysis, an HbA1c level of 6.5%- 7.4% group was significantly associated with advanced fibrosis compared with the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index and uric acid, total cholesterol, and triglyceride levels, the higher HbA1c groups were significantly associated with advanced fibrosis compared with the lowest HbA1c group. On the other hand, compared with the lowest HbA1c group, the higher HbA1c groups were also associated with a high NAS in both multivariate analyses., Conclusion: Glycemic control is associated with NAFLD exacerbation, with even a mild deterioration in glycemic control, especially a HbA1c level of 6.5%-7.4%, contributing to NAFLD progression.

Background/aims: Although certain allergic diseases have been reported to be associated with the prevalence of functional dyspepsia (FD) and irritable bowel syndrome (IBS), it is unclear whether the presence of multiple allergic diseases further increases the prevalence of FD and IBS. The aim of this study is to determine this issue in young people., Methods: A cohort of 8923 Japanese university students was enrolled and diagnoses of FD and IBS were confirmed using Rome III criteria. Allergic disorders diagnosed at medical institutions were obtained by means of a self-administered questionnaire., Results: The prevalence of FD, IBS, and their overlap was found to be 1.9%, 6.5%, and 1.1%, respectively. Pollen allergy was independently positively correlated with FD, IBS, and overlap of FD and IBS. Allergic rhinitis was positively linked to IBS. Drug allergy was positively associated with FD. The presence of multiple allergic diseases was positively correlated with FD and IBS (FD: adjusted OR for 2 allergic diseases: 1.95 [95% CI, 1.24-2.98], P for trend = 0.003; and IBS: adjusted OR for 1 allergic disease: 1.40 [95% CI, 1.15-1.69], 2 allergic diseases 1.47 [95% CI, 1.12-1.91], and 3 or more allergic diseases: 2.22 [95% CI, 1.45-3.28], P for trend = 0.001). Additionally, the concomitant existence of multiple allergic diseases was also demonstrated to have a trend that correlated with the overlap of FD and IBS ( P for trend = 0.018)., Conclusion: Allergic disease multimorbidity is positively correlated with the prevalence of FD and IBS in a young population.

Aim: Advanced fibrosis has a strong influence on the occurrence of liver-related events in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), while diabetes mellitus (DM), which is often complicated by MASLD, is associated with the progression of MASLD. We stratified patients with MASLD according to the severity of liver pathological findings and the presence of DM, aiming to examine whether these indices could be used to accurately assess the risk of developing liver-related events., Methods: A total of 282 patients with liver biopsy-proven MASLD were included. Liver-related events were defined as the occurrence of hepatocellular carcinoma (HCC) and complications of liver cirrhosis, such as ascites, hepatic encephalopathy, Child-Pugh class B and C, as well as treatment-eligible esophageal and gastric varices., Results: Multivariate analysis adjusted for age, sex, body mass index, alanine aminotransferase, creatinine, hemoglobin A1c, smoking habits, dyslipidemia, hypertension, nonalcoholic fatty liver disease activity score (NAS), or fibrosis stage showed that advanced fibrosis with or without DM was a risk factor for liver-related events. The combined effect of DM and advanced fibrosis increased the risk of HCC onset. However, DM alone or in combination with NAS did not affect the development of liver-related events, including the occurrence of HCC and complications of liver cirrhosis., Conclusions: While the assessment of fibrosis in patients with MASLD is important for evaluating the risk of developing liver-related events, combining the assessment of DM may be possible to stratify groups at higher risk of developing HCC., (© 2024 Japan Society of Hepatology.)

Background: Left ventricular (LV) decompression is an essential strategy for improving early survival in patients with refractory cardiogenic shock. Low pump flow in patients on extracorporeal life support (ECLS) with LV apex decompression is a life-threatening issue. However, identifying the underlying causes of low flow can be challenging., Case Presentation: A 38-year-old woman with COVID-19-related fulminant myocarditis was treated with central ECLS with LV apex decompression. The pump flow in the intensive care unit (ICU) was intermittently low, and low flow alerts were frequent. The initial evaluation based on pressure monitor waveforms and transthoracic echocardiography failed to identify the underlying cause. Prompt bedside transesophageal echocardiography (TEE) revealed that the anterolateral papillary muscle was suctioned into the vent cannula of the LV apex during systole. The patient underwent a repeat sternal midline incision in the operating room, and the cannula at the LV apex was repositioned. There were no further suction events after the repositioning, and the patient was weaned from ECLS 12 days after admission to the ICU. The patient was discharged in a stable condition and without neurological deficits., Conclusions: TEE is an important diagnostic tool to identify the underlying cause of low flow flow in patients undergoing ECLS with LV apex decompression., (© 2024. The Author(s).)

The association between ulcerative colitis (UC) and erectile dysfunction (ED) has been previously reported. Numerous previous studies have also reported an association between gastrointestinal symptoms and ED. Constipation and diarrhea are common in patients with UC. However, the specific association between bowel movement frequency and ED remains unclear. The aim of this study is to investigate the association between bowel movement frequency and ED in 164 patients with UC. The definition of ED, moderate to severe ED, and severe ED was the Sexual Health Inventory for Men score <22, <12, and <8, respectively. Bowel movement frequency was divided into three categories: (1) high (More than once a day), (2) normal (once a day, reference), and low (less than one time/day). The definition of constipation was based on the Rome I criteria and/or medication for constipation. The prevalence of constipation and ED was 10.4% and 86.0%, respectively. The rate of high, normal, and low bowel movement frequency was 56.1%, 25.0%, and 18.9%, respectively. High bowel movement frequency was independently and positively associated with ED and moderate to severe ED (ED: adjusted odds ratio [OR] 4.42, 95% confidence interval [CI] 1.35-15.98; moderate to severe: adjusted OR 2.98, 95% CI 1.22-7.61). Low bowel movement frequency was independently and positively associated with moderate to severe ED and severe ED (moderate to severe: adjusted OR 3.96, 95% CI 1.27-13.08; severe: adjusted OR 3.20, 95% CI 1.08-9.86). No association between constipation and ED was found. In conclusion, in Japanese patients with UC, both high and low bowel movement frequency were independently and positively associated with ED., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Bone metastasis significantly affects the quality of life of patients with metastatic breast cancer, and can shorten overall survival. Identifying patients with early-stage breast cancer at high risk for bone metastasis and preventing bone metastasis may lead to a better quality of life and prolonged survival. The present study investigated whether serum tartrate-resistant acid phosphatase-5b (TRACP-5b), a bone turnover marker, can be a prognostic factor for bone metastasis. Female patients who underwent resectable breast surgery between May 2002 and August 2006 were consecutively investigated. A total of 304 patients with a median follow-up of 3,722 days were retrospectively analyzed. TRACP-5b levels in sera prepared from patients' blood drawn preoperatively without any presurgical treatments were measured using an enzyme-linked immunosorbent assay. The cutoff of TRACP-5b levels, in order to separate patients into high and low TRACP-5b groups, was set at median (347 mU/dl). The associations of clinicopathological factors, including TRACP-5b, with bone metastasis-free interval (BMFI), which was defined as the duration between surgery and the diagnosis of bone metastasis at any time point, were examined. Multivariate analysis of various clinicopathological features revealed that lymph node metastasis and histological grade were independent factors associated with BMFI (P=0.017 and 0.030, respectively). In patients with node-positive breast cancer (n=114), a high TRACP-5b level and a high grade were significantly and independently associated with worse BMFI (log-rank P=0.041 and 0.011, respectively). In conclusion, these findings indicated that TRACP-5b may predict bone metastasis in patients with node-positive breast cancer., Competing Interests: Nittobo Co., Ltd. funded TRACP-5b measurements for 111 out of 320 samples. MS and KS are conducting joint research unrelated to this study with Nittobo Co., Ltd. The other authors have no potential conflicts of interest., (Copyright: © 2024 Shimoda et al.)

Background and Purpose: Fraction metabolized (f m ) and fraction transported (f t ) are important for understanding drug-drug interactions (DDIs) in drug discovery and development. However, current in vitro systems cannot accurately estimate in vivo f m due to inability to reflect the f t by efflux transporters (f t,efflux ). This study demonstrates how CYP3A-mediated DDI for CYP3A/P-gp substrates can be predicted using Hu-PXB mice as human liver chimeric mice., Experimental Approach: For estimating human in vitro f m by CYP3A enzyme (f m,CYP3A,in vitro ), six drugs, including CYP3A/P-gp substrates (alprazolam, cyclosporine, docetaxel, midazolam, prednisolone, and theophylline) and human hepatocytes were incubated with or without ketoconazole as a CYP3A inhibitor. We calculated f m,CYP3A,in vitro based on hepatic intrinsic clearance. To estimate human in vivo f m,CYP3A (f m,CYP3A,in vivo ), we collected information on clinical DDI caused by ketoconazole for these six drugs. We calculated f m,CYP3A,in vivo using the change of total clearance (CL total ). For evaluating the human DDI predictability, the six drugs were administered intravenously to Hu-PXB and SCID mice with or without ketoconazole. We calculated the change of CL total caused by ketoconazole. We compared the CL total change in humans with that in Hu-PXB and SCID mice., Key Results: The f m,CYP3A,in vitro was overestimated compared to the f m,CYP3A,in vivo . Hu-PXB mice showed much better correlation in the change of CL total with humans (R 2  = 0.95) compared to SCID mice (R 2  = 0.0058)., Conclusions and Implications: CYP3A-mediated DDI can be predicted by correctly estimating human f m,CYP3A,in vivo using Hu-PXB mice. These mice could be useful predicting hepatic f m and f t,efflux ., (© 2023 British Pharmacological Society.)

This study aimed to reproduce and analyse the in vivo dynamic rotational motion of the forearm and to clarify forearm motion involvement and the anatomical function of the interosseous membrane (IOM). The dynamic forearm rotational motion of the radius and ulna was analysed in vivo using a novel image-matching method based on fluoroscopic and computed tomography images for intensity-based biplane two-dimensional-three-dimensional registration. Twenty upper limbs from 10 healthy volunteers were included in this study. The mean range of forearm rotation was 150 ± 26° for dominant hands and 151 ± 18° for non-dominant hands, with no significant difference observed between the two. The radius was most proximal to the maximum pronation relative to the ulna, moved distally toward 60% of the rotation range from maximum pronation, and again proximally toward supination. The mean axial translation of the radius relative to the ulna during forearm rotation was 1.8 ± 0.8 and 1.8 ± 0.9 mm for dominant and non-dominant hands, respectively. The lengths of the IOM components, excluding the central band (CB), changed rotation. The transverse CB length was maximal at approximately 50% of the rotation range from maximum pronation. Summarily, this study describes a detailed method for evaluating in vivo dynamic forearm motion and provides valuable insights into forearm kinematics and IOM function., (© 2024. The Author(s).)

Purpose: Breast cancer tumors frequently have intratumoral heterogeneity (ITH). Tumors with high ITH cause therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to a poor prognosis for HER2-targeted adjuvant therapy resistance in primary breast cancers., Methods: This study included patients with primary breast cancer ( n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with the HER2 gene copy number within a tumor sample. Each tumor was classified into a biphasic grade graph (high heterogeneity [HH]) group or a monophasic grade graph (low heterogeneity [LH]) group based on heterogeneity. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up., Results: Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: p < 0.001 (HH:63% vs. LH:91% at 10 years) and for the OS: p = 0.012 (HH:78% vs. LH:95% at 10 years)., Conclusions: High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach to heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy., Competing Interests: The authors declare no conflicts of interest.

Background: Although pharmacists often identify numerous clinical questions, they face several barriers, including the lack of mentors for research activities in clinical settings. Therefore, a workshop for the appropriate selection of a study design, which is a fundamental first step, may be necessary. The purpose of this study was to evaluate the effectiveness of a workshop on study design for hospital and community pharmacists. Moreover, the characteristics of pharmacists with little involvement in research activities were extracted using decision-tree analysis to guide the design of future workshops., Methods: A workshop was conducted on October 1, 2023. It comprised three parts: lectures, group work, and presentations. Questionnaire-based surveys were conducted with workshop participants regarding their basic information, their background that influenced research activities, their satisfaction, and their knowledge/awareness. For the questions on knowledge/awareness, the same responses were requested before and after the workshop using a five-scale scoring system. Multivariate logistic regression analysis was conducted to identify independent factors influencing research activities. Decision tree analysis was performed to extract low-effort characteristics of the research activities., Results: Of the 40 workshop attendees, the overall satisfaction score for the workshop was 4.38 of 5, and the score for each question was 4 or higher. Significant increases were observed in the scores of knowledge/awareness after the workshop. Moreover, 95% of the pharmacists answered that it would be highly useful to conduct a joint workshop between hospitals and community pharmacists. Although independent influencing factors were not detected in the multivariate logistic regression analysis, the decision tree analysis revealed that pharmacists who were no member of an academic society (85%, 11/13) or members without any certifications or accreditations related to pharmacy practice (80%, 4/5) were the least active in clinical research. In contrast, those belonging to academic societies and holding certifications or accreditations related to pharmacy practice frequently conducted clinical research., Conclusion: The present study revealed that a joint workshop on study design may have the potential to change pharmacists' knowledge and awareness of research activities. Moreover, future workshops should be conducted with pharmacists who do not belong to academic societies., (© 2024. The Author(s).)

Background and Aim: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC., Methods: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy., Results: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001)., Conclusions: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)