Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

Machine learning improves the prediction of significant fibrosis in Asian patients with metabolic dysfunction-associated steatotic liver disease - The Gut and Obesity in Asia (GO-ASIA) Study.

BACKGROUND: The precise estimation of cases with significant fibrosis (SF) is an unmet goal in non-alcoholic fatty liver disease (NAFLD/MASLD). AIMS: We evaluated the performance of machine learning (ML) and non-patented scores for ruling out SF among NAFLD/MASLD patients. METHODS: Twenty-one ML models were trained (N = 1153), tested (N = 283), and validated (N = 220) on clinical and biochemical parameters of histologically-proven NAFLD/MASLD patients (N = 1656) collected across 14 centres in 8 Asian countries. Their performance for detecting histological-SF (≥F2fibrosis) were evaluated with APRI, FIB4, NFS, BARD, and SAFE (NPV/F1-score as model-selection criteria). RESULTS: Patients aged 47 years (median), 54.6% males, 73.7% with metabolic syndrome, and 32.9% with histological-SF were included in the study. Patients with SFvs.no-SF had higher age, aminotransferases, fasting plasma glucose, metabolic syndrome, uncontrolled diabetes, and NAFLD activity score (p < 0.001, each). ML models showed 7%-12% better discrimination than FIB-4 to detect SF. Optimised random forest (RF) yielded best NPV/F1 in overall set (0.947/0.754), test set (0.798/0.588) and validation set (0.852/0.559), as compared to FIB4 in overall set (0.744/0.499), test set (0.722/0.456), and validation set (0.806/0.507). Compared to FIB-4, RF could pick 10 times more patients with SF, reduce unnecessary referrals by 28%, and prevent missed referrals by 78%. Age, AST, ALT fasting plasma glucose, and platelet count were top features determining the SF. Sequential use of SAFE < 140 and FIB4 < 1.2 (when SAFE > 140) was next best in ruling out SF (NPV of 0.757, 0.724 and 0.827 in overall, test and validation set). CONCLUSIONS: ML with clinical, anthropometric data and simple blood investigations perform better than FIB-4 for ruling out SF in biopsy-proven Asian NAFLD/MASLD patients.

Novel Noninvasive Hybrid Flap Preconditioning (HFP) Surpasses Surgical Delay in the Murine Model.

BACKGROUND: Ischemic necrosis in the distal portion of the flap is a challenging complication in plastic surgery. We hypothesize a novel hybrid flap preconditioning (HFP) device combining foam-mediated external suction and non-surgical delay can promote skin flap survival better than surgical delay. METHOD: Twenty-eight mouse were divided into four groups. Control group: a 4*1.5 dorsal flap was made with no preconditioning. Surgical delay (SD) group: surgical delay was made 7 days before flap elevation. Foam-mediated external suction (FMES) group: foam-mediated external suction at -100mmHg was employed 5 hours per day for 6 days, and the flap was elevated on the seventh day. Hybrid Flap Preconditioning (HFP) group: silicone strips was applied along the contour of the foam interface. Same negative pressure protocol was used as the FMES group. Seven days after flap elevation, macroscopic, histologic, and Western blot analyses were performed. RESULTS: The flap survival rate was 46.25% (8.12%) in the control group, 68.72% (7.00%) in the SD group, 57.03% (8.17%) in the FMES group and 80.66% (3.27%) in the HFP group. Immunohistologic analysis of CD 31+ cell in distal end of viable tissue procured seven days after flap elevation showed a significantly higher angiogenesis in SD group and HFP group. Western Blot results showed an increased expression of VEGF in SD group and HFP group. CONCLUSION: We have developed and fabricated a novel hybrid flap precondition (HFP) device combining foam-mediated external suction and non-surgical delay. The concept of HFP is proved to promote flap survival better than surgical delay.

Machine-learning model comprising five clinical indices and liver stiffness measurement can accurately identify MASLD-related liver fibrosis.

BACKGROUND & AIMS: aMAP score, as a hepatocellular carcinoma risk score, is proven to be associated with the degree of chronic hepatitis B-related liver fibrosis. We aimed to evaluate the ability of aMAP score for metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD)-related fibrosis diagnosis and establish a machine-learning (ML) model to improve the diagnostic performance. METHODS: A total of 946 biopsy-proved MASLD patients from China and the United States were included in the analysis. The aMAP score, demographic/clinical indices and liver stiffness measurement (LSM) were included in seven ML algorithms to build fibrosis diagnostic models in the training set (N = 703). The performance of ML models was evaluated in the external validation set (N = 125). RESULTS: The AUROCs of aMAP versus fibrosis-4 index (FIB-4) and aspartate aminotransferase-platelet ratio (APRI) in cirrhosis and advanced fibrosis were (0.850 vs. 0.857 [P = 0.734], 0.735 [P = 0.001]) and (0.759 vs. 0.795 [P = 0.027], 0.709 [P = 0.049]). When using dual cut-off values, aMAP had a smaller uncertainty area and higher accuracy (26.9%, 86.6%) than FIB-4 (37.3%, 85.0%) and APRI (59.0%, 77.3%) in cirrhosis diagnosis. The seven ML models performed satisfactorily in most cases. In the validation set, the ML model comprising LSM and 5 indices (including age, sex, platelets, albumin and total bilirubin used in aMAP calculator), built by logistic regression algorithm (called LSM-plus model), exhibited excellent performance. In cirrhosis and advanced fibrosis detection, the LSM-plus model had higher accuracy (96.8%, 91.2%) than LSM alone (86.4%, 67.2%) and Agile score (76.0%, 83.2%), respectively. Additionally, the LSM-plus model also displayed high specificity (cirrhosis: 98.3%; advanced fibrosis: 92.6%) with satisfactory AUROC (0.932, 0.875, respectively) and sensitivity (88.9%, 82.4%, respectively). CONCLUSIONS: The aMAP score is capable of diagnosing MASLD-related fibrosis. The LSM-plus model could accurately identify MASLD-related cirrhosis and advanced fibrosis.

A Population-based and Clinical Cohort Validation of the Novel Consensus Definition of Metabolic Hyperferritinemia.

BACKGROUND: There is limited data on the clinical significance of metabolic hyperferritinemia (MHF) based on the most recent consensus. We aimed to validate the clinical outcomes of MHF in general population and biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD) patients. METHODS: NHANES database and PERSONS cohort were included. MHF was defined as elevated serum ferritin with metabolic dysfunction (MD) and stratified into different grades according to ferritin (grade 1: 200 [females]/300 [males] - 550 ng/ml; grade 2: 550 - 1000 ng/ml; grade 3: > 1000 ng/ml). The clinical outcomes, including all-cause death, comorbidities and liver histology were compared between non-MHF and MHF in adjusted models. RESULTS: In NHANES, compared with non-MHF with MD, MHF was related to higher risks of advanced fibrosis (FIB-4, P = 0.036), elevated albumin-creatinine ratio (UACR, P = 0.001) and sarcopenia (P = 0.013). Although the association between all grades of MHF and mortality was insignificant (P = 0.122), grades 2/3 was associated with increased mortality (P = 0.029). While comparing with non-MHF without MD, the harmful effects of MHF were more significant in mortality (P < 0.001), elevated UACR (P < 0.001), cardiovascular disease (P = 0.028), and sarcopenia (P < 0.001). In PERSONS cohort, MHF was associated with more advanced grades of steatosis (P < 0.001), lobular inflammation (P < 0.001), advanced fibrosis (P = 0.017), and more severe hepatocellular iron deposition (P < 0.001). CONCLUSIONS: Both in general population and at-risk individuals with MAFLD, MHF was related with poorer clinical outcomes.

Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration.

Background & Aims: Liver regeneration is vital for the recovery of liver function after injury, yet the underlying mechanism remains to be elucidated. Forkhead box protein A3 (FOXA3), a member of the forkhead box family, plays important roles in endoplasmic reticulum stress sensing, and lipid and glucose homoeostasis, yet its functions in liver regeneration are unknown. Methods: Here, we explored whether Foxa3 regulates liver regeneration via acute and chronic liver injury mice models. We further characterised the molecular mechanism by chromatin immunoprecipitation sequencing and rescue experiments in vivo and in vitro. Then, we assessed the impact of Foxa3 pharmacological activation on progression and termination of liver regeneration. Finally, we confirmed the Foxa3-Cebpb axis in human liver samples. Results: Foxa3 is dominantly expressed in hepatocytes and cholangiocytes and is induced upon partial hepatectomy (PH) or carbon tetrachloride (CCl4) administration. Foxa3 deficiency in mice decreased cyclin gene levels and delayed liver regeneration after PH, or acute or chronic i.p. CCl4 injection. Conversely, hepatocyte-specific Foxa3 overexpression accelerated hepatocytes proliferation and attenuated liver damage in an CCl4-induced acute model. Mechanistically, Foxa3 directly regulates Cebpb transcription, which is involved in hepatocyte division and apoptosis both in vivo and in vitro. Of note, Cebpb overexpression in livers of Foxa3-deficient mice rescued their defects in cell proliferation and regeneration upon CCl4 treatment. In addition, pharmacological induction of Foxa3 via cardamonin speeded up hepatocyte proliferation after PH, without interfering with liver regeneration termination. Finally, Cebpb and Ki67 levels had a positive correlation with Foxa3 expression in human chronic disease livers. Conclusions: These data characterise Foxa3 as a vital regulator of liver regeneration, which may represent an essential factor to maintain liver mass after liver injury by governing Cebpb transcription. Impact and Implications: Liver regeneration is vital for the recovery of liver function after chemical insults or hepatectomy, yet the underlying mechanism remains to be elucidated. Herein, via in vitro and in vivo models and analysis, we demonstrated that Forkhead box protein A3 (FOXA3), a Forkhead box family member, maintained normal liver regeneration progression by governing Cebpb transcription and proposed cardamonin as a lead compound to induce Foxa3 and accelerate liver repair, which signified that FOXA3 may be a potential therapeutic target for further preclinical study on treating liver injury.

A Novel RAA Combined Test Strip Method Based on Dual Gene Targets for Pathogenic Vibrio vulnificus in Aquatic Products.

Vibrio vulnificus can cause disease in aquatic animals and humans, therefore, rapid and simple field detection of pathogenic V. vulnificus is important for early disease prevention. In this study, a novel recombinase-aided amplification (RAA) combined test strip with double T-lines (RAA-TS-DTL) was developed for the rapid detection of V. vulnificus in aquatic products. Pathogenic V. vulnificus was detected using the virulence vvhA gene and the housekeeping gene gyrB gene as the dual target of the test strip. The RAA-TS-DTL method showed 100% specificity for V. vulnificus, and no cross-reaction was observed with Vibrio spp. or other bacteria (n = 14). Furthermore, sensitive detection of V. vulnificus in oysters was achieved. The LODs of the gyrB and vvhA genes were 6 CFU/mL and 23 CFU/mL, respectively, which was about five times higher than that of the commercial test strip. The method was validated with spiked samples (n = 60) of fish, shrimp and oyster. The consistency between RAA-TS-DTL and the traditional culture method was 97.9%. In addition, the entire process of detection, including preparation of the sample, could be completed within 50 min. Our results indicated that the developed RAA-TS-DTL was a reliable and useful tool for rapid screening or on-site detection of pathogenic V. vulnificus in aquatic products and aquaculture water.

Novel and portable test strip platform for rapid and sensitive on-site detection of procymidone pesticide.

A novel and portable detection platform for procymidone (PRM) was developed by combining simple sample pretreatment, lateral flow test strips based on multi-branched gold nanoparticle (LFTS-MBGNP), and a smartphone. Based on the large surface area of MBGNPs, rapid detection of PRM was realized by simple naked eye observation. By utilizing a smartphone as a portable signal analyzer, ultrasensitive quantitative detection of PRM in red wine was realized with the limits of detection (LOD) of 1.60 ng/mL, which was 3000 times lower than the US limit (5 ppm). Moreover, rapid detection of four kinds of fruits and vegetables was achieved within 10 min, with LODs of 4.34 ng/g, 6.93 ng/g, 8.99 ng/g, and 5.03 ng/g, respectively, which could meet the PRM limit of the European Union (10 ng/g). Integrating the optimized QuEChERS pretreatment method, the developed platform realized a simple and sensitive on-site detection of PRM pesticide in foods and red wine within 45 min. This platform provides a useful tool and new idea for rapid screening and detection of pesticide residues in food.

MAFLD fibrosis score: Using routine measures to identify advanced fibrosis in metabolic-associated fatty liver disease.

BACKGROUND: Early screening may prevent fibrosis progression in metabolic-associated fatty liver disease (MAFLD). AIMS: We developed and validated MAFLD fibrosis score (MFS) for identifying advanced fibrosis (≥F3) among MAFLD patients. METHODS: This cross-sectional, multicentre study consecutively recruited MAFLD patients receiving tertiary care (Malaysia as training cohort [n = 276] and Hong Kong and Wenzhou as validation cohort [n = 431]). Patients completed liver biopsy, vibration-controlled transient elastography (VCTE), and clinical and laboratory assessment within 1 week. We used machine learning to select 'highly important' predictors of advanced fibrosis, followed by backward stepwise regression to construct MFS formula. RESULTS: MFS was composed of seven variables: age, body mass index, international normalised ratio, aspartate aminotransferase, gamma-glutamyl transpeptidase, platelet count, and history of type 2 diabetes. MFS demonstrated an area under the receiver-operating characteristic curve of 0.848 [95% CI 0.800-898] and 0.823 [0.760-0.886] in training and validation cohorts, significantly higher than aminotransferase-to-platelet ratio index (0.684 [0.603-0.765], 0.663 [0.588-0.738]), Fibrosis-4 index (0.793 [0.735-0.854], 0.737 [0.660-0.814]), and non-alcoholic fatty liver disease fibrosis score (0.785 [0.731-0.844], 0.750 [0.674-0.827]) (DeLong's test p < 0.05). MFS could include 92.3% of patients using dual cut-offs of 14 and 15, with a correct prediction rate of 90.4%, resulting in a larger number of patients with correct diagnosis compared to other scores. A two-step MFS-VCTE screening algorithm demonstrated positive and negative predictive values and overall diagnostic accuracy of 93.4%, 89.5%, and 93.2%, respectively, with only 4.0% of patients classified into grey zone. CONCLUSION: MFS outperforms conventional non-invasive scores in predicting advanced fibrosis, contributing to screening in MAFLD patients.

Chromatin-associated RNA Dictates the ecDNA Interactome in the Nucleus.

Extrachromosomal DNA (ecDNA) promotes cancer by driving copy number heterogeneity and amplifying oncogenes along with functional enhancers. More recent studies suggest two additional mechanisms for further enhancing their oncogenic potential, one via forming ecDNA hubs to augment oncogene expression 1 and the other through acting as portable enhancers to trans-activate target genes 2. However, it has remained entirely elusive about how ecDNA explores the three-dimensional space of the nucleus and whether different ecDNA have distinct interacting mechanisms. Here, by profiling the DNA-DNA and DNA-RNA interactomes in tumor cells harboring different types of ecDNAs in comparison with similarly amplified homogenously staining regions (HSRs) in the chromosome, we show that specific ecDNA interactome is dictated by ecDNA-borne nascent RNA. We demonstrate that the ecDNA co-amplifying PVT1 and MYC utilize nascent noncoding PVT1 transcripts to mediate specific trans-activation of both ecDNA and chromosomal genes. In contrast, the ecDNA amplifying EGFR is weak in this property because of more efficient splicing to remove chromatin-associated nascent RNA. These findings reveal a noncoding RNA-orchestrated program hijacked by cancer cells to enhance the functional impact of amplified oncogenes and associated regulatory elements.

Vibration Analysis and Damping Effect of Blade-Hard Coating Composite Structure Based on Base Excitation.

Hard coatings are widely employed on blades to enhance impact resistance and mitigate fatigue failure caused by vibration. While previous studies have focused on the dynamic characteristics of beams and plates, research on real blades remains limited. Specifically, there is a lack of investigation into the dynamic characteristics of hard-coated blades under base excitation. In this paper, the finite element model (FEM) of blade-hard coating (BHC) composite structure is established based on finite element methods in which the hard coating (HC) material and the substrate are considered as the isotropic material. Harmonic response analysis is conducted to calculate the resonance amplitude of the composite under base excitation. Numerical simulations and experimental tests are performed to examine the effects of various HC parameters, including energy storage modulus, loss factors, coating thickness, and coating positions, on the dynamic characteristics and vibration reduction of the hard-coated blade composite structures. The results indicate that the difference in natural frequency and modal loss factor of blades increases with higher storage modulus and HC thickness. Moreover, the vibration response of the BHC decreases with higher storage modulus, loss factor, and coating thickness of the HC material. Blades with a complete coating exhibit superior damping effects compared to other coating distributions. These findings are significant for establishing accurate dynamic models of HC composite structures, assessing the effectiveness of HC vibration suppression, and guiding the selection and preparation of HC materials.

AutoFibroNet: A deep learning and multi-photon microscopy-derived automated network for liver fibrosis quantification in MAFLD.

BACKGROUND: Liver fibrosis is the strongest histological risk factor for liver-related complications and mortality in metabolic dysfunction-associated fatty liver disease (MAFLD). Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) is a powerful tool for label-free two-dimensional and three-dimensional tissue visualisation that shows promise in liver fibrosis assessment. AIM: To investigate combining multi-photon microscopy (MPM) and deep learning techniques to develop and validate a new automated quantitative histological classification tool, named AutoFibroNet (Automated Liver Fibrosis Grading Network), for accurately staging liver fibrosis in MAFLD. METHODS: AutoFibroNet was developed in a training cohort that consisted of 203 Chinese adults with biopsy-confirmed MAFLD. Three deep learning models (VGG16, ResNet34, and MobileNet V3) were used to train pre-processed images and test data sets. Multi-layer perceptrons were used to fuse data (deep learning features, clinical features, and manual features) to build a joint model. This model was then validated in two further independent cohorts. RESULTS: AutoFibroNet showed good discrimination in the training set. For F0, F1, F2 and F3-4 fibrosis stages, the area under the receiver operating characteristic curves (AUROC) of AutoFibroNet were 1.00, 0.99, 0.98 and 0.98. The AUROCs of F0, F1, F2 and F3-4 fibrosis stages for AutoFibroNet in the two validation cohorts were 0.99, 0.83, 0.80 and 0.90 and 1.00, 0.83, 0.80 and 0.94, respectively, showing a good discriminatory ability in different cohorts. CONCLUSION: AutoFibroNet is an automated quantitative tool that accurately identifies histological stages of liver fibrosis in Chinese individuals with MAFLD.

Biosynthesis of uniform fluorescent-stable telluride quantum dots in Escherichia coli and its detection of Fe3+ in water.

Quantum dots (QDs) containing zinc (Zn) and tellurium (Te) have low toxicity and excellent optoelectronic properties, which make them ideal fluorescent probes for use in environmental monitoring. However, their size/shape distribution synthesized by existing methods is not as good as that of other nanoparticles, thus limiting their application. Exploring whether this kind of QD can be biosynthesized and whether it can act as a nanoprobe are favorable attempts to expand the synthesis method and the application of QDs. Telluride QDs were biosynthesized in Escherichia coli cells. The nanoparticles were characterized by transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), energy dispersive X-ray spectroscopy (EDX), and inductively coupled plasma-atomic emission spectrometry (ICP‒AES), indicating that they were Zn3STe2 QDs. The QDs were monodispersed, spherical and fluorescently stable, with a uniform particle size of 3.05 ± 0.48 nm. The biosynthesis conditions of the QDs, including substrate concentrations and their process time, were optimized respectively. It was verified that the cysE and cysK genes were involved in the biosynthesis of telluride QDs. The biosynthesis ability of the QDs was improved by knocking out the tehB gene and overexpressing the pckA gene. Escherichia coli BW25113 cells that synthesized Zn3STe2 QDs were used as environmentally friendly fluorescent bioprobes to specifically select and quantitatively detect Fe3+ in water with a low limit of detection (2.62 µM). The fluorescent cells were also photobleach resistant and had good fluorescence stability. This study expands on the synthesis method of telluride QDs and the application of fluorescent probes.

Adaptive Laboratory Evolution Reveals the Selenium Efflux Process To Improve Selenium Tolerance Mediated by the Membrane Sulfite Pump in Saccharomyces cerevisiae.

Selenium (Se) is a micronutrient in most eukaryotes, and Se-enriched yeast is the most common selenium supplement. However, selenium metabolism and transport in yeast have remained unclear, greatly hindering the application of this element. To explore the latent selenium transport and metabolism mechanisms, we performed adaptive laboratory evolution under the selective pressure of sodium selenite and successfully obtained selenium-tolerant yeast strains. Mutations in the sulfite transporter gene ssu1 and its transcription factor gene fzf1 were found to be responsible for the tolerance generated in the evolved strains, and the selenium efflux process mediated by ssu1 was identified in this study. Moreover, we found that selenite is a competitive substrate for sulfite during the efflux process mediated by ssu1, and the expression of ssu1 is induced by selenite rather than sulfite. Based on the deletion of ssu1, we increased the intracellular selenomethionine content in Se-enriched yeast. This work confirms the existence of the selenium efflux process, and our findings may benefit the optimization of Se-enriched yeast production in the future. IMPORTANCE Selenium is an essential micronutrient for mammals, and its deficiency severely threatens human health. Yeast is the model organism for studying the biological role of selenium, and Se-enriched yeast is the most popular selenium supplement to solve Se deficiency. The cognition of selenium accumulation in yeast always focuses on the reduction process. Little is known about selenium transport, especially selenium efflux, which may play a crucial part in selenium metabolism. The significance of our research is in determining the selenium efflux process in Saccharomyces cerevisiae, which will greatly enhance our knowledge of selenium tolerance and transport, facilitating the production of Se-enriched yeast. Moreover, our research further advances the understanding of the relationship between selenium and sulfur in transport.

Novel urinary protein panels for the non-invasive diagnosis of non-alcoholic fatty liver disease and fibrosis stages.

BACKGROUND & AIMS: There is an unmet clinical need for non-invasive tests to diagnose non-alcoholic fatty liver disease (NAFLD) and individual fibrosis stages. We aimed to test whether urine protein panels could be used to identify NAFLD, NAFLD with fibrosis (stage F ≥ 1) and NAFLD with significant fibrosis (stage F ≥ 2). METHODS: We collected urine samples from 100 patients with biopsy-confirmed NAFLD and 40 healthy volunteers, and proteomics and bioinformatics analyses were performed in this derivation cohort. Diagnostic models were developed for detecting NAFLD (UPNAFLD model), NAFLD with fibrosis (UPfibrosis model), or NAFLD with significant fibrosis (UPsignificant fibrosis model). Subsequently, the derivation cohort was divided into training and testing sets to evaluate the efficacy of these diagnostic models. Finally, in a separate independent validation cohort of 100 patients with biopsy-confirmed NAFLD and 45 healthy controls, urinary enzyme-linked immunosorbent assay analyses were undertaken to validate the accuracy of these new diagnostic models. RESULTS: The UPfibrosis model and the UPsignificant fibrosis model showed an AUROC of .863 (95% CI: .725-1.000) and 0.858 (95% CI: .712-1.000) in the training set; and .837 (95% CI: .711-.963) and .916 (95% CI: .825-1.000) in the testing set respectively. The UPNAFLD model showed an excellent diagnostic performance and the area under the receiver operator characteristic curve (AUROC) exceeded .90 in the derivation cohort. In the independent validation cohort, the AUROC for all three of the above diagnostic models exceeded .80. CONCLUSIONS: Our newly developed models constructed from urine protein biomarkers have good accuracy for non-invasively diagnosing liver fibrosis in NAFLD.

aMAP Score and Its Combination With Liver Stiffness Measurement Accurately Assess Liver Fibrosis in Chronic Hepatitis B Patients.

BACKGROUND & AIMS: The changes in liver stiffness measurement (LSM) are unreliable to estimate regression of fibrosis during antiviral treatment for chronic hepatitis B (CHB) patients. The age-male-albumin-bilirubin-platelets score (aMAP), as an accurate hepatocellular carcinoma risk score, may reflect the liver fibrosis stage. Here, we aimed to evaluate the performance of aMAP for diagnosing liver fibrosis in CHB patients with or without treatment. METHODS: A total of 2053 patients from 2 real-world cohorts and 2 multicentric randomized controlled trials in China were enrolled, among which 2053 CHB patients were included in the cross-sectional analysis, and 889 CHB patients with paired liver biopsies before and after 72 or 104 weeks of treatment were included in the longitudinal analysis. RESULTS: In the cross-sectional analysis, the areas under the receiver operating characteristic curve of aMAP in diagnosing cirrhosis and advanced fibrosis were 0.788 and 0.757, which were comparable with or significantly higher than those of the fibrosis index based on 4 factors and the aspartate aminotransferase-platelet ratio. The stepwise approach using aMAP and LSM further improved performance in detecting cirrhosis and advanced fibrosis with the smallest uncertainty area (29.7% and 46.2%, respectively) and high accuracy (82.3% and 79.8%, respectively). In the longitudinal analysis, we established a novel model (aMAP-LSM model) by calculating aMAP and LSM results before and after treatment, which had satisfactory performance in diagnosing cirrhosis and advanced fibrosis after treatment (area under the receiver operating characteristic curve, 0.839 and 0.840, respectively), especially for those with a significant decrease in LSM after treatment (vs LSM alone, 0.828 vs 0.748; P < .001 [cirrhosis]; 0.825 vs 0.750; P < .001 [advanced fibrosis]). CONCLUSIONS: The aMAP score is a promising noninvasive tool for diagnosing fibrosis in CHB patients. The aMAP-LSM model could accurately estimate fibrosis stage for treated CHB patients.

MSC-Exos: Important active factor of bone regeneration.

Bone defect and repair is a common but difficult problem in restorative and reconstructive surgery. Bone tissue defects of different sizes caused by different reasons bring functional limitations and cosmetic deformities to patients. Mesenchymal stem cells (MSC), a major hotspot in the field of regeneration in recent years, have been widely used in various studies on bone tissue regeneration. Numerous studies have shown that the bone regenerative effects of MSC can be achieved through exosome-delivered messages. Although its osteogenic mechanism is still unclear, it is clear that MSC-Exos can directly or indirectly support the action of bone regeneration. It can act directly on various cells associated with osteogenesis, or by carrying substances that affect cellular activators or the local internal environment in target cells, or it can achieve activation of the osteogenic framework by binding to materials. Therefore, this review aims to summarize the types and content of effective contents of MSC-Exos in bone regeneration, as well as recent advances in the currently commonly used methods to enable the binding of MSC-Exos to the framework and to conclude that MSC-Exos is effective in promoting osteogenesis.

Secondary bile acids improve risk prediction for non-invasive identification of mild liver fibrosis in nonalcoholic fatty liver disease.

BACKGROUND: Dysregulated bile acid (BA) metabolism has been linked to steatosis, inflammation, and fibrosis in nonalcoholic fatty liver disease (NAFLD). AIM: To determine whether circulating BA levels accurately stage liver fibrosis in NAFLD. METHODS: We recruited 550 Chinese adults with biopsy-proven NAFLD and varying levels of fibrosis. Ultra-performance liquid chromatography coupled with tandem mass spectrometry was performed to quantify 38 serum BAs. RESULTS: Compared to those without fibrosis, patients with mild fibrosis (stage F1) had significantly higher levels of secondary BAs, and increased diastolic blood pressure (DBP), alanine aminotransferase (ALT), body mass index, and waist circumstance (WC). The combination of serum BAs with WC, DBP, ALT, or Homeostatic Model Assessment for Insulin Resistance performed well in identifying mild fibrosis, in men and women, and in those with/without obesity, with AUROCs 0.80, 0.88, 0.75 and 0.78 in the training set (n = 385), and 0.69, 0.80, 0.61 and 0.69 in the testing set (n = 165), respectively. In comparison, the combination of BAs and clinical/biochemical biomarkers performed less well in identifying significant fibrosis (F2-4). In women and in non-obese subjects, AUROCs were 0.75 and 0.71 in the training set, 0.65 and 0.66 in the validation set, respectively. However, these AUROCs were higher than those observed for the fibrosis-4 index, NAFLD fibrosis score, and Hepamet fibrosis score. CONCLUSIONS: Secondary BA levels were significantly increased in NAFLD, especially in those with mild fibrosis. The combination of serum BAs and clinical/biochemical biomarkers for identifying mild fibrosis merits further assessment.

Study on SBS Optimal Block Ratio Based on Molecular Simulation.

The block ratio of SBS is an important factor influencing the swelling effect of modified asphalt, but the effect of the block ratio in the swelling process cannot be accurately studied by macro testing. In order to solve this problem and screen out the optimal SBS block ratio, molecular models of asphalt and SBS with different block ratios were established by molecular simulation technology at the microscopic level, and an asphalt-SBS interaction layer system was established on this basis. The diffusion and adhesion effects of SBS with different block ratios were evaluated by calculating the immersion depth, diffusion coefficient, and adhesion work of SBS in asphalt. The results show that SBS has a physical cross-linking reaction with asphalt during swelling, and SBS with a higher butadiene block ratio exhibits a deeper immersion depth; thus, SBS with a 3/7 block ratio has the best performance in the modification process, which is superior to SBS with other block ratios, in terms of both the diffusion and adhesion effect. The performance of asphalt modified by SBS with different block ratios was tested using penetration, softening point, and ductility, and the results were consistent with the simulation results, which proved the reliability of the microscopic conclusions from a macro perspective.