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Nonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor–deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro . This study highlights the glucose metabolism–independent effects of anagliptin on NASH and HCC development.

The effects of changes in various lifestyle habits on nonalcoholic fatty liver disease (NAFLD) have not been well elucidated. We aimed to clarify how weight change and lifestyle modifications were associated with the development or remission of NAFLD. In this longitudinal cohort study, we reviewed the periodic health checkup data of 1,421 subjects with no causes of liver disease besides NAFLD who had received at least two health checkups between 2009 and 2018. The prevalence of NAFLD at baseline was 34.1% (484/1,421). During follow-up period (4.6 ± 2.8 years), 104 subjects developed NAFLD and 127 subjects demonstrated NAFLD remission. The frequency of NAFLD development or that of NAFLD remission significantly increased as the larger weight gain or weight loss was, respectively (both, p < 0.001). Approximately 40% of the subjects who maintained ≥ 1%/year weight loss achieved NAFLD remission. By multivariate analysis, quitting smoking were independently associated with NAFLD development (adjusted odds ratio [AOR], 2.86; 95% CI, 1.24–6.62). Subjects who quit smoking demonstrated large weight gain (≥1%/year) significantly more frequently than the other subjects (p < 0.001). In sex-specific analysis, starting to exercise was independently associated with NAFLD remission in men (AOR, 2.38; 95% CI, 1.25–4.53).

The topology of the network of load transmitting connections plays an essential role in the cascading failure dynamics of complex systems driven by the redistribution of load after local breakdown events. In particular, as the network structure is gradually tuned from regular to completely random a transition occurs from the localized to mean field behavior of failure spreading. Based on finite size scaling in the fiber bundle model of failure phenomena, here we demonstrate that outside the localized regime, the load bearing capacity and damage tolerance on the macro-scale, and the statistics of clusters of failed nodes on the micro-scale obey scaling laws with exponents which depend on the topology of the load transmission network and on the degree of disorder of the strength of nodes. Most notably, we show that the spatial structure of damage governs the emergence of the localized to mean field transition: as the network gets gradually randomized failed clusters formed on locally regular patches merge through long range links generating a percolation like transition which reduces the load concentration on the network. The results may help to design network structures with an improved robustness against cascading failure.

To clarify the association of detailed angiographic findings with in-hospital outcome after primary percutaneous coronary intervention (p-PCI) for ST-elevation myocardial infarction (STEMI) in Japan. Data regarding the association of detailed angiographic findings with in-hospital outcome after STEMI are limited in the p-PCI era. Between January-2004 and December-2018, 1735 patients with STEMI (mean age, 68.5 years; female, 24.6%) who presented to the hospital in the 24-hours after symptom onset and underwent p-PCI were evaluated using the disease registries. The registry is an ongoing, retrospective, single-center hospital-based registry. The 30-day mortality rate and in-hospital mortality rate were 7.7% and 9.2%, respectively. Independent predictors of in-hospital mortality were ejection fraction (EF) < 40% [adjusted Odds Ratio (aOR), 4.446, p < 0.001], culprit lesions in the left coronary artery (LCA) (aOR, 2.940, p II (aOR, 7.438; p < 0.001), chronic kidney disease (CKD) (aOR, 4.056; p < 0.001), final thrombolysis in myocardial infarction (TIMI) grades 0/1/2 (aOR, 1.809; p = 0.03), absence of robust collaterals (aOR, 17.309; p = 0.01) and hypertension (aOR, 0.449; p = 0.01). Among the consecutive patients with STEMI, the in-hospital mortality rate after p-PCI significantly improved in the second half. Not only CKD, Killip class > II, and EF < 40%, but also the angiographic findings such as culprit lesions in the LCA, absence of very robust collaterals, and final TIMI grades <3 were associated with an increased risk of in-hospital mortality.

Durvalumab plus tremelimumab (Durva/Treme) combined immunotherapy is the first-line therapy recommended for unresectable hepatocellular carcinoma (HCC). Since sequential therapy is more effective in improving prognosis, tumor markers have been used as predictive biomarkers for response to systemic therapy. This study aimed to investigate the predictive ability of objective response (OR) by tumor markers for Durva/Treme therapy against HCC. In this multicenter study, 110 patients with HCC who received Durva/Treme therapy were retrospectively enrolled. The OR rate was 15.5%. To aid early decision-making regarding OR, we evaluated the predictors contributing to OR in two steps: before (first step) and 4 weeks after (second step) treatment induction. Changes in tumor markers (alpha-fetoprotein [AFP] and des-gamma-carboxy prothrombin [DCP]) from baseline to 4 weeks after treatment (ΔAFP/ΔDCP) were included as the input factors. In the first step, multivariable analysis identified only the baseline AFP level (odds ratio 3.497, p = 0.029) as a predictor of OR. Patients with AFP ≥ 400 ng/mL had a significantly higher OR rate than those with < 400 ng/mL (28.2 vs. 8.5%, p = 0.011), and there was no significant difference in progression-free survival (PFS) between the two groups. When AFP/DCP response was defined as a ≥10% reduction from baseline, multivariable analysis showed that AFP response (odds ratio 6.023, p = 0.042) and DCP response (odds ratio 11.657, p = 0.006) were both independent predictors of OR in the second step. The PFS of patients with AFP or DCP response was significantly longer than that of patients without AFP or DCP response. The study demonstrated that the use of AFP and DCP can predict the OR of patients with HCC receiving Durva/Treme therapy.

Background Evidence regarding the association between hyperuricemia and arrhythmia recurrence after catheter ablation for paroxysmal atrial fibrillation (AF) is scarce. We investigated whether hyperuricemia predicts arrhythmia recurrence after catheter ablation for paroxysmal AF and the relationship between hyperuricemia and alcohol consumption in AF recurrence. Methods Patients who underwent catheter ablation for paroxysmal AF were divided into the hyperuricemia (index serum uric acid [UA] >7.0 mg/dL; n = 114) and control (UA ≤7.0 mg/dL; n = 609) groups and were followed for a median of 24 (12–48) months after ablation. Results The hyperuricemia group had more patients with an alcohol intake of ≥20 g/day (33.3% vs. 22.7%, p = .017) and a lower incidence of AF‐free survival (p = .019). Similarly, those with an alcohol intake of ≥20 g/day had a lower incidence of AF‐free survival than other patients. Multivariate Cox regression analysis revealed the following independent predictors of AF recurrence (adjusted hazard ratio, 95% confidence interval): hyperuricemia (1.64, 1.12–2.40), female gender (1.91, 1.36–2.67), brain natriuretic peptide level >100 pg/mL (1.59, 1.14–2.22), and alcohol consumption ≥20 g/day (1.49, 1.03–2.15) (all p < .05). In addition, causal mediation analysis revealed that alcohol consumption of ≥20 g/day directly affected AF recurrence, independent of hyperuricemia. Conclusions Patients with hyperuricemia may be at a high risk of arrhythmia recurrence after catheter ablation for paroxysmal AF. Although high alcohol consumption may contribute to increased UA levels, the presence of hyperuricemia may independently predict AF recurrence. Patients with hyperuricemia show increased risk of arrhythmia recurrence after catheter ablation for paroxysmal atrial fibrillation. Although high alcohol consumption (≥20 g/day) may weakly contribute to increased serum uric acid levels, hyperuricemia has independent predictive value.

•Ustalic acid is the toxic component in poisonous mushroom, Tricholoma ustale.•The quantitative analysis of the ustalic acid content in food samples was conducted.•The quantitation limits were 10ng/g (shiitake mushroom) and 0.40ng/g (miso soup).•This method was applied to leftover samples from a food poisoning case.•This is the first report to determine ustalic acid in the leftovers of the case. Tricholoma ustale, a poisonous member of the Tricholomataceae family, causes gastrointestinal symptoms such as diarrhea and vomiting. In Japan, 86 cases (affecting a total of 347 patients) of poisoning with Tricholoma ustale have been reported between 1989 and 2010. Ustalic acid is one of the primary toxic components in Tricholoma ustale. In the present study, the quantitative analysis of the ustalic acid content in mushroom and food samples was conducted by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Mushroom and food samples were extracted using methanol containing 0.5% formic acid and 50% aqueous methanol, respectively. Purification using SAX solid-phase extraction (SPE) was conducted prior to LC–MS/MS analysis, which was performed in the ESI negative mode using a C18 column. The method developed for the LC–MS/MS analysis of ustalic acid was extremely sensitive. The limits of quantitation calculated at a signal-to-noise ratio of 10 were 10ng/g (shiitake mushroom) and 0.40ng/g (miso soup). The accuracies of quantitation in the shiitake mushroom and miso soup samples ranged from 99.8%–105% and 98.8%–102%, respectively. This method was applied to leftover mushroom samples from a food poisoning case; here, ustalic acid was detected at 0.57, 3.7μg/g. This analytical method using LC–MS/MS could be useful in food poisoning cases involving mushrooms. This is the first report in which the ustalic acid content was determined using the leftovers of a food poisoning case.

The aim of this study was to investigate whether super-resolution deep learning reconstruction (SR-DLR) is superior to conventional deep learning reconstruction (DLR) with respect to interobserver agreement in the evaluation of neuroforaminal stenosis using 1.5T cervical spine MRI. This retrospective study included 39 patients who underwent 1.5T cervical spine MRI. T2-weighted sagittal images were reconstructed with SR-DLR and DLR. Three blinded radiologists independently evaluated the images in terms of the degree of neuroforaminal stenosis, depictions of the vertebrae, spinal cord and neural foramina, sharpness, noise, artefacts and diagnostic acceptability. In quantitative image analyses, a fourth radiologist evaluated the signal-to-noise ratio (SNR) by placing a circular or ovoid region of interest on the spinal cord, and the edge slope based on a linear region of interest placed across the surface of the spinal cord. Interobserver agreement in the evaluations of neuroforaminal stenosis using SR-DLR and DLR was 0.422–0.571 and 0.410–0.542, respectively. The kappa values between reader 1 vs. reader 2 and reader 2 vs. reader 3 significantly differed. Two of the three readers rated depictions of the spinal cord, sharpness, and diagnostic acceptability as significantly better with SR-DLR than with DLR. Both SNR and edge slope (/mm) were also significantly better with SR-DLR (12.9 and 6031, respectively) than with DLR (11.5 and 3741, respectively) (p < 0.001 for both). In conclusion, compared to DLR, SR-DLR improved interobserver agreement in the evaluations of neuroforaminal stenosis using 1.5T cervical spine MRI.

A nitronyl nitroxide derivative, 2-phenylethynyl-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-1-oxyl-3-oxide (1), and two verdazyl derivatives carrying a phenylacetylene unit, 1,5-diphenyl-3-phenylethynyl-6-oxo-1,2,4,5-tetrazin-2-yl (2) and 1,5-diisopropyl-3-phenylethynyl-6-oxo-1,2,4,5-tetrazin-2-yl (3), were synthesized and their packing structures were studied by X-ray crystallographic analysis and magnetically characterized in the solid state. While 1 and 3 had an isolated doublet spin state, 2 formed an antiferromagnetically coupled pair (2J/kB = −118 K). Density functional theory (DFT) calculations reveal that the spin density polarized in the phenyl group decreases as the dihedral angle between the phenyl ring and radical plane increases.

Background Facial massage is empirically known to be associated with morphological changes, such as improvements in facial sagging. However, quantified objective evaluations of massage‐induced changes have not been performed to date. This preliminary pilot study aimed to verify the effectiveness of facial massages by using breakthrough computed tomographic technology. Materials and methods Five healthy adult volunteers (three women and two men; age, 29–37 years) were enrolled, and computed tomography (CT) examinations using a 320 detectors‐spiral CT system known as 320‐multidetector‐row CT (MDCT) were performed before and after facial massages. Each participant performed a self‐massage twice daily for 2 weeks. Massage‐induced changes in the cheeks and the superficial musculoaponeurotic system (SMAS) were analyzed by two radiologists on a workstation with a high‐accuracy imaging analysis system. Results After facial massage, the malar top became thinner by −0.8% ± 0.45% and shifted cranially and horizontally over a distance of 3.9 ± 1.94 mm. The SMAS‐height, defined as the highest vertical distance of the SMAS, increased by 2.6% ± 2.6%. The change rate in cheek thickness and SMAS‐height showed a significant correlation (r = −0.63; P < 0.05). These changes were attributed to the lifting and tightening effects of facial massage. Conclusion We conducted a detailed analysis of the effects of facial massages by using the breakthrough CT technology. Our results provide useful information for beauty treatments and could contribute to the collection of objective scientific evidence for facial massages.