MyD88 in myofibroblasts enhances nonalcoholic fatty liver disease-related hepatocarcinogenesis via promoting macrophage M2 polarization.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver diseases and has emerged as the leading factor in the pathogenesis of hepatocellular carcinoma (HCC). MyD88 contributes to the development of HCC. However, the underlying mechanism by which MyD88 in myofibroblasts regulates NAFLD-associated liver cancer development remains unknown. RESULTS: Myofibroblast MyD88-deficient (SMAMyD88-/-) mice were protected from diet-induced obesity and developed fewer and smaller liver tumors. MyD88 deficiency in myofibroblasts attenuated macrophage M2 polarization and fat accumulation in HCC tissues. Mechanistically, MyD88 signaling in myofibroblasts enhanced CCL9 secretion, thereby promoting macrophage M2 polarization. This process may depend on the CCR1 receptor and STAT6/ PPARß pathway. Furthermore, liver tumor growth was attenuated in mice treated with a CCR1 inhibitor. CCLl5 (homologous protein CCL9 in humans) expression was increased in myofibroblasts of HCC and was associated with shorter survival of patients with HCC. Thus, our results indicate that MyD88 in myofibroblasts promotes NAFLD-related HCC progression and may be a promising therapeutic target for HCC treatment. CONCLUSION: This study demonstrates that MyD88 in myofibroblasts can promote nonalcoholic fatty liver disease-related hepatocarcinogenesis by enhancing macrophage M2 polarization, which might provide a potential molecular therapeutic target for HCC.

The equity road ahead for financing non-national immunization program vaccines in China: challenges and opportunities from a qualitative study.

BACKGROUND: In China, national immunization program (NIP) vaccines benefit from robust financial support and have achieved high coverage. Non-NIP vaccines rely on fragmented funding sources, mostly out-of-pocket payment, and face sub-optimal and inequitable coverage. Sustainable financing needs to be secured for addressing equity in non-NIP vaccine delivery. However, discussion and understanding of this issue remain limited. This study aims to analyze the current situation, comprehensively identify challenges and opportunities in non-NIP vaccine financing, and offer suggestions to enhance vaccine uptake and improve public health. METHODS: Between July and December 2023, we conducted a series of semi-structured, in-person interviews with 55 stakeholders from the Health Bureau, Centers for Disease Control and Prevention, Medical Insurance Bureau, and Finance Bureau across five provinces in China. Participants were selected through stratified sampling, and the interviews mainly included their involvement in non-NIP vaccine financing, challenges faced, and strategies for improvement to enhance financing performance. Informed consent was obtained, and thematic analysis was used to analyze the data. RESULTS: Non-NIP vaccine financing sources include out-of-pocket payments, government fiscal, health insurance and other external funds. These four channels differ in vaccine types covered, costs, and target populations, each with unique challenges and opportunities. High out-of-pocket costs remain a significant barrier to equitable vaccine uptake, while market competition has lowered the vaccine price and improved accessibility. Local fiscal support for free vaccination programs faces challenges related to sustainability and regional disparity, though governmental commitment to vaccination is growing. Nevertheless, centralized procurement organized by the government has lowered the price and reduced the financial burden. Despite legal restrictions on using basic health insurance for vaccinations and limited commercial insurance options, private medical savings accounts and mutual-aid mechanisms present new opportunities. Although the scope and impact of external support are limited, it has successfully increased awareness and social attention to vaccination. CONCLUSION: Relying on individual payments as the main financing channel for non-NIP vaccines is unsustainable and inadequate for ensuring universal vaccine access. A concerted and synergistic approach is essential to ensure sufficient, sustainable resources and enhance public financial management to improve equity in the non-NIP vaccines.

From both sides of the needle: Understanding effective interventions for facilitating non-national immunization program vaccine decision making in China.

Vaccination decisions are influenced by various psychological and practical factors. In China, non-National Immunization Program (non-NIP) vaccines, which are voluntary and self-paid, add uncertainty and autonomy to the decision-making process. Effective communication between providers and recipients is crucial but understudied. This study aims to integrate their perspectives, identify strategies for facilitating vaccination decisions, and analyze their mechanisms. From July to December 2023, semi-structured interviews were conducted with 17 caregivers and 12 vaccination providers across five Chinese provinces. Participants shared their experiences and decision-making processes regarding non-NIP vaccines. The Behaviour Change Wheel framework guided the analysis, utilizing iterative coding and directed content analysis. Thirteen Behavior Change Techniques were identified, with feedback, monitoring, and environmental restructuring being the most common. Key intervention functions included Persuasion, Education, and Training. We further mapped how these interventions influence non-NIP vaccine decisions. Capability was enhanced through education and effective communication, providing necessary knowledge and skills. Opportunity was increased via infrastructural improvements and societal support, making vaccines more accessible and endorsed by the community. Motivation was driven by clear communication of vaccination benefits and risks, reinforced by societal norms through public health messaging. By understanding the mechanisms influencing vaccination behaviors and interacting with stakeholders, tailored strategies can be developed. Healthcare providers can enhance service accessibility and offer evidence-based guidance with reminders, monitoring, and incentives to ensure compliance. For recipients, reliable information, sustained engagement, timely communication, and motivational opportunities are essential. A multi-dimensional approach involving multiple stakeholders is crucial for promoting non-NIP vaccine uptake.

Hepatocyte-specific Smad4 deficiency inhibits hepatocarcinogenesis by promoting CXCL10/CXCR3-dependent CD8+- T cell-mediated anti-tumor immunity.

Rationale: Sma mothers against decapentaplegic homologue 4 (Smad4) is a key mediator of the transforming growth factor ß (TGF-ß) pathway and plays complex and contradictory roles in hepatocellular carcinoma (HCC). However, the specific role of Smad4 in hepatocytes in regulating hepatocarcinogenesis remains poorly elucidated. Methods: A diethylnitrosamine/carbon tetrachloride-induced HCC model was established in mice with hepatocyte-specific Smad4 deletion (AlbSmad4-/-) and liver tumorigenesis was monitored. Immune cell infiltration was examined by immunofluorescence and fluorescence activated cell sorting (FACS). Cytokine secretion, glycolysis, signal pathway, and single-cell RNA sequencing were analysed for mechanism. Results: AlbSmad4-/- mice exhibited significantly fewer and smaller liver tumor nodules, less fibrosis, reduced myeloid-derived suppressor cell infiltration and increased CD8+ T cell infiltration. Smad4 deletion in hepatocytes enhanced C-X-C motif ligand 10 (CXCL10) secretion, promoting tumor necrosis factor-α (TNF-α) production in CD8+ T cells. The loss of Smad4 activated the CXCL10/mammalian target of rapamycin (mTOR)/lactate dehydrogenase A (LDHA) pathway, which increased glycolytic activity in CD8+ T cells. HCC patients with high Smad4 expression exhibited decreased CD8+ T cell infiltration and altered glycolysis. Conclusion: Our results demonstrate that Smad4 in hepatocytes promotes hepatocarcinogenesis and is a potential and candidate target for the prevention and therapy of HCC.

The coverage and challenges of increasing uptake of non-National Immunization Program vaccines in China: a scoping review.

BACKGROUND: Non-National Immunization Program (NIP) vaccines have played an important role in controlling vaccine-preventable diseases (VPDs) in China. However, these vaccines are paid out of pocket and there is room to increase their coverage. We focused on four selected non-NIP vaccines in this study, namely Haemophilus influenzae type b (Hib) vaccine, human papillomavirus (HPV) vaccine, pneumococcal conjugate vaccine (PCV), and rotavirus vaccine. We aimed to conduct a scoping review of their vaccination rates and the major barriers faced by health systems, providers, and caregivers to increase coverage. METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). We searched five English databases (PubMed, Web of Science, EMBASE, Scopus, and WHO IRIS) and four Chinese databases using the search strategy developed by the study team. Two independent reviewers screened, selected studies, and examined their quality. We summarized the non-NIP vaccine coverage data by vaccine and applied the 5A framework (Access, Affordability, Acceptance, Awareness, Activation) to chart and analyze barriers to increasing coverage. RESULTS: A total of 28 articles were included in the analysis (nine pertaining to vaccine coverage, and another 19 reporting challenges of increasing uptake). Among the four selected vaccines, coverage for the Hib vaccine was the highest (54.9-55.9% for 1 dose or more from two meta-analyses) in 2016, while the coverage of the other three vaccines was lower than 30%. Eight of the nine included articles mentioned the regional disparity of coverage, which was lower in under-developing regions. For example, the three-dose Hib vaccination rate in eastern provinces was 38.1%, whereas the rate in central and western provinces was 34.3% and 26.2%, respectively in 2017. Within the 5A framework, acceptance, awareness, and affordability stood out as the most prominent themes. Among the 12 identified sub-themes, high prices, low vaccine awareness, concerns about vaccine safety and efficacy were the most cited barriers to increasing the uptake. CONCLUSIONS: There is an urgent need to increase coverage of non-NIP vaccines and reduce disparities in access to these vaccines across regions. Concerted efforts from the government, the public, and society are required to tackle the barriers and challenges identified in this study, both on the demand and supply side, to ensure everybody has equal access to life-saving vaccines in China. Particularly, the government should take a prudent approach to gradually incorporate non-NIP vaccines into the NIP step by step, and make a prioritizing strategy based on key factors such as disease burden, financial resources, and market readiness, with special attention to high-risk populations and underdeveloped regions.

An Ultrastrong and Antibacterial Silver Nanowire/Aligned Cellulose Scaffold Composite Film for Electromagnetic Interference Shielding.

Constructing multifunctional electromagnetic interference (EMI) shielding films with superior mechanical strength has sparked a lot of interest in the fields of wearable electronics. In this work, the conductive silver nanowires (AgNWs) were synthesized and impregnated into the highly aligned cellulose scaffold (CS) fabricated by wood delignification followed by hot-pressing and polydimethylsiloxane (PDMS) dipping processes to obtain the outstanding EMI shielding cellulosic film (d-AgNWs@CS-PDMS). The consecutively conductive pathway of AgNWs was constructed in the microchannels of the CS as a result of the hydrogen bonding between AgNWs and cellulose fibers, which is conducive to the reflection of incident EM waves. The higher degree of nanofiber alignment and the compact conductive network were improved by densification upon hot pressing, which endows the composite film with striking mechanical properties (maximum tensile strength of 511.8 MPa) and superb EMI shielding performance (shielding effectiveness value of 46 dB with a filler content of 21.6 wt %) at the X band (8.2-12.4 GHz). Moreover, the existence of an intensive AgNWs network and the introduction of the PDMS layer improve the hydrophobicity and antibacterial activity of the composite film, avoiding serious health concerns in the long-term wearing. These results demonstrate that the obtained d-AgNWs@CS-PDMS composite film has high potential as an EMI shielding material used for wearable devices.

Flexible, Transparent, and Hazy Composite Cellulosic Film with Interconnected Silver Nanowire Networks for EMI Shielding and Joule Heating.

An optical transparent and hazy film with admirable flexibility, electromagnetic interference (EMI) shielding, and Joule heating performance meeting the requirements of optoelectronic devices is significantly desirable. Herein, a cellulose paper was infiltrated by epoxy resin to fabricate a transparent cellulose paper (TCP) with high transparency, optical haze, and favorable flexibility, owing to effective light scattering and mechanical enhancement of the cellulose network. Moreover, a highly connected silver nanowire (AgNW) network was constructed on the TCP substrate by the spray-coating method and appropriate thermal annealing technique to realize high electrical conductivity and favorable optical transmittance of the composite film at the same time, followed by coating of a polydimethylsiloxane (PDMS) layer for protection of the AgNW network. The obtained PDMS/AgNWs/TCP composite film features considerable optical transmittance (up to 86.8%) and haze (up to 97.7%), while satisfactory EMI shielding effectiveness (SE) (up to 39.1 dB, 8.2-12.4 GHz) as well as strong mechanical strength (higher than 41 MPa) were achieved. The coated PDMS layer prevented the AgNW network from falling off and ensured the long-term stability of the PDMS/AgNWs/TCP composite film under deformations. In addition, the multifunctional PDMS/AgNWs/TCP composite film also exhibited excellent Joule heating performance with low supplied voltages, rapid response, and sufficient stability. This work demonstrates a novel pathway to improve the performance of multifunctional transparent composite films for future advanced optoelectronic devices.