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关键词： COVID-19   Influenza   Interleukin-6 (IL-6)   JAK-STAT   Mendelian randomization  

摘要： Seasonal influenza is a significant cause of mortality across all age groups. Recent reports have confirmed highly pathogenic avian influenza A (H5N1) infections in humans, including a case with critical illness. Our current evidence-based therapi...

关键词： IL6Ra   Liquid-liquid phase separation   Molecular evolution  

摘要： Phase separation has been discovered as a new form of regulation in innate immunity. Here, we found that IL6Ra in teleost fish has a unique intrinsic disordered region (IDR) in its amino acid sequence, distinguishing it from the IL6Ra of higher vertebrates. This unique feature endows IL6Ra with the ability to undergo liquid-liquid phase separation, enabling the organism to swiftly initiate an immune response at the early stages of viral infection. Mechanistically, we discovered that zebrafish IL6Ra through its phase separation ability, can competitively recruit the G3bp1 protein. This competitive recruitment mechanism effectively blocks the early replication process of the virus while promoting the rapid activation of host antiviral signaling pathways. In addition, the synergy between IL6Ra and G3bp1 triggers a dynamic recruitment of neutrophils and robust host antiviral defense. Importantly, the IL6Ra protein without the IDR region that cannot undergo phase separation will significantly weaken its antiviral capability. Furthermore, we further confirmed that the characteristics and length of the IDR region of IL6Ra in teleost fish is positively correlated with its phase separation ability and antiviral capacity. In summary, our research results provide a phase separation immune defense strategy obtained from an evolutionary perspective. Significance: This study reveals the evolutionary plasticity of IL6Ra gene's IDR sequences in bony fishes: Migratory species, facing dynamic viral pressures during freshwater-marine transitions, evolved elongated and complex IL6Ra IDR sequences to enhance LLPS capacity for rapid response to heterogeneous pathogens. Marine fishes developed highly complex IDR architectures to counter high viral diversity, while freshwater species retained simplified IDR sequences under low viral selection. This IDR sequence divergence demonstrates that vertebrates, constrained by innate immunity, can fine-tune non-domain sequences of key immune recepto

关键词： IFN gamma-IL8 signaling   immune response   neutrophils   publicly accessible dataset   single-cell transcriptomic profiles  

摘要： Streptococcus agalactiae is a significant pathogen in both humans and animals, yet the immune cell subtype dynamics during infection remain poorly defined. Leveraging the high susceptibility and tractability of Nile tilapia (Oreochromis niloticus), 113,356 single immune cells are profiled from head kidney and spleen across multiple infection time points (0, 1, 5, 10, 75 days post-infection and 3 days post-reinfection). This single-cell transcriptomic and flow cytometry analyses revealed distinct activation and transition patterns among neutrophils, macrophages, T cells, and B cells. Neutrophils exhibited early transcriptional remodeling enriched in inflammatory and interferon gamma (IFN gamma) signaling pathways. Cross-species integration identified a conserved IFN gamma-driven transition toward il8(+) neutrophils. Furthermore, recombinant interleukin-8 (IL8) enhanced antibacterial responses in tilapia and human neutrophils, while inhibition of STAT1 reduced IL8 expression. IL8 stimulation increased phagocytosis and reactive oxygen species (ROS) production, supporting its role in neutrophil-mediated bacterial clearance. Together, this findings establish IFN gamma-IL8 as a conserved mechanism in vertebrate immunity and a potential target for antibacterial therapies.

关键词： Tocilizumab   Interleukin-6   COVID-19   Viral pneumonia   Acute respiratory distress syndrome   Randomized controlled trial  

摘要： Background The objective of this clinical trial is to evaluate the efficacy and safety of IL-6 driven personalized treatment strategy with tocilizumab in patients with severe COVID-19 pneumonia. Trial design Randomized, controlled, open-label, single-center trial of a tocilizumab treatment strategy in adult patients hospitalized with severe COVID-19 pneumonia and IL-6 serum levels > 40 pg/mL. Methods Patients were randomized 1:1 to receive standard of care (SOC) or SOC plus one dose of tocilizumab. The primary outcome was death or need for invasive mechanical ventilation (IMV) within 28 days after randomization. Secondary outcomes included ICU admission, days on IMV and hospital stay. A meta-analysis of clinical trials to evaluate the effect of tocilizumab on mortality and need of IMV in patients with COVID-19 pneumonia was performed. Results Sixty-two patients were included: 30 in the SOC arm and 32 in the standard-treatment plus tocilizumab arm. The primary outcome occurred in 12.9% in the tocilizumab arm and 32.3% in the SOC arm(p = 0.068). There was a trend towards fewer days on IMV (7.5 vs 19.5 days, p = 0.073) and a shorter hospital stay (4 vs 8 days, p = 0.134) in the tocilizumab group. No serious adverse events were reported. The meta-analysis revealed a RR for death or IMV of 0.83 (95% CI: 0.77-0.89) in patients receiving tocilizumab, compared to patients receiving SOC. Conclusion Tocilizumab could be effective to prevent death or IMV in patients with severe COVID-19 pneumonia and high IL-6 serum levels. Safety profile of tocilizumab does not arise major concern in patients with severe COVID19.

关键词： HLA‐B*39:188   next‐generation sequencing   novel allele  

摘要： HLA-B*39:188 differs from HLA-B*39:15 by a single nucleotide substitution at position 1043 C>T.

关键词： inflammatory bowel disease   head-to-head trials   risankizumab   guselkumab   comparative efficacy  

摘要： INTRODUCTION:We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing interleukin (IL)-23p19 antagonists with ustekinumab, stratified by prior biologic exposure, in patients with moderate-to-severe Crohn's disease (CD).METHODS:Through a systematic review through August 17, 2024, we identified phase 2 and 3 RCTs comparing IL-23p19 antagonists vs ustekinumab in adults with moderate-to-severe CD. The primary outcome was achieving clinical remission at similar to 1 year, and secondary outcomes were achieving endoscopic remission and serious adverse events. We performed subgroup analyses based on prior exposure to biologic therapy, primarily tumor necrosis factor antagonists. Certainty of evidence was appraised using the Grading of Recommendations Assessment, Development, and Evaluation ***:We included 5 head-to-head RCTs with a treat-through design (n = 2,506), of which 1 was conducted exclusively in patients with prior tumor necrosis factor antagonist exposure. On meta-analysis, patients treated with IL-23p19 inhibitors may be more likely to achieve clinical remission (relative risk [RR], 1.18 95% confidence interval [CI] 1.02-1.36) (low certainty of evidence) and endoscopic remission (RR 1.53, 95% CI 1.07-2.20) compared with ustekinumab. On subgroup analysis, IL-23p19 antagonists are probably more efficacious than ustekinumab in patients with prior biologic exposure (clinical remission: RR 1.31, 95% CI 1.16-1.48;endoscopic remission: RR 1.61, 95% CI 1.27-2.05) (moderate to high certainty), but not in biologic-naive patients (clinical remission: RR 0.99, 95% CI 0.90-1.08;endoscopic remission: RR 1.16, 95% CI 0.82-1.65). IL-23p19 antagonists may be associated with a lower risk of serious adverse events as compared with ustekinumab (RR 0.79, 95% CI 0.61-1.02).DISCUSSION:IL-23p19 antagonists are probably more efficacious and safer than ustekinumab in patients with moderate-to-severe CD in patients with prior biologic

关键词： Competitive advantage   Strategic development planning   Economic ecosystem   Continuous sustainable improvement   Kingdom's 2030 Vision   And sustainable strategic management  

摘要： The study aimed to assess Ha'il's economic advantages, including quality, cost reduction, innovation, responsiveness, and value. It analyzed the region's progress toward these advantages based on the 2030 Vision and strategic development initiatives. A descriptive correlational study was conducted, involving 269 managers, and field study data were analyzed using descriptive correlational analysis. The conclusions and findings of the study contribute to understanding and shaping the reality of Ha'il's economic landscape. The study employed a questionnaire to examine Ha'il's economic ecology, strategic development strategy, and competitive edge in light of the 2030 Vision. The findings indicated that Ha'il has made improvements in local supply chains, economic diversity, strong local suppliers, global integration, labor market-aligned education, product diversification, and regional security. However, the study also highlighted areas where Ha'il's economy needs further improvement in order to effectively compete and attract investment. These areas include poor regulation, market management, and IT implementation, which have favored specialists and strategic approaches. The research findings indicated that Ha'il institutions possess strengths that give them a competitive edge. They excel at resource gathering and efficiency improvement, as reported by the respondents. Organizations in Ha'il utilized their strengths to adapt to market demands. The survey results also revealed that Ha'il firms have a clear vision, goals, and well-known staff and consumers. Additionally, the study identified the university's desire for manufacturing excellence. Strategic planning in Ha'il focuses on the external environment and differentiation, prioritizing factors like quality, innovation, and adaptability, which greatly benefit firms. The study highlighted the intimate connection between Ha'il's unique features and the external environment, emphasizing the importance of business ecosyst