Immunosuppression induces regression of fibrosis in primary biliary cholangitis with moderate-to-severe interface hepatitis.

BACKGROUND: In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy. METHODS: We conducted a multicenter study involving PBC patients with moderate-to-severe interface hepatitis who underwent paired liver biopsies. Firstly, we compared the efficacy of the combination therapy with UDCA monotherapy on improving biochemistry, histology, survival rates, and prognosis. Subsequently we investigated the predictors of a beneficial response. RESULTS: This retrospective cohort study with prospectively collected data was conducted in China from January 2009 to April 2023. Of the 198 enrolled patients, 32 underwent UDCA monotherapy, while 166 received combination therapy, consisting of UDCA combined with prednisolone, prednisolone plus mycophenolate mofetil (MMF), or prednisolone plus azathioprine (AZA). The monotherapy group was treated for a median duration of 37.6 months (IQR 27.5-58.1), and the combination therapy group had a median treatment duration of 39.3 months (IQR 34.5-48.8). The combination therapy showed a significantly greater efficacy in reducing fibrosis compared to UDCA monotherapy, with an 8.3-fold increase in the regression rate (from 6.3% to 52.4%, P < 0.001). Other parameters, including biochemistry, survival rates, and prognosis, supported its effectiveness. Baseline IgG >1.3 × ULN and ALP <2.4 × ULN were identified as predictors of regression following the combination therapy. A predictive score named FRS, combining these variables, accurately identified individuals achieving fibrosis regression with a cut-off point of ≥ -0.163. The predictive value was validated internally and externally. CONCLUSION: Combination therapy with IS improves outcomes in PBC patients with moderate-to-severe interface hepatitis compared to UDCA monotherapy. Baseline IgG and ALP are the most significant predictors of fibrosis regression. The new predictive score, FRS, incorporating baseline IgG and ALP, can effectively identify individuals who would benefit from the combination therapy.

Efficient CsPbBr3 Perovskite Light-Emitting Diodes via Novel Multi-Step Ligand Exchange Strategy Based on Zwitterionic Molecules.

Perovskite nanocrystals have absorbed increasing interest, especially in the field of optoelectronics, owing to their unique characteristics, including their tunable luminescence range, robust solution processability, facile synthesis, and so on. However, in practice, due to the inherent instability of the traditional long-chain insulating ligands surrounding perovskite quantum dots (PeQDs), the performance of the as-fabricated QLED is relatively disappointing. Herein, the zwitterion 3-(decyldimethylammonio)propanesulfonate (DLPS) with the capability of double passivating perovskite quantum dots could effectively replace the original long-chain ligand simply through a multistep post-treatment strategy to finally inhibit the formation of defects. It was indicated from theexperimental results that the DLPS, as one type of ligand with the bimolecular ion, was very adavntageous in replacing long-chain ligands and further suppressing the formation of defects. Finally, the perovskite quantum dots with greatly enhanced PLQY as high as 98% were effectively achieved. Additionally, the colloidal stability of the corresponding PeQDs has been significantly enhanced, and a transparent colloidal solution was obtained after 45 days under ambient conditions. Finally, the as-fabricated QLEDs based on the ligand-exchanged PeQDs exhibited a maximum brightness of 9464 cd/m2 and an EQE of 12.17%.

High-Resolution Quantum Dot Light-Emitting Diodes by Electrohydrodynamic Printing.

Quantum dot light-emitting diodes (QLEDs) have attracted increasing attention due to their excellent electroluminescent properties and compatibility with inkjet printing processes, which show great potential in applications of pixelated displays. However, the relatively low resolution of the inkjet printing technology limits its further development. In this paper, high-resolution QLEDs were successfully fabricated by electrohydrodynamic (EHD) printing. A pixelated quantum dot (QD) emission layer was formed by printing an insulating Teflon mesh on a spin-coated QD layer. The patterned QLEDs show a high resolution of 2540 pixels per inch (PPI), with a maximum external quantum efficiency (EQE) of 20.29% and brightness of 35816 cd/m2. To further demonstrate its potential in full-color display, the fabrication process for the QD layer was changed from spin-coating to EHD printing. The as-printed Teflon effectively blocked direct contact between the hole transport layer and the electron transport layer, thus preventing leakage currents. As a result, the device showed a resolution of 1692 PPI with a maximum EQE of 15.40%. To the best of our knowledge, these results represent the highest resolution and efficiency of pixelated QLEDs using inkjet printing or EHD printing, which demonstrates its huge potential in the application of high-resolution full-color displays.

Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1.

Background & Aims: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients. Methods: We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls. Results: A total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels. Conclusions: Our study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH. Impact and implications: This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.

TLR8 agonist partially improves IFN-γ deficiency of NK cells in chronic hepatitis B through the synergy of monocytes.

BACKGROUND: Natural killer (NK) cells exhibit a selective deficiency of IFN-γ production in chronic hepatitis B (CHB). Toll-like receptor 8 (TLR8) agonists could induce IFN-γ production in immune cells, although their effects on the deficiency in NK cells remain unclear. AIMS: To investigate TLR8 expression in NK cells and the effect of TLR8 agonists in patients with CHB METHODS: We enrolled 32 patients with CHB and 19 healthy controls to assess TLR8 expression and IFN-γ production in NK cells. The sorted NK cells and monocytes were co-cultured to compare the extent of IFN-γ and IL-10 production after TLR8 agonist ssRNA40 stimulation. The synergic effect of NK cells and monocytes was assessed by blocking IL-12 and IL-18. We recruited another 22 patients with CHB undergoing nucleotide analogue (NA) therapy to explore the impact of antiviral treatment on the ssRNA40-mediated response of NK cells. RESULTS: In patients with CHB, TLR8 expression in NK cells was up-regulated, accompanied by insufficient IFN-γ production. The enhanced IFN-γ secretion by ssRNA40 in NK cells depended on monocyte-derived IL-12 and IL-18. NK cells displayed an imbalanced response to ssRNA40 in patients with CHB with a weak increase in IFN-γ despite a higher IL-10 production. The response was improved in patients with CHB undergoing NA therapy. CONCLUSIONS: In patients with CHB, targeting TLR8 partially rescues the IFN-γ insufficiency in NK cells. However, NK cells show an inhibitory response to TLR8 agonist stimulation. TLR8 agonist combined with NA may enhance the antiviral effect of NK cells.

Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease. APPROACH AND RESULTS: We conducted a case-control association study of 1,622 Chinese patients with AIH type 1 and 10,466 population controls from two independent cohorts. A meta-analysis was performed to ascertain variants associated with AIH type 1. A single-nucleotide polymorphism within the human leukocyte antigen (HLA) region showed the strongest association with AIH (rs6932730: OR = 2.32; p = 9.21 × 10-73 ). The meta-analysis also identified two non-HLA loci significantly associated with AIH: CD28/CTLA4/ICOS on 2q33.3 (rs72929257: OR = 1.31; p = 2.92 × 10-9 ) and SYNPR on 3p14.2 (rs6809477: OR = 1.25; p = 5.48 × 10-9 ). In silico annotation, reporter gene assays, and CRISPR activation experiments identified a distal enhancer at 2q33.3 that regulated expression of CTLA4. In addition, variants near STAT1/STAT4 (rs11889341: OR = 1.24; p = 1.34 × 10-7 ), LINC00392 (rs9564997: OR = 0.81; p = 2.53 × 10-7 ), IRF8 (rs11117432: OR = 0.72; p = 6.10 × 10-6 ), and LILRA4/LILRA5 (rs11084330: OR = 0.65; p = 5.19 × 10-6 ) had suggestive association signals with AIH. CONCLUSIONS: Our study identifies two novel loci (CD28/CTLA4/ICOS and SYNPR) exceeding genome-wide significance and suggests four loci as potential risk factors. These findings highlight the importance of costimulatory signaling and neuro-immune interaction in the pathogenesis of AIH.

Prevalence of mild cognitive impairment in patients with hypertension: a systematic review and meta-analysis.

Mild cognitive impairment (MCI) is common in patients with hypertension. Prevalence estimates of MCI in hypertensive patients are needed to guide both public health and clinical decision making. A literature search was conducted in four databases, including PubMed, Embase, Cochrane Library, and Web of Science, from their inception to February 2021. The methodological quality assessment used the risk of bias tool. The pooled prevalence of MCI in hypertensive patients was determined by a random-effects model. Heterogeneity was explored using sensitivity analysis, subgroup analysis, and random effects meta-regression. Of 2314 references, 11 studies (47,179 participants) were included in the meta-analysis. The overall pooled prevalence of MCI in patients with hypertension was 30% (95% CI, 25-35), with significant heterogeneity present (I2 = 99.3%, p < 0.001). In subgroup analyses, Asian and European samples had a prevalence of 26% (95% CI, 20-31) and 40% (95% CI, 14-66), respectively; cross-sectional and cohort studies had a prevalence of 28% (95% CI, 24-32) and 38% (95% CI, -5-81); age older than 60 years had a prevalence of 28% (95% CI, 23-33); community-based and clinic-based samples had a prevalence of 17% (95% CI, 15-19) and 42% (95% CI, 23-62); and MCI diagnosis using the MoCA, NIA-AA, MMSE, and Peterson criteria had a prevalence of 64% (95% CI, 59-68), 18% (95% CI, 16-19), 19% (95% CI, 15-23), and 13% (95% CI, 9-17). Meta-regression analysis showed that different MCI diagnostic criteria could be the source of heterogeneity in the pooled results. MCI is common in patients with hypertension, with an overall prevalence of 30%. Earlier cognitive screening and management in hypertensive patients should be advocated.

A single-modal linear ultrasonic motor based on multi vibration modes of PZT ceramics.

We have developed a single-modal linear motor which contains two kinds of PZT ceramics. The linear motor works by exciting the transverse vibration mode of the PZT ceramic on the upper surface of stator elastomer and the shear vibration mode of PZT ceramics at two ends simultaneously. The operation principle of the motor is analyzed in detail. And the rule of the driving foot amplitude varies with the size of the end protruding structure has been further researched by FEM analysis. The prototype is manufactured, and its operating characteristics are experimentally studied and analyzed. The no-load velocity and the maximum output force are tested to be 169.4 mm/s and 1.1 N, respectively. The results show that extra arrangement of PZT ceramics which works on shear vibration mode can efficiently improve the output of motor.

The efficacy of extracorporeal shock wave for chronic musculoskeletal pain conditions: A protocol of systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: This systematic review is the first one to assess the effectiveness and safety of extracorporeal shock-wave therapy (ESWT) for patients with chronic musculoskeletal pain conditions (CMPC). METHODS: Seven electronic databases were searched for all relevant literature from inception to December 2019, including PubMed, the Web of Science, EMBASE, Cochrane library, China National Knowledge Infrastructure Database (CNKI), Chinese Scientific Journal Database (VIP), and Wanfang database. Only randomized controlled trials (RCTs) of ESWT for chronic musculoskeletal pain will be included. Two reviewers will independently select eligible studies and collected the detailed information, assessed the methodological quality. A third reviewer will join in discussion to solve disagreements. The mean difference (MD) or standard mean difference (SMD) with 95% confidence intervals (CIs) will be presented to demonstrate the effectiveness of ESWT for patients with chronic MSK pain conditions. RevMan 5.4 software will be used for statistical analysis. RESULTS: This systematic review will explore the effectiveness and safety of ESWT for patients with CMPC. The primary outcome includes pain level, and secondary outcome includes function limitation and adverse events. CONCLUSION: It can provide the updated evidence which is of great importance for patients, clinical practice and health related policy maker in ESWT treating CMPC.