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BackgroundProgression to cirrhosis in non-alcoholic steatohepatitis (NASH) is associated with a decrease in liver fat. However, the prognostic significance of liver fat content in NASH-related significant fibrosis and cirrhosis is unclear.AimTo investigate the risk of decompensation, hepatocellular carcinoma (HCC) and mortality stratified by liver fat content in NASH-related significant fibrosis and cirrhosis.MethodsIn this meta-analysis of individual participant data, 456 patients with both magnetic resonance elastography (MRE) and MRI-derived protein density fat fraction (MRI-PDFF) were enrolled, and 296 patients with longitudinal follow-up were analysed. MRE combined with fibrosis-4 (MEFIB-index), and MRI-PDFF were used to measure liver fibrosis and fat, respectively. MEFIB-negative, MEFIB-positive+ MRI-PDFF ≥5% and MEFIB-positive+ MRI-PDFF

Abstract Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. Here, we synthesize a competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation. Metadynamics simulations suggest that the interaction of KSI-6666 with a methionine residue Met124 in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1. Consistently, in vitro functional and mutational analyses reveal that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the Met124 of the protein and substituents on the distal benzene ring of KSI-6666. Moreover, in vivo study suggests that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666.

BackgroundData are scarce regarding the development of hepatic decompensation in patients with non-alcoholic fatty liver disease (NAFLD) with and without type 2 diabetes. We aimed to assess the risk of hepatic decompensation in people with NAFLD with and without type 2 diabetes.MethodsWe did a meta-analysis of individual participant-level data from six cohorts in the USA, Japan, and Turkey. Included participants had magnetic resonance elastography between Feb 27, 2007, and June 4, 2021. Eligible studies included those with liver fibrosis characterisation by magnetic resonance elastography, longitudinal assessment for hepatic decompensation and death, and included adult patients (aged ≥18 years) with NAFLD, for whom data were available regarding the presence of type 2 diabetes at baseline. The primary outcome was hepatic decompensation, defined as ascites, hepatic encephalopathy, or variceal bleeding. The secondary outcome was the development of hepatocellular carcinoma. We used competing risk regression using the Fine and Gray subdistribution hazard ratio (sHR) to compare the likelihood of hepatic decompensation in participants with and without type 2 diabetes. Death without hepatic decompensation was a competing event.FindingsData for 2016 participants (736 with type 2 diabetes; 1280 without type 2 diabetes) from six cohorts were included in this analysis. 1074 (53%) of 2016 participants were female with a mean age of 57·8 years (SD 14·2) years and BMI of 31·3 kg/m2 (SD 7·4). Among 1737 participants (602 with type 2 diabetes and 1135 without type 2 diabetes) with available longitudinal data, 105 participants developed hepatic decompensation over a median follow-up time of 2·8 years (IQR 1·4-5·5). Participants with type 2 diabetes had a significantly higher risk of hepatic decompensation at 1 year (3·37% [95% CI 2·10-5·11] vs 1·07% [0·57-1·86]), 3 years (7·49% [5·36-10·08] vs 2·92% [1·92-4·25]), and 5 years (13·85% [10·43-17·75] vs 3·95% [2·67-5·60]) than participants without type 2 diabetes (p

The Ariake catfish, Tachysurus aurantiacus, is a freshwater fish endemic to Kyushu Island, Japan. However, these catfish are now endangered owing to environmental changes. Despite their status, there is scant quantitative research on the Ariake catfish regarding their potential conservation. The Yabe River is a typical catfish habitat situated in the northern part of Kyushu Island (Ariake Area) and has a unique civil engineering heritage, as represented by the so-called ‘detour canal’. The canals were created owing to competition by two Domains to divert additional water resources into their own territory for rice cultivation during the Edo Period (1603–1867). To fill the research gap on the Ariake catfish and assess the ecological value of detour canals, in this study, we conducted a survey of local catfish populations and nine environmental parameters that can affect them. We found that the population volume of the Ariake catfish was significantly higher in canals than in ordinary branch rivers. Although the detour canals were not originally constructed for biodiversity conservation, they nonetheless unintentionally provide catfish habitat at present. As these canals represent a remarkable example of a contribution by a civil engineering heritage structure to biodiversity conservation, our study should be used as a potential justification for preserving the canals, as well as conserving the aquatic species that utilise them as vital habitat.

Abstract Germline loss-of-function mutations in USP9X have been reported to cause a wide spectrum of congenital anomalies. Here, we report a Japanese girl with a novel heterozygous nonsense mutation in USP9X who exhibited intellectual disability with characteristic craniofacial abnormalities, including hypotelorism, brachycephaly, hypodontia, micrognathia, severe dental crowding, and an isolated submucous cleft palate. Our findings provide further evidence that disruptions in USP9X contribute to a broad range of congenital craniofacial abnormalities.

Introduction: Portal annular pancreas (PAP) is a congenital anomaly resulting from aberrant fusion of the ventral and dorsal pancreatic buds around the portal vein (PV). PAP was classified into three types by Joseph et al., based on the location of the main pancreatic duct around the PV. The presence of PAP is important for the surgical procedure because it is associated with the postoperative pancreatic fistula. There are no standardized surgical procedures of resection and reconstruction for PAP. Case Presentation: We report 2 cases of subtotal stomach-preserving pancreatoduodenectomy in patients with PAP. One case of PAP was discovered coincidentally intraoperatively, and the other case was diagnosed before surgery. The first case was an 84-year-old male patient who underwent surgery for distal bile duct cancer. PAP was noticed intraoperatively when the uncinate process of the pancreas was detached from behind the PV. The second case was an 84-year-old female patient who also underwent surgery for distal bile duct cancer. We recognized PAP from preoperative computed tomography images. In both cases, the ductal anatomy was consistent with type IIIA PAP, and the dorsal pancreas was resected using a stapling device. During the postoperative period, there was no clinically relevant postoperative pancreatic fistula. Conclusion: PAP is rarely encountered intraoperatively; however, it is important to recognize it before surgery and take it into consideration when deciding upon the procedures for resection and reconstruction.

The rare genus Pseudalomya Telenga comprises two species, which are found only in the Eastern Palaearctic region and high mountains of the Oriental region. The phylogenetic position of Pseudalomya remains unclear because of its intermediate morphology between two ichneumonine tribes, Alomyini and Phaeogenini. This article reports the discovery of a new species of Pseudalomya: Pseudalomya truncaticornis sp. nov. Specimens were collected during a survey of insect fauna in the Dasyueshan area of Shei-Pa National Park, one of the high-altitude regions in Taiwan. The new species can be diagnosed by its body coloration, frontal horn shape, facial punctures, metasomal tergite sculpture, and wing venation. To the best of our knowledge, this is the first record of Pseudalomya in Taiwan. This article also presents a diagnostic key to the global species of Pseudalomya. In this study, molecular phylogenetic analyses were performed using one mitochondrial and two nuclear gene sequences from P. truncaticornis sp. nov. and other members of the Ichneumoniformes group. The results indicate that Pseudalomya should be classified within Phaeogenini, distinct from Alomyini, but more comprehensive phylogenomic studies are needed to confirm this placement.

Background: Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are crucial for ending the pandemic of coronavirus disease 2019 (COVID-19). Currently, the cumulative effect of booster shots of mRNA vaccines on adverse events is not sufficiently characterized. Methods: A survey-based study on vaccine adverse events was conducted in a Japanese medical institute after the third dose of Pfizer BNT162b2. Adverse events were grouped using network analysis, and a heteroscedastic probit model was built to analyse adverse events. Results: There were two main clusters of adverse events, systemic and local injection site-associated events. Subject background and the experience of previous vaccine-related adverse events were variably associated with the occurrence and intensity of adverse events following the third dose. Among adverse events, only lymphadenopathy increased prominently following the third dose, while the largest increase in other systemic adverse events occurred generally following the second dose. Conclusions: The effect of repeated booster vaccines on the frequency and intensity of adverse events differs depending on the kind of adverse event.

Background & aimsA two-step strategy combining a serum marker and magnetic resonance elastography (MRE) for detecting advanced fibrosis (stage 3-4) among patients with nonalcoholic fatty liver disease (NAFLD) has been proposed, but its diagnostic accuracy has not been evaluated. In this multicenter study, we aimed to investigate the diagnostic accuracy of a two-step strategy including Fibrosis-4 (FIB-4) followed by MRE.MethodsIn this multicenter study, 806 patients with biopsy-proven NAFLD who underwent contemporaneous MRE were enrolled and randomly assigned to training and validation cohorts. As a first step, patients with FIB-4

To survive, animals must convert sensory information into appropriate behaviours1,2. Vision is a common sense for locating ethologically relevant stimuli and guiding motor responses3-5. How circuitry converts object location in retinal coordinates to movement direction in body coordinates remains largely unknown. Here we show through behaviour, physiology, anatomy and connectomics in Drosophila that visuomotor transformation occurs by conversion of topographic maps formed by the dendrites of feature-detecting visual projection neurons (VPNs)6,7 into synaptic weight gradients of VPN outputs onto central brain neurons. We demonstrate how this gradient motif transforms the anteroposterior location of a visual looming stimulus into the fly's directional escape. Specifically, we discover that two neurons postsynaptic to a looming-responsive VPN type promote opposite takeoff directions. Opposite synaptic weight gradients onto these neurons from looming VPNs in different visual field regions convert localized looming threats into correctly oriented escapes. For a second looming-responsive VPN type, we demonstrate graded responses along the dorsoventral axis. We show that this synaptic gradient motif generalizes across all 20 primary VPN cell types and most often arises without VPN axon topography. Synaptic gradients may thus be a general mechanism for conveying spatial features of sensory information into directed motor outputs.

This study is grounded in an examination of a prominent electrical appliance corporation, with the aim of proposing an innovative framework in which to evaluate integration of distinct decision-making logics, namely Causation and Effectuation, within Business Model Innovation (BMI) in large-scale enterprises. Specifically, our research reveals the enduring positive effects resulting from combination of these two logics, underscoring the critical importance of dissociating effectuation practices from short-term causation evaluation criteria. Following a sequence of business development procedures, the intrapreneur disengages from the organization, which has relatively de-emphasized effectuating processes, and transitions to a novel intra-organization characterized by a BMI orientation. Consequently, the holistic system operates seamlessly. We posit that these findings contribute a novel perspective to scholarly investigations of the innovation processes in enterprises that exhibit a substantial departure from established business paradigms. Furthermore, our insights extend into the domain of effectuation research, enriching the existing academic discourse.

Purpose The effect of hepatic fibrosis stage on quantitative ultrasound based on the attenuation coefficient (AC) for liver lipid quantification is controversial. The objective of this study was to determine how the degree of fibrosis assessed by magnetic resonance (MR) elastography affects AC based on the ultrasound-guided attenuation parameter according to the grade of hepatic steatosis, using magnetic resonance imaging (MRI)–derived proton density fat fraction (MRI-derived PDFF) as the reference standard. Methods Between February 2020 and April 2021, 982 patients with chronic liver disease who underwent AC and MRI-derived PDFF measurement as well as MR elastography were enrolled. Multiple regression was used to investigate whether AC was affected by the degree of liver stiffness. Results AC increased as liver stiffness progressed in 344 patients without hepatic steatosis (P=0.009). In multivariable analysis, AC was positively correlated with skin-capsule distance (P

Abstract The number of cancer cases diagnosed during the coronavirus disease 2019 (COVID-19) pandemic has decreased. This study investigated the impact of the pandemic on the clinical practice of hepatocellular carcinoma (HCC) using a novel nationwide REgistry for Advanced Liver diseases (REAL) in Japan. We retrieved data of patients initially diagnosed with HCC between January 2018 and December 2021. We adopted tumor size as the primary outcome measure and compared it between the pre-COVID-19 (2018 and 2019) and COVID-19 eras (2020 and 2021). We analyzed 13,777 patients initially diagnosed with HCC (8074 in the pre-COVID-19 era and 5703 in the COVID-19 era). The size of the maximal intrahepatic tumor did not change between the two periods (mean [SD] = 4.3 [3.6] cm and 4.4 [3.6] cm), whereas the proportion of patients with a single tumor increased slightly from 72.0 to 74.3%. HCC was diagnosed at a similar Barcelona Clinic Liver Cancer stage. However, the proportion of patients treated with systemic therapy has increased from 5.4 to 8.9%. The proportion of patients with a non-viral etiology significantly increased from 55.3 to 60.4%. Although the tumor size was significantly different among the etiologies, the subgroup analysis showed that the tumor size did not change after stratification by etiology. In conclusion, the characteristics of initially diagnosed HCC remained unchanged during the COVID-19 pandemic in Japan, regardless of differences in etiology. A robust surveillance system should be established particularly for non-B, non-C etiology to detect HCC in earlier stages.

Background & aimsMagnetic resonance elastography (MRE) is an accurate biomarker of liver fibrosis; however, limited data characterize its association with clinical outcomes. We conducted an individual participant data pooled meta-analysis on patients with nonalcoholic fatty liver disease to evaluate the association between liver stiffness on MRE and liver-related outcomes.MethodsA systematic search identified 6 cohorts of adults with nonalcoholic fatty liver disease who underwent a baseline MRE and were followed for hepatic decompensation, hepatocellular carcinoma, and death. Cox and logistic regression were used to assess the association between liver stiffness on MRE and liver-related outcomes, including a composite primary outcome defined as varices needing treatment, ascites, and hepatic encephalopathy.ResultsThis individual participant data pooled meta-analysis included 2018 patients (53% women) with a mean (± standard deviation) age of 57.8 (±14) years and MRE at baseline of 4.15 (±2.19) kPa, respectively. Among 1707 patients with available longitudinal data with a median (interquartile range) of 3 (4.2) years of follow-up, the hazard ratio for the primary outcome for MRE of 5 to 8 kPa was 11.0 (95% confidence interval [CI]: 7.03-17.1, P < .001) and for ≥ 8 kPa was 15.9 (95% CI: 9.32-27.2, P < .001), compared with those with MRE

Integrated photonic neural networks (PNNs) usually adopt traditional convolutional neural network (CNN) or multilayer perceptron (MLP) network models. These models consist of horizontally cascaded deep layer architectures interleaved by nonlinear activation functions. However, there are practical challenges for on-chip realizing such architectures, including the optical loss and the lack of efficient on-chip optical activation nonlinearity. Here, we propose a vertically hierarchical photonic neural network leveraging electro-optical element-wise multiplication to extract an element-wise feature in a polynomial projection space, which enables high-accuracy classification. For this network architecture, the light propagates through only two fully connected linear layers; thus, vertical extension to the deep layer is not limited by optical loss. This electro-photonic network can perform equivalently to or outperform optical CNN and MLP models even without interleaving deep layers by activation functions, benchmarking ∼97.9%, ∼87.7%, and ∼90.3% average blind-testing accuracies, for the whole test sets of MNIST handwritten digits, Fashion-MNIST images, and KMNIST Japanese cursive characters, respectively. It also demonstrates a >99% accuracy for boundary prediction of 12-labeled clusters. This work presents a different PNN architecture, which offers both high performance and better amenability to an integrated photonics platform.

Silicon (Si) uptake is generally beneficial for plants that need protection from insect herbivores. In pursue of mechanisms involved in Si-mediated defense, we comprehensively explored the impact of Si on several defensive and metabolic traits in rice exposed to simulated and real herbivory of Mythimna loreyi Duponchel larvae. Hydroponic experiments showed that Si-deprived rice supplemented with Si 72 h prior to insect infestation were similarly resistant to larvae as plants continuously grown in Si-containing media. Both Si and herbivory altered primary metabolism in rice, including the levels of several sugars, amino acids, and organic acids. While the accumulation of sugars was generally positively correlated with Si presence, multiple amino acids showed a negative correlation trend with Si supplementation. The levels of secondary metabolites, including isopentylamine, p-coumaroylputrescine and feruloylputrescine, were typically higher in the leaves of Si-supplemented plants exposed to herbivory stress compared to Si-deprived plants. In addition, simulated herbivory treatment in Si-supplemented plants induced more volatile emissions relative to Si-deprived plants, which was consistent with the increased transcripts of key genes involved in volatile biosynthesis. In ecological interactions, Si alone did not affect the oviposition choice of M. loreyi but gravid females showed a significant preference for simulated herbivory-treated/Si-deprived compared to Si-supplemented plants. Our data suggest that apart from mechanical defense, Si may affect rice metabolism in multiple ways that might enhance/modulate defense responses of rice under herbivory stress.

Abstract Background and Aim Magnetic resonance elastography (MRE) is used for the evaluation of liver fibrosis; however, it remains unclear whether MRE‐based liver stiffness is associated with hepatocellular carcinoma (HCC) development, particularly in patients with chronic hepatitis B. Methods A total of 504 patients with chronic hepatitis B receiving MRE were enrolled. The primary endpoint was the association between MRE‐based liver stiffness and HCC. Results In a cross‐sectional analysis at the time of MRE measurement, the median (interquartile range) liver stiffness values in patients with presence or history of HCC and those without HCC were 3.68 (2.89–4.96) and 2.60 (2.22–3.45) kPa, respectively, and liver stiffness was significantly higher in patients with presence or history of HCC than in those without HCC (P

Abstract Background and aim In patients with chronic hepatitis C, 8 weeks of glecaprevir and pibrentasvir (GLE/PIB) treatment for chronic hepatitis (non‐cirrhosis) and 12 weeks for cirrhosis have been approved in Japan. However, whether 8 weeks of treatment for cirrhosis may reduce treatment efficacy has not been adequately investigated. Methods This prospective, nationwide, multicenter cohort study enrolled 1275 patients with chronic hepatitis C who received GLE/PIB therapy. The effect of liver fibrosis and treatment periods on the efficiency of GLE/PIB therapy was investigated. The primary endpoint was the sustained virological response (SVR) rate in patients with chronic hepatitis (non‐cirrhosis) and cirrhosis. The association between treatment periods and liver fibrosis on the SVR after 12 weeks of treatment rate was investigated. Results The SVR rates in patients with chronic hepatitis with 8 weeks of treatment, chronic hepatitis with 12 weeks of treatment, cirrhosis with 8 weeks of treatment, and cirrhosis with 12 weeks of treatment were 98.9% (800/809), 100% (87/87), 100% (166/166), and 99.1% (211/213), respectively, and were was not different among these groups (P = 0.4). Conclusion GLE/PIB therapy for chronic hepatitis C had high efficacy regardless of liver fibrosis status and treatment periods. Periods of GLE/PIB therapy could be chosen with available modalities, and high SVR rates could be achieved regardless of the decision.