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Introduction: Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) are at increased risk of central nervous system (CNS) metastasis at initial diagnosis and throughout treatment. In a phase 3 trial, lorlatinib, a third-generation ALK tyrosine kinase inhibitor, significantly improved progression-free survival. In further analysis, lorlatinib revealed superior intracranial efficacy and prolonged time to intracranial progression compared with crizotinib., Case Presentation: Herein, we report a case of ALK-positive NSCLC with leptomeningeal metastasis that was successfully treated with lorlatinib after progression to brigatinib and alectinib. This case demonstrates the potential of lorlatinib in managing leptomeningeal metastasis in ALK-positive NSCLC., Conclusion: The case suggests a paradigm shift in therapeutic approaches for CNS metastasis, including brain and leptomeningeal metastases., Competing Interests: Y.F. reports receiving personal fees for honoraria for lectures from AstraZeneca, Amgen, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Merck Biopharma, Merck Sharp & Dohme, Novartis, Novocure, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical, outside the submitted work; personal fees for being on the advisory board from AstraZeneca, Chiome Bioscience, Daiichi-Sankyo, Micron, Otsuka Pharmaceutical, and Ono Pharmaceutical, outside the submitted work; and research grants from AbbVie, Amgen, AnHeart, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Incyte, Merck KGaA, Merck Sharp & Dohme, and Taiho Pharmaceutical, outside the submitted work. R.M. reports receiving personal fees for honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, Merck Sharp & Dohme, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical, outside the submitted work. T.Y. reports receiving personal fees for honoraria for lectures from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck Biopharma, Merck Sharp & Dohme, Ono Pharmaceutical, and Taiho Pharmaceutical, outside the submitted work, and reports receiving personal fees for being on the advisory board from Daiichi-Sankyo. J.S. reports receiving personal fees for honoraria for lectures from AstraZeneca, Amgen, Chugai, Merck Biopharma, Merck Sharp & Dohme, Novartis, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical, outside the submitted work. The other authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Purpose: The purpose of this study was to evaluate the relationship between the joint line convergence angle (JLCA) and the severity of medial knee osteoarthritis (OA). We hypothesise that JLCA is the most associated factor with the severity of medial knee OA., Methods: This retrospective study included a total of 202 knees that underwent either high tibial osteotomy or medial meniscus repair/partial resection. Kellgren-Lawrence grade and hip-knee-ankle angle (HKAA), mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA) and JLCA were assessed from preoperative radiographs. Medial meniscus extrusion (MME) was measured using preoperative magnetic resonance imaging. The International Cartilage Research Society (ICRS) grade on the medial femoral condyle and medial tibial plateau were also assessed. The relationships between JLCA and Kellgren-Lawrence grades and MME and ICRS grades were analysed using Spearman's correlation test and regression analysis., Results: The JLCA was correlated with the Kellgren-Lawrence grade ( R  = 0.765, p  < 0.001), MME ( R  = 0.638, p  < 0.001), ICRS grade on the MFC ( R  = 0.586, p  < 0.001) and the MTP ( R  = 0.586, p  < 0.001). Regression analysis showed that age ( p  = 0.002) and JLCA ( p  < 0.001) were associated with Kellgren-Lawrence grade. Furthermore, JLCA was related to ICRS grade on the MFC ( p  < 0.001) and MTP ( p  < 0.001)., Conclusion: The JLCA, reflecting radiological severity, meniscus status, and cartilage lesion, was the most associated alignment parameter in the severity of medial knee OA. The JLCA may be beneficial for quantitative assessment of medial knee OA., Level of Evidence: Level III, retrospective cohort study., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Immunological imprinting by ancestral SARS-CoV-2 strains is thought to impede the robust induction of Omicron-specific humoral responses by Omicron-based booster vaccines. Here, we analyzed the specificity and neutralization activity of memory B (B mem ) cells after repeated BA.5 exposure in individuals previously imprinted by ancestral strain-based mRNA vaccines. After a second BA.5 exposure, B mem cells with BA.5 spike protein-skewed reactivity were promptly elicited, correlating with preexisting antibody titers. Clonal lineage analysis identified BA.5-skewed B mem cells that had redirected their specificity from the ancestral strain to BA.5 through somatic hypermutations. Moreover, B mem cells with redirected BA.5 specificity exhibited accelerated development compared with de novo B mem cells derived from naïve repertoires. This redirected BA.5 specificity demonstrated greater resilience to viral point mutation and adaptation to recent Omicron variants HK.3 and JN.1, months after the second BA.5 exposure, suggesting that existing B mem cells elicited by older vaccines can redirect their specificity toward newly evolving variants.

Few reports have analyzed the fusion genes involved in carcinogenesis in the oropharynx, where the incidence of human papillomavirus-associated tumors is relatively low. The aim of this study was to identify novel driver fusion genes in patients with oropharyngeal cancer. The study enrolled fifty-seven patients who were diagnosed with oropharyngeal carcinoma. RNA sequencing data from fresh-frozen specimens were used to identify candidate fusion genes via the JAFFA, arriba, and STAR-Fusion pipelines. Candidate fusion genes were confirmed by direct sequencing. The expression level of a candidate fusion gene was compared to that of tumors without fusion genes. Finally, filtering was performed for driver genes using the annoFuse pipeline. In addition, the VIRTUS pipeline was used to analyze the presence of human papillomavirus in the tumors. We identified 5 (8.8 %) novel potential driver in-frame fusion genes, MKNK2::MOB3A, ICMT::RPS6KA3, ATP1B3::GRK7, CSNK2A1::KIF16B, and FGFR3::MAEA, and 1 (1.8 %) known in-frame fusion gene, FGFR3::TACC3, in 57 patients with pharyngeal carcinoma. Our results suggest that sporadic fusion genes may contribute to tumorigenesis in oropharyngeal carcinomas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Olfactory dysfunction is associated with aging and the earliest stages of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases; it is thought to be an early biomarker of cognitive decline. In marmosets, a small non-human primate model used in brain research, olfactory pathway activity during olfactory stimulation has not been well studied because of the difficulty in clearly switching olfactory stimuli inside a narrow MRI. Here, we developed an olfactory-stimulated fMRI system using a small-aperture MRI machine. The olfactory presentation system consisted of two tubes, one for supply and one for suction of olfactory stimulants and a balloon valve. A balloon valve installed in the air supply tube controlled the presentation of the olfactory stimulant, which enabled sharp olfactory stimulation within MRI, such as 30 s of stimulation repeated five times at five-minute intervals. The olfactory stimulation system was validated in vivo and in a simulated system. fMRI analysis showed a rapid increase in signal values within 30 s of olfactory stimulation in eight regions related to the sense of smell. As these regions include those associated with Alzheimer's and Parkinson's diseases, olfactory stimulation fMRI may be useful in clarifying the relationship between olfactory dysfunction and dementia in non-human primates., (© 2024. The Author(s).)

Classic genome-wide association studies (GWAS) look for associations between individual SNPs and phenotypes of interest. With the rapid progress of high-throughput genotyping and phenotyping technologies, GWAS have become increasingly powerful for detecting genetic determinants and their molecular mechanisms underpinning natural phenotypic variation. However, GWAS frequently yield results with neither expected nor promising loci, nor any significant associations. This is often because associations between SNPs and a single phenotype are confounded, for example with the environment, other traits, or complex genetic structures. Such confounding can mask true genotype-phenotype associations, or inflate spurious associations. To address these problems, numerous methods have been developed that go beyond the standard model. Such advanced GWAS models are flexible and can offer improved statistical power for understanding the genetics underlying complex traits. Despite this advantage, these models have not been widely adopted and implemented compared to the standard GWAS approach, partly because this literature is diverse and often technical. In this review, our aim is to provide an overview of the application and the benefits of various advanced GWAS models for handling complex traits and genetic structures, targeting plant biologists who wish to carry out GWAS more effectively., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.)

Background: Measurements of knee cartilage thickness derived from MR images are attractive biomarkers for osteoarthritis research. Although some cross-sectional multivendor studies exist, none have employed fully automatic three-dimensional MRI analysis. Our objective was to evaluate the variations in knee cartilage thickness measurements obtained using automated methods and MRI instruments from five different vendors., Methods: The subjects were 10 healthy volunteers aged 22-60 years. MRI models with 3 Tesla strength from five different companies were used. Cartilage thickness was quantified fully automatically for seven regions. We hypothesized that "the MRI model influences cartilage thickness measurements." Inter-measurement error, defined as the absolute difference between the targeted and median thicknesses determined by the five MRI models, was analyzed using histograms. The factors generating the largest inter-measurement error were also examined., Results: No exceptional trends attributable to a specific instrument model were observed, and the p-value from the Kruskal-Wallis test exceeded 0.05 in all seven regions. Therefore, the study hypothesis was rejected. Of the 350 measurements, the inter-measurement error was ≤0.05 mm in 53 %, ≤0.10 mm in 75 %, and ≤0.20 mm in 95 %. Analysis of the medial tibial cartilage, which had the largest inter-measurement error, revealed mis-extraction of synovial fluid as cartilage., Conclusions: The choice of MRI model did not influence cartilage thickness measurements. Overall, 95 % of the inter-measurement errors were within 0.20 mm. The greatest error resulted from mis-extracting synovial fluid as cartilage., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ichiro Sekiya reports financial support was provided by Fujifilm Holdings Corporation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Nursing- and healthcare-associated pneumonia (NHCAP) constitutes most of the pneumonia in elderly patients including aspiration pneumonia in Japan. Lascufloxacin (LSFX) possesses broad antibacterial activity against respiratory pathogens, such as Streptococcus spp. And anaerobes inside the oral cavity. However, the efficacy and safety of LSFX in NHCAP treatment remains unknown. We aimed to evaluate the efficacy and safety of LSFX tablets in the treatment of patients with NHCAP., Methods: In this single-arm, open-label, uncontrolled study, LSFX was administered to patients with NHCAP at 24 facilities. The study participants were orally administered 75 mg LSFX once daily for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC). The secondary endpoints included clinical efficacy at the time of end of treatment (EOT), early clinical efficacy, microbiological efficacy, and safety analysis., Result: During the study period, 75 patients provided written informed consent to participate and were included. Finally, 56 and 71 patients were eligible for clinical efficacy and safety analyses, respectively. The median age of the patients was significantly high at 86 years. All patients were classified as having moderate disease severity using the A-DROP scoring system. LSFX tablets demonstrated high efficacy rates of 78.6 % at TOC and 89.3 % at EOT. The risk factors for resistant bacteria or aspiration pneumonia did not affect clinical efficacy. No severe adverse events associated with the study drugs were observed., Conclusion: Oral LSFX is an acceptable treatment option for moderate NHCAP in elderly patients who can take oral medications., Competing Interests: Declaration of competing interest Hiroshi Mukae received lecture honoraria and research grants from KYORIN Pharmaceutical Co., Ltd. Outside of the submitted work., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Isolation of tumor-specific T cells and their antigen receptors (TCRs) from malignant pleural effusions (MPE) may facilitate the development of TCR-transduced adoptive cellular immunotherapy products for advanced lung cancer patients. However, the characteristics and markers of tumor-specific T-cells in MPE are largely undefined. To this end, to establish the phenotypes and antigen specificities of CD8 + T cells, we performed single-cell RNA and TCR sequencing of samples from three advanced lung cancer patients. Dimensionality reduction on a total of 4,983 CD8 + T cells revealed 10 clusters including naïve, memory, and exhausted phenotypes. We focused particularly on exhausted T cell clusters and tested their TCR reactivity against neoantigens predicted from autologous cancer cell lines. Four different TCRs specific for the same neoantigen and one orphan TCR specific for the autologous cell line were identified from one of the patients. Differential gene expression analysis in tumor-specific T cells relative to the other T cells identified CXCL13 , as a candidate gene expressed by tumor-specific T cells. In addition to expressing CXCL13 , tumor-specific T cells were present in a higher proportion of T cells co-expressing PDCD1 (PD-1)/ TNFRSF9 (4-1BB). Furthermore, flow cytometric analyses in advanced lung cancer patients with MPE documented that those with high PD-1/4-1BB expression have a better prognosis in the subset of 57 adenocarcinoma patients ( p  = .039). These data suggest that PD-1/4-1BB co-expression might identify tumor-specific CD8 + T cells in MPE, which are associated with patients' prognosis. (233 words)., Competing Interests: This study was partly funded by NEC Corporation., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Purpose: This study aimed to investigate the intraoperative knee kinematics of cruciate-retaining total knee arthroplasty with a medial stabilising technique (MST-TKA) and compare the kinematics between mobile- and fixed-bearing MST-TKAs. We hypothesised that mobile-bearing MST-TKA would result in greater physiological kinematic motion than fixed-bearing MST-TKA., Methods: Twenty-one and 20 knees underwent mobile- and fixed-bearing MST-TKAs using a navigation system (Orthopilot® ver. 6.0; B. Braun Aesculap), respectively. In the preoperative and postoperative kinematic analysis, the knee was moved manually from 0° to 120°, and femoral anteroposterior translations of the medial femoral condyle (MFC) and lateral femoral condyle (LFC) were recorded every 0.1 s from 0° to 120°. Data were subsequently extracted from the software every 10° of flexion and compared between the two groups, and the correlation coefficients between preoperative and postoperative kinematics were calculated., Results: In the postoperative analysis, the MFC in the mobile-bearing group showed significant posterior translation at 100°, 110° and 120° compared to the fixed-bearing group ( p  < 0.01). Similarly, the LFC in the mobile-bearing group showed significant posterior translation at 100°, 110° and 120° compared to the fixed-bearing group ( p  < 0.05, p  < 0.01 and p  < 0.05, respectively). In the mobile-bearing group, the preoperative and postoperative anteroposterior translations of the MFC and LFC were correlated ( p  < 0.01), while in the fixed-bearing group, there was no correlation., Conclusion: The femoral rollback motion in the mobile-bearing MST-TKA correlated with the preoperative kinematics and was larger than that in the fixed-bearing group., Level of Evidence: Level II, therapeutic prospective cohort study., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Recently, cases of carcinoma showing thymus-like differentiation (CASTLE) occurring in major salivary glands have been identified. To assess the diagnostic value of CD5 immunohistochemistry in distinguishing salivary CASTLE from other types of salivary gland tumors, we evaluated CD5 expression in 109 salivary gland tumors, encompassing 23 different histological types, including salivary CASTLE. In addition, we reviewed 10 previously reported cases of salivary CASTLE. Most salivary CASTLE cases (10/11, 91%) showed strong CD5 expression. In contrast, 104 of 108 (96%) non-salivary CASTLE tumors were negative for CD5, while the remaining four tumors (3.7%), all of which were histologically Warthin tumors, showed focal positivity for CD5 with weak to moderate intensity. In conclusion, the findings in this study support the potential use of CD5 immunohistochemistry for distinguishing salivary CASTLE from other histological types of salivary gland tumors. Aberrant CD5 expression in this tumor may be linked to the tumor microenvironment., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rheumatoid fibroblast-like synoviocytes (RFLS) have an important role in the inflammatory pathogenesis of rheumatoid arthritis (RA). Toll-like receptor 3 (TLR3) is upregulated in RFLS; its activation leads to the production of interferon-β (IFN-β), a type I IFN. IFN-stimulated gene 56 (ISG56) is induced by IFN and is involved in innate immune responses; however, its role in RA remains unknown. Therefore, the purpose of this study was to investigate the role of TLR3-induced ISG56 in human RFLS. RFLS were treated with polyinosinic-polycytidylic acid (poly I:C), which served as a TLR3 ligand. ISG56, melanoma differentiation-associated gene 5 (MDA5), and C-X-C motif chemokine ligand 10 (CXCL10) expression were measured using quantitative reverse transcription-polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. Using immunohistochemistry, we found that ISG56 was expressed in synovial tissues of patients with RA and osteoarthritis. Under poly I:C treatment, ISG56 was upregulated in RFLS. In addition, we found that the type I IFN-neutralizing antibody mixture suppressed ISG56 expression. ISG56 knockdown decreased CXCL10 expression and MDA5 knockdown decreased ISG56 expression. In addition, we found that ISG56 was strongly expressed in the synovial cells of patients with RA. TLR3 signaling induced ISG56 expression in RFLS and type I IFN was involved in ISG56 expression. ISG56 was also found to be associated with CXCL10 expression, suggesting that ISG56 may be involved in TLR3/type I IFN/CXCL10 axis, and play a role in RA synovial inflammation., 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 Ishibashi, Nakamura, Saruga, Imaizumi, Kurose, Kawaguchi, Seya, Sasaki and Ishibashi.)

NLR family proteins act as intracellular receptors. Gene duplication amplifies the number of NLR genes, and subsequent mutations occasionally provide modifications to the second gene that benefits immunity. However, evolutionary processes after gene duplication and functional relationships between duplicated NLRs remain largely unclear. Here, we report that the rice NLR protein Pit1 is associated with its paralogue Pit2. The two are required for the resistance to rice blast fungus but have different functions: Pit1 induces cell death, while Pit2 competitively suppresses Pit1-mediated cell death. During evolution, the suppression of Pit1 by Pit2 was probably generated through positive selection on two fate-determining residues in the NB-ARC domain of Pit2, which account for functional differences between Pit1 and Pit2. Consequently, Pit2 lost its plasma membrane localization but acquired a new function to interfere with Pit1 in the cytosol. These findings illuminate the evolutionary trajectory of tandemly duplicated NLR genes after gene duplication., (© 2024. The Author(s).)

The gut microbiome affects the health status of the host through complex interactions with the host's intestinal wall. These host-microbiome interactions may spatially vary along the physical and chemical environment of the intestine, but these changes remain unknown. This study investigated these intricate relationships through a gene co-expression network analysis based on dual transcriptome profiling of different intestinal sites-cecum, transverse colon, and rectum-of the primate common marmoset. We proposed a gene module extraction algorithm based on the graph theory to find tightly interacting gene modules of the host and the microbiome from a vast co-expression network. The 27 gene modules identified by this method, which include both host and microbiome genes, not only produced results consistent with previous studies regarding the host-microbiome relationships, but also provided new insights into microbiome genes acting as potential mediators in host-microbiome interplays. Specifically, we discovered associations between the host gene FBP1 , a cancer marker, and polysaccharide degradation-related genes ( pfkA and fucI ) coded by Bacteroides vulgatus , as well as relationships between host B cell-specific genes ( CD19 , CD22 , CD79B , and PTPN6 ) and a tryptophan synthesis gene ( trpB ) coded by Parabacteroides distasonis . Furthermore, our proposed module extraction algorithm surpassed existing approaches by successfully defining more functionally related gene modules, providing insights for understanding the complex relationship between the host and the microbiome.IMPORTANCEWe unveiled the intricate dynamics of the host-microbiome interactions along the colon by identifying closely interacting gene modules from a vast gene co-expression network, constructed based on simultaneous profiling of both host and microbiome transcriptomes. Our proposed gene module extraction algorithm, designed to interpret inter-species interactions, enabled the identification of functionally related gene modules encompassing both host and microbiome genes, which was challenging with conventional modularity maximization algorithms. Through these identified gene modules, we discerned previously unrecognized bacterial genes that potentially mediate in known relationships between host genes and specific bacterial species. Our findings underscore the spatial variations in host-microbiome interactions along the colon, rather than displaying a uniform pattern throughout the colon., Competing Interests: The authors declare no conflict of interest.

Purpose: Glioblastoma is a malignant brain tumor with a poor prognosis. Genetic mutations associated with this disease are complex are not fully understood and require further elucidation for the development of new treatments. The purpose of this study was to comprehensively analyze genetic mutations in glioblastomas and evaluate the usefulness of RNA sequencing., Patients and Methods: We analyzed 42 glioblastoma specimens that were resected in routine clinical practice and found wild-type variants of the IDH1 and IDH2 genes. RNA was extracted from frozen specimens and sequenced, and genetic analyses were performed using the CLC Genomics Workbench., Results: The most common genetic alterations in the 42 glioblastoma specimens were TP53 mutation (28.6%), EGFR splicing variant (16.7%), EGFR mutation (9.5%), and FGFR3 fusion (9.5%). Novel genetic mutations were detected in 8 patients (19%). In 12 cases (28.6%), driver gene mutations were not detected, suggesting an association with PPP1R14A overexpression. Our findings suggest the transcription factors SOX10 and NKX6-2 are potential markers in glioblastoma., Conclusion: RNA sequencing is a promising approach for genotyping glioblastomas because it provides comprehensive information on gene expression and is relatively cost-effective., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The Japanese Breast Cancer Society Clinical Practice Guidelines are published as timely guidance on clinical issues in breast cancer treatment in Japan. In the recent edition of these guidelines, we addressed a new clinical question 34 (CQ 34, systemic treatment part) "Is trastuzumab deruxtecan recommended for patients with unresectable or metastatic HER2-low breast cancer?" and a new future research question 7 (FRQ 7, pathological diagnosis part) "How is HER2-low breast cancer diagnosed for the indication of trastuzumab deruxtecan?". These questions address use of trastuzumab deruxtecan in patients with unresectable or metastatic HER2-low breast cancer who have previously received chemotherapy for metastatic disease. The strengths of evidence and recommendation were determined through a quantitative and qualitative systematic review using multiple outcomes, including efficacy and safety. We conclude that trastuzumab deruxtecan is recommended for this patient population (strength of recommendation: 1; strength of evidence: moderate; CQ34) and that HER2-low expression for the indication of trastuzumab deruxtecan should be diagnosed using companion diagnostics based on appropriate criteria (FRQ7)., (© 2024. The Author(s).)

Medial meniscus posterior root tear (MMPRT) is a common medial meniscus injury among elderly patients and often necessitates repair. Although the clinical outcomes of MMPRT repair have demonstrated improvements, subsequent second-look arthroscopy shows poor healing postrepair. Consequently, numerous repair techniques have been reported. Herein, we introduce a simple locking-suture method, the "delta-grip" stitch, for MMPRT repair. This technique exhibited sufficient pullout strength compared with conventional suturing methods, offering promising prospects for enhancing the outcomes of MMPRT repair., Competing Interests: The authors (Y.I., E.S., Y.K., T.T.) declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Fluorescence imaging is a powerful technique for visualizing biological events in living samples with high temporal and spatial resolution. Fluorescent probes emitting far-red to near infrared (NIR) fluorescence are particularly advantageous for in vivo imaging due to their high tissue permeability and low autofluorescence, as well as their suitability for multicolor imaging. Among the far-red to NIR fluorophores, Si-rhodamine is one of the most practical fluorophores for the development of tailor-made NIR fluorescent probes because of the relative ease of synthesis of various derivatives, the unique intramolecular spirocyclization behavior, and the relatively high water solubility and high photostability of the probes. This review summarizes these features of Si-rhodamines and presents recent advances in the synthesis and applications of far-red to NIR fluorescent probes based on Si-rhodamines, focusing on live-cell imaging applications such as fluorogenic probes, super-resolution imaging and dye-protein hybrid-based indicators.

Background: Anterolateral knee laxity (ALLx) has been linked to tears of the lateral meniscus (LM) and anterior cruciate ligament (ACL) injury., Purpose: To investigate the longitudinal relationship between the signal intensity (SI) of the repaired LM on magnetic resonance imaging (MRI) and residual ALLx after ACL reconstruction (ACLR)., Study Design: Cohort study; Level of evidence, 3., Methods: Included were 87 patients who underwent double-bundle ACLR and lateral meniscal repair (mean age, 23.5 years; body mass index, 23.7 kg/m 2 ; 56 women) at a single institution between 2010 and 2019. Proton density-weighted (PDW) and T2-weighted (T2W) MRI was performed at 3, 6, and 12 months postoperatively, and the SI ratio (SIR) was calculated as ( SI of the repaired LM )/( SI of the posterior cruciate ligament ). At the 12-month follow-up, ALLx was evaluated using the pivot-shift test; an International Knee Documentation Committee grade ≥1 indicated residual ALLx., Results: Overall, 12 patients (13.8%) exhibited ALLx at 12 months postoperatively. At 3 months postoperatively, the SIR on PDW images (SIR-PDW) was significantly higher in patients with ALLx versus those without ALLx (1.98 ± 0.77 vs 1.49 ± 0.52, respectively; P = .007); there was no difference in the SIR on T2W images between the groups. SIR-PDW at 3 months postoperatively was correlated negatively with patient age ( r = -0.308, P = .004). When patients were stratified into a younger (≤22 years; n = 53; ALLx = 7 [13.2%]) and an older (>22 years; n = 34; ALLx = 5 [14.7%]) group, the area under the receiver operating characteristic curves (AUCs) for SIR-PDW in the younger group were statistically significant for predicting the prevalence of ALLx at all follow-up times (AUCs, 0.733-0.788) with optimal cutoff values of 2.00 at 3 months, 1.50 at 6 months, and 1.50 at 12 months. Logistic regression analysis revealed that if younger patients consistently had higher SIR-PDW values than the cutoff values, they were more likely to have residual ALLx (odds ratios, 10.24-23.57)., Conclusion: For younger patients who underwent both ACLR and lateral meniscal repair, higher MRI SI of the repaired LM was associated with a higher prevalence of residual ALLx., Competing Interests: The authors have declared that there are no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto. Ethical approval for this study was obtained from Hirosaki University Graduate School of Medicine (ref No. 2012-250)., (© The Author(s) 2024.)

Purpose: The purpose of this study was to develop a neural network model for predicting second anterior cruciate ligament (ACL) injury risk following ACL reconstruction using patient features from medical records., Methods: Of 486 consecutive patients who underwent primary unilateral ACL reconstruction, 386 patients (198 women, 188 men) with a mean age of 25.1 ± 11.6 years were included in this study. Fifty-eight features, including demographic data, surgical, preoperative and postoperative data, were retrospectively collected from medical records, and features with an incidence of less than 5% were excluded. Finally, 14 features were used for the analysis. The multilayer perceptron was composed of four hidden layers with a rectified linear unit as activation and was trained to maximise the area under the receiver-operating characteristic curve (auROC). Subsequently, validation was carried out through a rigorous threefold cross-validation process. To ascertain the most efficacious combination of features with the highest auROC, a single feature with the least impact on auROC maximisation was systematically eliminated from the comprehensive variable set, ultimately resulting in the retention of a mere two variables., Results: The median follow-up period was 50.5 (24-142) months. Fifty-seven knees had a second ACL injury, with a graft rupture rate of 7.7% and a contralateral injury rate of 6.9%. The maximum auROC for predicting graft rupture was 0.81 with two features: young age and hamstring graft. Meanwhile, the maximum auROC for predicting contralateral ACL injury was 0.74 with seven features, including young age, presence of medial meniscus tear, small body mass index, hamstring graft, female sex and medial meniscus repair or treatment., Conclusion: A neural network model with patient features from medical records detected graft ruptures and contralateral ACL injuries with acceptable accuracy. This model can serve as a new, useful tool in clinical practice to inform decisions about ACL reconstruction and retuning to sports postoperatively., Level of Evidence: Level IV., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background : Abdominal vascular injury, a fatal complication of lumbar disc surgery, should concern spine surgeons. This study aimed to compare the position of the abdominal arteries in the supine and prone positions and the factors involved. Thirty patients who underwent lumbar surgery by posterior approach were included. Methods : All patients underwent computed tomography (CT) preoperatively in the supine position and intraoperatively in the prone position. In the CT axial image, at the L4, L4/5 disc, L5, and L5/S1 disc level, we measured the shortest distance between the abdominal arteries and the vertebral body (SDA: shortest distance to the aorta), and the amount of abdominal arterial translation, defined as "SDA on intraoperative CT" minus "SDA on preoperative CT". Additionally, the preoperative CT axial images were evaluated for the presence of aortic calcification. Results : No significant difference in SDA values based on patients' positions was observed at each level. In males, the supine position brought the abdominal artery significantly closer to the spine at the left side of the L5/S level ( p = 0.037), and, in cases of calcification of the abdominal artery, the abdominal artery was found to be closer to the spine at the left side of the L4/5 level ( p = 0.026). Conclusions : It is important to confirm preoperative images correctly to prevent great vessel injuries in lumbar spine surgery using a posterior approach.

Salivary gland-type tumors of the lung are thought to originate from the submucosal exocrine glands of the large airways. Due to their rare occurrence, reports of their study are limited to small-scale or case reports. Therefore, daily clinical practices often require a search for previous reports. In the last 20 years, several genetic rearrangements have been identified, such as MYB::NF1B rearrangements in adenoid cystic carcinoma, CRTC1::MAML2 rearrangements in mucoepidermoid carcinoma, EWSR1::ATF1 rearrangements in hyalinizing clear cell carcinoma and rearrangements of the EWSR1 locus or FUS (TLS) locus in myoepithelioma and myoepithelial carcinoma. These molecular alterations have been useful in diagnosing these tumors, although they have not yet been linked to molecularly targeted therapies. The morphologic, immunophenotypic, and molecular characteristics of these tumors are similar to those of their counterparts of extrapulmonary origin, so clinical and radiologic differential diagnosis is required to distinguish between primary and metastatic disease of other primary sites. However, these molecular alterations can be useful in differentiating them from other primary lung cancer histologic types. The management of these tumors requires broad knowledge of the latest diagnostics, surgery, radiotherapy, bronchoscopic interventions, chemotherapy, immunotherapy as well as therapeutic agents in development, including molecularly targeted agents. This review provides a comprehensive overview of the current diagnosis and treatment of pulmonary salivary gland tumors, with a focus on adenoid cystic carcinoma and mucoepidermoid carcinoma, which are the two most common subtypes., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Medial open-wedge high tibial osteotomy (OWHTO) is related to cartilage improvement in the medial compartment. This study aimed to evaluate factors associated with cartilage improvement and patient-reported outcomes (PRO) after OWHTO. It was hypothesised that cartilage improvement is associated with favourable PRO., Methods: This retrospective study included 94 patients who underwent OWHTO. The mean follow-up period was 5 years. The weight-bearing line ratio (WBLR) was defined as the ratio of the distance from the medial tibial edge to the tibial insertion of the weight-bearing line and the tibial width. The International Cartilage Research Society grade evaluated the medial femoral condyle (MFC) and medial tibial plateau (MTP) at initial and second-look arthroscopy, and cartilage improvement after OWHTO was assessed. Postoperative knee injury and osteoarthritis outcome scores (KOOS) were compared between the groups with improved and non-improved cartilage. Additionally, factors related to cartilage improvement and postoperative KOOS scores were analysed., Results: Regarding the MFC, KOOS pain, symptoms, activities of daily living (ADL) and quality of life (QOL) were significantly higher in the cartilage-improved group than in the non-improved group (p = 0.012, 0.003, 0.001, 0.006), and cartilage improvement was significantly related to KOOS pain, ADL and QOL (p = 0.021, 0.039, 0.013). In addition, the postoperative WBLR was associated with cartilage improvement, with a cutoff value of 54.0% (p = 0.046). Regarding the MTP, KOOS ADL and QOL (p = 0.026, 0.022) were significantly higher in the cartilage-improved group than in the nonimproved group. Body mass index (BMI) was significantly related to the postoperative QOL (p = 0.018) and associated with cartilage improvement, with a cutoff value of 25.9 kg/m 2 (p = 0.002)., Conclusion: A postoperative WBLR greater than 54.0% and a preoperative BMI below 25.9 kg/m 2 were associated with cartilage improvement, positively impacting PRO after OWHTO., Level of Evidence: Level III, retrospective comparative study., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

An adult male captive diamondback water snake ( Nerodia rhombifer ) was found dead after a 1-d history of lethargy and cutaneous ulcers. The snake had eaten 2 sunfish ( Mola spp.) 5 d before death. Gross examination revealed white-to-tan nodules in the lung and liver and segmental intestinal impactions with digested fish. Histopathology confirmed disseminated granulomas with numerous intrahistiocytic acid-fast bacteria in the skin, skeletal muscle, lung, liver, and intestines. Mycobacterium marinum and Mycolicibacterium fortuitum were identified by culture of the hepatic granuloma, followed by PCR and rpoB gene sequencing. To our knowledge, this is the first description of M. marinum and M. fortuitum coinfection in this species. Although M. fortuitum has been isolated from reptiles, lesions associated with its presence in tissues have not been described previously. Interestingly, the mineralization within granulomas that we observed in our case is not reported in mycobacterial infection in reptiles, whereas this finding is common in mammals., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article.

Assessment of social interactions and behavioral changes in nonhuman primates is useful for understanding brain function changes during life events and pathogenesis of neurological diseases. The common marmoset (Callithrix jacchus), which lives in a nuclear family like humans, is a useful model, but longitudinal automated behavioral observation of multiple animals has not been achieved. Here, we developed a Full Monitoring and Animal Identification (FulMAI) system for longitudinal detection of three-dimensional (3D) trajectories of each individual in multiple marmosets under free-moving conditions by combining video tracking, Light Detection and Ranging, and deep learning. Using this system, identification of each animal was more than 97% accurate. Location preferences and inter-individual distance could be calculated, and deep learning could detect grooming behavior. The FulMAI system allows us to analyze the natural behavior of individuals in a family over their lifetime and understand how behavior changes due to life events together with other data., (© 2024. The Author(s).)

The single-joint hybrid assistive limb (HAL-SJ), an exoskeletal robotic suit, offers functional improvement. In this prospective randomized controlled trial, we investigated the therapeutic effects of knee extension exercises using the HAL-SJ after total knee arthroplasty (TKA). Seventy-six patients with knee osteoarthritis were randomly assigned to HAL-SJ or conventional physical therapy (CPT) groups. The HAL-SJ group underwent exercise using the HAL-SJ for 10 days postoperatively, in addition to CPT; the CPT group underwent only CPT. Pain intensity and active and passive knee extension angles were evaluated preoperatively and on postoperative days 1-10 and weeks 2 and 4. Performance tests and Knee Injury and Osteoarthritis Outcome Scores (KOOS) were evaluated preoperatively and at postoperative weeks 2 and 4. Statistical analysis showed that the HAL-SJ group significantly improved active and passive knee extension angles compared with the CPT group. The HAL-SJ group showed immediate improvement in active knee extension angle through day 5. There were no significant differences in results between the performance tests and KOOS. Knee extension exercises with the HAL-SJ improved knee pain and the angle of extension in the acute phase after TKA., (© 2024. The Author(s).)

Various control strategies are available for building fluorogenic probes to visualize biological events in terms of a fluorescence change. Here, we performed the time-dependent density functional theory (TD-DFT) computational analysis of the twisted intramolecular charge transfer (TICT) process in rhodamine dyes. On the basis of the results, we designed and synthesized a series of rhodamine dyes and established a fluorescence quenching strategy that we call steric repulsion-induced TICT (sr-TICT), in which the fluorescence quenching process is greatly accelerated by simple intramolecular twisting. As proof of concept of this design strategy, we used it to develop a fluorogenic probe, 2-Me PeER (pentyloxyethylrhodamine), for the N -dealkylation activity of CYP3A4. We applied 2-Me PeER for CYP3A4 activity-based fluorescence-activated cell sorting (FACS), providing access to homogeneous, highly functional human-induced pluripotent stem cell (hiPSC)-derived hepatocytes and intestinal epithelial cells. Our results suggest that sr-TICT represents a general fluorescence control method for fluorogenic probes.

Recently, several studies using cultures of human embryos together with single-cell RNA-seq analyses have revealed differences between humans and mice, necessitating the study of human embryos 1-8 . Despite the importance of human embryology, ethical and legal restrictions have limited post-implantation-stage studies. Thus, recent efforts have focused on developing in vitro self-organizing models using human stem cells 9-17 . Here, we report genetic and non-genetic approaches to generate authentic hypoblast cells (naive hPSC-derived hypoblast-like cells (nHyCs))-known to give rise to one of the two extraembryonic tissues essential for embryonic development-from naive human pluripotent stem cells (hPSCs). Our nHyCs spontaneously assemble with naive hPSCs to form a three-dimensional bilaminar structure (bilaminoids) with a pro-amniotic-like cavity. In the presence of additional naive hPSC-derived analogues of the second extraembryonic tissue, the trophectoderm, the efficiency of bilaminoid formation increases from 20% to 40%, and the epiblast within the bilaminoids continues to develop in response to trophectoderm-secreted IL-6. Furthermore, we show that bilaminoids robustly recapitulate the patterning of the anterior-posterior axis and the formation of cells reflecting the pregastrula stage, the emergence of which can be shaped by genetically manipulating the DKK1/OTX2 hypoblast-like domain. We have therefore successfully modelled and identified the mechanisms by which the two extraembryonic tissues efficiently guide the stage-specific growth and progression of the epiblast as it establishes the post-implantation landmarks of human embryogenesis., (© 2023. The Author(s).)

Background: Innate immunity is known to be implicated in the etiology of synovitis in rheumatoid arthritis (RA). However, details of the molecular mechanisms have not been fully clarified. DExD/H-box helicase 60 (DDX60), a putative RNA helicase, is of consequence in anti-viral innate immune reactions followed by inflammation. Although DDX60 is involved in the pathogenesis of autoimmune diseases such as systemic lupus nephritis, the role of DDX60 in RA has not been elucidated. The objective of this study was to examine the expression and the role of DDX60 in RA synovial inflammation., Methods and Results: DDX60 protein expression was investigated by immunohistochemistry in synovial tissues resected from 4 RA and 4 osteoarthritis (OA) patients. We found that synovial DDX60 expression was more intense in RA than in OA. Treatment of human rheumatoid fibroblast-like synoviocytes in culture with polyinosinic-polycytidylic acid, a Toll-like receptor 3 (TLR3) ligand, increased DDX60 protein and mRNA expression. A knockdown experiment of DDX60 using RNA interference revealed a decrease in the expression of poly IC-induced C-X-C motif chemokine ligand 10 (CXCL10) which induces lymphocyte chemotaxis., Conclusions: The synovial DDX60 was more expressed in RA patients than in OA. In human RFLS, DDX60 stimulated by TLR3 signaling affected CXCL10 expression. DDX60 may contribute to synovial inflammation in RA., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Adverse early life experiences are well-established risk factors for neurological disorders later in life. However, the molecular mechanisms underlying the impact of adverse experiences on neurophysiological systems throughout life remain incompletely understood. Previous studies suggest that social attachment to parents in early development are indispensable for infants to grow into healthy adults. In situations where multiple offspring are born in a single birth in common marmosets, human hand-rearing is employed to ensure the survival of the offspring in captivity. However, hand-reared marmosets often exhibit behavioral abnormalities, including abnormal vocalizations, excessive attachment to the caretaker, and aggressive behavior. In this study, comprehensive transcriptome analyses were conducted on hippocampus tissues, a neuroanatomical region sensitive to social attachment, obtained from human hand-reared (N = 6) and parent-reared male marmosets (N = 5) at distinct developmental stages. Our analyses revealed consistent alterations in a subset of genes, including those related to neurodevelopmental diseases, across different developmental stages, indicating their continuous susceptibility to the effects of early parental deprivation. These findings highlight the dynamic nature of gene expression in response to early life experiences and suggest that the impact of early parental deprivation on gene expression may vary across different stages of development., (© 2024. The Author(s).)

Twisted intramolecular charge transfer (TICT) is a phenomenon involving intramolecular charge transfer together with intramolecular rotation upon photoexcitation, and in general this excited state of fluorescent dyes undergoes non-radiative decay (producing no fluorescence). We recently discovered that the magnitude of TICT in rhodamine derivatives could be regulated by altering the size of the substituents on the xanthene moiety, generating differing degrees of intramolecular steric repulsion. To further illustrate the usefulness and generality of this strategy, we describe here an application of quinone methide chemistry, which is widely used as a fluorescence off/on switching reaction for fluorescence probes detecting enzymatic activity, to construct a steric repulsion-induced (sr)-TICT-based fluorescence probe targeting nitroreductase (NTR) activity. The developed probe was almost non-fluorescent in phosphate-buffered saline (PBS) due to strong induction of the TICT state. On the other hand, when the probe was incubated with NTR and nicotinamide adenine dinucleotide (NADH), a large fluorescence increase was observed over time. We confirmed that the enzymatic reaction proceeded as expected, i.e., the nitro group of the probe was reduced to the corresponding amino group, followed by spontaneous elimination of iminoquinone methide. These results suggest that our simple design strategy based on the sr-TICT mechanism, i.e., controlling intramolecular steric repulsion, would be applicable to the development of fluorescence probes for a variety of enzymes.

Caryospora- like organisms (CLOs) form a clade of at least 11 genotypes of related coccidia that can cause epizootic mortality in marine turtles. The biology, transmission, host species range, and host cell tropism of these organisms are still largely unknown. The goal of this study was to characterize the host cell tropism, pathologic and ultrastructural features, and phylogeny associated with the first report of a mortality event due to CLO in the freshwater red-eared slider turtle ( Trachemys scripta elegans ). Sudden mortalities within a clutch of captive-raised red-eared slider hatchlings ( n = 8) were recorded, and deceased animals had severe segmental to diffuse, transmural, fibrinonecrotic enterocolitis and multifocal to coalescing hepatic necrosis, among other lesions associated with numerous intracytoplasmic developing stages of intralesional coccidia. Among the different developmental stages, merozoites were ultrastructurally characterized by an apical complex. A pan-apicomplexan polymerase chain reaction (PCR) yielded a 347 bp-amplicon matching the Schellackia / Caryospora -like clade with 99.1% identity to the US3 strain from green sea turtles ( Chelonia mydas ) and 99.1% identity to Schellackia sp. Isolate OC116. Surviving hatchlings were treated with toltrazuril sulfone (ponazuril) but were subsequently euthanized due to the risk of spreading the parasite to other chelonids in the collection. The ponazuril-treated hatchlings ( n = 4) had mild proliferative anterior enteritis, with few intraepithelial coccidia in one hatchling confirmed as CLO by PCR. This is the first report of Caryospora -like coccidiosis in non-cheloniid turtles, highlighting the relevance of this disease as an emerging highly pathogenic intestinal and extra-intestinal form of coccidiosis of turtles with potential cross-species infectivity., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: Inherent variations in human leukocyte antigen (HLA) alleles have been revealed epidemiologically to influence the development of autoimmune diseases. HLA alleles may thus also be associated with the development of immune-related adverse events (irAEs), such as thyroid irAE. Materials & methods: In this case-control study, 71 cancer patients who received immune checkpoint inhibitors were enrolled and HLA-genotyped and the frequency of HLA alleles was compared. Results: A*26:01 , DPA1*01:03 and DPB1*02:01 were significantly more frequent in patients with thyroid irAE than in patients without any irAEs (35.0 vs 3.2% [ p  = 0.004], 80.0 vs 45.2% [ p  = 0.020] and 55.0 vs 25.8% [ p  = 0.044], respectively). Conclusion: A*26:01 , DPA1*01:03 and DPB1*02:01 appear to be associated with thyroid irAE.

In Japan, exacerbations are underreported compared with other countries, possibly due in part to a failure to recognize them. This study aimed to create a simple chronic obstructive pulmonary disease (COPD) Exacerbation Recognition Tool (CERT-J) specifically for Japanese patients. Patients ≥40 years with confirmed COPD or asthma-COPD overlap were included. Focus groups were held to identify words and phrases used by patients to describe symptoms associated with an exacerbation, resulting in candidate items being identified. Following cognitive debriefing, the items were refined based on item frequency, level of endorsement and effect of demographic factors. Exploratory factor analysis (EFA) was then performed to inform an expert panel's choice of items to form the new tool. A total of 41 patients were included in the focus groups and nine patients performed the cognitive debrief. Following this, the expert panel identified 26 items for testing in a further 100 patients (mean age 72 years, forced expiratory volume in 1 s 54.8% predicted and 1.8 exacerbations in the preceding 12 months). Eleven items were associated with breathlessness or activity limitation and seven of these were the most frequently endorsed. EFA identified four factors, with one (breathlessness) being dominant. The expert panel recommended that the CERT-J should include six items: breathlessness and activity limitation (3 items), cough (1 item) and phlegm (2 items). The final CERT-J should benefit patients with COPD by providing them with an increased understanding and recognition of exacerbations. Clinical Trial Registration: GSK K.K (jRCT1080224526).

Anomalous pulmonary venous return (APVR) frequently occurs with other congenital heart defects (CHDs) or extra-cardiac anomalies. While some genetic causes have been identified, the optimal approach to genetic testing in individuals with APVR remains uncertain, and the etiology of most cases of APVR is unclear. Here, we analyzed molecular data from 49 individuals to determine the diagnostic yield of clinical exome sequencing (ES) for non-isolated APVR. A definitive or probable diagnosis was made for 8 of those individuals yielding a diagnostic efficacy rate of 16.3%. We then analyzed molecular data from 62 individuals with APVR accrued from three databases to identify novel APVR genes. Based on data from this analysis, published case reports, mouse models, and/or similarity to known APVR genes as revealed by a machine learning algorithm, we identified 3 genes-EFTUD2, NAA15, and NKX2-1-for which there is sufficient evidence to support phenotypic expansion to include APVR. We also provide evidence that 3 recurrent copy number variants contribute to the development of APVR: proximal 1q21.1 microdeletions involving RBM8A and PDZK1, recurrent BP1-BP2 15q11.2 deletions, and central 22q11.2 deletions involving CRKL. Our results suggest that ES and chromosomal microarray analysis (or genome sequencing) should be considered for individuals with non-isolated APVR for whom a genetic etiology has not been identified, and that genetic testing to identify an independent genetic etiology of APVR is not warranted in individuals with EFTUD2-, NAA15-, and NKX2-1-related disorders., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background: Bone marrow lesion (BML) is an important magnetic resonance finding (MRI) finding that predicts knee osteoarthritis. The purpose of this study was to investigate the influence of proximal tibial morphology on BML, including the spreading root sign (SRS), in women without radiographic knee osteoarthritis (OA). It was hypothesized that varus alignment and a greater posterior tibial slopes (PTS) are associated with BML., Materials and Methods: A total of 359 female volunteers without knee OA who were participants in the Iwaki Health Promotion Project in 2017 or 2019 were enrolled. Participants were divided into the non-OA and early knee OA (EKOA) groups based on the Luyten's classification criteria. The presence of pathological cartilage lesions, BMLs, attritions, meniscal lesions and effusions was scored on T2-weighted fat-suppressed magnetic resonance imaging (MRI) according to the Whole-Organ MRI Scoring system. The medial proximal tibial angle (MPTA) and medial and lateral PTS (MPTS and LPTS, respectively) were measured. Regression and receiver operating characteristic (ROC) analyses were performed to reveal the relationship between BMLs and proximal tibial morphological parameters., Results: Of the 359 participants, 54 (15%) were classified as having EKOA. The prevalence of cartilage lesions, BMLs, attritions, meniscal lesions and effusions was higher in the EKOA group than in the non-OA group. The two groups had no significant difference in the proximal tibial parameters. Regression analysis revealed that age and a smaller MPTA were associated with BML in both groups. Attrition (p = 0.029) and the MPTS (p = 0.025) were positively associated with BML in the EKOA group., Conclusion: The prevalence of BMLs was higher in women with EKOA and correlated with the varus and greater posterior slopes in those without radiographic knee OA., Level of Evidence: Level III, retrospective case-control study., (© 2023. The Author(s).)

Objectives: Inadequate bowel preparation (BP) negatively affects the efficacy and quality of colonoscopy. Although constipation has already been reported as one of the most important predictors of inadequate BP, there is limited information on the relation between inadequate BP and bowel habits including constipation-related symptoms, medications, and severity of constipation., Methods: This single-center, prospective observational study was conducted between August 2019 and May 2020. All participants answered questionnaires regarding personal bowel habits and received low-volume polyethylene glycol plus ascorbic acid for outpatient colonoscopy. Severity of constipation was evaluated by constipation scoring system. Bowel preparation cleansing was evaluated using Boston Bowel Preparation Scale (BBPS). Potential predictors of inadequate BP were analyzed using multivariate logistic regression models., Results: Overall, 1054 patients were enrolled, of which, 105 (10%) had inadequate BP (total BBPS ≤ 6 or any segmental BBPS < 2). The risk of inadequate BP increased with constipation severity (P = 0.01). Multivariate analysis showed that frequent straining (> 25% of defecations) (OR 2.09, 95% CI: 1.33-3.28) and chronic use of stimulant laxatives (OR 2.57, 95% CI: 1.59-4.17) were significant predictors of inadequate BP, among personal bowel habits., Conclusion: Frequent straining and chronic use of stimulant laxatives were predictors of inadequate BP. An intensified preparation regimen should be considered for severely constipated patients with straining and chronic use of stimulant laxatives., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lateral meniscus tear (LMT) accompanied by anterior cruciate ligament (ACL) injuries has been reported to provoke rotatory instability of the affected knee joint. Unfortunately, these previous papers did not determine whether LMT-derived rotatory knee instability is residual because only preoperative or time zero data exists. This study aimed to longitudinally investigate how the prevalence of comorbid LMT is associated with residual rotatory knee instability (RKI) 1 year after ACL reconstruction (ACLR). A total of 327 patients who underwent double-bundle ACLR (average age: 23.4 years, body mass index: 23.5 kg/m 2 , 215 females). The patients were divided into three groups based on arthroscopy: 1) intact lateral meniscus (LM); 2) unrepaired LMT; 3) repaired LMT. At the 1-year follow-up, the pivot-shift test was performed. The prevalence of RKI, determined according to IKDC grades (grade ≥1 denoted RKI), was compared with chi-square or Fisher's exact tests. Thirty-eight patients (11.6%) had RKI; 203 subjects (62.1%) showed LMT, and 124 patients were diagnosed with an intact LM. Out of the 203 patients, 79 (38.9%) underwent LM repair. RKI was more prevalent in the LMT group than in the intact group (13.8% versus 8.1%, p  = 0.117; Odds ratio: 1.499 [95%CI: 0.864 - 2.600]). In addition, the prevalence of RKI was significantly higher in the LM-repair group than in the intact-LM group (17.7% versus 8.1%, p  = 0.038; Odds Ratio: 2.455 [95%CI: 1.032 - 5.842]). Medial meniscus tear (MMT) was detected in 113 patients (34.6%); RKI prevalence was not statistically different between the intact-MM group and the MMT group (12.2% versus 10.6%, p  = 0.681). The current cohort study clarified that LMT comorbid with ACL injury was longitudinally associated with increased RKI prevalence 1 year after ACLR. Therefore, patients who underwent both ACLR and LM repair demonstrated a significantly higher prevalence of residual RKI., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Current microbiological tests fail to identify the causative microorganism in more than half of all pneumonia cases. We explored biomarkers that could be used for differentiating between bacterial and viral pneumonia in patients with community-acquired pneumonia (CAP)., Methods: In this prospective cohort study conducted in Japan, data obtained from adult patients with bacterial pneumonia, including bacterial and viral coinfections (bacterial pneumonia [BP] group), and purely viral pneumonia (VP group) at diagnosis were analyzed using multivariate logistic regression analysis to identify predictors of bacterial pneumonia. Furthermore, a decision tree was developed using the predictors., Results: A total of 210 patients were analyzed. The BP and VP groups comprised 108 and 18 patients, respectively. The other 84 patients had no identified causative microorganism. The two groups shared similar characteristics, including disease severity; however, a significant difference (p < 0.05) was observed between the two groups regarding sputum type; sputum volume score; neutrophil counts; and serum levels of interleukin (IL)-8, IL-10, and α1-antitrypsin (AAT). Sputum volume score (p < 0.001), IL-10 (p < 0.001), and AAT (p = 0.008) were ultimately identified as predictors of BP. The area under the curve for these three variables on the receiver operating characteristic (ROC) curve was 0.927 (95% confidence interval [CI]: 0.881-0.974). The ROC curve for sputum volume score and an AAT/IL-10 ratio showed a diagnostic cutoff of 1 + and 65, respectively. Logistic regression analysis using dichotomized variables at the cutoff values showed that the odds ratios for the diagnosis of BP were 10.4 (95% CI: 2.2-50.2) for sputum volume score (absence vs. presence) and 19.8 (95% CI: 4.7-83.2) for AAT/IL-10 ratio (< 65 vs. ≥ 65)., Conclusions: Considering that obtaining a definitive etiologic diagnosis with the current testing methods is difficult and time consuming, a decision tree with two predictors, namely sputum volume and the AAT/IL-10 ratio, can be useful in predicting BP among patients diagnosed with CAP and facilitating the appropriate use of antibiotics., Trial Registration: UMIN000034673 registered on November 29, 2018., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Primate germ cell development remains largely unexplored due to limitations in sample collection and the long duration of development. In mice, primordial germ cell-like cells (PGCLCs) derived from pluripotent stem cells (PSCs) can develop into functional gametes by in vitro culture or in vivo transplantation. Such PGCLC-mediated induction of mature gametes in primates is highly useful for understanding human germ cell development. Since marmosets generate functional sperm earlier than other species, recapitulating the whole male germ cell development process is technically more feasible. Here, we induced the differentiation of iPSCs into gonocyte-like cells via PGCLCs in marmosets. First, we developed an mRNA transfection-based method to efficiently generate PGCLCs. Subsequently, to promote PGCLC differentiation, xenoreconstituted testes (xrtestes) were generated in the mouse kidney capsule. PGCLCs show progressive DNA demethylation and stepwise expression of developmental marker genes. This study provides an efficient platform for the study of marmoset germ cell development., Competing Interests: Declaration of interests The authors declare competing interests., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Recent population genomic studies in plants have shed new light on natural epigenetic variation by identifying key genetic determinants, "trans modifiers," that influence epigenetic states genome-wide and their interplay with environmental factors. Here, we review this progress by focusing on the epigenetic control of transposition and life-cycle transitions to highlight the ecological consequences of this genetic architecture and its evolutionary significance. This knowledge provides new opportunities to address long-standing questions about the establishment of environment-associated epigenetic variation and its relevance in adaptation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We discuss leveraging a cutting-edge technology known as the Metaverse to tackle healthcare challenges, with a particular focus on enhancing patient satisfaction and improving working conditions for medical professionals. We plan to achieve this by improving real-digital collaboration and utilizing the advantages of the Metaverse, such as novel communication and experiences and increased work efficiency and quality. This article showcases several concrete examples of Metaverse services in the medical field, as demonstrated by the "Medical Metaverse Joint Research Course" established through a collaboration between IBM and Juntendo University, and also highlights possible future prospects.

Background: We aimed to define the indications for sentinel lymph node biopsy (SLNB), the third option for cervical treatment in oral cancer with negative cervical lymph nodes., Methods: The greatest depth of invasion (DOI) and long diameter (LD) of the primary site were used as exposures. SLN metastasis was considered the outcome., Results: In three trials conducted between 2009 and 2016, 158 patients were eligible and reassigned to this study group. The scatterplot based on the respective values of DOI and LD would eventually be divided into three sections. In cases of sections T1, T2, and T3, the proportions of SLN metastasis positivity were 21.3%, 35.3%, and 51.2%, respectively. In certain cases of T1 with 2 mm < DOI ≤ 5 mm and 8 mm < LD ≤ 20 mm, the proportion of SLN metastasis positivity was 40.9%., Conclusions: SLNB-navigated or assisted neck dissection can be added as an effective procedure for N0 neck control., (© 2023 Wiley Periodicals LLC.)

D,L-Propargylglycine (PAG) has been widely used as a selective inhibitor to investigate the biological functions of cystathionine γ-lyase (CSE), which catalyzes the formation of reactive sulfur species (RSS). However, PAG also inhibits other PLP (pyridoxal-5'-phosphate)-dependent enzymes such as methionine γ-lyase (MGL) and L-alanine transaminase (ALT), so highly selective CSE inhibitors are still required. Here, we performed high-throughput screening (HTS) of a large chemical library and identified oxamic hydrazide 1 as a potent inhibitor of CSE (IC 50  = 13 ± 1 μM (mean ± S.E.)) with high selectivity over other PLP-dependent enzymes and RSS-generating enzymes. Inhibitor 1 inhibited the enzymatic activity of human CSE in living cells, indicating that it is sufficiently membrane-permeable. X-Ray crystal structure analysis of the complex of rat CSE (rCSE) with 1 revealed that 1 forms a Schiff base linkage with the cofactor PLP in the active site of rCSE. PLP in the active site may be a promising target for development of selective inhibitors of PLP-dependent enzymes, including RSS-generating enzymes such as cystathionine β-synthase (CBS) and cysteinyl-tRNA synthetase 2 (CARS2), which have unique substrate binding pocket structures., (© 2023. Springer Nature Limited.)