BACKGROUND:Chronic hepatitis B virus (HBV) infection accounts for more than 40% of hepatocellular carcinoma (HCC) cases worldwide. The GALAD (Gender, Age, alpha fetoprotein heterogeneity [AFP-L3], AFP, and des-gamma-carboxy prothrombin [PIVKA-II/DCP]) model has potential for enhancing HCC diagnosis. However, its diagnostic performance in HBV-associated chronic liver disease requires further optimization. This study aimed to establish a diagnostic model for HBV-associated HCC. METHODS:The data from 2190 patients with HBV-related liver diseases, including chronic hepatitis B (CHB), cirrhosis, and HCC were analysed. The GADA model was developed by omitting AFP-L3 for improved accessibility, and its performance was assessed via the area under the receiver operating characteristic curve (AUC). Validation was performed on 20,908 patients across ten hospitals. RESULTS:The simplified GADA model demonstrated exceptional diagnostic performance in identifying HBV-related HCC in the modeling group, achieving an AUC of 0.940 (95% CI, 0.927-0.952), with a sensitivity and specificity of 82.57% and 91.53%, respectively, surpassing the original GALAD model's AUC of 0.907 (95% CI, 0.891-0.921). In the internal validation cohort, the GADA model had an AUC of 0.935 (95% CI, 0.914-0.953), sensitivity of 82.04%, and specificity of 92.65%. For early-stage HCC detection, the AUC in the modeling group was 0.858 (95% CI, 0.837-0.877), and in the internal validation group was 0.868 (95% CI, 0.836-0.895), significantly better than the original GALAD model. External validation with 20,908 participants yielded an AUC of 0.919 (95% CI, 0.916-0.923), with sensitivity of 86.00% and specificity 81.88%. For early-stage HCC diagnosis, the AUC was 0.903 (95% CI: 0.898-0.907), with sensitivity of 88.16% and specificity 74.50%. CONCLUSIONS:The GADA model shows exceptional promise for diagnosing HBV-related HCC, enhancing early detection and reducing misdiagnosis rates. Its clinical utility is supported by robust validation, indicating significant implications for patient prognosis and treatment options.

Objective To evaluate the diagnostic utility of serum Golgi Protein-73 (GP73) in staging hepatic inflammatory activity and evaluating fibrosis in patients with Drug-Induced Liver Injury (DILI). Methods A retrospective analysis was conducted on 130 patients with DILI who underwent liver biopsy. Patients were categorized according to inflammation grade (G0∼G1: n = 49, G2∼G3: n = 62, G4: n = 19) and fibrosis stages (S0∼S1: n = 24, S2∼S3: n = 45, S4: n = 14). Correlations between GP73 levels and markers of liver inflammation, fibrosis, and biochemical indicators were examined. Logistic regression and ROC curves evaluated diagnostic precision. Results Serum GP73 levels exhibited a positive correlation with liver injury markers such as ALT, AST, TBIL, ALP, HA, PC-III, and APRI (p < 0.05), while demonstrating a negative correlation with ALB, CHE, PA, and FIB (p < 0.05). GP73 and ALB were recognized as independent risk factors for hepatic inflammation (p < 0.05). The integrated diagnostic efficacy of GP73 and ALB for moderate (G ≥ 2) and severe inflammation (G ≥ 3) produced AUCs of 0.860 and 0.945, respectively, surpassing those of ALT and AST (AUCs: 0.679, 0.716 and 0.762, 0.805, respectively). When ALT levels were normal, the combined AUCs of GP73 and ALB for diagnosing moderate (G ≥ 2) and severe inflammation (G ≥ 3) were 0.853 and 0.987, respectively. Furthermore, GP73 was identified as an independent predictor of fibrosis (p < 0.05), exhibiting AUCs of 0.707 and 0.856 for moderate and severe fibrosis, respectively, indicating enhanced diagnostic efficacy relative to FIB-4 and APRI. Conclusion GP73 is significantly increased in the serum of patients experiencing drug-induced liver injury. GP73, whether utilized independently or alongside other diagnostic methods, exhibits significant potential for evaluating liver inflammation and fibrosis. Its efficacy in diagnosing liver inflammation exceeds its utility for fibrosis, potentially reducing the necessity for liver biopsy procedures.

Extreme ultraviolet interference lithography systems are powerful fabrication tools in the semiconductor manuremove facturing industry. Typically, key materials and key components used in interference lithography systems, such as photoresist, pinhole spatial filters and monochromators, require comprehensive optimization and calibration in advance. Synchrotron undulators, X-ray lasers, and Free-electron lasers have been demonstrated to perform such tasks, but at extremely high cost and low throughput. The high-order harmonic generation (HHG) beam remove line provides a perfect alternative due to its excellent laboratory affordability, high turnaround rate, and more importantly, phase coherence across the full field, which is essential in generating high-resolution interference patterns. This paper first examines how the configuration of a two-mirror system influences the generation of inremove terference patterns and, consequently, the characterization of the EUV illumination beam under single-harmonic conditions. We establish a quantitative model between the two-mirror system configuration and the detectable interference pattern generated by single-order HHG illumination. However, HHG sources present a challenge for EUV interference lithography: the low photon flux. By utilizing multiple harmonics without monochromatization, we gain higher usable photon flux and study the resulting interference pattern intensity. The intensity distribution of interference patterns under multi-harmonic conditions is also investigated and discussed.

We present a table-top Extreme ultraviolet interference lithography (EUV-IL) system at 29.6 nm central wavelength of high harmonic generation radiation. The EUV-IL generates periodic aerial images of 22 nm half-pitch (HP) at the two-mirror interference system. In this letter, we investigated the influence of femtosecond EUV laser on high resolution interference pattern. The simulation results of the interference pattern are discussed.

BACKGROUND:Fibrosis is a critical event in the progression of pediatric nonalcoholic fatty liver disease (NAFLD). AIM:To develop less invasive models based on machine learning (ML) to predict significant fibrosis in Chinese NAFLD children. METHODS:In this cross-sectional study, 222 and 101 NAFLD children with available liver biopsy data were included in the development of screening models for tertiary hospitals and community health centers, respectively. Predictive factors were selected using least absolute shrinkage and selection operator regression and stepwise logistic regression analyses. Logistic regression (LR) and other ML models were applied to construct the prediction models. RESULTS:Simplified indicators of the ATS and BIU indices were constructed for tertiary hospitals and community health centers, respectively. When models based on the ATS and BIU parameter combinations were constructed, the random forest (RF) model demonstrated higher screening accuracy compared to the LR model (0.80 and 0.79 for the RF model and 0.72 and 0.77 for the LR model, respectively). Using cutoff values of 90% for sensitivity and 90% for specificity, the RF models could effectively identify and exclude NAFLD children with significant fibrosis in the internal validation set (with positive predictive values and negative prediction values exceeding 0.80), which could prevent liver biopsy in 60% and 71.4% of NAFLD children, respectively. CONCLUSION:This study developed new models for predicting significant fibrosis in NAFLD children in tertiary hospitals and community health centers, which can serve as preliminary screening tools to detect the risk population in a timely manner.

Objectives: Hepatic inflammation, the driver of fibrosis progression in liver disease, can impact the accuracy of liver stiffness measurement (LSM). We wondered whether the decline in LSM value during the early antiviral phase was mainly attributed to the control of hepatic inflammation or the regression of fibrosis in patients with fibrotic/cirrhotic chronic hepatitis B (CHB). Patients and Methods: The study cohort was composed of 82 patients with CHB who underwent antiviral and antifibrotic therapy at the Fifth Medical Center of PLA General Hospital. All patients had liver biopsies at both baseline and 72 weeks posttherapy. Liver pathology and clinical data, including the LSM value, were collected. Results: After 72 weeks of treatment, both the histologic activity index score and fibrosis score, as well as the LSM value, were significantly decreased (P < 0.001), compared with their baseline values. The pretreatment correlation of LSM value with either histologic activity index score (r = 0.526 vs r = 0.286) or fibrosis score (r = 0.677 vs r = 0.587) was attenuated at 72 weeks. Notably, logistic regression analysis revealed that the improvement in inflammation (odds ratio = 1.018, 95% CI: 1.002-1.031, P = 0.023) but not fibrosis (odds ratio = 0.994, 95% CI: 0.980-1.009, P = 0.414), had an impact on the change in LSM values between baseline and at 72-week treatment. Conclusions: The findings of this study suggest that in patients with fibrotic CHB receiving antiviral medication, the early phase reduction in LSM value was related to improved hepatic inflammation rather than fibrosis regression.

Objective Short wavelength, short - pulse, and high - coherence laser sources are urgently needed for research on ultra - wide dynamics at the microscopic scale. Additionally, with the demand for an ever - increasing chip computing speed, the semiconductor field urgently requires small and low - cost extreme ultraviolet light sources for material development and wafer defect detection. Highorder harmonic (HHG) technology is used to realize laboratory desktop applications and produce high - coherence and high - resolution extreme ultraviolet (EUV) light sources, which is one of the most reliable technologies and is gradually becoming one of the most important tools for atomic, molecular, advanced quantum, and other materials research as well as nano - imaging. Based on the semiconductor field and experimental requirements, we build a set of HHG - EUV sources using a commercial Ti:sapphire laser, which is a highly stable, high - power 13.5 - nm source. This will advance research in material development, semiconductor performance characterization, biomedical imaging, wafer defect detection, and other fields of research. Methods Highorder harmonic processes can be explained by the semiclassical three - step model, and several experiments have demonstrated that Ti:sapphire lasers are among the best driving sources for generating an EUV source. Focused high - average - power laser pulses interacting with rare gases produce harmonics that cover the extreme ultraviolet(UV)and soft X - ray regions, thereby making them the most efficient source for electrodynamics studies. The reaction region is commonly characterized using nozzles, gas cells, and hollow waveguides. The latter has the highest harmonic conversion efficiency owing to the phase modulation process; however, it is difficult to calibrate and achieve a stable output over long periods. To achieve a high flux and stable output from a 13.5 - nm harmonic source, we design and build a beam stabilization control system to assist the alignment process and maintain beam stability. In addition, we build a dual - optical and flat - field spectrometer that can effectively optimize the harmonic aberration in the harmonics generated by the device. Results and Discussions When helium is used as the generation gas, the spectral distribution around 13.46 nm is filtered with Zr films. A calibrated photodiode is used to measure the optical power signal, and the total power generated by the light source is calculated as approximately 1.9 mu W. The spot shape is captured using complementary metal - oxide semiconductor (CMOS) at a distance of 1.9 m from the light source [Fig. 2(b)], and the 1/e 2 spot size is calculated to be 1.92 mmx 1.67 mm with the x - divergence full - angle of the spot calculated to be 1.01 mrad, and the y - divergence full - angle of the spot calculated to be 0.88 mrad. When argon is used as the generation gas, two 250 - nm thick Al films are used for spectral filtering, and the spectral distribution is around 30 nm. The calculated average power is 120 mu W at the light source. Furthermore, in order to measure the pointing and power stability of the EUV beams, a CMOS is placed at a distance of 1. 9 m from the light source. The root - mean - square (RMS) of the pointing stability is then calculated using the offset of the spot center from the initial position over a 12 - h period, with the pointing offset of the beam in the x - direction controlled to within 6.3 mu rad and that in the y - direction controlled to within 7.2 mu rad. The average RMS power stability over a 12 - h period is 4.37%. Wavelength calibration is performed using an in - house - designed dual - optics flat - field spectrometer with Al and Si films, as shown in Fig. 4(b), which demonstrates the filtered HHG spectral signals of the different films collected using a grating with groove density of 500 line/mm. With the help of the steep absorption edge of the Si film at approximately 12.5 nm (the absorption peak of the Ai film is at approximately 17.05 nm), the position of the 59th harmonic peak at 13.46 nm is obtained. Combined with the slit, our flat - field spectrometer can output any chosen harmonic that minimizes the aberration. As shown in Fig. 6, we analyze the first - , second - , and third - order diffraction harmonic intensities of the grating acquired by CMOS, which are consistent with the results of the theoretical coupling calculations. We significantly improve the harmonic spectral resolution using a gold - plated planar grating with groove density of 1200 line/mm. We determine that the 13. 46 - nm harmonic contains an average power of about 0.32 mu W, and that its true bandwidth is less than 0.124 nm. Conclusions A high - power, high - stability HHG source with a spectrum ranging from 10 nm to 40 nm is developed based on an inflatable hollow optical waveguide using a titanium gemstone laser as the driving light source. Using helium or argon as the reaction gas, multiple harmonics covering 10 nm to 40 nm are obtained, and the total power can be as high as 120 mu W. Combined with an in - house designed dual - optics flat - field spectrometer and a monochromator, a single harmonic with an average power of about 0.32 mu W, a bandwidth of about 0.124 nm and a center wavelength of 13.46 nm is obtained. The engineering design is adopted for the system and a technical breakthrough for this type of light source in terms of the pointing stability and power stability index is therefore successfully realized, which are world - leading results. Our study lays a solid foundation for the application and promotion of this light source in the industry. This light source will be popularized and validated in the fields of EUV interference lithography experiments, photoresist research and development, material parameter measurements in EUV lithography technology, nanometer or quantum material research and development, and semiconductor wafer defect detection.

A theoretical investigation of the influence of pump parameters of quasi-continuous-wave laser-diode (LD) pumped Yb:KYW/Cr4+:YAG laser on pulse characteristics based on passively Q-switched rate equations is presented. Through numerical calculation, the relationship between the characteristics of Q-switched pulse delay, pulse width, sub-pulse sequence, and pump rate is analyzed to obtain the optimal pump-light duty cycle and effectively reduce the thermal effect caused by continuous-wave pump. Furthermore, the high-repetition- rate LD pump source is used in the experiment, and the accurate locking and control of output characteristics such as repetition rate, pulse delay, and the number of pulse trains of the passively Q-switched laser are realized by adjusting the pump parameters. When the duty cycles of 15. 6-W pump power are 6. 5%, 8%, and 9. 65%, stable outputs of single pulse, double pulse, and triple pulse, respectively, are obtained, and the coupling resonance of pump pulse and laser pulse is improved. The experimental results are in agreement with the theoretical calculation.

进展期肝纤维化和肝硬化严重影响人民健康.近年来,随着医疗诊断技术的发展,肝病领域已开发出多种检查方法用于主动筛查肝纤维化患者,尤其非侵入性肝纤维化测试(non-invasive fibrosis tests,NIT)序贯检测(序贯无创检测)可逐步将晚期肝纤维化患者从高危人群中筛选出来.NIT序贯检测在降低医疗成本的同时,可有效减少不必要的转诊,进而可提高肝纤维化的筛查和诊疗效率并实现对肝纤维化患者的精准管理.本文概述了肝纤维化的筛查和诊断方法、NIT序贯检测的策略及其临床意义,以及近年报道的新型肝纤维化生物标志物,旨在为优化肝纤维化序贯无创检测的策略提供新思路,从而提高肝纤维化的筛查效率.

1.3-μm Nd laser has significant practical applications in various fields, such as fiber communication, medical treatment, frequency conversion, and scientific research. Many applications of a 1.3-μm laser, particularly frequency conversion, benefit greatly from a short pulse width with high peak power. In the paper, an electro-optical cavity dumping Nd:YVO4 laser at 1342 nm wavelength is studied theoretically and experimentally.The pulse width for an electro-optical cavity dumping laser is determined by the optical length of the cavity. A narrower pulse width is obtained by reducing the length of the cavity and the round trip time of the laser in the cavity. However, when the round trip time in the cavity approaches to the falling edge time of the electro-optical switch, shortening the length of the cavity will not obtain a narrower pulse width, and the falling edge time of the electro-optical switch will influence the laser pulse width. The temporal characteristics of the laser pulse are simulated when the falling edge time of the electro-optical switch is close to the round trip time in the cavity.The influence of the falling edge time of the electro-optical switch on the laser pulse duration is analyzed theoretically. The modified rate equation is used to study the relationship between the falling edge time and the laser pulse width.We demonstrate an electro-optical cavity dumping Nd:YVO4 laser. The atom percent of 0.3% Nd:YVO4 placed in a short Plano-concave cavity is in-band pumped by an 880 nm quasi-continuous-wave diode. A fiber-coupled diode laser module (NA = 0.22) with a power of 30 W is used. An LiNbO3 electro-optical switch is employed for the cavity-dumping. The 1342-nm cavity-dumping laser operates at a repetition rate of 1 kHz, single-pulse energy of 0.21 mJ, and pulse width of 2.8 ns. Near-diffraction-limited beam quality with an \begin{document}$ M^2 $\end{document}value of < l.2 is achieved. The setup uses MgO:PPLN crystal to generate efficient second harmonic at 671 nm, with a pulse width of 1.8 ns. To the best of our knowledge, this is the shortest pulse duration ever obtained from 1.3 μm actively Q-switched Nd-doped laser.

Chronic hepatitis B virus (HBV) infection is a major global public health problem. Approximately 887,000 people die of HBV infection-related diseases annually, with cirrhosis and hepatocellular carcinoma (HCC) being the principal causes of mortality.[1] Timely antiviral therapy greatly reduces the risks of cirrhosis and HCC. However, unfortunately, of those patients who are eligible for antiviral treatment, only 25% of patients in clinic settings and 12% of those in community settings obtain timely antiviral therapy.[2] Therefore, reliable means of identifying patients with chronic HBV infection that require antiviral therapy are necessary, particularly for use in the community. Liver biopsy has long been considered the gold-standard method for evaluating liver inflammation and fibrosis, but its routine use for diagnosis and community surveillance is limited because of its invasiveness. Golgi protein 73 (GP73) is a type II transmembrane protein that is located in the Golgi membrane and is recognized and cleaved by proprotein convertases, releasing it into the circulation.[3] Previous clinical studies had shown that serum GP73 concentration is high in patients with obvious liver lesions, including inflammation, fibrosis, and cirrhosis, which suggests that serum GP73 may represent a useful biomarker for the assessment of liver injury.[4] However, it is unclear whether the measurement of serum GP73 concentration would be an effective means of identifying patients with chronic HBV infection in the community who require antiviral therapy. Therefore, in the present study, we aimed to evaluate the use of serum GP73 for the identification of chronic HBV infection requiring antiviral therapy in a community setting. We performed a cross-sectional study of serum Hepatitis B surface antigen (HBsAg) positive community-dwelling patients who had accepted the health examination from July 2017 to September 2019 in the Beijing Center for Disease Prevention and Control (Beijing, China). The inclusion criteria were as follows: (1) age ≥18 years; (2) HBsAg-positivity (HBsAg ≥0.05 IU/mL) for ≥6 months; (3) availability of blood samples. The exclusion criteria were as follows: (1) history of hepatitis virus infection other than HBV; (2) history of antiviral treatment during the preceding 6 months; (3) pregnancy or other non-viral liver diseases, such as alcohol-related, autoimmune, or drug-induced liver disease. The study was conducted in accordance with the Declaration of Helsinki and its amendments and was approved by the Biomedical Ethics Committee of Peking University (No. IRB00001052-19081). Written informed consent was obtained from all the participants. At present, the latest Chinese guidelines for the prevention and treatment of chronic hepatitis B (CHB) state that the decision to start antiviral therapy should depend on a comprehensive analysis of serum HBV deoxyribonucleic acid (DNA) levels, alanine aminotransferase (ALT) levels, the severity of liver disease, as well as their age, family history, and concomitant diseases.[5] Therefore, the indications for antiviral therapy in this study include the following: (1) serum HBV DNA is positive, ALT levels are persistently abnormal (>upper limit of normal [ULN]), and other causes have been excluded; (2) HBV-related compensated cirrhosis patients with positive serum HBV DNA and HBV-related decompensated cirrhosis patients with positive HBsAg; (3) noninvasive tests or liver biopsy revealing obvious liver inflammation or fibrosis in those with persistently normal ALT levels and age >30 years old.[5] Liver fibrosis and cirrhosis were evaluated by liver stiffness measurement (LSM) using transient elastography. And the participants were allocated to three groups according to the expert consensus[6]: no/mild fibrosis, significant/advanced fibrosis, and cirrhosis [Supplementary Figure 1, https://links.lww.com/CM9/A979]. A total of 1529 patients with a mean age of 48.1 ± 13.13 years were included in this study, of whom 782 (51.1%) were men. The fibrosis/cirrhosis status of each patient was evaluated following the recommended diagnosis work-flow,[6] which showed that 1246 patients had no/mild fibrosis, 205 patients had significant/advanced fibrosis, and 68 patients had cirrhosis. The remaining 10 individuals were not assessed for liver fibrosis due to ALT ≥200 U/L or total bilirubin (TBil) ≥51 μmol/L, but still required antiviral therapy. A total of 422 (27.6%) patients met the recommended criteria for antiviral therapy, with abnormal ALT (>ULN) and/or significant or severe fibrosis/cirrhosis. To determine whether serum GP73 could reflect the severity of liver fibrosis, the concentrations in patients at different stages of fibrosis were compared. This showed that the serum GP73 levels of the non/mild fibrosis group were significantly lower than those of the significant/advanced fibrosis and cirrhosis groups (54.57 ng/mL vs. 67.79 ng/mL vs. 67.70 ng/mL, respectively; P < 0.001), implying that the measurement of serum GP73 may represent a means of identifying patients with significant/advanced fibrosis or cirrhosis. The potential utility of serum GP73 for the identification of patients with significant/advanced liver fibrosis and cirrhosis was further evaluated using receiver operating characteristic (ROC) analysis. The area under the ROC curve of serum GP73 for the identification of significant/advanced liver fibrosis and cirrhosis was 0.605 (95% confidence interval: 0.58–0.64, P < 0.001), and the sensitivity and specificity were 62.6% and 56.6%, respectively. There were no significant differences in the screening efficiencies of serum GP73 vs. the aspartate aminotransferase-to-platelet ratio index and fibrosis-4 index, two established non-invasive diagnostic indices of liver fibrosis (P = 0.338 and 0.925, respectively). The findings of community screening were also consistent with serum GP73 concentration reflecting liver inflammation. The participants were allocated to three groups, using ALT levels of >40 U/L and >80 U/L as cutoff values, and the serum GP73 concentrations of each group were compared. The serum GP73 concentration increased significantly with increases in ALT levels (60.63 ng/mL vs. 78.46 ng/mL vs. 103.1 ng/mL, respectively; P < 0.001). Further correlation analysis also showed that serum GP73 positively correlated with ALT serum concentrations, albeit relatively weakly (r = 0.275, P < 0.001). Serum GP73 could not only be used as a serum marker of significant fibrosis and cirrhosis but also for the evaluation of the severity of liver inflammation in patients with CHB. In this community-based study, we also evaluated the utility of serum GP73 for the screening of a population to identify patients who require antiviral therapy. The results showed that patients that needed antiviral therapy had significantly higher serum GP73 concentrations than those who did not (68.99 ng/mL vs. 53.17 ng/mL; P < 0.001). In addition, the ROC curve yielded a cut-off value of serum GP73 for the screening of patients for a requirement for antiviral therapy was 59.08 ng/mL, with a true-positive rate (TPR) and false-negative rate (FNR) of 62.8% and 37.2%, respectively. When ALT >40 U/L alone was used to screen such patients, the TPR and FNR were only 50.2% and 49.8%, and the screening efficacy slightly lower than that of serum GP73 (62.8% vs. 50.2%). When serum GP73 was combined with ALT for the screening of the patients, the TPR increased to 78.9%, the FNR decreased to 21.1%, and the patient detection rate was further improved [Table 1]. Table 1 - Use of serum GP73 concentration, ALT activity, and a combination for the screening of patients with CHB for a requirement for antiviral therapy. Needing antiviral therapy, n (%) Indicators Yes No Serum GP73 alone (+) 265 (62.8) 452 (40.8) Serum GP73 alone (−) 157 (37.2) 655 (59.2) ALT alone (+) 212 (50.2) 10 (0.9) ALT alone (−) 210 (49.8) 1097 (99.1) GP73 (+) and/or ALT (+) 333 (78.9) 458 (41.4) GP73 (−) and ALT (−) 89 (21.1) 649 (58.6) Total 422 (100) 1107 (100) Serum GP73 (+): GP73 > 59.08 ng/mL; serum GP73 (−): GP73 ≤ 59.08 ng/mL; ALT (+): ALT > 40 U/L; ALT (−): ALT ≤ 40 U/L. ALT: Alanine aminotransferase; CHB: Chronic hepatitis B; GP73: Golgi protein 73. Timely detection and the administration of antivirals are important ways of delaying the development of end-stage liver disease in and improving the quality of life of patients with CHB. In 2015, the World Health Organization produced its first set of guidelines regarding the prevention, care, and management of chronic HBV infection, in which it advocated the use of simple, non-invasive diagnostic tests to assess the stage of liver disease and eligibility for treatment. The current mainstream guidelines for CHB state that HBV DNA and abnormal ALT levels should be used to evaluate liver injury and serve as the marker to start antiviral treatment. However, previous studies have shown that 13.8% to 47.5% of HBsAg-positive individuals have ongoing liver damage but normal ALT levels,[7] which implies that the conventional means of identifying patients that require antiviral therapy is inadequate. Thus, new non-invasive biomarkers of liver injury are still required to identify patients who need antiviral treatment. Serum GP73 is an emerging serological marker in recent years, but its biological significance and clinical application value remain to be further investigated. In this community screening study, although limited by the availability of trials using LSM and ALT as criteria to identify patients requiring antiviral therapy, the results confirm serum GP73 not only reflects the severity of liver injury but also identifies more patients in need of antiviral treatment than ALT. In particular, a combination of serum GP73 and ALT significantly improved the efficacy of screening, which should help clinicians identify more patients with CHB who require antiviral treatment, improve the antiviral treatment rate, and contribute to achieving the goal of eliminating HBV infection by 2030. Funding This work was supported by the National Natural Science Foundation of China (No. 81902115), the National Key Research and Development Program of China (No. SQ2020YFF0426358), and the National S and T Major Project for Infectious Diseases (No. 2017ZX10201201). Conflicts of interest None.

目的:探索血嗜酸性粒细胞对新型冠状病毒感染疑似病例与确诊病例的区分价值.方法:回顾性收集于2020年1月～2020年2月期间,在郑州大学第一附属医院入院就诊的22例新型冠状病毒肺炎确诊病例及25例新型冠状病毒肺炎疑似病例的临床信息,使用受试者工作特征曲线(ROC)进行统计学分析.结果分析结果表明疑似病例与确诊病例C反应蛋白、白细胞计数、淋巴细胞水平差异均无统计学意义,在疑似病例与确诊病例中均出现C反映蛋白升高现象,异常率分别为76.2％、76％,两组差异无统计学意义(P=0.988);在疑似病例与确诊病例中白细胞降低的比例分别为8％、22.7％,升高比例分别为8％、22.7％,正常比例占84％、54.5％,差异无统计学意义(P=0.084).嗜酸性粒细胞、凝血酶原时间、谷草转氨酶、乳酸脱氢酶水平差异有统计学意义.其中嗜酸性粒细胞差异最为明显[中位数,疑似病例:0.10(0.06～0.12)×109/L,确诊病例:0.00(0.00～0.03)×109/L,P＜0.0001),疑似病例与确诊病例的异常率分别为0％与59.1％.血嗜酸性粒细胞用于诊断新冠肺炎确诊病例的cut-off值为0.04×109/L,相应的AUROC为0.917(95％CI:0.799～0.978),敏感性为81.82％,特异性为84.00％.结论血嗜酸性粒细胞在疑似病例中区分确诊病例有良好的敏感性和特异性,可以作为在疑似病例中区分确诊病例的重要辅助手段,在临床上应引起关注.

Background There is lack of reliable serum biomarkers to reflect the severity of liver necroinflammation for those who suffer autoimmune liver diseases (AILDs). In this study, a previously established patient cohort was used to explore the potential of serum Golgi protein 73 (GP73) as a noninvasive marker of AILD-related liver necroinflammation. Methods Serum GP73 concentration was measured in a retrospective cohort of 168 AILD patients, which included 74 patients with autoimmune hepatitis (AIH) and 94 with primary biliary cholangitis (PBC) who had undergone liver biopsy. Spearman's correlation and multivariate analysis were used to evaluate the relationship between serum GP73 and liver necroinflammation. A receiver operating characteristic curve was constructed to evaluate the value of GP73 for the prediction of moderate or severe liver necroinflammation. The diagnostic value of serum GP73 was also compared with that of alkaline phosphatase (ALP) in patients with PBC. Histologically, immunohistochemical analysis was performed to assess hepatic GP73 expression. Results Both the serum level and hepatic tissue expression of GP73 protein were aberrantly elevated and correlated well with the severity of necroinflammation in both AIH (rho = 0.655, P < 0.001) and PBC (rho = 0.547, P < 0.001) patients. The results here suggested that serum GP73 could be an independent biomarker to reflect the severity of liver necroinflammation. The AUROCs for GP73 to predict moderate necroinflammation (≥G2) and severe necroinflammation (≥G3) in patients with AIH were 0.828 and 0.832, respectively. Moreover, the AUROCs of serum GP73 for the identification of moderate necroinflammation (≥G2) (AUROC = 0.820, P < 0.001) and severe necroinflammation (≥G3) (AUROC = 0.803, P < 0.001) were superior to those of ALP (≥G2: AUROC = 0.607, P = 0.028 and ≥G3: AUROC = 0.559, P = 0.357) in patients with PBC. Mechanically, interlukin-6 (IL-6), the proinflammatory and prohepatic regenerating cytokine, could transcriptionally upregulate GP73 gene expression. Conclusion Serum GP73 is a potential noninvasive biomarker to evaluate the severity of liver necroinflammation in patients with AILDs.

Background and Aims: As a hepatocellular carcinoma biomarker, serum Golgi protein 73 (GP73) is reportedly related to inflammation. Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation. In this study, we aimed to explore the association between the GP73 level and short-term mortality in patients with alcohol-associated liver disease-related ACLF (ALD-ACLF). Methods: This retrospective cohort study involved 126 Chinese adults with ALD-ACLF. Baseline serum GP73 level was measured using enzyme-linked immunosorbent assay. Patients were followed-up for 90 d and outcomes were assessed. Data were analyzed using multivariate Cox regression and piecewise linear regression analyses. The predictive value of GP73 and classic models for the short-term prognosis of participants were evaluated and compared using receiver operating characteristic curves. Results: The serum GP73 level was independently associated with an increased mortality risk in patients with ALD-ACLF. Compared with the lowest tertile, the highest serum GP73 level predisposed patients with ALD-ACLF to a higher mortality risk in the fully adjusted model [at 28 days: hazard ratio (HR): 4.29 (0.99-18.54), p=0.0511; at 90 days: HR: 3.52 (1.15-10.79), p=0.0276]. Further analysis revealed a positive linear association. GP73 significantly improved the accuracy of the Child-Turcotte-Pugh score, model for end-stage liver disease score, and model for end-stage liver disease-sodium score in predicting short-time prognosis of patients with ALD-ACLF. Conclusions: The serum GP73 level is a significant predictor of the subsequent risk of death in patients with ALD-ACLF. GP73 improved the predictive value of classic prognostic scores.

Abstract. Yb3  +    :  KY  (  WO4)2 (Yb:KYW) possesses various excellent properties, such as its highly polarized emission cross section, that makes it an excellent option for developing highly efficient diode-pumped solid-state lasers. A high-energy, high-beam-quality passively Q-switched Yb:KYW laser was demonstrated. The small-signal gain characteristics of the Yb:KYW crystal under quasi-continuous-wave laser diode (LD) pumping were obtained by theoretical analysis. Under LD end-pumping at a repetition rate of 500 Hz and a pumping width of 200  μs, the Q-switched Yb  :  KYW  /  Cr4  +    :  YAG laser operated at a wavelength of 1025 nm, and a single-pulse energy of 0.5 mJ was obtained with a pulse width of 5.8 ns. Near-diffraction-limited beam quality with an M2 value of ∼1.02 was achieved. The compact setup provided efficient second-harmonic generation at 512.5 nm via type-I phase matching using a LiB3O5 (LBO) crystal, and the output single-pulse energy was 0.13 mJ. We believe that these results further demonstrate the utility of Yb:KYW as a passively Q-switched laser crystal for solid-state lasers, particularly for applications that require nonlinear frequency conversion.

目的:通过对药物性肝损伤(drug-induced liver injury,DILI)相关研究文献的可视化分析,了解DILI的研究概况和研究热点,为开展DILI相关研究提供参考.方法:以"Chemical and Drug Induced Liver Injury"为主题词检索PubMed数据库发表的DILI相关文献,运用Bicomb 2.02软件对文献资料进行提取和统计,得到高频主题词的词篇矩阵和共现矩阵,用gClu-t01.0软件进行聚类分析,使用Ucinet 6.216软件中的NetDraw绘制社会网络图,并利用Ucinet 6.216软件进行中心度分析.结果:从1950年首次报道到2019年年发文量464篇,共纳入刊载在1090种期刊上的5912篇文献,其中"Annals of Internal Medicine、Hepatology"刊载的文献数最多;选取词频≥60的37个主题词作为本研究的高频词,其中"Chemical and Drug In-duced Liver Injury/etiology(化学和药物引起的肝损伤/病因学)"点中心度最大,为1329.000,处于网络的核心地位.通过高频词聚类分析结果显示:人类免疫缺陷病毒阳性患者在预防或治疗结核病期间是DILI发生的危险因素;对乙酰氨基酚诱发的DILI及其预后;对乙酰氨基酚诱导的DILI机制和解毒剂;草药和膳食补充剂相关的胆汁淤积型DILI;甲氨蝶呤相关的DILI是目前的研究热点.结论:DILI的研究整体呈逐年增长趋势,对乙酰氨基酚、草药和膳食补充剂、抗结核治疗及甲氨蝶呤引起的相关DILI应引起重视.

ObjectiveTo establish a model for evaluating the severity of nonalcoholic fatty liver disease (NAFLD) based on a combined analysis of transient elastography parameters. MethodsA retrospective analysis was performed for the clinical information and liver elasticity parameters of 184 NAFLD patients who attended 7 hospitals in China from July 2014 to July 2017 and underwent liver biopsy for pathological diagnosis. Liver elasticity parameters were named as P1-P18 according to the amplitude, frequency, dispersion, and attenuation of ultrasound signals. The Spearman rank correlation test and the linear regression analysis were used to establish the models for evaluating steatosis degree, inflammatory activity, and fibrosis degree, and the receiver operating characteristic (ROC) curve was used to evaluate the value of each diagnostic model. ResultsThe ultrasound parameters based on transient elastography were well correlated with steatosis degree, inflammatory activity, and liver fibrosis degree in NAFLD patients. The multivariate analysis showed that P1 and P12 were independent indicators for predicting steatosis degree; P1, P3, P6, and P11 were independent indicators for predicting inflammatory activity; P2 and P3 were significantly correlated with liver fibrosis degree. The model Y=0.013×P1+0.055×P12-0.318 5 for predicting steatosis degree established based on linear regression had an area under the ROC curve (AUC) of 0.895 (95% confidence interval ［CI］: 0.842-0.936) and 0.939 (95%CI: 0.894-0.969), respectively, in the diagnosis of mild steatosis and moderate-to-severe steatosis, with a sensitivity of 82.35% and 86.26%, respectively, and a specificity of 89.23% and 93.27%, respectively (P＜0.001). The model Y=0.008×P1+0.030×P3+0.029×P6-1.875×10-4×P11+0.416 for predicting inflammatory activity had an AUC of 0.828 (95%CI: 0.793-0865) and 0.874 (95%CI: 0.817-0.918), respectively, in the diagnosis of early-stage inflammation and significant inflammation, with a sensitivity of 70.6% and 73.96%, respectively, and a specificity of 85.7% and 93.33%, respectively (P＜0.001). The model Y=-0.003×P1 + 0.601×(lnP2)+0.285×(lnP3)+0.036×P15 + 0.078 for predicting liver fibrosis degree had an AUC of 0.805 (95%CI: 0.740-0.869), 0.767 (95%CI: 0.699-0.827), and 0.803 (95%CI: 0.701-0.906), respectively, in the diagnosis of significant fibrosis, severe fibrosis, and early liver cirrhosis, with a sensitivity of 72.27%, 77.63%, and 90.00%, respectively, and a specificity of 79.69%, 66.42%, and 66.47%, respectively (P＜0.001). ConclusionDifferent parameters of transient elastography can effectively reflect steatosis degree, inflammatory activity, and fibrosis degree in NAFLD patients, and a combined model can improve the accuracy of disease severity prediction in NAFLD patients.

Golgi protein 73 (GP73) is upregulated in a variety of liver diseases, yet the detailed mechanism is poorly characterized. We analyzed GP73 in a retrospective cohort including 4211 patients with chronic liver disease (CLD) or hepatocellular carcinoma (HCC). The effect of deoxycholic acid (DCA) and nuclear factor-kappa B (NF-κB) on expression and release of GP73 in Huh-7 and SMMC7721 cells were studied. A mouse study was used to confirm our findings in vivo. A positive correlation was found between serum GP73 and total bile acid (TBA) in cirrhotic patients (r = 0.540, p < 0.001), higher than that in non-cirrhotic CLD (r = 0.318, p < 0.001) and HCC (r = 0.353, p < 0.001) patients. In Huh-7 and SMMC7721 cells, DCA upregulated the expression and release of GP73 in a dose- and time-dependent manner. After overexpressing NF-κB p65, the promoter activity, GP73 messenger RNA (mRNA) level, and supernatant GP73 level were increased. The promotion effect of DCA on GP73 release was attenuated after inhibiting the NF-κB pathway. Mutating the binding sites of NF-κB in the sequence of the GP73 promoter led to a declined promoting effect of DCA on GP73. The upregulation role of DCA in GP73 expression through the NF-κB pathway was confirmed in vivo. In addition, exposure to DCA caused disassembly of Golgi apparatus. In summary, DCA upregulates the expression and release of GP73 via activating the NF-κB pathway and destroying the Golgi structure.

This study was designed to explore if antiviral treatment influences the performance of serum alpha‐fetoprotein (AFP) for hepatocellular carcinoma (HCC) among the high‐risk chronic HBV‐infected patients. A total of 5936 patients who had evidence of chronic HBV infection were enrolled from four independent centres in this retrospective study, including 1721 chronic hepatitis B (CHB), 2286 liver cirrhosis (LC), 798 HCC within Milan criteria and 1131 HCC beyond Milan criteria patients. Stratified by whether they received treatment or not, the patients were further divided into antiviral and non‐antiviral groups. Then, the performance of AFP for discriminating HCC was evaluated. Patients receiving antivirals had significantly lower median levels of AFP compared with the non‐antiviral patients ( P < .001), and there were significantly less patients with abnormal AFP levels in antiviral groups ( P < .001). Antiviral therapy improved the AUROCs of AFP for discriminating HCC within Milan criteria. When setting the cut‐off values at 20 ng/mL and 100 ng/mL as surveillance and confirmatory tests respectively for HCC among patients receiving antiviral treatment, AFP exhibited a significantly higher sensitivity than those of 200 ng/mL and 400 ng/mL, which are currently recommended by some guidelines, without compromising specificity. Further analysis in antiviral patients revealed that serum AFP had better performance for discriminating HCC within Milan criteria in ALT ≤ 1ULN patients than that in ALT > 1ULN patients. In conclusion, in the era of antiviral therapy, serum AFP's surveillance performance was substantially improved for HCC within Milan criteria among the high‐risk population of CHB and LC patients.

高尔基体蛋白73(GP73)是细胞高尔基体上的一种跨膜蛋白,可被切割后释放入血[1].GP73在正常人体组织的多种细胞中表达,尤其在上皮细胞中,但不同上皮细胞的表达水平之间存在很大的差异[2].在正常肝组织,GP73主要由汇管区的胆管上皮细胞表达,在肝细胞中表达水平较低或不表达[2-3 ].临床研究证据表明,血清GP73的升高与肝脏疾病密切相关,在病毒感染(如HBV感染、腺病毒感染)、肝硬化或 HCC存在的情况下,GP73在肝细胞中高表达,有望作为慢性肝脏疾病的新型血清学标志物[5-7 ].