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Bilateral communication between bones and muscles is essential for healing composite bone-muscle injuries from orthopedic surgeries and trauma. However, these injuries are often characterized by exaggerated inflammation, which can disrupt bone-muscle crosstalk, thereby seriously delaying the healing of either tissue. Existing approaches are largely effective at healing single tissues. However, simultaneous healing of multiple tissues remains challenging, with little research conducted to date. Here we introduce collagen patches that overcome this overlooked issue by harnessing the plasticity of macrophage phenotypes. Phosphatidylserine liposomes (PSLs) capable of shifting the macrophage phenotype from inflammatory M1 into anti-inflammatory/prohealing M2 were coated on collagen patches via a layer-by-layer method. Original collagen patches failed to improve tissue healing under inflammatory conditions coordinated by M1 macrophages. In contrast, PSL-coated collagen patches succeeded in accelerating bone and muscle healing by inducing a microenvironment dominated by M2 macrophages. In cell experiments, differentiation of preosteoblasts and myoblasts was completely inhibited by secretions of M1 macrophages but unaffected by those of M2 macrophages. RNA-seq analysis revealed that type I interferon and interleukin-6 signaling pathways were commonly upregulated in preosteoblasts and myoblasts upon stimulation with M1 macrophage secretions, thereby compromising their differentiation. This study demonstrates the benefit of PSL-mediated M1-to-M2 macrophage polarization for simultaneous bone and muscle healing, offering a potential strategy toward simultaneous regeneration of multiple tissues. STATEMENT OF SIGNIFICANCE: Existing approaches for tissue regeneration, which primarily utilize growth factors, have been largely effective at healing single tissues. However, simultaneous healing of multiple tissues remains challenging and has been little studied. Here we demonstrate that collagen patches releasing phosphatidylserine liposomes (PSLs) promote M1-to-M2 macrophage polarization and are effective for simultaneous healing of bone and muscle. Transcriptome analysis using next-generation sequencing reveals that differentiation of preosteoblasts and myoblasts is inhibited by the secretions of M1 macrophages but promoted by those of M2 macrophages, highlighting the importance of timely regulation of M1-to-M2 polarization in tissue regeneration. These findings provide new insight to tissue healing of multiple tissues., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Riki Toita received a research grant from NGK Spark Plug Co., Ltd. (currently Niterra Co., Ltd.) Masahiro Kitamura, Atsushi Kato, Hideto Yamada, Shogo Yamaguchi, and Shinjiro Kasahara are employees of Niterra Co., Ltd. The remaining authors declare no competing interests., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Teicoplanin (TEIC) is a nephrotoxic agent. However, little is known about the effects of concomitant medications on nephrotoxicity. In this study, we investigated the effects of concomitant drugs on nephrotoxicity., Methods: A retrospective observational case-control study was conducted on patients (≥18 years) who started TEIC at the Tokyo Dental College, Ichikawa General Hospital, between January 2013 and April 2023. The primary outcome was nephrotoxicity, defined as an increase in serum creatinine levels of ≥50% or ≥0.5 mg/dL from baseline. Logistic regression analysis was used to determine the risk factors for nephrotoxicity associated with TEIC. In addition, we investigated the relationship between nephrotoxicity and predicted free TEIC concentrations., Results: Of 305 patients, 43 (14.1%) developed nephrotoxicity. The multivariate logistic regression analysis identified that serum albumin (odds ratio [OR] = 0.50, 95% confidence interval [CI] 0.27-0.89, p=0.02), concomitant use of loop diuretics (OR = 2.22, 95% CI 1.10-4.59, p = 0.03), antivirals (OR = 3.24, 95% CI 1.32-7.62, p <0.01), and vasopressors (OR = 2.57, 95% CI 1.10-5.78, p = 0.03) were the associated risk factors for nephrotoxicity in patients administered with TEIC. In 216 patients, predicted TEIC concentrations were 3.6 [interquartile range (IQR), 2.6-4.9] μg/mL in the nephrotoxicity group versus 3.6 [IQR, 2.5-4.7] μg/mL in the non-nephrotoxicity group, with no significant difference (p = 0.69)., Conclusion: Our results indicate the importance of modifying the concomitant use of loop diuretics, antivirals, and vasopressors., Competing Interests: Declaration of Competing Interest: None., (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.)

Background: Periodontal disease is the leading cause of tooth loss, and an association between periodontal disease and non-oral systemic diseases has been shown. Formation of biofilm by periodontal pathogens such as Fusobacterium nucleatum, Porphyromonas gingivalis, and Streptococcus mutans and their resistance to antimicrobial agents are at the root of persistent and chronic bacterial infections., Methods: The bactericidal effect of far-ultraviolet (F-UV) light irradiation at 222 nm on periodontal bacteria was assessed qualitatively and quantitatively. The effect of biofilm disruption by F-UV light on periodontal bacteria was examined by crystal violet staining, and the morphologic changes of the biofilm after F-UV irradiation were explored by confocal laser microscopy and scanning electron microscopy. We developed a thin fiber-type 222 nm F-UV irradiator and studied its safety and effect of reducing bacteria in rodent models., Results: F-UV light at 222 nm had a bactericidal effect on F. nucleatum, P. gingivalis, and S. mutans. Irradiation with F-UV light reduced the biofilm formed by the bacteria and sterilized them from within. Confocal laser microscopy showed a clear reduction in biofilm thickness, and scanning electron microscopy confirmed disintegration of the biofilm architecture. F-UV irradiation was less damaging to DNA and less cytotoxic than deep-ultraviolet light, and it reduced bacterial counts on the tooth surface., Conclusion: F-UV irradiation has the potential to destroy biofilm and act as a bactericide against pathogenic bacteria in the biofilm., Competing Interests: Declaration of competing interest J.N., T.F., S.F., and K.H. are the inventors of the device in the patent application (2022-073254) filed by Ushio Inc. and Yamaguchi University for biofilm dispersion by far-ultraviolet light described in this manuscript. The application is currently under examination. The other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: A relationship between endoscopic submucosal dissection (ESD) and deep vein thrombosis has been recognized. We previously reported that a high corrected midazolam dose (total midazolam dose/initial dose of midazolam used to induce sedation) is related to elevated D-dimer levels after ESD. In this study, the effect of compression stockings (CSs) in preventing thrombosis following ESD under sedation was evaluated by measuring D-dimer levels before and after ESD., Methods: The participants were patients who underwent ESD for upper gastrointestinal tumors during the period between April 2018 and October 2022. Patients with pre-ESD D-dimer levels ≥1.6 µg/m and patients with corrected midazolam doses ≤3.0 were excluded. A retrospective investigation of the relationship between CS use and high post-ESD D-dimer levels (difference in D-dimer levels ≥1.0 µg/mL between before and after ESD) was conducted., Results: There were 27 patients in the non-CS group (NCS) and 33 patients in the CS group. The number of patients with high post-ESD D-dimer levels was 13 (48.2%) in the non-CS group and six (18.2%) in the CS group; the number in the CS group was significantly lower ( p = 0.024). On logistic regression analysis, a relationship was seen between the wearing of CSs and a lower number of patients with high post-ESD D-dimer levels (odds ratio 0.24, 95% confidence interval 0.08-0.79, p = 0.019)., Conclusion: Wearing CSs was related to a lower risk of high post-ESD D-dimer levels. This result suggests that thrombus formation is a cause of elevated D-dimer levels after ESD., Competing Interests: None., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Notably, certain nutrients are effective in preventing migraine. Nonetheless, zinc replacement therapy for migraine treatment has yet to be explored. We herein report four patients with migraine who were refractory to prophylactic therapy and whose headache frequency and severity improved with zinc supplementation. Zinc administration may be an option for treating patients with prophylaxis-refractory migraine. Further investigation is required to determine the efficacy of zinc replacement therapy as a treatment option for migraine.

Mesophotic coral ecosystems (MCEs) are light-dependent tropical or subtropical communities occurring at depths of 30-150 m. Broader surveys of MCEs are needed to better understand stony corals, the keystone species of coral-reef ecosystems. While MCEs have been studied by professional SCUBA divers and with deep-sea robots, comprehensive surveys of MCEs are required. An eDNA metabarcoding method has recently been used to survey scleractinian corals in shallow reefs. We tested whether MCEs might be more comprehensively surveyed by collecting seawater samples using an underwater mini-remote operated vehicle (mini-ROV). Seawater was collected 1-2 m above reef tops at depths of 20-80 m at 24 sites in six locations around the Zamami Islands (Okinawa, Japan). Water samples were then subjected to coral-specific eDNA amplification. Metabarcoding analyses of amplicons showed that except for one site, coral-specific eDNA from approximately 0.5 l seawater samples was sufficient to identify genera. The proportion of Acropora eDNA was higher at shallow reefs and upper ridges of slopes, while the proportion of Porites increased at mesophotic sites . Although further technical improvements are required, this study suggests that it may be possible to monitor mesophotic corals to the generic level using eDNA collected using mini-ROVs., Competing Interests: We declare no competing interests., (© 2024 The Authors.)

Recent studies have shown a role of inflammation in muscle atrophy and sarcopenia. However, no anti-inflammatory pharmacotherapy has been established for the treatment of sarcopenia. Here, we investigate the potential role of PPARα and its ligands on inflammatory response and PGC-1α gene expression in LPS-treated C2C12 myotubes. Knockdown of PPARα, whose expression was upregulated upon differentiation, augmented IL-6 or TNFα gene expression. Conversely, PPARα overexpression or its activation by ligands suppressed 2-h LPS-induced cytokine expression, with pemafibrate attenuating NF-κB or STAT3 phosphorylation. Of note, reduction of PGC-1α gene expression by LPS treatment for 24 hours was partially reversed by fenofibrate. Our data demonstrate a critical inhibitory role of PPARα in inflammatory response of C2C12 myotubes and suggest a future possibility of PPARα ligands as a candidate for anti-inflammatory therapy against sarcopenia., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tomohiro Tanaka reports a relationship with Kowa Company Ltd that includes: speaking and lecture fees. All the other 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 Inc. All rights reserved.)

Although tyrosine kinase inhibitor (TKI) therapy shows marked clinical efficacy in patients with anaplastic lymphoma kinase-positive (ALK+) and ROS proto-oncogene 1-positive (ROS1+) non-small cell lung cancer (NSCLC), most of these patients eventually relapse with acquired resistance. Therefore, genome-wide CRISPR/Cas9 knockout screening was performed using an ALK+ NSCLC cell line established from pleural effusion without ALK-TKI treatment. After 9 days of ALK-TKI therapy, sequencing analysis was performed, which identified several tumor suppressor genes, such as NF2 or MED12, and multiple candidate genes. Among them, this study focused on ERRFI1, which is known as MIG6 and negatively regulates EGFR signaling. Interestingly, MIG6 loss induced resistance to ALK-TKIs by treatment with quite a low dose of EGF, which is equivalent to plasma concentration, through the upregulation of MAPK and PI3K/AKT/mTOR pathways. Combination therapy with ALK-TKIs and anti-EGFR antibodies could overcome the acquired resistance in both in vivo and in vitro models. In addition, this verified that MIG6 loss induces resistance to ROS1-TKIs in ROS1+ cell lines. This study found a potentially novel factor that plays a role in ALK and ROS1-TKI resistance by activating the EGFR pathway with low-dose ligands.

Laparoscopy provides extensive data for the decannulation of a peritoneal dialysis catheter and is being increasingly used to diagnose encapsulating peritoneal sclerosis. However, there are few reports on the methods of decannulation of peritoneal dialysis catheters. In this study, we examined the laparoscopic findings and postoperative complications of patients undergoing peritoneal dialysis catheter removal. A total of 119 laparoscopic decannulations of peritoneal dialysis catheters were performed between 2003 and 2018 at the Juntendo University Hospital and Juntendo University Nerima Hospital. Laparoscopy was performed during peritoneal dialysis catheter removal by a gastrointestinal surgeon. Patient characteristics such as age, sex, duration of peritoneal dialysis, history of peritonitis and age at the time of peritoneal dialysis termination were assessed. Of these 119 cases, 19 (16.0%) showed adhesion between the peritoneal dialysis catheter and intraperitoneal organs. There were 13 (10.9%) cases involving a tangled omentum, 4 (3.4%) cases involving the small intestine and 2 (1.7%) cases of adhesions extending from the bowels to the abdominal wall. No postoperative complications were associated with the laparoscopic surgery. In these cases, blind decannulation of the peritoneal dialysis catheter may result in injury to the gastrointestinal tract in patients with adhesions. Therefore, we need to pay attention to adhesions between peritoneal dialysis catheters and intraperitoneal organs, and laparoscopy could be a valuable tool in detecting such adhesions and ensuring patient safety., (© 2023 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

A new, to the best of our knowledge, method of generating interference patterns based on a non-orthogonal Lloyd's mirror interferometer with a spatial phase modulation is proposed. In the proposed method, a spatial light modulator (SLM) is introduced to a conventional non-orthogonal Lloyd's mirror interferometer so that arbitrary interference patterns, such as line interference patterns with varied line-spacing or two-dimensional patterns, can be generated by controlling the wavefronts of the laser beams at each position on the substrate. In this paper, as the first step of the research, the feasibility of the proposed method is theoretically confirmed by calculating interference patterns to be obtained when a spatial modulation of the phase delay is applied to the laser beams. A prototype of a non-orthogonal one-axis Lloyd's mirror interferometer with an SLM in its optical path is also designed and constructed. Some basic experiments are carried out to demonstrate the feasibility of the generation of interference patterns having varied line-spacing and two-dimensional patterns by the proposed method.

Tau PET tracers are expected to be sufficiently sensitive to track the progression of age-related tau pathology in the medial temporal cortex. The tau PET tracer N -(4-[ 18 F]fluoro-5-methylpyridin-2-yl)-7-aminoimidazo[1,2-a]pyridine ([ 18 F]SNFT-1) has been successfully developed by optimizing imidazo[1,2-a]pyridine derivatives. We characterized the binding properties of [ 18 F]SNFT-1 using a head-to-head comparison with other reported 18 F-labeled tau tracers. Methods: The binding affinity of SNFT-1 to tau, amyloid, and monoamine oxidase A and B was compared with that of the second-generation tau tracers MK-6240, PM-PBB3, PI-2620, RO6958948, JNJ-64326067, and flortaucipir. In vitro binding properties of 18 F-labeled tau tracers were evaluated through the autoradiography of frozen human brain tissues from patients with diverse neurodegenerative disease spectra. Pharmacokinetics, metabolism, and radiation dosimetry were assessed in normal mice after intravenous administration of [ 18 F]SNFT-1. Results: In vitro binding assays demonstrated that [ 18 F]SNFT-1 possesses high selectivity and high affinity for tau aggregates in Alzheimer disease (AD) brains. Autoradiographic analysis of tau deposits in medial temporal brain sections from patients with AD showed a higher signal-to-background ratio for [ 18 F]SNFT-1 than for the other tau PET tracers and no significant binding with non-AD tau, α-synuclein, transactiviation response DNA-binding protein-43, and transmembrane protein 106B aggregates in human brain sections. Furthermore, [ 18 F]SNFT-1 did not bind significantly to various receptors, ion channels, or transporters. [ 18 F]SNFT-1 showed a high initial brain uptake and rapid washout from the brains of normal mice without radiolabeled metabolites. Conclusion: These preclinical data suggest that [ 18 F]SNFT-1 is a promising and selective tau radiotracer candidate that allows the quantitative monitoring of age-related accumulation of tau aggregates in the human brain., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Photoresponsiveness is a promising characteristic of stimulus-responsive materials. Photoresponsiveness can be achieved by incorporating photoresponsive molecules into polymeric materials. In addition, multiple-stimuli-responsive materials have attracted scientists' interest. Among the numerous multiple-stimuli-responsive materials, moisture- and photoresponsive materials are the focus of this report. These stimuli-responsive materials responded to the stimuli synergistically or orthogonally. Unlike most stimulus-responsive materials utilizing moisture and light as stimuli, the materials studied herein switch their photoresponsiveness in the presence of moisture. Appropriate copolymers consisting of hydrophilic acrylamide-based monomers for the main chain and hydrophobic azobenzene moieties switched their bending behaviors at 6-9 wt% water contents. At water contents lower than 6 wt%, the polymeric materials bent away from the light source, while they bent toward the light source at water contents higher than 10 wt%. At a low water content, the bending behaviors can be described on the molecular scale. At a high water content, the bending behavior requires consideration of the phase scale, not only the molecular scale. By controlling the balance between hydrophilicity and hydrophobicity, the switching behavior was achieved. This switching behavior may inspire additional strategies for the application of polymeric material as actuators.

Endoscopic submucosal dissection (ESD) is almost always performed with a sedative because of the longer procedure times involved. The risk of post-ESD deep vein thrombosis (DVT) has been reported as relatively high, and D-dimer levels are sometimes elevated after ESD. This retrospective study evaluated factors affecting changes in D-dimer levels from before to after ESD to identify causes of elevated D-dimer levels after ESD. This retrospective analysis included 117 patients with gastrointestinal tumors resected using ESD. After excluding eight patients with pre-ESD levels of D-dimer >1.5 μg/mL, factors correlating with changes in D-dimer from before to after ESD were analyzed using logistic regression analysis in 109 patients. Sedation was accomplished primarily using midazolam, but, because the sedative effect of midazolam shows marked inter-individual variability, a "corrected midazolam dose" was determined by dividing the total midazolam dose by the initial dose to correct for inter-individual differences in the sedative effect of midazolam. This value was used as one potential explanatory variable in the subgroup analysis of the 103 patients who received midazolam. In the subgroup analysis using the corrected midazolam dose as an explanatory variable, only the corrected midazolam dose correlated with a change in D-dimer ≥1.0 μg/mL in multivariate analysis (odds ratio (OR) = 1.5, 95% confidence interval (CI) 0.43-0.95; p = 0.030). The corrected midazolam dose correlated with increases in post-ESD D-dimer levels. This potential relationship indicates that patients undergoing ESD and requiring extended sedation may be at increased risk of DVT.

Saccharomyces boulardii group (SB group) calves were fed 2.0 × 10 10 CFU/day of S. boulardii in milk replacer after 2 wk of age. All calves received inactivated vaccine for Histophilus somni, Pasteurella multocida , and Mannheimia haemolytica at 3 wk of age and 3 wk later. After vaccination, the SB group calves showed significantly higher (mean difference: 1.56-fold) antibody titer against H. somni than the control group. The number of calves with the antibody titer above the cut-off value for M. haemolytica of the SB group was significantly higher than that of the control, and the percentage was twice as high. In addition, the mRNA transcription of IL4 and IL10 in peripheral blood mononuclear cells at the booster of the SB group was significantly higher than those of the control. In conclusion, S. boulardii may have positively affected immune responses to the inactivated multi-bacterial vaccine in young calves in the field., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Antisense oligonucleotide (ASO)-mediated exon skipping has become a valuable tool for investigating gene function and developing gene therapy. Machine-learning-based computational methods, such as eSkip-Finder, have been developed to predict the efficacy of ASOs via exon skipping. However, these methods are computationally demanding, and the accuracy of predictions remains suboptimal. In this study, we propose a new approach to reduce the computational burden and improve the prediction performance by using feature selection within machine-learning algorithms and ensemble-learning techniques. We evaluated our approach using a dataset of experimentally validated exon-skipping events, dividing it into training and testing sets. Our results demonstrate that using a three-way-voting approach with random forest, gradient boosting, and XGBoost can significantly reduce the computation time to under ten seconds while improving prediction performance, as measured by R 2 for both 2'-O-methyl nucleotides (2OMe) and phosphorodiamidate morpholino oligomers (PMOs). Additionally, the feature importance ranking derived from our approach is in good agreement with previously published results. Our findings suggest that our approach has the potential to enhance the accuracy and efficiency of predicting ASO efficacy via exon skipping. It could also facilitate the development of novel therapeutic strategies. This study could contribute to the ongoing efforts to improve ASO design and optimize gene therapy approaches.

This study aimed to investigate the appropriate subgroups for surgery and adjuvant chemotherapy in patients with non-small-cell lung cancer (NSCLC) and nodal metastases. We retrospectively reviewed 210 patients with NSCLC and nodal metastases who underwent surgery and examined the risk factors for poor overall survival (OS) and recurrence-free probability (RFP) using multivariate Cox proportional hazards analysis. Pathological N1 and N2 were observed in 114 (52.4%) and 96 (47.6%) patients, respectively. A single positive node was identified in 102 patients (48.6%), and multiple nodes were identified in 108 (51.4%). Multivariate analysis revealed that vital capacity < 80% (hazard ratio [HR]: 2.678, 95% confidence interval [CI]: 1.483-4.837), radiological usual interstitial pneumonia pattern (HR: 2.321, 95% CI: 1.506-3.576), tumor size > 4.0 cm (HR: 1.534, 95% CI: 1.035-2.133), and multiple-node metastases (HR: 2.283, 95% CI: 1.517-3.955) were significant independent risk factors for poor OS. Tumor size > 4.0 cm (HR: 1.780, 95% CI: 1.237-2.562), lymphatic permeation (HR: 1.525, 95% CI: 1.053-2.207), and multiple lymph node metastases (HR: 2.858, 95% CI: 1.933-4.226) were significant independent risk factors for recurrence. In patients with squamous cell carcinoma ( n = 93), there were no significant differences in OS or RFP between those who received platinum-based adjuvant chemotherapy ( n = 25) and those who did not ( n = 68), at p = 0.690 and p = 0.292, respectively. Multiple-node metastases were independent predictors of poor OS and recurrence. Patients with NSCLC and single-node metastases should be considered for surgery despite N2 disease. Additional treatment with platinum-based adjuvant chemotherapy may be expected, especially in patients with squamous cell carcinoma.

Background: Mantle cell lymphoma is considered an aggressive B-cell lymphoma. The optimal induction regimen remains controversial as no randomized controlled trial has compared the efficacy of different induction therapies., Method: Herein, we performed a retrospective analysis of the clinical characteristics of 10 patients who received induction treatment consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab, bendamustine, and cytarabine (R-BAC) at Toranomon Hospital between November 2016 and February 2022., Result: Although one patient discontinued R-BAC therapy due to a rash, the other nine completed the scheduled chemotherapy. All patients achieved complete response, underwent high-dose chemotherapy and autologous stem cell transplantation, and maintained complete remission with a median follow-up of 15 months. Hematological adverse events (AEs) occurred in all patients; however, none developed documented infection. There were also no fatal non-hematological AEs specific to R-BAC., Conclusion: R-CHOP/R-BAC may be a good induction therapy for transplant-eligible patients with mantle cell lymphoma., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The importance of a shared decision-making (SDM) approach is widely recognized worldwide. In Japan, hospital accreditation involves the promotion of SDM for patients with end-stage renal disease (ESRD) when considering renal replacement therapy (RRT). This study aimed to clarify the effectiveness and long-term medical benefits of SDM in RRT. Patients with ESRD who underwent dialysis therapy were retrospectively divided into those who visited outpatient clinics specific for ESRD (ESRD clinic) supporting RRT selection with an SDM approach (visited group) and those who did not visit the ESRD clinic (non-visited group). Data of 250 patients (129 in the non-visited group and 121 in the visited group) were analyzed. Mortality was significantly higher in the non-visited group than in the visited group. Not seeing an ESRD specialist was associated with emergent initiation of dialysis and subsequent 1 year mortality. The number of patients who chose peritoneal dialysis as a modality of RRT was significantly larger in the visited group. These findings demonstrate the association between the ESRD clinic, 1 year survival in patients with ESRD after initiating dialysis, and the different RRT modalities. This specific approach in the ESRD clinic may improve the management of patients with ESRD., (© 2023. The Author(s).)

We examined the impact of statins on protein kinase D (PKD) activation by G protein-coupled receptor (GPCR) agonists. Treatment of intestinal IEC-18 cells with cerivastatin inhibited PKD autophosphorylation at Ser 916 induced by angiotensin II (ANG II) or vasopressin in a dose-dependent manner with half-maximal inhibition at 0.2 µM. Cerivastatin treatment inhibited PKD activation stimulated by these agonists for different times (5-60 min) and blunted HDAC5 phosphorylation, a substrate of PKD. Other lipophilic statins, including simvastatin, atorvastatin, and fluvastatin also prevented PKD activation in a dose-dependent manner. Using IEC-18 cell lines expressing PKD1 tagged with EGFP (enhanced green fluorescent protein), cerivastatin or simvastatin blocked GPCR-mediated PKD1-EGFP translocation to the plasma membrane and its subsequent nuclear accumulation. Similar results were obtained in IEC-18 cells expressing PKD3-EGFP. Mechanistically, statins inhibited agonist-dependent PKD activation rather than acting directly on PKD catalytic activity since exposure to cerivastatin or simvastatin did not impair PKD autophosphorylation or PKD1-EGFP membrane translocation in response to phorbol dibutyrate, which bypasses GPCRs and directly stimulates PKC and PKD. Furthermore, cerivastatin did not inhibit recombinant PKD activity determined via an in vitro kinase assay. Using enteroids generated from intestinal crypt-derived epithelial cells from PKD1 transgenic mice as a model of intestinal regeneration, we show that statins oppose PKD1-mediated increase in enteroid area, complexity (number of crypt-like buds), and DNA synthesis. Our results revealed a previously unappreciated inhibitory effect of statins on receptor-mediated PKD activation and in opposing the growth-promoting effects of PKD1 on intestinal epithelial cells.

A measurement method based on a confocal probe on the second harmonic generation that can measure linear and angular displacements in the focusing point is proposed. In the proposed method, a pinhole or an optical fiber placed in front of the detector in conventional confocal probes is replaced by a nonlinear optical crystal, which is utilized as a medium generating second harmonic wave whose light intensity changes by the linear and angular displacements of a target under measurement. The feasibility of the proposed method is verified by theoretical calculations and experiments with the newly designed optical setup. Experimental results have demonstrated that the developed confocal probe has a resolution of 20 nm and 5 arc-seconds for measurement of linear and angular displacements, respectively.

Background: Anemia in patients with chronic kidney disease (p-CKDs) may initiate or exacerbate left ventricular hypertrophy (LVH). This study aimed to determine whether treatment using long-acting erythropoietin-stimulating agents (L-ESAs) is independently associated with LVH during the pre-dialysis to maintenance dialysis period in p-CKDs., Methods: Physical and laboratory examinations were performed 120 days before initiating dialysis in p-CKDs (baseline). To evaluate the left ventricular mass index (LVMI) after starting dialysis, the mean hemoglobin (Hb) was defined as the average at the start of dialysis and 6 months after starting dialysis. Changes in the LVMI were observed in three groups according to mean Hb levels (Hb < 10.1, 10.1 < Hb < 11.0, and Hb > 11.0 g/dL for Groups 1, 2, and 3, respectively). LVMI was evaluated using echocardiography at the pre-dialysis, initiation, and maintenance dialysis periods., Results: A lower LVMI at dialysis initiation and an improvement in LVMI were detected in the highest tertile group of mean Hb (11.0 g/dl). Consequently, in the high Hb group (Hb level > 11.0 g/dl), LVMI remained low from dialysis initiation until after 6 months.The relationship between Hb and LVMI was not significant; however, a constant correlation with β ≥ 0.4 in the absolute value was maintained., Conclusion: L-ESAs may correlate with Hb and LVMI after administration, independent of the baseline LVMI and Hb values. These findings have therapeutic implications in the treatment strategies for p-CKDs during the pre-dialysis to maintenance dialysis period., (© 2023. The Author(s).)

Background Bcor: CCNB3 sarcoma is a rare mesenchymal tumor that was formerly included in the undifferentiated/unclassified sarcoma group and was recently reclassified as one of undifferentiated small round cell sarcomas with a genetically distinct subtype in the WHO 2020 classification. Because of its rarity, still not much is known, especially about its clinical features. CASE REPORT A 15-year-old boy presented with almost 1-year intermittent thigh pain. On the first visit, a pathologic fracture of the femur and a big mass expanding through the femoral cortex with lobular shape and homogenous appearance were recognized on radiography and magnetic resonance imaging. Plain radiography, which was taken 6 months before at a local clinic, showed an expansion and thickening of the right proximal femoral shaft. Biopsy specimen of the lesion revealed a proliferation of round to spindle tumor cells with diffuse and strong immunohistochemical nuclear positivity for BCOR and CCNB3. Under the diagnosis of BCOR::CCNB3 sarcoma of the femur, a chemotherapy based on a protocol of Ewing sarcoma, followed by a wide resection and total femoral replacement surgery, were conducted. The effect of chemotherapy was favorable, showing no microscopic residual tumor. Although postoperative chemotherapy was not completed because of a minor infection detected on the surgical site, the patient was doing well, without any recurrence, for 26 months., Conclusions Bcor: CCNB3 sarcoma of the bone is a quite rare tumor with much lower incidence than Ewing sarcoma. Notable clinical characteristics of the current case were a 1-year-long symptomatic period and homogenous appearance on MRI.

Objective: To identify the risks of myocarditis or pericarditis after vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in Japan., Methods: We conducted an observed-to-expected analysis (OE analysis) of spontaneous reports of suspected adverse events from pharmaceutical companies, calculating rate ratios with myocarditis and pericarditis after the vaccination of the mRNA vaccines Comirnaty (BNT162b2) and Spikevax (mRNA-1273) and expected rate of myocarditis and pericarditis in the population before the COVID-19 pandemic. These reports dated from 17/2/2021 to 14/11/2021 and from 22/5/2021 to 14/11/2021 for Comirnaty and Spikevax, respectively. The observed-to-expected ratios (OE ratios) for each vaccine were estimated by age groups and sex., Results: We identified 281 and 195 cases of myocarditis or pericarditis for Comirnaty and Spikevax, respectively, which were administrated 163,059,502 and 31,768,352 doses for Comirnaty and Spikevax until the 14th of November 2021, respectively. The OE ratios were statistically significantly higher in adolescent and young adult males in their age of teens and twenties after the second dose in a two-dose series [Comirnaty in teens male: 6.15 (95% CI, 2.26-21.98), Comirnaty in twenties male: 2.86 (95% CI, 1.13-8.38), Spikevax in teens male: 41.59 (95% CI, 5.64-43,281.94), Spikevax in twenties male: 16.84 (95%CI, 6.77-57.49)]., Conclusions: Risks of myocarditis and pericarditis following SARS-CoV-2 mRNA vaccines in Japan seems to be significantly elevated for adolescent and young adult males., (© 2022. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Background: Surgical margin recurrence following segmentectomy is a critical issue because it may have been avoided by lobectomy., Methods: Between January 2000 and December 2018, we retrospectively investigated 199 patients who underwent segmentectomy for c-StageⅠ non-small cell lung cancer at our hospital., Results: Recurrence occurred in 20 cases, of which 3 cases had surgical margin recurrence. In our previous study, the recurrence risk factor after segmentectomy was radiologic solid tumor size( cut-off value 1.5 cm). Of the 130 patients in the low-risk group with radiologic solid tumor size of less than 1.5 cm, five had any recurrence, three of which had surgical margin recurrence. In the high-risk group with radiologic solid tumor size of 1.5 cm or more, no surgical margin recurrence was observed. Three cases of surgical margin recurrence were accompanied by lepidic components, and the tumors were difficult to identify intraoperatively and were located close to adjacent areas., Conclusion: Surgical margin recurrence may be avoided by carefully considering the segments to be resected and improving the method for identifying the intersegmental plane.

A modified two-axis surface encoder is proposed to separately measure both the in-plane displacement and the Z -directional out-of-plane displacement with minor crosstalk errors. The surface encoder is composed of a scale grating and a small-sized sensor head. In the modified surface encoder, the measurement laser beam from the sensor head is designed to be projected onto the scale grating at a right angle. For measurement of the X - and Y -directional in-plane scale displacement, the positive and negative first-order diffracted beams from the scale grating are superimposed on each other in the sensor head, producing interference signals. On the other hand, the Z -directional out-of-plane scale displacement is measured based on the principle of a Michelson-type interferometer. To avoid the influence of reflection from the middle area of the transparent grating, which causes periodic crosstalk errors in the previous research, a specially fabricated transparent grating with a hole in the middle is employed in the newly designed optical system. A prototype sensor head is constructed, and basic performances of the modified surface encoder are tested by experiments.

A new method based on the interferometric pseudo-lateral-shearing method is proposed to evaluate the pitch variation of a large-scale planar variable-line-spacing (VLS) grating. In the method, wavefronts of the first-order diffracted beams from a planar VLS grating are measured by a commercial Fizeau form interferometer. By utilizing the differential wavefront of the first-order diffracted beam before and after the small lateral shift of the VLS grating, the pitch variation of the VLS grating can be evaluated. Meanwhile, additional positioning errors of the grating in the lateral shifting process could degrade the measurement accuracy of the pitch variation. To address the issue, the technique referred to as the reference plane technique is also introduced, where the least squares planes in the wavefronts of the first-order diffracted beams are employed to reduce the influences of the additional positioning errors of the VLS grating. The proposed method can also reduce the influence of the out-of-flatness of the reference flat in the Fizeau interferometer by taking the difference between the measured positive and negative diffracted wavefronts; namely, self-calibration can be accomplished. After the theoretical analysis and simulations, experiments are carried out with a large-scale VLS grating to verify the feasibility of the proposed methods. Furthermore, the evaluated VLS parameters are verified by comparing them with the readout signal of an absolute surface encoder employing the evaluated VLS grating as the scale for measurement.

Prevention of hypothermia induced by anesthesia and enhanced by low environmental temperatures is difficult in magnetic resonance imaging (MRI) examinations in dogs as forced warming devices, including magnetic materials, are not acceptable for use in the MRI room. A hot water bottle (HWB) can be carried into an MRI examination room and can contribute to the prevention or attenuation of hypothermia. Here, we retrospectively investigated the effects of HWB on body temperature during MRI examinations in dogs under general anesthesia (GA). From anesthesia records of the Veterinary Medical Teaching Hospital, Okayama University of Science, validated data of 100 dogs that underwent an MRI examination under GA were obtained and divided into the following two groups: one group received HWB, while the other did not. Decrease in rectal temperature 15 min after intubation was significantly smaller in the group using HWB than in the group without HWB. In conclusion, the use of hot water bottles might be one of the methods to attenuate hypothermia in the early period but should not be expected for complete prevention of hypothermia, and it was not recommendable necessarily for body temperature management during MRI examinations in dogs under general anesthesia.

Purpose: The size of the distal electrode and the method of measuring local impedance (LI) are different between the IntellaNav MiFi-OI™ (MiFi-OI) and IntellaNav STABLE POINT™ (SP) catheters. We investigated the impact of these differences on LI, efficacy, and safety of radiofrequency (RF) applications., Methods: RF applications at a range of powers (30 W, 40 W, and 50 W), contact forces (10 g and 20 g), and durations (10-120 s) were performed in excised porcine hearts (N = 48). LI variation was defined by δLI-drop (= initial LI - post-RF LI) and %LI-drop (= δLI-drop/initial LI) × 100, and the relationship between lesion characteristics and LI variation was compared., Results: A total of 576 lesions were examined. Although absolute δLI-drop during RF applications was significantly larger for the SP than MiFi-OI catheter (47[31-65]ohm for SP vs 37[24-51]ohm for MiFi-OI, p < 0.0001), %LI-drop was similar (23.3 [15.5-30.6]% in SP vs 24.9[17.3-32.5]% in MiFi-OI, p = 0.10). Although lesions produced by both catheters were similarly correlated with LI variation, the SP catheter produced generally larger lesions (depth; 5.0 [3.7-6.1]mm vs 4.7 [3.3-6.0]mm, p = 0.06; surface areas, 46.9 [36.8-58.8]mm 2 vs 44.7 [34.3-55.5]mm 2 , p = 0.02; volume, 321 [165-533]mm 3 vs 265[141-471]mm 3 , p = 0.02). Steam pops were similarly observed with both catheters. In both catheters, %LI-drop was superior to δLI-drop in correlation to lesion size (p < 0.0001) and in predicting steam pops (p < 0.01)., Conclusions: Although no difference in safety profile is observed between MiFi-OI and SP catheters, the SP catheter produces larger lesions. %LI-drop is superior to δLI-drop in correlation to lesion size and in predicting steam pops as well as in normalizing the difference between catheters., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Local impedance (LI) measurement from an ablation catheter is useful in predicting lesion size and acute success of pulmonary vein isolation (PVI). The LI variation can be described by absolute LI drop (ΔLID) or ΔLID/initial LI (%LID). We evaluated the utility of these parameters in predicting acute lesion durability during PVI using a novel catheter capable of measuring both LI and contact force (CF)., Methods: PVI with a targeted CF, power, and duration was performed in 23 consecutive patients with paroxysmal atrial fibrillation. LI was blinded to operators during ablation. Parameters for each RF application were collected and compared for acute successful lesions and gaps., Results: A total of 1633 RF applications including 97 (5.9%) gap lesions were analyzed. Successful lesions were more frequently observed at non-carinal sites and those with higher contact force, FTI, initial LI, and larger variation of LI and generator impedance (GI). Multivariate analysis demonstrated that absolute GI drop (ΔGID) [OR 1.09 (1.04-1.15), p < 0.001], ΔLID [1.12 (1.09-1.16), p < 0.001], ΔGID/initial GI (%GID) [OR 1.04 (1.01-1.07), p = 0.01], and %LID [OR 1.15 (1.12-1.28), p < 0.001] were significantly associated with successful lesions, and carinal site [OR 0.15(0.09-0.24), p < 0.001] was significantly related to gaps. Both ΔLID and %LID equally predicted the acute durability of lesions during PVI. ΔLID ≥ 24Ω and %LID ≥ 15% at the carina, and ΔLID ≥ 21Ω and %LID ≥ 14% at non-carinal sites significantly predicted acute successful lesions with negative predictive values of 93-99%., Conclusions: Both ΔLID and %LID were equally useful in predicting acute successful lesions during PVI. Larger cut-off values should be applied to carinal sites., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Although differential pacing conventionally has been used to confirm the achievement of block across linear lesion sets, high-resolution mapping demonstrates that pseudo-block is observed in 20%-30% of cases., Objectives: The purpose of this study was to examine the reliability and versatility of a method using "activation vectors" based on omnipolar technology to confirm the block line., Methods: Linear ablation was performed during pacing, with the HD Grid catheter (Abbott) placed beside the linear lesion opposite the pacing site. The endpoint of complete linear lesion was complete inversion of the activation vectors to the opposite direction. When inversion of the activation vectors was not observed after 10 minutes of radiofrequency (RF) application, high-resolution mapping was performed to assess whether complete block was achieved., Results: In 33 patients, 24 cavotricuspid isthmus lines, 11 mitral isthmus (MI) lines, 16 posterior lines, and 2 intercaval lines were performed using this method. Of the total of 53 lines, 10 (18.9%) required intermediate evaluation of the block line with high-resolution mapping because of the absence of inversion of activation vectors despite 10 minutes of RF application, resulting in incomplete block with endocardial gaps or epicardial conductions. Additional RF applications finally achieved inversion in direction of activation vectors in the 10 lines. In total, the present method can diagnose achievement of complete block line with 100% accuracy, whereas conventional differential pacing misdiagnosed incomplete block with epicardial conduction in posterior lines in 3 cases and in MI lines in 2 cases., Conclusion: Confirmation of complete linear lesions using "activation vectors" based on omnipolar technology is a reliable and versatile method., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Arterial calcification is an important factor in determining the prognosis of patients with chronic kidney disease (CKD). Few studies on aortic calcification have involved radial artery calcification (RAC). This study aimed to analyze risk factors for RAC in patients with end-stage kidney disease (ESKD) and investigate the relationship between subsequent cardiovascular events (CVE) and vascular access trouble (VAT). Methods: This cohort study included 64 consecutive patients with ESKD who initiated hemodialysis and underwent a procedure for the creation of a primary radiocephalic arteriovenous fistula (RCAVF). Small arterial specimens were obtained from patients during RCAVF surgery. Tissue samples were stained with von Kossa, and arterial microcalcification was evaluated. We analyzed the association between preexisting arterial microcalcifications, clinical characteristics, CVE, and VAT. Results: In the univariate analysis, RAC patients demonstrated high systolic blood pressure (sBP), low hemoglobin (Hb), and low transferrin saturation (TSAT) (<0.05, <0.05, and <0.05, respectively). In the multivariate analysis, Hb (HR−0.516 (0.278−0.959), p < 0.05), TSAT (HR−0.0012 (0.00000248−0.597), p < 0.05), and sBP (HR−1.037 (1.001−1.073), p < 0.05) were independent risk factors for RAC. The cumulative incidence rate of CVE/VAT was not associated with RAC for one year. Conclusion: RAC was associated with sBP, TSAT, and anemia; however, no association with CVE/VAT was observed.

Neuroendocrine carcinomas (NECs), a poorly differentiated subtype of neuroendocrine neoplasms, are aggressive and have a poor prognosis. Colorectal neuroendocrine carcinomas (CRC-NECs) are observed in about 0.6% of all patients with CRC. Interestingly, patients with CRC-NECs show higher frequencies of BRAF mutation than typical CRC. BRAF V600E mutation-positive CRC-NECs were shown to be sensitive to BRAF inhibitors and now are treated by BRAF inhibitors. Similar to the other BRAF V600E mutated cancers, resistances against BRAF inhibitors have been observed, but the resistance mechanisms are still unclear. In this study, we established BRAF V600E mutated CRC-NEC cell line directly from surgical specimens and experimentally obtained BRAF inhibitor dabrafenib resistant cell lines. The resistant cells are revealed to express at least three types of BRAF splicing variants harboring V600E-mutation, and contribute to RAF/MEK/ERK pathway activation. In these cells, MEK and ERK inhibitors but not dabrafenib significantly suppressed cell growth and survival. Thus, in BRAF V600E mutation-positive CRC-NECs, BRAF splicing variants activate the RAF/MEK/ERK pathway and contribute to acquire BRAF inhibitor resistance. Hence, MEK or ERK are potential therapeutic targets to overcome BRAF resistance., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Sulfamethoxazole/trimethoprim (SMX/TMP) potentially increases the serum creatinine levels, resulting in acute kidney injury (AKI). However, the clinical characteristics of the AKI associated with SMX/TMP and the risk factors for its development have not been fully characterized., Methods: A retrospective cohort observational analysis was conducted on adult inpatients who started SMX/TMP treatment at the Tokyo Women's Medical University, Yachiyo Medical Center, from April 2018 to March 2020. The primary outcome was AKI, defined as an increase in serum creatinine level of ≥ 50% from baseline. Multivariate logistic regression analysis was used to determine the risk factors for the AKI associated with SMX/TMP., Results: Of the 281 patients, 32 (11.4%) developed AKI. The multivariate logistic regression analysis identified that body mass index (BMI) (odds ratio [OR] = 0.86, 95% confidence interval [95% CI] 0.76-0.97, p < 0.01), presence of hypertension (OR = 2.69, 95% CI 1.11-6.49, p = 0.02), SMX/TMP daily dose (OR = 1.16, 95% CI 1.03-1.30, p = 0.02), and concomitant loop diuretic use (OR = 2.91, 95% CI 1.08-7.78, p = 0.04) were the associated risk factors for AKI in patients who were administered SMX/TMP., Conclusions: This study showed that low BMI, hypertension, high-dose SMX/TMP, and concomitant loop diuretic use increased the risk of AKI in patients administered SMX/TMP. Clinicians should consider monitoring the renal function in patients at a high risk of AKI., (© 2022. The Author(s).)

Moral reasoning develops rapidly in early childhood. Recent evidence from cognitive neuroscience literature suggests that the development of moral reasoning is supported by an integration of cognitive and affective components. However, the role of culture in the development of moral reasoning in young children is under-investigated. Previous cross-cultural research suggests that culture shapes how people interpret other's behaviors. In particular, people raised in independent cultures, such as the United States, tend to form impressions of others and attribute others' behaviors to their personal dispositions more quickly than people raised in interdependent cultures, such as Japan. In the present cross-cultural study, we examined parents' discourse with children in Japan and the United States. Parents and their 3- to 4-year-old children were asked to view and discuss cartoon characters depicting prosocial and antisocial acts. Results indicated that in both cultures, parents discussed about moral actions (e.g., helping, harming) of characters. Furthermore, United States parents were more likely to evaluate dispositional characteristics of characters based on their pro-social and anti-social acts, whereas Japanese parents were more likely to refer to emotion of the characters who got hurt. We discuss implications of cross-cultural differences and similarities in parental moral socialization and the development of moral reasoning in young children., 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 © 2022 Senzaki, Cowell, Shimizu and Calma-Birling.)

The number of patients with ischemic cardiovascular diseases is significantly increasing as populations age. Therapeutic angiogenesis has been developed as a new treatment strategy for such patients. In recent years, the presence of mesenchymal stem cells in adipose tissues was reported, and regenerative medicine using these cells has attracted attention worldwide. In this review, we describe how the transplantation of adipose-derived regenerative cells enhances angiogenesis and tissue regeneration because of their multilineage potential and cytokine secretion. Then, the current status of therapeutic angiogenesis using adipose-derived regenerative cells in the field of cardiovascular medicine was also described. These cells present great advantages over bone marrow mononuclear cells, as these need easier, shorter, and less invasive preparations as well as less ethical concerns and immunological problems. The efficacy of adipose-derived regenerative cell transplantation in the treatment of various diseases was examined in several clinical trials with favorable results. Currently, a multicenter study of therapeutic angiogenesis using these cells is being conducted in patients with critical limb ischemia. In conclusion, we expect that this method will soon be established as a treatment for cardiovascular diseases that have been refractory to conventional treatments., Competing Interests: The authors declare that there are no conflicts of interest.

Social contexts shape the development of attention; however, little is known about joint attention beyond infancy. This study employed behavioral and eye-tracking measurements to investigate cultural variations in how caregivers direct 3- to 4-year-old children's attention and subsequent changes in children's attention to objects and contextual backgrounds in the United States (predominantly non-Hispanic Whites) and Japan (N = 60 mother-child dyads, 29 girls, 31 boys). The findings revealed that caregivers directed children's attention to culturally sensitive information, and significant cross-cultural differences in attention emerged after caregiver-child interaction, with Japanese children shifting their attention to the backgrounds. Results provide new insights into the role of social interaction and cultural diversity in the development of attention., (© 2022 The Authors. Child Development © 2022 Society for Research in Child Development.)

Radial glial cells (RGCs) play an essential role in developing, maintaining, and repairing the central nervous system (CNS). However, a specific reporter line of RGCs is limited in medaka. Glial fibrillary acid protein (GFAP) is abundant in teleost CNS, including the brain and spinal cord, and is a possible candidate for a marker for RGCs in medaka CNS. We generated a transgenic medaka in which enhanced green fluorescent protein (EGFP) expression is regulated under putative medaka gfap regulatory elements. We observed EGFP expression in the CNS of live larval and juvenile medaka through the transparent body of the See-through medaka strain. Histological analysis for juvenile and adult Tg(gfap:EGFP) medaka showed that EGFP was expressed in GFAP-positive cells in the telencephalon, optic tectum, retina, and spinal cord. We further found another EGFP expressing cells in the optic tectum and retina. These cells are possibly neuroepithelial-like stem cells, deducing from the distribution of these EGFP-positive cells. We concluded that this reporter line would be valuable in the investigation of neural stem cell function during the development and regeneration of medaka CNS visualizing two types of neural stem cells, RGCs and neuroepithelial-like stem cells., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This paper proposes a new optical configuration for a two-axis surface encoder that can measure the in-plane ( X -axis) and out-of-plane ( Z -axis) displacements of a positioning stage. The two-axis surface encoder is composed of a scale grating and a sensor head. A transparent grating is employed in the sensor head for measurement of the Z -directional displacement of the scale grating based on the Fizeau-type measurement method; a reference beam reflected from the transparent grating and the zeroth-order diffracted beam from the scale grating are superimposed to generate an interference signal. A pair of prisms and a beam splitter are also employed in the sensor head, so that the positive and negative first-order diffracted beams can be superimposed over a long working distance to generate an interference signal for measurement of the X -directional displacement of the scale grating. Focusing on the new, extended Z -directional measurement mechanism, proof-of-principle experiments were carried out to verify the feasibility of the proposed optical configuration for the surface encoder that can measure the uni-directional displacements of a scale grating along the X - and Z -axis. Experimental results from the developed optical configuration demonstrated the achievement of a Z -directional measuring range of ±1.5 mm.

Anaplastic lymphoma kinase (ALK) fusion is found in ~3%-5% of patients with non-small-cell lung cancers (NSCLCs). Although the third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib shows high clinical efficacy in ALK-positive NSCLC, most of the patients eventually relapse with acquired resistance. Recently, drug-tolerant persister (DTP) cells have been considered an important seed of acquired resistance cells. In this study, we established lorlatinib intermediate resistant cells from a patient-derived cell model. Glycogen synthase kinase 3 (GSK3) inhibitions significantly suppressed lorlatinib intermediate resistant cell growth. GSK3 inhibition also sensitized acquired resistance cells derived from alectinib-treated patients with or without secondary mutations to lorlatinib. Therefore, GSK3 plays a crucial role in developing acquired resistance against lorlatinib in ALK-positive NSCLC mediated by lorlatinib intermediate resistant cells and could be a potential molecular target to prevent acquired lorlatinib resistance and overcome ALK-TKI resistance., (© 2022. The Author(s).)

While zebrafish have a superior capacity to regenerate their central nervous system (CNS), medaka has a lower CNS regenerative capacity. A brain injury model was developed in the adult optic tectum of zebrafish and medaka and comparative histological and molecular analyses were performed to elucidate the molecular mechanisms regulating the high regenerative capacity of this tissue across these fish species. Here a stab wound injury model is presented for the adult optic tectum using a needle and histological analyses for proliferation and differentiation of the neural stem cells (NSCs). A needle was manually inserted into the central region of the optic tectum, and then the fish were intracardially perfused, and their brains were dissected. These tissues were then cryosectioned and evaluated using immunostaining against the appropriate NSC proliferation and differentiation markers. This tectum injury model provides robust and reproducible results in both zebrafish and medaka, allowing for comparing NSC responses after injury. This method is available for small teleosts, including zebrafish, medaka, and African killifish, and enables us to compare their regenerative capacity and investigate unique molecular mechanisms.

( S )-(2-Methylpyrid-5-yl)-6-[(3-[ 18 F]fluoro-2-hydroxy)propoxy]quinoline ([ 18 F]SMBT-1) was recently developed as a novel class of selective and reversible monoamine oxidase-B (MAO-B) tracers for in vivo imaging of reactive astrogliosis via positron emission tomography. To investigate the effect of the chirality of [ 18 F]SMBT-1 on tracer performance, we synthesized ( S )-[ 18 F] 6 ([ 18 F]SMBT-1) and ( R )-[ 18 F] 6 and compared their binding properties, pharmacokinetics, and metabolism. ( S )- 6 showed higher binding affinity to MAO-B and lower binding affinity to MAO-A than ( R )- 6 , demonstrating a higher selectivity ratio (MAO-B/MAO-A). A pharmacokinetic study in mice demonstrated that both ( S )-[ 18 F] 6 and ( R )-[ 18 F] 6 showed sufficient initial brain uptake. However, ( S )-[ 18 F] 6 was cleared significantly faster from the body. An abundant sulfoconjugate metabolite M2 was observed in plasma for ( S )-[ 18 F] 6 but not for ( R )-[ 18 F] 6 . In vitro sulfation assays confirmed that ( S )- 6 was more reactive than ( R )- 6 , consistent with the in vivo findings. Mefenamic acid, a selective sulfotransferase 1A1 (SULT1A1) inhibitor, strongly inhibited the in vitro sulfation of ( S )- 6 by mouse liver fractions, human liver cytosol fractions, and human recombinant SULT1A1 enzyme. Genetic polymorphisms of SULT1A1 did not affect the sulfation of ( S )- 6 in vitro. In conclusion, ( S )-[ 18 F] 6 had a more favorable binding affinity and binding selectivity for MAO-B than ( R )-[ 18 F] 6 . Additionally, ( S )-[ 18 F] 6 also possessed better pharmacological and metabolic properties than ( R )-[ 18 F] 6 . These results suggest that ( S )-[ 18 F] 6 ([ 18 F]SMBT-1) is a promising candidate for application in the imaging of MAO-B in vivo.

Background: Implantations of leadless pacemakers in the septum lower the risk of cardiac perforation. However, the relationship between the implantation site and the success rate, complication rate, and pacemaker parameters are not well-investigated., Methods: Patients who underwent leadless pacemaker implantation with postprocedural computed tomography (CT) between September 2017 and November 2020 were analyzed. Septum was targeted with fluoroscopic guidance with contrast injection. We divided patients into two groups based on the implantation site confirmed by CT: septal and non-septal, which included the anterior/posterior edge of the septum and free wall. We compared the complication rates and pacemaker parameters between the two groups., Results: A total of 67 patients underwent CT after the procedure; among them, 28 were included in the septal group and 39 were included in the non-septal group. The non-septal group had significantly higher R wave amplitudes (6.5 ± 3.3 vs. 9.7 ± 3.9 mV, p = .001), lower pacing threshold (1.0 ± 0.94 vs. 0.63 ± 0.45 V/0.24 ms, p = .02), and higher pacing impedance (615 ± 114.1 vs. 712.8 ± 181.3 ohms, p = .014) after the procedure compared to the septal group. Cardiac injuries were observed in four patients (one cardiac tamponade, one possible apical hematoma, two asymptomatic pericardial effusion), which were only observed in the non-septal group., Conclusions: Leadless pacemaker implantation may be technically challenging with substantial number of patients with non-septal implantation when assessed by CT. Septal implantation may have a lower risk of cardiac injury but may lead to inferior pacemaker parameters than non-septal implantation., (© 2022 Wiley Periodicals LLC.)

Smoking cessation increases body weight. The underlying mechanisms, however, have not been fully understood. We here report an establishment of a mouse model that exhibits an augmented body weight gain after nicotine withdrawal. High fat diet-fed mice were infused with nicotine for two weeks, and then with vehicle for another two weeks using osmotic minipumps. Body weight increased immediately after nicotine cessation and was significantly higher than that of mice continued on nicotine. Mice switched to vehicle consumed more food than nicotine-continued mice during the first week of cessation, while oxygen consumption was comparable. Elevated expression of orexigenic agouti-related peptide was observed in the hypothalamic appetite center. Pair-feeding experiment revealed that the accelerated weight gain after nicotine withdrawal is explained by enhanced energy intake. As a showcase of an efficacy of pharmacologic intervention, exendin-4 was administered and showed a potent suppression of energy intake and weight gain in mice withdrawn from nicotine. Our current model provides a unique platform for the investigation of the changes of energy regulation after smoking cessation., Competing Interests: Declaration of competing interest Tomohiro Tanaka reports financial support was provided by Japan Society for the Promotion of Science. Daisuke Aotani reports financial support was provided by Japan Society for the Promotion of Science. Takashi Yagi reports financial support was provided by Japan Society for the Promotion of Science. Tingting Guo reports financial support was provided by Japan Society for the Promotion of Science. Tomohiro Tanaka reports financial support was provided by Smoking Research Foundation. Daisuke Aotani reports financial support was provided by Smoking Research Foundation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Peritoneal dialysis (PD) catheter exit-site care is critically important for the prevention of catheter-related infections (CRIs) and subsequent peritonitis. The postoperative management of the site is particularly essential because it has an open wound that is always adjacent to a PD catheter tube. This study aimed to examine the effectiveness of negative-pressure wound therapy (NPWT) for postoperative PD catheter exit sites. Thirty patients with end-stage renal disease who underwent simultaneous PD catheter insertion and exit-site formation were randomly assigned to receive NPWT (NPWT group) or conventional dressing (non-NPWT group) for the first seven postoperative days. The exit-site scores on the seventh postoperative day was lower in the NPWT group than in the non-NPWT group (p = 0.0049). Analysis of variance F statistic for the effect of NPWT over 180 days was highly significant (11.482595, p = 0.007). There were no statistically significant differences between the time to first CRI and PD-related peritonitis between the two groups. There was one case of CRI with relapsing peritonitis and catheter loss in the non-NPWT group. These findings demonstrate the association between NPWT and low exit-site score. NPWT can be recommended for the management of PD catheter exit sites in the early postoperative period., (© 2022. The Author(s).)

Formamides are useful starting materials for pharmaceutical syntheses. Although various synthetic methods have been documented in this regard, the use of N-formylcarbazole as a formylation reagent for amines has not yet been reported. We report here the first examples of the use of N-formylcarbazole for the formylation of amines. The characteristic reactivity of N-formylcarbazole enables the selective formylation of sterically less hindered aliphatic primary and secondary amines. In contrast, sterically bulkier amines and weakly nucleophilic amines such as anilines are less reactive under the reaction conditions.

An interferometric self-calibration method for the evaluation of the pitch deviation of scale grating has been extended to evaluate the pitch deviation of the long-range type linear scale by utilizing the stitching interferometry technique. Following the previous work, in which the interferometric self-calibration method was proposed to assess the pitch deviation of the scale grating by combing the first-order diffracted beams from the grating, a stitching calibration method is proposed to enlarge the measurement range. Theoretical analysis is performed to realize the X -directional pitch deviation calibration of the long-range linear scale while reducing the second-order accumulation effect by canceling the influence of the reference flat error in the sub-apertures' measurements. In this paper, the stitching interferometry theory is briefly reviewed, and theoretical equations of the X -directional pitch deviation stitching are derived for evaluation of the pitch deviation of the long-range linear scale. Followed by the simulation verification, some experiments with a linear scale of 105 mm length from a commercial interferential scanning-type optical encoder are conducted to verify the feasibility of the self-calibration stitching method for the calibration of the X -directional pitch deviation of the linear scale over its whole area.