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Objectives To investigate the details of disaster-related deaths due to the indirect health effects of the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident following the Great East-Japan Earthquake in 2011 and serve as a source of reference in the event of similar circumstances in the future.Design A retrospective observational study.Setting Minamisoma City, Fukushima Prefecture, Japan, which is located 13–38 km north of the FDNPP.Participants 520 residents of Minamisoma City, Fukushima Prefecture, who were certified as having died from disaster-related causes between September 2011 and February 2021.Results The most common cause of death was circulatory system diseases (27.7%), followed by respiratory system diseases (25.0%) and neoplasms (15.4%). The prevalence of circulatory and respiratory diseases is higher in older people, suggesting that they are more susceptible to indirect health effects due to the environmental changes related to evacuation. Malignant neoplasms accounted for the third and leading cause of death overall and for people in their 50s, respectively, implying the potential impact of evacuation on cancer diagnosis and treatment. Suicide is the leading cause of death among younger people and can occur even long after a disaster, which shows the psychological impact of environmental changes.Conclusion To prevent indirect disaster-related deaths in the future, it is important to consider appropriate intervention methods by age group and period since disaster occurrence. It is especially important to improve the environment of evacuation shelters and establish a healthcare system for evacuees, create a system for cancer screening and treatment during evacuation and expand long-term suicide prevention measures.

Abstract Recent studies have suggested that the clinical features of elderly-onset adult-onset Still’s disease (AOSD) differ from those of young and middle-aged-onset patients, whereas the details remain unclear, and cytokine profiles of elderly-onset AOSD have not been reported. To clarify the clinical features and cytokine profiles of elderly-onset AOSD, we examined patients with AOSD who developed the disease between January 2006 and September 2021. We divided the patients into the young and middle-aged-onset group (aged

Abstract We herein propose a PraNet-based deep-learning model for estimating the size of non-perfusion area (NPA) in pseudo-color fundus photos from an ultra-wide-field (UWF) image. We trained the model with focal loss and weighted binary cross-entropy loss to deal with the class-imbalanced dataset, and optimized hyperparameters in order to minimize validation loss. As expected, the resultant PraNet-based deep-learning model outperformed previously published methods. For verification, we used UWF fundus images with NPA and used Bland–Altman plots to compare estimated NPA with the ground truth in FA, which demonstrated that bias between the eNPA and ground truth was smaller than 10% of the confidence limits zone and that the number of outliers was less than 10% of observed paired images. The accuracy of the model was also tested on an external dataset from another institution, which confirmed the generalization of the model. For validation, we employed a contingency table for ROC analysis to judge the sensitivity and specificity of the estimated-NPA (eNPA). The results demonstrated that the sensitivity and specificity ranged from 83.3–87.0% and 79.3–85.7%, respectively. In conclusion, we developed an AI model capable of estimating NPA size from only an UWF image without angiography using PraNet-based deep learning. This is a potentially useful tool in monitoring eyes with ischemic retinal diseases.

Abstract Background Desmoid tumors are extremely rare borderline benign and malignant tumors that do not exhibit accumulation on fluorodeoxyglucose positron emission tomography–computed tomography. In the present study, we report a rare case of a desmoid tumor with fluorodeoxyglucose accumulation at the anastomotic postoperative gastric cancer site. Case presentation A 68-year-old Japanese man underwent robot-assisted laparoscopic distal gastrectomy for early-stage gastric cancer in 2019. The pathological diagnosis was stage IA cancer, and no adjuvant chemotherapy was administered. Two years after surgery, a soft mass appeared on the greater curvature side of the anastomosis on computed tomography. Fluorodeoxyglucose positron emission tomography–computed tomography revealed fluorodeoxyglucose accumulation, which suggested a malignancy; therefore, surgery was performed for diagnostic treatment. The histopathological findings led to the diagnosis of a desmoid tumor. The patient has not experienced recurrence to date. Conclusions In the present study, we encountered a desmoid tumor arising from the anastomotic site of a postoperative gastric cancer. This case is rare as fluorodeoxyglucose positron emission tomography–computed tomography showed fluorodeoxyglucose accumulation in the desmoid tumor, and a preoperative diagnosis could not be reached. We hope that further studies will improve the accuracy of preoperative diagnosis.

Abstract To reveal waning humoral immunity after second dose BNT162b2 vaccinations in a rural Japanese community and determine factors affecting antibody titers. We aimed to report Immunoglobulin G (IgG) antibody against the SARS-CoV-2 spike (S1) protein levels and neutralizing activity in a large scale community based cohort. Methods: Participants in the observational cross-sectional study received a second dose of vaccination with BNT162b2 (Pfizer/BioNTech) and were not previously infected with COVID-19. Questionnaire-collected data on sex, age, adverse vaccine reactions, and medical history was obtained. Results: Data from 2496 participants revealed that older age groups reached a low antibody titer 90–120 days after the second vaccination. Neutralizing activity decreased with age; 35 (13.3%) of those aged ≥ 80 years had neutralizing activity under the cut-off value. Neutralizing activity > 179 days from the second vaccination was 11.6% compared to that at

Abstract This study aimed to evaluate the feasibility and efficacy of Endoscopic ultrasound elastography-guided fine needle biopsy (EUS-EG-FNB) for the diagnosis of pancreatic mass lesions. EUS-EG images were classified into heterogeneous and homogeneous groups. For the heterogeneous group, EUS-FNB was separately performed in both hard areas and soft areas. Only samples obtained during the first two passes (hard/soft areas) were used to compare the diagnostic accuracy as well as the quality and quantity of the specimens. We investigated the association of EUS-EG findings using strain histogram analysis with the histological findings. Fifty-five patients were enrolled including 25 patients with heterogeneous group. The homogeneous group had significantly lower mean strain value (hard) lesions. The adequate sampling rates from hard and soft areas were 88 and 92%, respectively (P = 0.6374). Comparison of the diagnostic accuracy and the quality and quantity of the histological core between hard and soft areas showed no significant differences. In pancreatic adenocarcinoma cases, the proportion of fibrous stroma in the core tissue was significantly correlated with the elasticity of the region. (R2 = 0.1226: P = 0.0022) EUS-EG may reflect tissue composition in pancreatic tumors, however, EUS-EG did not affect either the quality and quantity of the tissues obtained. Clinical Trial Registry No: UMIN-000033073.

Abstract During tumorigenesis, certain tissues are colonized by mutant clones with oncogenic driver mutations as precancer lesions. These mutations can facilitate clonal expansion and may contribute to malignant transformation. The molecular features of low-grade non-muscle invasive bladder cancer (NMIBC) and high-grade bladder cancer are so distinct that they are thought to follow different evolutionary tumorigenesis pathways. Although NMIBC accounts for most bladder tumors, the somatic mutation patterns in “precancer” urothelium of patients with NMIBC remain unclear. Here, we analyzed specimens of normal urothelium and bladder tumors from patients with low-grade and high-grade NMIBC and investigated the genomic evolution of the cancer. Somatic mutations were analyzed using 50 oncogene-targeted sequences and droplet digital polymerase chain reaction for TERT promoter mutations. Somatic mutations in TERT promoter, FGFR3, and CDKN2A were characteristically identified in the normal urothelium of patients with NMIBC. These mutations, consistently identified in both tumor and normal specimens, likely affect clonal expansion during the malignant transformation of NMIBC. Though larger samples and comprehensive study are warranted to confirm our results, the difference in mutational landscape of the precancerous urothelium of patients with bladder cancer could offer deeper understandings of genomic evolution in bladder tumorigenesis.

Abstract Background Ligation of CD28 with ligands such as CD80 or CD86 provides a critical second signal alongside antigen presentation by class II major histocompatibility complex expressed on antigen-presenting cells through the T cell antigen receptor for naïve T cell activation. A number of studies suggested that CD28 plays an important role in the pathogenesis of various human diseases. Recent genome-wide association studies (GWASs) identified CD28 as a susceptibility locus for lymphocyte and eosinophil counts, multiple sclerosis, ulcerative colitis, celiac disease, rheumatoid arthritis, asthma, and primary biliary cholangitis. However, the primary functional variant and molecular mechanisms of disease susceptibility in this locus remain to be elucidated. This study aimed to identify the primary functional variant from thousands of genetic variants in the CD28 locus and elucidate its functional effect on the CD28 molecule. Results Among the genetic variants exhibiting stronger linkage disequilibrium (LD) with all GWAS-lead variants in the CD28 locus, rs2013278, located in the Rbfox binding motif related to splicing regulation, was identified as a primary functional variant related to multiple immunological traits. Relative endogenous expression levels of CD28 splicing isoforms (CD28i and CD28Δex2) compared with full-length CD28 in allele knock-in cell lines generated using CRISPR/Cas9 were directly regulated by rs2013278 (P

Abstract The detection of object movement that is contingent on one’s own actions (i.e., movements with action contingency) influences social perception of the object; such interactive objects tend to create a good impression. However, it remains unclear whether neural representation of action contingency is associated with subsequent socio-cognitive evaluation of “contacting agents”, or whether the appearance of agents (e.g., face- or non-face-like avatars) is essential for this effect. In this study, we conducted a functional magnetic resonance imaging (fMRI) task with two phases: contact (contact with face- or non-face-like avatars moving contingently or non-contingently) and recognition (rating a static image of each avatar). Deactivation of the frontoparietal self-agency network and activation of the reward network were the main effects of action contingency during the contact phase, consistent with previous findings. During the recognition phase, static avatars that had previously moved in a contingent manner deactivated the frontal component of the frontoparietal network (bilateral insula and inferior-middle frontal gyri), regardless of person-like appearance. Our results imply that frontal deactivation may underlie the effect of action contingency on subsequent social perception, independent of person-like appearance.

Abstract Podocytopathy, which is characterized by injury to podocytes, frequently causes proteinuria or nephrotic syndrome. There is currently a paucity of effective therapeutic drugs to treat proteinuric kidney disease. Recent research suggests the possibility that glycosphingolipid GM3 maintains podocyte function by acting on various molecules including nephrin, but its mechanism of action remains unknown. Here, various analyses were performed to examine the potential relationship between GM3 and nephrin, and the function of GM3 in podocytes using podocytopathy mice, GM3 synthase gene knockout mice, and nephrin injury cells. Reduced amounts of GM3 and nephrin were observed in podocytopathy mice. Intriguingly, this reduction of GM3 and nephrin, as well as albuminuria, were inhibited by administration of valproic acid. However, when the same experiment was performed using GM3 synthase gene knockout mice, valproic acid administration did not inhibit albuminuria. Equivalent results were obtained in model cells. These findings indicate that GM3 acts with nephrin in a collaborative manner in the cell membrane. Taken together, elevated levels of GM3 stabilize nephrin, which is a key molecule of the slit diaphragm, by enhancing the environment of the cell membrane and preventing albuminuria. This study provides novel insight into new drug discovery, which may offer a new therapy for kidney disease with albuminuria.

Abstract Tip-enhanced Raman spectroscopy (TERS) is a powerful tool for analyzing chemical compositions at the nanoscale owing to near-field light localized at a metallic tip. In TERS, atomic force microscopy (AFM) is commonly used for tip position control. AFM is often controlled under the contact mode for TERS, whereas the tapping mode, which is another major operation mode, has not often been employed despite several advantages, such as low sample damage. One of the reasons is the low TERS signal intensity because the tip is mostly away from the sample during the tapping motion. In this study, we quantitatively investigated the effect of the tapping amplitude on the TERS signal. We numerically evaluated the dependence of the TERS signal on tapping amplitude. We found that the tapping amplitude had a significant effect on the TERS signal, and an acceptable level of TERS signal was obtained by reducing the amplitude to a few nanometers. We further demonstrated amplitude-controlled tapping-mode TERS measurement. We observed a strong dependence of the TERS intensity on the tapping amplitude, which is in agreement with our numerical calculations. This practical but essential study encourages the use of the tapping mode for further advancing TERS and related optical techniques.

Abstract Rapid identification of lung-cancer micro-lesions is becoming increasingly important to improve the outcome of surgery by accurately defining the tumor/normal tissue margins and detecting tiny tumors, especially for patients with low lung function and early-stage cancer. The purpose of this study is to select and validate the best red fluorescent probe for rapid diagnosis of lung cancer by screening a library of 400 red fluorescent probes based on 2-methyl silicon rhodamine (2MeSiR) as the fluorescent scaffold, as well as to identify the target enzymes that activate the selected probe, and to confirm their expression in cancer cells. The selected probe, glutamine-alanine-2-methyl silicon rhodamine (QA-2MeSiR), showed 96.3% sensitivity and 85.2% specificity for visualization of lung cancer in surgically resected specimens within 10 min. In order to further reduce the background fluorescence while retaining the same side-chain structure, we modified QA-2MeSiR to obtain glutamine-alanine-2-methoxy silicon rhodamine (QA-2OMeSiR). This probe rapidly visualized even borderline lesions. Dipeptidyl peptidase 4 and puromycin-sensitive aminopeptidase were identified as enzymes mediating the cleavage and consequent fluorescence activation of QA-2OMeSiR, and it was confirmed that both enzymes are expressed in lung cancer. QA-2OMeSiR is a promising candidate for clinical application.

Abstract In today’s advanced information society, creativity in work is highly valued, and there is growing interest in the kinds of work environments that produce more creative outcomes. Recent researchers have demonstrated that when environmental factors change a worker’s attentional state to a diffused state, the worker has access to more information than usual, which can contribute to creativity. Here, we examined whether manipulating environmental factors (the presence of a cell phone and exposure to natural environment) that could affect such attention states would improve performance on the Remote Associates Task, a measure of creativity. Our results showed that the presence of a cell phone increased creative performance regardless of immersion in natural environment. In contrast, exposure to nature did not facilitate creative performance; instead, feelings of pleasure increased, and frustration decreased. These results suggest that the presence of a cell phone can enhance creativity by influencing workers’ attentional states. The current study provides a meaningful approach to enhancing creativity by modulating attentional states through environmental factors. It also highlights the essential features of environmental factors that can moderate creative abilities.

Abstract Teriparatide (TPTD) administration has a potent osteogenic action and promotes the healing of osteoporotic vertebral fractures (OVFs). We aimed to investigate the outcomes of vertebroplasty with posterior spinal fusion (VP + PSF) and determine the impact of perioperative TPTD administration. We included 73 patients (18 male and 55 female patients; mean age: 78 years) with thoracolumbar OVFs who underwent VP + PSF and were followed-up for at least 2 years. Twenty-three patients who received TPTD perioperatively for > 3 months were included in the TPTD group, and the remaining 50 patients were included in the non-TPTD group. Radiographic findings regarding sagittal alignment and clinical outcomes in both groups were compared. The mean duration of TPTD administration was 17.5 ± 5.0 months (range 4–24 months). The mean loss of correction of local kyphosis angle in the TPTD group (4.0°) was lesser than that in the non-TPTD group (7.5°; p

Abstract Although loneliness itself is a natural emotion, prolonged loneliness is detrimental to human health. Despite its detrimental effect, few loneliness-related neuroimaging studies have been published and some have limitations on the sample size number. This study aims to find the difference in resting-state functional connectivity associated with loneliness within a big sample size via the seed-based approach. Functional connectivity analysis was performed on a large cohort of young adults (N = 1336) using the seed-based functional connectivity approach to address the concern from previous studies. The analysis yielded statistically significant positive correlations between loneliness and functional connectivities between the inferior frontal gyrus and supplementary motor area, precentral gyrus, and superior parietal lobule. Additionally, the analysis replicated a finding from a previous study, which is increased functional connectivities between the inferior frontal gyrus and supplementary motor area. In conclusion, greater loneliness is reflected by stronger functional connectivity of the visual attention brain area.

In Japan, the prevalence of low birth weight (LBW) has been estimated to be approximately 10%, which is the highest among developed countries. This high prevalence might affect the occurrence of LBW-associated diseases in the adult population of Japan. LBW has been recognized as a contributing factor to post-adaptive focal segmental glomerulosclerosis (FSGS) in adulthood; however, few reports to date have evaluated the clinical and pathological characteristics of post-adaptive FSGS. A 13-year-old girl was referred to our hospital owing to mild proteinuria, which was detected at a school urinary screening. She was born at a gestational age of 23 weeks, with a very LBW of 630 g. Dipstick urinalysis revealed grade (2+) proteinuria. Her serum creatinine level was 1.02 mg/dL, and she was diagnosed as having stage 2 chronic kidney disease (CKD). Her serum uric acid level was 7 mg/dL. Furthermore, her mother and 16-year old brother had hyperuricemia. A percutaneous renal biopsy leads to a diagnosis of FSGS. After 3 years of treatment with an angiotensin receptor blocker, her proteinuria decreased. However, her serum creatinine level was 1.07 mg/dL, and she still had stage 2 CKD. We considered that in this patient, the first hit was her LBW, and the second hit was hyperuricemia. The second hit might be associated with the development of CKD. The birth history of patients is not usually confirmed by nephrologists. Our case demonstrates that obtaining information regarding the preterm birth and LBW of patients is important in the diagnosis of noncommunicable diseases because school urinary screening is not routinely performed in countries other than Japan.

Abstract Sarcopenia is thought to be related to the microbiome, but not enough reports in chronic liver disease (CLD) patients. In addition to the differences in microbiome, the role of the microbiome in the gut is also important to be clarified because it has recently been shown that the microbiome may produce branched-chain amino acids (BCAAs) in the body. In this single-center study, sixty-nine CLD patients were divided by skeletal muscle mass index (SMI) into low (L-SMI: n = 25) and normal (N-SMI: n = 44). Microbiome was analyzed from stool samples based on V3-4 region of bacterial 16S rRNA). L-SMI had a lower Firmicutes/Bacteroidetes ratio than N-SMI. At the genus level, Coprobacillus, Catenibacterium and Clostridium were also lower while the Bacteroides was higher. Predictive functional profiling of the L-SMI group showed that genes related to nitrogen metabolism were enriched, but those related to amino acid metabolism, including BCAA biosynthesis, were lower. The genes related to 'LPS biosynthesis' was also higher. The microbiome of CLD patients with low muscle mass is characterized not only by high relative abundance of gram-negative bacteria with LPS, but also by the possibility of low potential for amino acid synthesis including BCAAs.

Abstract The genetic diversity of the Coronaviruses gives them different biological abilities, such as infect different cells and/or organisms, a wide spectrum of clinical manifestations, their different routes of dispersion, and viral transmission in a specific host. In recent decades, different Coronaviruses have emerged that are highly adapted for humans and causing serious diseases, leaving their host of unknown origin. The viral genome information is particularly important to enable the recognition of patterns linked to their biological characteristics, such as the specificity in the host-parasite relationship. Here, based on a previously computational tool, the Seq2Hosts, we developed a novel approach which uses new variables obtained from the frequency of spike-Coronaviruses codons, the Relative Synonymous Codon Usage (RSCU) to shed new light on the molecular mechanisms involved in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) host specificity. By using the RSCU obtained from nucleotide sequences before the SARS-CoV-2 pandemic, we assessed the possibility of know the hosts capable to be infected by these new emerging species, which was first identified infecting humans during 2019 in Wuhan, China. According to the model trained and validated using sequences available before the pandemic, bats are the most likely the natural host to the SARS-CoV-2 infection, as previously suggested in other studies that searched for the host viral origin.

Abstract Regulatory T cells (Tregs) suppress the host immune response and maintain immune homeostasis. Tregs also promote cancer progression and are involved in resistance to immune checkpoint inhibitor treatments. Recent studies identified selective CCR8 expression on tumor-infiltrating Tregs; CCR8+ Tregs have been indicated as a possible new target of cancer immunotherapy. Here, we investigated the features of CCR8+ Tregs in lung cancer patients. CCR8+ Tregs were highly activated and infiltration of CCR8+ Tregs in tumors was associated with poor prognosis in lung cancer patients. We also investigated their immune suppressive function, especially the influence on cytotoxic T lymphocyte cell function. The Cancer Genome Atlas analysis revealed that CD8 T cell activities were suppressed in high CCR8-expressing tumors. Additionally, depletion of CCR8+ cells enhanced CD8 T cell function in an ex vivo culture of lung tumor-infiltrating cells. Moreover, CCR8+ Tregs, but not CCR8− Tregs, induced from human PBMCs markedly suppressed CD8 T cell cytotoxicity. Finally, we demonstrated the therapeutic effect of targeting CCR8 in a murine model of lung cancer. These findings reveal the significance of CCR8+ Tregs for immunosuppression in lung cancer, especially via cytotoxic T lymphocyte cell suppression, and suggest the potential value of CCR8-targeted therapy for cancer treatment.

Abstract Tissue-resident macrophages expressing lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) are found in multiple tissues and organs. We aimed to evaluate the dynamics and biological functions of LYVE-1+ macrophages in dental pulp during post-injury tissue remodeling. Immunofluorescence staining of mouse embryos revealed that LYVE-1+ macrophages colonized dental pulp before birth. In mature rat molar dental pulp, LYVE-1+ macrophages were the main subset of macrophages expressing CD163, an M2 marker, and were distributed throughout the tissue. In response to dental pulp injury induced by cavity preparation, LYVE-1+ macrophages quickly disappeared from the affected area of the pulp and gradually repopulated during the wound healing process. RAW264.7 mouse macrophages cultured with a mixture of macrophage colony-stimulating factor, interleukin-4, and dexamethasone increased LYVE-1 expression, whereas lipopolysaccharide-stimulation decreased LYVE-1 expression. Enforced expression of Lyve1 in RAW264.7 cells resulted in increased mRNA expression of matrix metalloproteinase 2 (Mmp2), Mmp9, and vascular endothelial growth factor A (Vegfa). Lyve1-expressing macrophages promoted the migration and tube formation of human umbilical vein endothelial cells. In conclusion, LYVE-1+ tissue-resident M2-like macrophages in dental pulp showed dynamism in response to pulp injury, and possibly play an important role in angiogenesis during wound healing and tissue remodeling.

Abstract The persistence of covalently closed circular DNA (cccDNA) poses a major obstacle to curing chronic hepatitis B (CHB). Here, we used droplet digital PCR (ddPCR) for cccDNA quantitation. The cccDNA-specific ddPCR showed high accuracy with the dynamic range of cccDNA detection from 101 to 105 copies/assay. The ddPCR had higher sensitivity, specificity and precisely than qPCR. The results of ddPCR correlated closely with serum HB core-related antigen and HB surface antigen (HBsAg) in 24 HBV-infected human-liver-chimeric mice (PXB-mice). We demonstrated that in 2 PXB-mice after entecavir treatment, the total cccDNA content did not change during liver repopulation, although the cccDNA content per hepatocyte was reduced after the treatment. In the 6 patients with HBV-related hepatocellular carcinoma, ddPCR detected cccDNA in both tumor and non-tumor tissues. In 13 HBeAg-negative CHB patients with pegylated interferon alpha-2a, cccDNA contents from paired biopsies were more significantly reduced in virological response (VR) than in non-VR at week 48 (p = 0.0051). Interestingly, cccDNA levels were the lowest in VR with HBsAg clearance but remained detectable after the treatment. Collectively, ddPCR revealed that cccDNA content is stable during hepatocyte proliferation and persists at quantifiable levels, even after serum HBsAg clearance.

Abstract Depressive disorders contribute heavily to global disease burden; This is possibly because patients are often treated homogeneously, despite having heterogeneous symptoms with differing underlying neural mechanisms. A novel treatment that can directly influence the neural circuit relevant to an individual patient’s subset of symptoms might more precisely and thus effectively aid in the alleviation of their specific symptoms. We tested this hypothesis in a proof-of-concept study using fMRI functional connectivity neurofeedback. We targeted connectivity between the left dorsolateral prefrontal cortex/middle frontal gyrus and the left precuneus/posterior cingulate cortex, because this connection has been well-established as relating to a specific subset of depressive symptoms. Specifically, this connectivity has been shown in a data-driven manner to be less anticorrelated in patients with melancholic depression than in healthy controls. Furthermore, a posterior cingulate dominant state—which results in a loss of this anticorrelation—is expected to specifically relate to an increase in rumination symptoms such as brooding. In line with predictions, we found that, with neurofeedback training, the more a participant normalized this connectivity (restored the anticorrelation), the more related (depressive and brooding symptoms), but not unrelated (trait anxiety), symptoms were reduced. Because these results look promising, this paradigm next needs to be examined with a greater sample size and with better controls. Nonetheless, here we provide preliminary evidence for a correlation between the normalization of a neural network and a reduction in related symptoms. Showing their reproducibility, these results were found in two experiments that took place several years apart by different experimenters. Indicative of its potential clinical utility, effects of this treatment remained one-two months later. Clinical trial registration: Both experiments reported here were registered clinical trials (UMIN000015249, jRCTs052180169).

Chronic pancreatitis (CP) is pathologically characterized by the loss of exocrine pancreatic parenchyma, irregular fibrosis, cellular infiltration, and ductal abnormalities. Diagnosing CP objectively is difficult because standard diagnostic criteria are insufficient. The change of parenchymal hardness is the key factor for the diagnosis and understanding of the severity of CP. The ultrasonography (US) or endoscopic ultrasonography (EUS) elastography have been used to diagnose pancreatic diseases. Both strain elastography (SE) and shear wave elastography are specific diagnostic techniques for measuring tissue hardness. Most previous studies were conducted with SE. There are three methods of interpreting SE; the method of recognizing the patterns in SE distribution images in the region of interest, the method of using strain ratio to compare the hardness of adipose tissue or connective tissue with that of the lesion, and the method of evaluating the hardness distribution of a target by histogram analysis. These former two methods have been used primarily for neoplastic diseases, and histograms analysis has been used to assess hardness distribution in the evaluation of CP. Since the hardness of the pancreas increases with aging, it is necessary to consider the age in the diagnosis of pancreatic disorders using US or EUS elastography.

Abstract Accelerated dental pulp mineralization is a common complication in avulsed/luxated teeth, although the mechanisms underlying this remain unclear. We hypothesized that hypoxia due to vascular severance may induce osteo/odontoblast differentiation of dental pulp stem cells (DPSCs). This study examined the role of B-cell CLL/lymphoma 9 (BCL9), which is downstream of hypoxia-inducible factor 1α (HIF1α) and a Wnt/β-catenin transcriptional cofactor, in the osteo/odontoblastic differentiation of human DPSCs (hDPSCs) under hypoxic conditions. hDPSCs were isolated from extracted healthy wisdom teeth. Hypoxic conditions and HIF1α overexpression induced significant upregulation of mRNAs for osteo/odontoblast markers (RUNX2, ALP, OC), BCL9, and Wnt/β-catenin signaling target genes (AXIN2, TCF1) in hDPSCs. Overexpression and suppression of BCL9 in hDPSCs up- and downregulated, respectively, the mRNAs for AXIN2, TCF1, and the osteo/odontoblast markers. Hypoxic-cultured mouse pulp tissue explants showed the promotion of HIF1α, BCL9, and β-catenin expression and BCL9-β-catenin co-localization. In addition, BCL9 formed a complex with β-catenin in hDPSCs in vitro. This study demonstrated that hypoxia/HIF1α-induced osteo/odontoblast differentiation of hDPSCs was partially dependent on Wnt/β-catenin signaling, where BCL9 acted as a key mediator between HIF1α and Wnt/β-catenin signaling. These findings may reveal part of the mechanisms of dental pulp mineralization after traumatic dental injury.

Abstract This study aimed whether the uptake of amino tracer positron emission tomography (PET) can be used as an additional imaging biomarker to estimate the prognosis of glioma. Participants comprised 56 adult patients with newly diagnosed and untreated World Health Organization (WHO) grade II–IV astrocytic glioma who underwent surgical excision and were evaluated by 11C-methionine PET prior to the surgical excision at Osaka City University Hospital from July 2011 to March 2018. Clinical and imaging studies were retrospectively reviewed based on medical records at our institution. Preoperative Karnofsky Performance Status (KPS) only influenced progression-free survival (hazard ratio [HR] 0.20; 95% confidence interval [CI] 0.10–0.41, p

Abstract The gut microbiota interacts with infectious diseases and affects host immunity. Liver disease is also reportedly associated with changes in the gut microbiota. To elucidate the changes in the gut microbiota before and after hepatitis C virus (HCV) eradication through direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C (CHC), we investigated 42 samples from 14 patients who received DAA therapy for HCV. Fecal samples were obtained before treatment (Pre), when treatment ended (EOT), and 24 weeks after treatment ended (Post24). The target V3–4 region of the 16S rRNA gene from fecal samples was amplified using the Illumina Miseq sequencing platform. The diversity of the gut microbiota did not significantly differ between Pre, EOT, and Post24. Principal coordinates analysis showed that for each patient, the values at Pre, EOT, and Post24 were concentrated within a small area. The linear discriminant analysis of effect size showed that the relative abundances of Faecalibacterium and Bacillus increased at EOT, further increased at Post24, and were significantly increased at Post24 compared to Pre. These suggest that changes in the gut microbiota should be considered as among the various effects observed on living organisms after HCV eradication.

Abstract Background The chorioretinal inflammatory lesions occurring in punctate inner choroiditis evolve into punched-out atrophic scars. Typically, the progression is gradual. We report a case of highly myopic punctate inner choroiditis with rapid progression of chorioretinal atrophy. Case presentation A 48-year-old Japanese woman with high myopia presented with decreased visual acuity. Best-corrected visual acuity was 20/28 in the right eye and 20/16 in the left eye; axial length was 29.0 mm and 28.7 mm, respectively. Fundoscopy revealed an epiretinal membrane in the left eye. Three years later, the best-corrected visual acuity in the left eye had decreased to 20/33; at this time, the patient underwent vitrectomy with epiretinal membrane and internal limiting membrane peeling in this eye. Six months later, the best-corrected visual acuity in the left eye decreased suddenly to 20/100. Optical coherence tomography showed a nodule-like lesion in the outer retina with disruption of the retinal pigment epithelium and a focally thickened choroid, compatible with PIC. One month later, the choroidal thickness had decreased. The central chorioretinal atrophy expanded rapidly at a rate of 0.45 mm2/year over the next 3 years, and new areas of patchy focal chorioretinal atrophy developed in the perifovea. Conclusions Rapid progression of chorioretinal atrophy was observed in a patient with punctate inner choroiditis. Because punctate inner choroiditis is often associated with degenerative myopia, the retina is fragile and may be susceptible to mechanical damage. This case report alerts clinicians to the need for careful management of patients with punctate inner choroiditis, especially after vitrectomy.

Abstract It is important to identify prognostic and predictive markers of metastatic urothelial carcinoma (mUC) treated with immunocheckpoint inhibitors. We sought to establish a prognostic marker for patients with mUC treated with pembrolizumab based on only blood test results. We included 165 patients with mUC in the discovery cohort and 103 with mUC who were treated with pembrolizumab in the validation cohort. Multivariate and Cox regression analyses were used to analyse the data. In the discovery cohort, the fibrosis-4 index (hazard ratio [HR]: 2.13, 95% confidence interval [CI] 1.20–3.76, p = 0.010), albumin–bilirubin score (HR 1.91, 95% CI 1.27–2.88, p = 0.002), and neutrophil–lymphocyte ratio (HR: 1.84, 95% CI 1.22–2.79, p = 0.004) were independent significant prognostic factors. We established a ‘FAN score’ that included these three aforementioned items, which were assigned one point each. We divided patients into the 0–1 point (n = 116) and 2–3 points (n = 49) groups. The FAN score was a significant prognostic marker for cancer-specific survival (CSS) (HR 1.48, 95% CI 1.19–1.83, p

Abstract Electromyography (EMG) and mechanomyography (MMG) have been used to directly evaluate muscle function through the electromechanical aspect of muscle contraction. The purpose of this study was to establish new absolute indices to describe muscle contraction performance during dynamic exercise by combining EMG and displacement MMG (dMMG) measured simultaneously using our previously developed MMG/EMG hybrid transducer system. Study participants were eight healthy male non-athletes (controls) and eight male athletes. EMG and dMMG of the vastus medialis were measured for 30 s during four cycles of recumbent bicycle pedaling (30, 60, 90, and 120 W) and on passive joint movement. Total powers were calculated based on the time domain waveforms of both signals. Muscle contraction performance was verified with the slope of regression line (SRL) and the residual sum of squares (RSS) obtained from EMG and dMMG correlation. EMG and dMMG has increased with the work rate. Force and EMG were similar between groups, but dMMG showed a significant difference with load increase. Athletes had significantly higher SRL and significantly lower RSS than controls. The average value divided by SRL and RSS was higher in athletes than in controls. The indices presented by the combined approach of EMG and dMMG showed a clear contrast between the investigated groups and may be parameters that reflect muscle contraction performance during dynamic exercise.

Melphalan is widely used for hematopoietic stem cell transplantation (HSCT) conditioning. However, the relationship between its pharmacokinetic (PK) and transplantation outcomes in children has not been thoroughly investigated. We prospectively analyzed the relationship between melphalan area under the curve (AUC) and transplantation outcome and examined the development of a predictive model for melphalan clearance in children. This study included 43 children aged 0 to 19 years who underwent HSCT following a melphalan-based conditioning regimen from 2017 to 2021. In univariable analysis, high-melphalan AUC resulted in a significantly lower cumulative incidence of acute graft-versus-host disease and a higher cumulative incidence of thrombotic microangiopathy, although no significant difference was observed in survival. Regression analysis of a randomly selected derivation cohort ( n = 21) revealed the following covariate PK model: predicted melphalan clearance (mL/min) = 6.47 × 24-h urinary creatinine excretion rate (CER, g/day) × 24-h creatinine clearance rate (CCR, mL/min) + 92.8. In the validation cohort ( n = 22), the measured melphalan clearance values were significantly correlated with those calculated based on the prediction equation ( R 2 = 0.663). These results indicate that melphalan exposure may be optimized by adjusting the melphalan dose according to CER and CCR.

Objectives SARS-CoV-2 vaccination is a crucial intervention for infection control; however, the immune response to vaccination in dialysis patients has been reported to be moderate compared with healthy adults. There are few studies available on humoral response in immunised dialysis patients compared with well-matched control group, we conducted a prospective cohort study measuring SARS-CoV-2 antibody titres in Fukushima Prefecture, Japan since September 2021.Participants We compared the titres of both anti-SARS-CoV-2 S1 IgG and neutralising antibodies of 65 haemodialysis patients (dialysis group) with 500 residents in Soma, Fukushima (control group).Methods Coarsened exact matching was used to balance sex, age and days from the second dose between dialysis and control groups.Results Significant differences in the titres of anti-SARS-CoV-2 S1 IgG and neutralising antibodies were observed between the dialysis and control groups; anti-SARS-CoV-2 S1 IgG: 168.35 (4.48–1074.29) AU/mL and 269.81 (4.72–945.96) AU/mL in dialysis and control groups, p=0.02, neutralising antibodies: 35.77 (2.94–826.06) AU/mL and 62.22 (0.00–535.57) AU/mL, p=0.007, respectively).Conclusions We observed significantly reduced anti-SARS-CoV-2 S1 antibody and neutralising antibodies in haemodialysis patients compared with cohorts matched for duration after vaccination. Patients receiving haemodialysis should be carefully monitored for immunological responses to the vaccination and COVID-19 infection.

To determine the source of Streptobacillus notomytis bacteremia in a woman in Japan with signs of rat-bite fever, we examined rat feces from her home. After culture and PCR failed to identify the causative organism in the feces, next-generation sequencing detected Streptobacillus spp., illustrating this procedure’s value for identifying causative environmental organisms.

Abstract Objective We aimed to simplify our fetal RHD genotyping protocol by changing the method to attach Illumina’s sequencing adaptors to PCR products from the ligation-based method to a PCR-based method, and to improve its reliability and robustness by introducing unique molecular indexes, which allow us to count the numbers of DNA fragments used as PCR templates and to minimize the effects of PCR and sequencing errors. Results Both of the newly established protocols reduced time and cost compared with our conventional protocol. Removal of PCR duplicates using UMIs reduced the frequencies of erroneously mapped sequences reads likely generated by PCR and sequencing errors. The modified protocols will help us facilitate implementing fetal RHD genotyping for East Asian populations into clinical practice.

Abstract Artificial lipid bilayer single-channel recording technique has been employed to determine the biophysical and pharmacological properties of various ion channels. However, its measurement efficiency is very low, as it requires two time-consuming processes: preparation of lipid bilayer membranes and incorporation of ion channels into the membranes. In order to address these problems, we previously developed a technique based on hydrophilically modified gold probes on which are immobilized ion channels that can be promptly incorporated into the bilayer membrane at the same time as the membrane is formed on the probes’ hydrophilic area. Here, we improved further this technique by optimizing the gold probe and developed an automated channel current measurement system. We found that use of probes with rounded tips enhanced the efficiency of channel current measurements, and introducing a hydrophobic area on the probe surface, beside the hydrophilic one, further increased measurement efficiency by boosting membrane stability. Moreover, we developed an automated measurement system using the optimized probes; it enabled us to automatically measure channel currents and analyze the effects of a blocker on channel activity. Our study will contribute to the development of high-throughput devices to identify drug candidates affecting ion channel activity.

Abstract The aim of this study was to compare aqueous humour (AqH) cytokine profiles before and after Descemet’s membrane endothelial keratoplasty (DMEK) in eyes with bullous keratopathy (BK) and age-matched normal eyes. A total of 49 participants (mean age 75.0 ± 13.5 years) were divided into three groups: (1) BK patients scheduled for DMEK (BK group); (2) patients after DMEK (DMEK group; average postoperative time 1,018 ± 460 days); and (3) control participants without corneal endothelial disease scheduled for cataract surgery (control group). AqH (0.2 mL) was collected from all participants, and the levels of various AqH cytokines were simultaneously measured using a multiplex bead immunoassay. The DMEK group exhibited significantly lower concentrations of several pro-inflammatory cytokines, such as IL-1β, IL-5, IL-6, IL-10, and IL-8, and granulocyte colony stimulating factor than the BK group. In addition, the levels of IL-1β and IL-5 were significantly lower in the DMEK group than in the control group. The AqH levels of several pro-inflammatory cytokines were significantly reduced after DMEK, indicating that regeneration of the endothelial pump owing to the transplantation of a healthy endothelium might have a positive effect on anterior chamber inflammation.

Summary: Background: Cold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo lung perfusion (EVLP) would provide conditions for cellular “recharge”, allowing for multi-day lung preservation. Methods: Donor lungs from male Yorkshire pigs were preserved using 10°C CSP with two cycles of 4h EVLP. After a total of 3 days of preservation, a left lung transplant was performed followed by 4h of graft evaluation. As controls, 2 lungs were preserved solely with continuous 10°C preservation for 3 days and transplanted. Findings: For animals receiving lungs preserved using a cyclic EVLP protocol, lung function and histological structures were stable and the recipient systemic partial pressure of oxygen/fraction of inspired oxygen (P/F Ratio) after excluding the contralateral lung was 422 ± 61 mmHg. In contrast, lungs preserved solely in continuous cold static storage at 10°C for 72h developed massive lung failure, resulting in recipient death. Metabolomic analysis revealed that EVLP plays a critical role in the re-vitalization of key central carbon energy metabolites (Glucose, Succinate, N-Acetyl Aspartate) and reducing the expression of the inflammasome activation marker CASP1. Interpretation: In conclusion, we demonstrate for the first time the feasibility of 3-day lung preservation leading to excellent early post-transplant outcomes. The thoughtful combination of cold storage (10°C) and intermittent EVLP can open new opportunities in organ transplantation. Funding: This work was supported by the UHN Foundation (Grant#1013612).

Background: Although people can pay attention to targets while ignoring distractors, previous research suggests that target enhancement and distractor suppression work separately and independently. Here, we sought to replicate previous findings and re-establish their independence. Methods: We employed an internet-based psychological experiment. We presented participants with a visual search task in which they searched for a specified shape with or without a singleton. We replicated the singleton-presence benefit in search performance, but this effect was limited to cases where the target color was fixed across all trials. In a randomly intermixed probe task (30% of all trials), the participants searched for a letter among colored probes; we used this task to assess how far attention was separately allocated toward the target or distractor dimensions. Results: We found a negative correlation between target enhancement and distractor suppression, indicating that the participants who paid closer attention to target features ignored distractor features less effectively and vice versa. Averaged data showed no benefit from target color or cost from distractor color, possibly because of the substantial differences in strategy across participants. Conclusions: These results suggest that target enhancement and distractor suppression guide attention in mutually dependent ways and that the relative contribution of these components depends on the participants’ search strategy.

Background The Tokyo 2020 Summer Olympic Games (23 July–8 August 2021) were held in the middle of Japan’s fifth wave of COVID-19, when the number of cases was on the rise, and coincided with the fourth state of emergency implemented by the host city, Tokyo.Aim This study aimed to assess whether the hosting of the Games was associated with a change in the number of COVID-19 cases in Japan using a synthetic control method.Methods A weighted average of control countries with a variety of predictors was used to estimate the counterfactual trajectory of daily COVID-19 cases per 1 000 000 population in the absence of the Games in Japan. Outcome and predictor data were extracted using official and open sources spanning several countries. The predictors comprise the most recent country-level annual or daily data accessible during the Games, including the stringency of the government’s COVID-19 response, testing capacity and vaccination capacity; human mobility index; electoral democracy index and demographic, socioeconomic, health and weather information. After excluding countries with missing data, 42 countries were ultimately used as control countries.Results The number of observed cases per 1 000 000 population on the last day of the Games was 109.2 (7-day average), which was 115.7% higher than the counterfactual trajectory comprising 51.0 confirmed cases per 1 000 000 population. During the Olympic period (since 23 July), the observed cumulative number of cases was 61.0% higher than the counterfactual trajectory, comprising 143 072 and 89 210 confirmed cases (p=0.023), respectively. The counterfactual trajectory lagged 10 days behind the observed trends.Conclusions Given the increasing likelihood that new emerging infectious diseases will be reported in the future, we believe that the results of this study should serve as a sentinel warning for upcoming mega-events during COVID-19 and future pandemics.

Abstract Acute retinal necrosis (ARN) is a form of infectious uveitis caused by alpha herpesviruses, including herpes simplex virus type 1 (HSV-1). We previously found that the long non-coding RNA (lncRNA) U90926 is upregulated in murine retinal photoreceptor cells following HSV-1 infection, leading to host cell death. However, to date, an orthologous transcript has not been identified in humans. We investigated U90926 orthologous transcript in humans and examined its utility as a prognostic marker for visual acuity in patients with ARN. We identified two human orthologous transcripts (1955 and 592 bases) of lncRNA U90926. The amount of the longer human U90926 transcript was approximately 30- and 40-fold higher in the vitreous fluid of patients with ARN than in those with sarcoidosis and intraocular lymphoma, respectively. Furthermore, the expression of the longer human U90926 transcript in the vitreous fluid was highly correlated with the final best-corrected logarithm of the minimum angle of resolution visual acuity in patients with ARN (r = 0.7671, p = 0.0079). This suggests higher expression of the longer human U90926 transcript in the vitreous fluid results in worse visual prognosis; therefore, expression of the longer human U90926 transcript is a potential negative prognostic marker for visual acuity in patients with ARN.

Abstract Pediatric solid tumors are a heterogeneous group of neoplasms with over 100 subtypes. Clinical and histopathological diagnosis remains challenging due to the overlapping morphological and immunohistochemical findings and the presence of atypical cases. To evaluate the potential utility of including RNA-sequencing (RNA-seq) in the diagnostic process, we performed RNA-seq in 47 patients with suspected pediatric sarcomas. Histopathologists specialized in pediatric cancer re-evaluated pathological specimens to reach a consensus diagnosis; 42 patients were diagnosed with known subtypes of solid tumors whereas 5 patients were diagnosed with undifferentiated sarcoma. RNA-seq analysis confirmed and refined consensus diagnoses and further identified diagnostic genetic variants in four of the five patients with undifferentiated sarcoma. Genetic lesions were detected in 23 patients, including the novel SMARCA4-THOP1 fusion gene and 22 conventional or recently reported genetic events. Unsupervised clustering analysis of the RNA-seq data identified a distinct cluster defined by the overexpression of rhabdomyosarcoma-associated genes including MYOG and CHRNG. These findings suggest that RNA-seq-based genetic analysis may aid in the diagnosis of suspected pediatric sarcomas, which would be useful for the development of stratified treatment strategies.

We report a Japanese 5-year-old boy with primary ciliary dyskinesia (PCD) which was diagnosed owing to Clostridium difficile (CD) infection caused by prolonged antibiotic exposure. He had intractable otitis media with effusion (OME) and had abdominal pain and diarrhea for 4 months after starting antibiotics administration. His stool contained CD toxin. After vancomycin treatment, his symptoms improved and his stools did not contain CD toxin. His past medical history included frequent pneumonia. We, therefore, performed electron microscopy of the biopsy specimen from his nasal mucosa and genetic testing, and he was diagnosed with PCD. PCD is a rare inherited genetic disease causing ciliary dysfunction, which is very difficult to diagnose because some children without PCD also develop the same symptoms. Therefore, children who have intractable OME, rhinosinusitis, frequent pneumonia, or bronchitis and are taking antibiotics for long periods of time should be checked for underlying diseases, such as PCD.

Abstract Power devices (PD) are ubiquitous elements of the modern electronics industry that must satisfy the rigorous and diverse demands for robust power conversion systems that are essential for emerging technologies including Internet of Things (IoT), mobile electronics, and wearable devices. However, conventional PDs based on “bulk” and “single-crystal” semiconductors require high temperature (> 1000 °C) fabrication processing and a thick (typically a few tens to 100 μm) drift layer, thereby preventing their applications to compact devices, where PDs must be fabricated on a heat sensitive and flexible substrate. Here we report next-generation PDs based on “thin-films” of “amorphous” oxide semiconductors with the performance exceeding the silicon limit (a theoretical limit for a PD based on bulk single-crystal silicon). The breakthrough was achieved by the creation of an ideal Schottky interface without Fermi-level pinning at the interface, resulting in low specific on-resistance R on,sp (

Abstract Bile duct and anastomotic strictures and intrahepatic stones are common postoperative complications of congenital biliary dilatation (CBD). We performed double-balloon endoscopic retrograde cholangiography (DBERC) for diagnostic and therapeutic purposes after radical surgery. We focused on the effectiveness of DBERC for the treatment of postoperative complications of CBD patients. Bile duct and anastomotic strictures and intrahepatic stones are common postoperative complications of congenital biliary dilatation (CBD). We performed double-balloon endoscopic retrograde cholangiography (DBERC) for diagnostic and therapeutic purposes after radical surgery. We focused on the effectiveness of DBERC for the treatment of postoperative complications of CBD patients. This retrospective study included 28 patients who underwent DBERC (44 procedures) after radical surgery for CBD between January 2011 and December 2019. Strictures were diagnosed as “bile duct strictures” if endoscopy confirmed the presence of bile duct mucosa between the stenotic and anastomotic regions, and as “anastomotic strictures” if the mucosa was absent. The median patient age was 4 (range 0–67) years at the time of primary surgery for CBD and 27.5 (range 8–76) years at the time of DBERC. All anastomotic strictures could be treated with only by 1–2 courses of balloon dilatation of DBERC, while many bile duct strictures (41.2%) needed ≥ 3 treatments, especially those who underwent operative bile duct plasty as the first treatment (83.3%). Although the study was limited by the short follow-up period after DBERC treatment, DBERC is recommended as the first-line treatment for hepatolithiasis associated with biliary and anastomotic strictures in CBD patients, and it can be safely performed multiple times.

Abstract This study aimed to evaluate the predictions of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for prognosis of triple-negative breast cancer (TNBC), especially with residual disease (RD) after preoperative chemotherapy. This retrospective analysis included 74 TNBC patients who received preoperative chemotherapy. DCE-MRI findings from three timepoints were examined: at diagnosis (MRIpre), at midpoint (MRImid) and after chemotherapy (MRIpost). These findings included cancer lesion size, washout index (WI) as a kinetic parameter using the difference in signal intensity between early and delayed phases, and time-signal intensity curve types. Distant disease-free survival was analysed using the log-rank test to compare RD group with and without a fast-washout curve. The diagnostic performance of DCE-MRI findings, including positive predictive value (PPV) for pathological responses, was also calculated. RD without fast washout curve was a significantly better prognostic factor, both at MRImid and MRIpost (hazard ratio = 0.092, 0.098, p

Abstract Posterior cortical atrophy is a rare degenerative condition with prominent visuospatial dysfunction which commonly occurs between ages 50 and 65. A diagnosis of mild posterior cortical atrophy sometimes challenging and can be delayed because there are currently no established neuropsychological examination methods that can easily be used in clinical settings. In this study, we examined whether the tapping span test is a potential diagnostic tool for posterior cortical atrophy and what impairment the tapping span test is indicative of in this condition. Eight patients with mild posterior cortical atrophy were recruited. Age- and severity-matched individuals with amnesic Alzheimer’s disease (n = 9) were also recruited as a control group. The participants were subjected to the tapping span test and several visuospatial working memory tests. The results of the tapping span and visuospatial working memory tests were worse for the posterior cortical atrophy group when compared with the control group. The results from the tapping span tests were strongly correlated with those from the visuospatial working memory tests. The tapping span test is a simple and potentially useful diagnostic tool for patients with mild posterior cortical atrophy, as it reflects visuospatial working memory function.

Abstract The structural flexibility at three substitution sites in LaFeAsO enabled investigation of the relation between superconductivity and structural parameters over a wide range of crystal compositions. Substitutions of Nd for La, Sb or P for As, and F or H for O were performed. All these substitutions modify the local structural parameters, while the F/H-substitution also changes band filling. It was found that the superconducting transition temperature $$T_{\text{c}}$$ T c is strongly affected by the pnictogen height $$h_{Pn}$$ h Pn from the Fe-plane that controls the electron correlation strength and the size of the $$d_{xy}$$ d xy hole Fermi surface (FS). With increasing $$h_{Pn}$$ h Pn , weak coupling BCS superconductivity switches to the strong coupling non-BCS one where electron correlations and the $$d_{xy}$$ d xy hole FS may be important.

Abstract Shear wave elastography (SWE) is a technique to non-invasively and quantitatively evaluate tissue stiffness. We aimed to investigate whether we can differentiate pancreatic cancer (PC) from normal pancreatic parenchyma (NPP) by SWE using transabdominal ultrasound. We investigated a total of 106 patients (84 with NPP and 22 with PC) whose pancreatic elastic modulus was measured by two-dimensional SWE (2D-SWE). Intra-rater reliability in this study was examined, and three measurements were sufficiently reliable. There were no differences between the two groups in factors that could affect SWE measurements. The median value of the elastic modulus was 5.70 kPa in the PC patients and 5.66 kPa in the NPP group, which was not significantly different (P = 0.785). On the contrary, the range was 8.64 kPa and 4.72 kPa, with a significantly greater range in the PC patients (P = 0.001). In conclusion, the median elastic modulus measured by 2D-SWE was not significantly different between PC and NPP, and evaluating the obtained elastic modulus itself is not useful in differentiation. However, the variability was significantly greater in PC than in NPP. Evaluating the range of elasticities will provide additional information in SWE, which may be useful in the diagnosis of PC.

Abstract Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight for one week. Compound 20p dose-dependently induced small heterodimer partner (SHP) mRNA and decreased cytochrome P450 7A1 (CYP7A1) in the liver at 10 and 30 mg/kg, respectively, which were used as FXR agonist markers. Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.

Abstract Current advanced imaging modalities with applied tracing and processing techniques provide excellent visualization of almost all human internal structures in situ; however, the actual 3D internal arrangement of the human cardiac conduction system (CCS) is still unknown. This study is the first to document the successful 3D visualization of the CCS from the sinus node to the bundle branches within the human body, based on our specialized physical micro-dissection and its CT imaging. The 3D CCS transformation by cardiac inclination changes from the standing to the lying position is also provided. Both actual dissection and its CT image-based simulation identified that when the cardiac inclination changed from standing to lying, the sinus node shifted from the dorso-superior to the right outer position and the atrioventricular conduction axis changed from a vertical to a leftward horizontal position. In situ localization of the human CCS provides accurate anatomical localization with morphometric data, and it indicates the useful correlation between heart inclination and CCS rotation axes for predicting the variable and invisible human CCS in the living body. Advances in future imaging modalities and methodology are essential for further accurate in situ 3D CCS visualization.

Abstract DNA replication inhibitors are utilized extensively in studies of molecular biology and as chemotherapy agents in clinical settings. The inhibition of DNA replication often triggers double-stranded DNA breaks (DSBs) at stalled DNA replication sites, resulting in cytotoxicity. In East Asia, some traditional medicines are administered as anticancer drugs, although the mechanisms underlying their pharmacological effects are not entirely understood. In this study, we screened Japanese herbal medicines and identified two benzylisoquinoline alkaloids (BIAs), berberine and coptisine. These alkaloids mildly induced DSBs, and this effect was dependent on the function of topoisomerase I (Topo I) and MUS81-EME1 structure-specific endonuclease. Biochemical analysis revealed that the action of BIAs involves inhibiting the catalytic activity of Topo I rather than inducing the accumulation of the Topo I-DNA complex, which is different from the action of camptothecin (CPT). Furthermore, the results showed that BIAs can act as inhibitors of Topo I, even against CPT-resistant mutants, and that the action of these BIAs was independent of CPT. These results suggest that using a combination of BIAs and CPT might increase their efficiency in eliminating cancer cells.