Impact Deposition of a Single Droplet of Low-Melting-Point Alloy as the Top Electrode for Organic Photovoltaics.

Top electrodes of organic photovoltaics (OPVs) are usually thermally evaporated in the vacuum, which is non-continuous and time-consuming and has been the bottleneck for the OPV fabrication process. Printable top electrodes that are free of vacuum, high temperature, and solvents will make OPVs more attractive. Low-melting-point alloys (LMPAs) are promising candidates for printable OPV electrodes thanks to the merits of matching work functions, high electron conductivity, high environment stability, and no need for post-treatment. Here, LMPA electrodes are directly deposited on OPVs by simply falling a single LMPA droplet onto the substrate. The LMPA droplet spreads to form a thin film with a smooth interface intimately contacting the substrate. The electrode area can be tailored by adjusting the droplet diameter or the Weber number, which is the ratio of inertia to surface tension. The interface morphology is mainly affected by the contact temperature. The degree of oxidation and charges on the droplet can also influence the electrode area and interface morphology. OPVs with droplet-impacted LMPA electrodes exhibit power conversion efficiencies of up to 16.17%. This work demonstrates the potential of single-droplet impact deposition as a simple method for printing OPV electrodes for scalable manufacturing.

Multiple Low-Level Viraemia Suggest Hindered Liver Fibrosis Regression in Chronic Hepatitis B Patients During Antiviral Therapy.

Low-level viraemia (LLV) occurs in chronic hepatitis B (CHB) patients despite antiviral treatment, which may cause failed histological regression. Our study aimed to investigate the impact of different LLV types on fibrosis regression. The prospective study enrolled CHB patients with paired liver biopsies before and after 260 weeks of entecavir treatment. Fibrosis regression was defined by the Ishak score or P-I-R system. Patients were grouped as the SVR (HBV DNA < 20 IU/mL persistently) or LLV (HBV DNA between 20 and 2000 IU/mL), which were further grouped as very low-level viraemia (VLLV, HBV DNA < 50 IU/mL), occasionally LLV (OLLV, HBV DNA ≥ 50 IU/mL only once) and multiple LLV (MLLV, HBV DNA ≥ 50 IU/mL more than once). Logistic regression models were used to calculate the adjusted odds ratios (aORs) and 95% confidence intervals (CIs). The analysis included 111 CHB patients. In the SVR group (n = 54), 39 (72.2%) patients had fibrosis regression, which was higher than the LLV (56.1%, p = 0.080). The fibrosis regression rates for VLLV (30 patients), OLLV (17 patients) and MLLV (10 patients) were 70.0%, 52.9% and 30.0%, respectively. Compared with SVR, VLLV (aOR = 0.78; 95% CI: 0.28-2.21; p = 0.644) was not associated with fibrosis regression, but patients with non-VLLV (aOR = 0.27; 95% CI: 0.09-0.85; p = 0.025), especially with MLLV (aOR = 0.19; 95% CI: 0.04-0.97; p = 0.046) is significantly associated with hindered fibrosis regression. Our study suggests that patients with detectable serum HBV DNA levels higher than 50 IU/mL need to be monitored carefully, especially in those with more than once. Trial Registration: ClinicalTrials.gov identifiers NCT01938781 and NCT01938820.

ART altered DNA methylation of the imprinted gene H19 in fetal tissue after multifetal pregnancy reduction.

PURPOSE: This study aimed to assess whether assisted reproductive technology alters DNA methylation levels at the H19 promoter and H19 imprinting control element (ICE) in fetal tissues obtained after multifetal pregnancy reduction. METHODS: Fetal tissues from multiple pregnancies were obtained, including fresh and frozen-thawed embryos: nine from conventional in vitro fertilization (c-IVF), four from intracytoplasmic sperm injection (ICSI), ten from cryopreserved IVF embryos (cryo-IVF), and six from cryopreserved ICSI (cryo-ICSI) embryos. Next-generation sequencing-based bisulfite PCR was used to determine the DNA methylation status of three CpG islands (H19-1, H19-2, and H19-3) in the H19 promoter and H19 ICE. The primary outcome was H19-1 DNA methylation status, whereas secondary outcomes assessed H19-2, H19-3, and ICE methylation. RESULTS: The ICSI (ß = -3.189, 95% CI = -5.034 to -1.345, p = 0.0026), cryo-IVF (ß = -2.150, 95% CI = -3.706 to -0.593, p = 0.0129), and cryo-ICSI (ß = -2.238, 95% CI = -3.817 to -0.659, p = 0.0110) groups exhibited significantly lower methylation levels in the primary outcome H19-1 region than the c-IVF group after adjustment. For the secondary outcome H19-2 region, significant decreases were observed in the cryo-IVF (ß = -2.132, 95% CI = -4.071 to -0.192, p = 0.0425) and cryo-ICSI groups (ß = -2.598, 95% CI = -4.566 to -0.630, p = 0.0168). CONCLUSIONS: These findings further indicate that embryo cryopreservation and potentially ICSI can lower the methylation level of the H19 promoter, advocating for careful use of these techniques when necessary.

Targeting NPM1 inhibits proliferation and promotes apoptosis of hepatic progenitor cells via suppression of mTOR signalling pathway.

BACKGROUND: Hepatic progenitor cells serve not only as the origin of combined hepatocellular cholangiocarcinoma (cHCC-CCA) but are also responsible for malignancy recurrence after surgical resection. Nucleophosmin 1 (NPM1) has been implicated in cancer metastasis and poor prognosis. This study aimed to determine the expression of NPM1 by hepatic progenitor cells in cHCC-CCA and the effects of targeting NPM1 on hepatic progenitor cells and BEL-7402 cells with characteristics of both progenitor cells and cHCC-CCA. METHODS: First, NPM1 was detected by RT‒PCR, western blotting, and double-immunofluorescence staining in cHCC-CCA tissues. NPM1 expression was subsequently analysed in rat hepatic progenitor cells cultured in vitro and in interleukin 6 (IL6)-treated cells. The effects and mechanism of NPM1 on hepatic progenitor cells were determined by knocking down NPM1 and performing RNA sequencing analysis. Finally, NSC348884, a small-molecule inhibitor that disrupts NPM1 dimer formation, was used to confirm the function of NPM1 in BEL-7402 cells. RESULTS: Both human hepatic progenitor cells in cHCC-CCA tissues and rat in vitro cultured hepatic progenitor cells highly expressed NPM1. IL6, a cytokine involved in the malignant transformation of hepatic progenitor cells, dose-dependently increased NPM1 and PCNA expression. Knocking down NPM1 reduced IL6R transcription (P < 0.0001) and inhibited the proliferation (P = 0.0065) of hepatic progenitor cells by suppressing the mTOR signalling pathway and activating the apoptosis pathway. Furthermore, knocking down NPM1 in hepatic progenitor cells resulted in more apoptotic cells (7.33 ± 0.09% vs. 3.76 ± 0.13%, P < 0.0001) but fewer apoptotic cells in the presence of NSC348884 (47.57 ± 0.49% vs. 63.40 ± 0.05%, P = 0.0008) than in the control cells, suggesting that low-NPM1-expressing cells are more resistant to NSC348884. In addition, NSC348884 induced the apoptosis of BEL-7402 cells with an IC50 of 2.77 µmol/L via the downregulation of the IL-6R and mTOR signalling pathways and inhibited the growth of BEL-7402 cells in a subcutaneous xenograft tumour model (P = 0.0457). CONCLUSIONS: Targeting NPM1 inhibits proliferation and induces apoptosis in hepatic progenitor cells and BEL-7402 cells, thus serving as a potential therapy for cHCC-CCA.

UAMC-3203 inhibits ferroptosis and promotes functional recovery in rats with spinal cord injury.

Spinal cord injury (SCI) results in irreversible neurological impairment. After SCI, Ferritinophagy-induced free iron released from ferritin can lead to extensive lipid peroxidation and aggravate neurological damage. NRF2/HO-1 pathway is to endow cells with a protective effect against oxidative stress, and it plays an important role in the transcriptional activation of a series of antioxidant and detoxification genes. UAMC-3203 is a ferrostatin-1(Fer-1) analogue with better solubility and stability, which can more effectively inhibit ferroptosis after SCI. A rat SCI model was constructed, and the recovery of motor function was observed after treatment with UAMC-3203. ELISA was employed to assess the impact of UAMC-3203 on inflammation-related factors, while immunofluorescence was utilized to investigate the influence of UAMC-3203 on neuronal count as well as the activation of astrocytes and microglia/macrophages. Malondialdehyde (MDA) were detected to reflect the level of oxidation products. Western blot analysis was used to measure the level of ferroptosis markers and the expression of NRF2/HO-1. Our findings demonstrate that UAMC-3203 inhibits the production of reactive oxygen species (ROS) and lipid peroxides, preventing ferroptosis and reducing neuronal degeneration. Additionally, UAMC-3203 suppresses astrocyte proliferation and microglia/macrophage activation, as well as the release of ferroptosis-related inflammatory factors. These combined effects contribute to the preservation of spinal cord tissue and the facilitation of motor function recovery. UAMC-3203 maybe inhibit ferroptosis after SCI to promote functional recovery.

Delicate and thin fibrous septa indicate a regression tendency in metabolic dysfunction-associated steatohepatitis patients with advanced fibrosis.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis is reversible. However, the dynamic morphology change in fibrosis regression remains unclear. We aim to explore the morphological characteristics of fibrosis regression in advanced MASH patients. METHODS: Clinical and histological data of 79 biopsy-proved MASH patients with advanced fibrosis (F3-F4) were reviewed. The second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) image technology was used to quantitatively identify the R (regressive) septa from P (progressive) septa and PS (perisinusoidal) fibrosis. Non-invasive tests were used to compare the fibrosis level with and without R septa groups. Transcriptomics was used to explore hub genes and the underlying mechanism of the formation of R septa. RESULTS: The R septa were different from the P septa and PS fibrosis in detail collagen quantitation identified by SHG/TPEF technology. The R septa were found in MASH fibrosis-regressed patients, which met the definition of the "Beijing classification". Therefore, patients were divided into two groups according to septa morphology: with R septa (n = 10, 12.7%), and without R septa (n = 69, 87.3%). Patients with R septa had lower values in most non-invasive tests, especially for liver stiffness assessed by TE (12.3 vs. 19.4 kPa, p = 0.010) and FAST (FibroScan®-AST) score (0.43 vs. 0.70, p = 0.003). Transcriptomics analysis showed that the expressions of five hub fibrogenic genes, including Col3A1, BGN, Col4A1, THBS2, and Col4A2 in the R septa group, were significantly lower. CONCLUSIONS: The R septa can be differentiated from the P septa and PS fibrosis by quantitative assessment of SHG/TPEF, and it represents a tendency of fibrosis regression in MASH patients. TRIAL REGISTRATION: NCT03386890, 29/12/2017.

Effect of Paravertebral Muscle Degeneration on Lumbar and Pelvic Sagittal Alignment in Patients With Degenerative Scoliosis.

STUDY DESIGN: Retrospective study. OBJECTIVES: To explore the relationship between lumbar spine muscle mass and lumbar pelvic sagittal parameters in patients with degenerative scoliosis. METHODS: This study included ADS patients who were treated in our hospital from 2019 to 2023. The spinal parameters were evaluated through X-rays, and the relative muscle volume (RMV) and fat infiltration (FI) were measured through three-dimensional reconstruction. Patients were categorized into 3 groups based on SRS-Schwab sagittal balance correction (0, +, ++), and into 3 groups based on GAP score (proportioned, moderately dis-proportioned, severely dis-proportioned). Finally, patients were classified into low-quality and high-quality groups based on the FI of Paraspinal muscles (PSM). RESULTS: The study included a total of 63 patients. Significant statistical differences were observed in the FI and RMV of MF, ES and PS among patients classified by SRS-Schwab PT classification. Additionally, significant statistical differences were found in the RMV of MF and PS among patients classified by SRS-Schwab PI-LL classification and GAP score. Furthermore, a significant correlation was found between the FI and RMV of PSM and lumbopelvic sagittal parameters. The ordinal regression model analysis revealed that FI of ES significantly impacted PT imbalance, while RMV of MF significantly impacted PI-LL imbalance. Moreover, significant differences were noted in PT and PI between the low-quality and high-quality multifidus groups. CONCLUSIONS: As sagittal imbalance worsens, PSM degeneration also intensifies, primarily characterized by an increase in FI and a decrease in RMV. Notably, PT and PI-LL are positively correlated with RMV and negatively correlated with FI.

Peridroplet mitochondria are associated with the severity of MASLD and the prevention of MASLD by diethyldithiocarbamate.

Mitochondria can contact lipid droplets (LDs) to form peridroplet mitochondria (PDM) which trap fatty acids in LDs by providing ATP for triglyceride synthesis and prevent lipotoxicity. However, the role of PDM in metabolic dysfunction associated steatotic liver disease (MASLD) is not clear. Here, the features of PDM in dietary MASLD models with different severity in mice were explored. Electron microscope photographs show that LDs and mitochondria rarely come into contact with each other in normal liver. In mice fed with high-fat diet, PDM can be observed in the liver as early as the beginning of steatosis in hepatocytes. For the first time, we show that PDM in mouse liver varies with the severity of MASLD. PDM and cytosolic mitochondria were isolated from the liver tissue of MASLD and analyzed by quantitative proteomics. Compared with cytosolic mitochondria, PDM have enhanced mitochondrial respiration and ATP synthesis. Diethyldithiocarbamate (DDC) alleviates choline-deficient, L-amino acid-defined diet-induced MASLD, while increases PDM in the liver. Similarly, DDC promotes the contact of mitochondria-LDs in steatotic C3A cells in vitro. Meanwhile, DDC promotes triglyceride synthesis and improves mitochondrial dysfunction in MASLD. In addition, DDC upregulates perilipin 5 both in vivo and in vitro, which is considered as a key regulator in PDM formation. Knockout of perilipin 5 inhibits the contact of mitochondria-LDs induced by DDC in C3A cells. These results demonstrate that PDM might be associated with the progression of MASLD and the prevention of MASLD by DDC.

Using a Flexible Fountain Pen to Directly Write Organic Semiconductor Patterns with Crystallization Regulated by the Precursor Film.

Organic semiconductor (OSC) films fabricated by meniscus-guided coating (MGC) methods are suitable for cost-effective and flexible electronics. However, achieving crystalline thin films by MGC methods is still challenging because the nucleation and crystal growth processes are influenced by the intertwined interactions among solvent evaporation, stochastic nucleation, and the fluid flow instabilities. Herein, a novel flexible fountain pen with active ink supply is designed and used to print OSCs. This direct-write method allows the flexible pen tip to contact the substrate, maintaining a robust meniscus by eliminating the gap found in conventional MGCs. An in situ optical microscopy observation system shows that the precursor film plays a critical role on the crystallization and the formation of coffee rings and dendrites. The computational fluid dynamics simulations demonstrate that the microstructure of the pen promotes extensional flows, facilitating mass transport and crystal alignment. Highly-aligned ribbon-shaped crystals of a small organic molecule (TIPS-pentacene), as well as a semiconducting polymer (N2200) with highly-ordered orientations, have been successfully printed by the flexible fountain pen. Organic field-effect transistors based on the flexible pen printed OSCs exhibit high performances and strong anisotropic mobility. In addition, the flexible fountain pen is expandable for printing multiple lines or large-area films.

Sugar import mediated by sugar transporters and cell wall invertases for seed development in Camellia oleifera.

Seed development and yield depend on the transport and supply of sugar. However, an insufficient supply of nutrients from maternal tissues to embryos results in seed abortion and yield reduction in Camellia oleifera. In this study, we systematically examined the route and regulatory mechanisms of sugar import into developing C. oleifera seeds using a combination of histological observations, transcriptome profiling, and functional analysis. Labelling with the tracer carboxyfluorescein revealed a symplasmic route in the integument and an apoplasmic route for postphloem transport at the maternal-filial interface. Enzymatic activity and histological observation showed that at early stages [180-220 days after pollination (DAP)] of embryo differentiation, the high hexose/sucrose ratio was primarily mediated by acid invertases, and the micropylar endosperm/suspensor provides a channel for sugar import. Through Camellia genomic profiling, we identified three plasma membrane-localized proteins including CoSWEET1b, CoSWEET15, and CoSUT2 and one tonoplast-localized protein CoSWEET2a in seeds and verified their ability to transport various sugars via transformation in yeast mutants and calli. In situ hybridization and profiling of glycometabolism-related enzymes further demonstrated that CoSWEET15 functions as a micropylar endosperm-specific gene, together with the cell wall acid invertase CoCWIN9, to support early embryo development, while CoSWEET1b, CoSWEET2a, and CoSUT2 function at transfer cells and chalazal nucellus coupled with CoCWIN9 and CoCWIN11 responsible for sugar entry in bulk into the filial tissue. Collectively, our findings provide the first comprehensive evidence of the molecular regulation of sugar import into and within C. oleifera seeds and provide a new target for manipulating seed development.

Prevalence and clinical profiles of primary sclerosing cholangitis in China: Data from electronic medical records and systematic literature retrieval.

BACKGROUND & AIMS: Epidemiology of primary sclerosing cholangitis (PSC) is lacking in China. We aimed to estimate the period prevalence and depict the clinical features of PSC in China. METHODS: We identified and included PSC cases between 2000 and 2023 from two sources: electronic medical records (EMR) and systematical literature retrieval (SLR). The period prevalence of PSC was estimated by the multiplier method. Rate ratios (RRs) for PSC prevalence in relation to macroeconomic indicators were calculated by the negative binomial regression model. RESULTS: A total of 1358 PSC cases were retrieved from 299 hospitals (162 from EMR and 1196 from SLR). Males accounted for 55.7 % of the PSC cases and 25.7 % had concomitant inflammatory bowel disease (IBD). The estimated period prevalence of PSC from 2000 to 2023 was 2.36 (95 % CI: 1.82, 3.34) per 100,000. Males had a numerically higher PSC prevalence than females (2.56, 95 % CI: 1.97, 3.63 vs. 2.14, 95 % CI: 1.65, 3.04 per 100,000). The highest prevalence of PSC was in East China at 4.87 (95 % CI: 3.44, 7.18) per 100,000, followed by North China at 2.94 (95 % CI: 2.33, 3.74) per 100,000, and the lowest in South China at 0.92 (95 % CI: 0.66, 1.30) per 100,000. Regional per capita GDP (RR 1.65, 95 % CI: 1.03, 2.65) and healthcare expenditure (RR 1.94, 95 % CI: 1.13, 3.38) were identified to be associated with PSC prevalence. CONCLUSION: Our study showed the estimated PSC prevalence varied within China, but was generally lower than that in Western countries.

Paracetamol-induced Liver Injury in An Experimental Rat Model: Noninvasive Assessment using DKI and the Effect of Gadoxetate on DKI Parameters.

PURPOSE: To explore the potential of diffusion kurtosis imaging (DKI) for assessing the degree of liver injury in a paracetamol-induced rat model and to simultaneously investigate the effect of intravenous gadoxetate on DKI parameters. METHODS: Paracetamol was used to induce hepatoxicity in 39 rats. The rats were pathologically classified into 3 groups: normal (n=11), mild necrosis (n=18), and moderate necrosis (n=10). DKI was performed before and, 15 min, 25 min, and 45 min after gadoxetate administration. Repeated-measures ANOVA with Tukey's multiple comparison test was used to investigate the effect of gadoxetate on mean diffusivity (MD) and mean diffusion kurtosis (MK) and to assess the differences in MD and MK among the three groups. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of the MD values when discriminating between the necrotic groups. RESULTS: Gadoxetate had no significant effect on either the MD or the MK, and the effect size was small. The MD in the moderate necrosis group was significantly lower than that in the other two groups (F = 13.502, p < 0.001; η2 = 0.428 [95% CI: 0.082-0.637]), while the MK did not significantly differ among the three groups (F = 2.702, p = 0.081; η2 = 0.131 [95% CI: 0.001-0.4003]). The AUCs of MD for discriminating the moderate necrosis or normal group from the other groups were 0.921 (95% CI: 0.832-1.000) and 0.831 (95% CI: 0.701-0.961), respectively. CONCLUSION: It would be better to measure the MD and MK before gadoxetate injection. MD showed potential for assessing the degree of liver necrosis in a paracetamol-induced liver injury rat model.

Dual-Ligand Europium-Organic Gels as a Highly Efficient Anodic Annihilation Electrochemiluminescence Emitter for Ultrasensitive Detection of MicroRNA.

In this study, a novel europium dual-ligand metal-organic gel (Eu-D-MOGs) with high-efficient anodic annihilation electrochemiluminescence (ECL) was synthesized as an ECL emitter to construct a biosensor for ultrasensitive detection of microRNA-221 (miR-221). Impressively, compared to the ECL signal of europium single-ligand metal-organic gels (Eu-S-MOGs), the ECL signal of Eu-D-MOGs was significantly improved since the two organic ligands could jointly replace the H2O and coordinate with Eu3+, which could remarkably reduce the nonradiative vibrational energy transfer caused by the coordination between H2O and Eu3+ with a high coordination demand. In addition, Eu-D-MOGs could be electrochemically oxidized to Eu-D-MOGs•+ at 1.45 V and reduced to Eu-D-MOGs•- at 0.65 V to achieve effective annihilation of ECL, which overcame the side reaction brought by the remaining emitters at negative potential. This benefited from the annihilation ECL performance of the central ion Eu3+ caused by its redox in the electrochemical process. Furthermore, the annihilation ECL signal of Eu3+ could be improved by sensitizing Eu3+ via the antenna effect. In addition, combined with the improved rolling circle amplification-assisted strand displacement amplification strategy (RCA-SDA), a sensitive biosensor was constructed for the sensitive detection of miR-221 with a low detection limit of 5.12 aM and could be successfully applied for the detection of miR-221 in the lysate of cancer cells. This strategy offered a unique approach to synthesizing metal-organic gels as ECL emitters without a coreactant for the construction of ECL biosensing platforms in biomarker detection and disease diagnosis.

SUGP2 p.(Arg639Gln) variant is involved in the pathogenesis of hemochromatosis via the CIRBP/BMPER signaling pathway.

Pathogenic variants in HFE and non-HFE genes have been identified in hemochromatosis in different patient populations, but there are still a certain number of patients with unexplained primary iron overload. We recently identified in Chinese patients a recurrent p.(Arg639Gln) variant in SURP and G-patch domain containing 2 (SUGP2), a potential mRNA splicing-related factor. However, the target gene of SUGP2 and affected iron-regulating pathway remains unknown. We aimed to investigate the pathogenicity and underlying mechanism of this variant in hemochromatosis. RNA-seq analysis revealed that SUGP2 knockdown caused abnormal alternative splicing of CIRBP pre-mRNA, resulting in an increased normal splicing form of CIRBP V1, which in turn increased the expression of BMPER by enhancing its mRNA stability and translation. Furthermore, RNA-protein pull-down and RNA immunoprecipitation assays revealed that SUGP2 inhibited splicing of CIRBP pre-mRNA by a splice site variant at CIRBP c.492 and was more susceptible to CIRBP c.492 C/C genotype. Cells transfected with SUGP2 p.(Arg639Gln) vector showed up-regulation of CIRBP V1 and BMPER expression and down-regulation of pSMAD1/5 and HAMP expression. CRISPR-Cas9 mediated SUGP2 p.(Arg622Gln) knock-in mice showed increased iron accumulation in the liver, higher total serum iron, and decreased serum hepcidin level. A total of 10 of 54 patients with hemochromatosis (18.5%) harbored the SUGP2 p.(Arg639Gln) variant and carried CIRBP c.492 C/C genotype, and had increased BMPER expression in the liver. Altogether, the SUGP2 p.(Arg639Gln) variant down-regulates hepcidin expression through the SUGP2/CIRBP/BMPER axis, which may represent a novel pathogenic factor for hemochromatosis.

Long-term antiviral therapy is associated with changes in the profile of transcriptionally active HBV integration in the livers of patients with CHB.

Hepatitis B virus (HBV) integration exists throughout the clinical course of chronic hepatitis B (CHB). This study investigated the effects of long-term antiviral therapy on the level and profiles of transcriptionally active HBV integration. Serial liver biopsies and paired blood samples were obtained from 16, 16, and 22 patients with CHB at baseline, 78, and 260 weeks of entecavir monotherapy or combined with pegylated interferon alfa, respectively. Serum HBV biomarkers were longitudinally assessed. RNA-seq and HIVID2 program was used to identify HBV-host chimeric RNAs transcribed from integrated DNA. The counts of HBV integration reads were positively related to both serum HBV DNA levels (r = 0.695, p = 0.004) and HBeAg titers (r = 0.724, p = 0.021) at baseline, but the positive correlation exited only to the serum HBsAg levels after 260 weeks of antiviral therapy (r = 0.662, p = 0.001). After 78 weeks of antiviral therapy, the levels of HBV integration expression decreased by 12.25 folds from baseline. The viral junction points were enriched at the S and HBx genes after the long-term antiviral therapy. HBs-FN1 became one of the main transcripts, with the mean proportion of HBs-FN1 in all integrated expression increased from 2.79% at baseline to 10.54% at Week 260 of antiviral treatment. Antiviral therapy may reduce but not eliminate the HBV integration events and integration expression. Certain integration events, such as HBs-FN1 can persist in long-term antiviral treatment.

PRTA:Joint extraction of medical nested entities and overlapping relation via parameter sharing progressive recognition and targeted assignment decoding scheme.

Nested entities and relationship extraction are two tasks for analysis of electronic medical records. However, most of existing medical information extraction models consider these tasks separately, resulting in a lack of consistency between them. In this paper, we propose a joint medical entity-relation extraction model with progressive recognition and targeted assignment (PRTA). Entities and relations share the information of sequence and word embedding layers in the joint decoding stage. They are trained simultaneously and realize information interaction by updating the shared parameters. Specifically, we design a compound triangle strategy for the nested entity recognition and an adaptive multi-space interactive strategy for relationship extraction. Then, we construct a parameter-shared information space based on semantic continuity to decode entities and relationships. Extensive experiments were conducted on the Private Liver Disease Dataset (PLDD) provided by Beijing Friendship Hospital of Capital Medical University and public datasets (NYT, ACE04 and ACE05). The results show that our method outperforms existing SOTA methods in most indicators, and effectively handles nested entities and overlapping relationships.

Liver fibrosis showed a two-phase regression rate during long-term anti-HBV therapy by three-time biopsies assessments.

BACKGROUND: Evidence has proven that liver fibrosis or even cirrhosis can be reversed by anti-HBV treatment. However, the difference of fibrosis regression rates in short-term and long-term antiviral therapy remain unclear. Therefore, we aimed to identify the dynamic changes in fibrosis regression rate in patients with three-time liver biopsies during 5 years antiviral therapy. METHODS: CHB patients with three times of liver biopsies (baseline, after 1.5-year and 5-year antiviral therapy) from a prospective cohort were enrolled. All patients were biopsy-proved Ishak stage ≥ 3 at baseline (n = 92). Fibrosis regression was defined as Ishak stage decreased ≥ 1 or predominantly regressive categorized by P-I-R score. RESULTS: Totals of 65.2% (60/92) and 80.4% (74/92) patients attained fibrosis regression after 1.5-year and 5-year therapy, respectively. Median HBV DNA level declined from 6.5 log IU/ml (baseline) to 0 log IU/ml (1.5 years and 5 years, P < 0.001). The mean level of Ishak fibrosis stage in all patients decreased from stage 4.1 (baseline) to 3.7 (1.5 years) then 3.2 (5 years). Fibrosis regression rates were 0.27 stage/year between baseline to year 1.5 and 0.14 stage/year between year 1.5 and year 5. Furthermore, for patients who attained fibrosis regression after 5-year antiviral therapy, the two-phase regression rates were 0.39 stage/year (0 year-1.5 years) and 0.20 stage/year (1.5 years-5 years). This two-phase feature of regression rate was further confirmed by fully-quantification assessment of liver fibrosis based on SHG/TPEF. CONCLUSION: During the 5 years of long-term antiviral treatment, liver fibrosis rapidly regresses in the first 1.5 years before slowing down in the following 3.5 years.

Multiscale X-ray phase-contrast CT unveils the evolution of bile infarct in obstructive biliary disease.

Bile infarct is a pivotal characteristic of obstructive biliary disease, but its evolution during the disease progression remains unclear. Our objective, therefore, is to explore morphological alterations of the bile infarct in the disease course by means of multiscale X-ray phase-contrast CT. Bile duct ligation is performed in mice to mimic the obstructive biliary disease. Intact liver lobes of the mice are scanned by phase-contrast CT at various resolution scales. Phase-contrast CT clearly presents three-dimensional (3D) images of the bile infarcts down to the submicron level with good correlation with histological images. The CT data illustrates that the infarct first appears on day 1 post-BDL, while a microchannel between the infarct and hepatic sinusoids is identified, the number of which increases with the disease progression. A 3D model of hepatic acinus is proposed, in which the infarct starts around the portal veins (zone I) and gradually progresses towards the central veins (zone III) during the disease process. Multiscale phase-contrast CT offers the comprehensive analysis of the evolutionary features of the bile infarct in obstructive biliary disease. During the course of the disease, the bile infarcts develop infarct-sinusoidal microchannels and gradually occupy the whole liver, promoting the disease progression.

Obliteration of portal venules contributes to portal hypertension in biliary cirrhosis.

The effects of the obliteration of portal venules (OPV) in cirrhotic portal hypertension are poorly understood. To investigate its contribution to portal hypertension in biliary cirrhosis and its underlying mechanism, we evaluated OPV using two-dimensional (2D) histopathology in liver explants from patients with biliary atresia (BA, n = 63), primary biliary cholangitis (PBC, n = 18), and hepatitis B-related cirrhosis (Hep-B-cirrhosis, n = 35). Then, three-dimensional (3D) OPV was measured by X-ray phase-contrast CT in two parallel models in rats following bile duct ligation (BDL) or carbon tetrachloride (CCl4) administration, representing biliary cirrhosis and post-necrotic cirrhosis, respectively. The portal pressure was also measured in the two models. Finally, the effects of proliferative bile ducts on OPV were investigated. We found that OPV was significantly more frequent in patients with biliary cirrhosis, including BA (78.57 ± 16.45%) and PBC (60.00 ± 17.15%), than that in Hep-B-cirrhotic patients (29.43 ± 14.94%, p < 0.001). OPV occurred earlier, evidenced by the paired liver biopsy at a Kasai procedure (KP), and was irreversible even after a successful KP in the patients with BA. OPV was also significantly more frequent in the BDL models than in the CCl4 models, as shown by 2D and 3D quantitative analysis. Portal pressure was significantly higher in the BDL model than that in the CCl4 model. With the proliferation of bile ducts, portal venules were compressed and irreversibly occluded, contributing to the earlier and higher portal pressure in biliary cirrhosis. OPV, as a pre-sinusoidal component, plays a key role in the pathogenesis of portal hypertension in biliary cirrhosis. The proliferated bile ducts and ductules gradually take up the 'territory' originally attributed to portal venules and compress the portal venules, which may lead to OPV in biliary cirrhosis. © 2024 The Pathological Society of Great Britain and Ireland.

Validation of the revised electronic version of RUCAM for diagnosis of DILI in Chinese patients.

BACKGROUND AIMS: The Revised Electronic Causality Assessment Method (RECAM), a computerized update of the Roussel Uclaf Causality Assessment Methodology (RUCAM), was recently proposed. In this study, we validated and compared the utility of the RECAM and RUCAM in Chinese patients with a single conventional or herbal agent-induced liver injury. METHODS: In this retrospective multicenter cohort of well-established DILI and non-DILI patients from 5 centers in China, the diagnostic performance of the RUCAM and RECAM was compared by AUC analysis. The consistency was evaluated by weighted kappa. The major causes of discrepancy were explored. RESULTS: A total of 481 DILI and 100 non-DILI patients were included. In total, 62.6% of the DILI cases were induced by conventional agents, and 37.4% were induced by herbs. The RECAM had relatively higher AUC than RUCAM for overall [0.947 (0.926-0.964) vs. 0.867 (0.836-0.893), p=0.0016], conventional agents [0.923 (0.890-0.949) vs. 0.819 (0.775-0.858), p=0.0185], and herbs [0.972 (0.941-0.989) vs.0.911 (0.866-0.944), p=0.0199]. Latency, scores associated with hepatitis B, and hepatotoxicity information of the insulting drugs were the 3 main causes for the inconsistency between RECAM and RUCAM scores. CONCLUSIONS: The RECAM had relatively better diagnostic performance than RUCAM, with a higher AUC for Chinese DILI patients. Timely updates of the LiverTox category and refinement of serum markers to exclude hepatitis B activity would further improve the applicability of RECAM in areas where the use of herbs and resolution of past HBV infections are common.