OBJECTIVES:Severe fever with thrombocytopenia syndrome (SFTS) carries high fatality, often complicated by cardiac injury. However, the clinical profile and prognostic significance of tachyarrhythmia in SFTS remain under-investigated. This study aimed to identify risk factors for tachyarrhythmia and evaluate its impact on 30-day mortality. METHODS:We retrospectively reviewed 140 confirmed SFTS patients (2017-2021). Relevant laboratory parameters from the first seven days of onset were evaluated as baseline predictors, and the occurrence of tachyarrhythmia documented at any point during hospitalization was analyzed as the clinical outcome. Multivariate logistic and Cox regression models-force-adjusting for age and viral load-were employed to identify independent risk factors for tachyarrhythmia and predictors of 30-day mortality, respectively. RESULTS:Of 140 patients, 33.5% (47/140) developed clinically relevant cardiac injury, with 57.4% (27/47) of those experiencing tachyarrhythmia. The tachyarrhythmia group showed significantly higher 30-day mortality (48.1% vs 10.0%, P = 0.014). Multivariate analysis identified neutrophil count, platelet count, and potassium as independent risk factors for tachyarrhythmia. Although tachyarrhythmia correlated with poor survival in Kaplan-Meier analysis, only lower platelet count remained an independent prognostic factor for mortality in the Cox model. CONCLUSION:Tachyarrhythmia is a frequent complication in SFTS with cardiac injury and a marker of high mortality risk. Clinical management should emphasize monitoring neutrophils, platelets, and potassium for early risk stratification.

Severe fever with thrombocytopenia syndrome(SFTS),caused by Dabie bandavirus(DBV),triggers aberrant immune activation and cytokine storms,contributing to poor prognosis;however,its immune dysfunction mechanism remains unclear.Current management relies on symptomatic treatment and glucocorticoids,but no standardized treatment guidelines exist.This study investigated the mechanisms of abnormal lymphocyte function in acute-phase SFTS and the effects of glucocorticoid treatment on lymphoid cells using single-cell RNA sequencing(scRNA-seq)and bioinformatics analysis.We enrolled three healthy volunteers and 13 patients with acute SFTS and divided them into four groups.ScRNA-seq was performed on peripheral blood mononuclear cells from all 16 participants,capturing transcripts from the 3' ends of mRNA.Bioinformatics analyses were used to profile patient immunological signatures,characterize subpopulation compositions,infer developmental trajectories,and assess lymphoid cell interactions.We obtained 120 886 lymphoid cells,which were clustered into 23 functionally heterogeneous subsets.Results showed that patients with severe SFTS exhibited stronger inflammatory and adaptive immune responses.Glucocorticoid treatment suppressed inflammation and the interferon response but also inhibited the production of virus-specific antibodies.These findings suggest that appropriate glucocorticoid administration may alleviate the hyperinflammatory state in severe SFTS during the acute phase,although it is not recommended as a conventional treatment because of its potential to suppress antiviral immunity.This study provides insights into SFTS immunopathology and informs the optimized clinical use of glucocorticoids.

Background Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease with high mortality and limited therapeutic options. Poly(rC)-binding protein 2 (PCBP2) is a multifunctional RNA-binding protein involved in post-transcriptional regulation and innate immune modulation. Although PCBP2 has been reported to negatively regulate antiviral signaling in other viral infections, its role in Dabie bandavirus (DBV) infection remains unclear. Methods Single-cell transcriptomic analysis was performed to characterize PCBP2 mRNA expression across immune cell populations in peripheral blood. PCBP2 expression levels were further examined in DBV-infected clinical samples, IFNAR⁻/⁻ mouse models, and THP-1 cells using quantitative RT-PCR, western blotting, and immunohistochemistry. THP-1 cells with plasmid-mediated PCBP2 overexpression or lentivirus-mediated PCBP2 knockdown were established to investigate the functional role of PCBP2. Activation of the RIG-I-like receptor (RLR) signaling pathway was evaluated by assessing key signaling molecules and downstream interferon responses. The impact of PCBP2 on DBV replication was determined by TCID50 assay, viral nucleoprotein (NP) expression, and immunofluorescence analysis. Results PCBP2 expression was significantly downregulated during DBV infection in clinical samples, animal models, and cell cultures, and reduced PCBP2 expression was associated with increased disease severity and unfavorable clinical outcomes. Functional analyses demonstrated that PCBP2 suppressed DBV-induced activation of type I interferon signaling and interferon-stimulated genes, including ISG12a and G1P3. Mechanistically, PCBP2 directly interacted with the mitochondrial antiviral signaling protein MAVS and promoted its K48-linked polyubiquitination, resulting in proteasome-dependent degradation and attenuation of the MAVS-TBK1-IRF3 signaling axis. Consistent with its immunosuppressive role, PCBP2 knockdown significantly reduced DBV replication, whereas PCBP2 overexpression enhanced viral replication in THP-1 cells. Conclusions These findings identify PCBP2 as a critical negative regulator of RLR-mediated antiviral signaling during DBV infection. By facilitating MAVS degradation and suppressing innate immune responses, PCBP2 promotes viral replication, providing new insights into DBV immune evasion mechanisms and highlighting PCBP2 as a potential host-directed therapeutic target for SFTS.

Purpose:Hyperactive immune responses in severe fever with thrombocytopenia syndrome (SFTS) is considered to associated with disease severity, prognosis and complications. This article aims to evaluate the validity of complement C3a, C5a, and sC5b-9 in predicting the severity and clinical outcomes in SFTS. Patients and Methods:Patients diagnosed with SFTS at the First Affiliated Hospital with Nanjing Medical University from March to November 2021 were enrolled in this retrospective analysis. The study evaluated C3a, C5a, and sC5b-9 levels between SFTS patients and healthy controls. The diagnostic and prognostic efficiency of C3a, C5a, and sC5b-9 for SFTS was assessed utilizing receiver operating characteristic (ROC) curve analysis. Correlation analysis was performed to examine the relationships between these complement components and clinical laboratory parameters in SFTS patients. Results:A total of 67 hospitalized SFTS patients were enrolled. SFTS patients exhibited significantly higher concentrations of C3a, C5a, and sC5b-9 compared to healthy controls. Non-survival and severe SFTS patients had notably higher C3a and sC5b-9 levels than survival and mild, respectively. ROC curve analysis revealed that C3a and sC5b-9 demonstrated effective performance for distinguishing severity in SFTS patients, with the area under the curve (AUC) of 0.784 (95% CI: 0.671-0.896, p < 0.001) and 0.703 (95% CI: 0.573-0.832, p = 0.005), respectively. The correlation analysis indicated that C3a and sC5b-9 positively correlated with SFTS RNA, CRP, PCT, ALT, AST, ALP, LDH, CK, HBDH, APPT, TT and D-dimer, while C3a negatively correlated with PLT. Conclusion:This study revealed abnormalities in complement components among patients with SFTS. C3a and sC5b-9 levels show promise as biomarkers for linking with disease severity and prognosis, potentially providing therapeutic targets for the management of SFTS patients and guide future mechanistic research.

BACKGROUND:Sepsis remains a leading cause of mortality in intensive care units (ICU), but optimal energy delivery strategies remain unclear. This post hoc analysis examines the association between early energy delivery and 28-day all-cause mortality in ICU patients with sepsis. METHODS:This post hoc analysis of the multicentre NEED trial (ISRCTN12233792) included ICU patients with sepsis and ≥ 7-day stays. Early energy delivery (first 7 days) was calculated as a percentage of the target 25 kcal/kg ideal body weight. Patients were stratified by mNUTRIC score (<5 vs ≥5). Associations with 28-day mortality were assessed using Cox models and Kaplan-Meier analysis, with subgroup and spline analyses exploring effect modification and nonlinearity. RESULTS:This analysis included 1162 sepsis patients (median age 66.0 years, 66.3 % male), with 183 (15.7 %) patients deceased within 28-day after ICU admission. The optimal energy delivery thresholds were identified as 100 % of the target for low-risk and 60 % for high-risk patients. Cox proportional hazards models further confirmed that in the high-risk group, achieving≥60 % of the target was associated with a lower 28-day mortality risk (hazard ratio = 0.588, 95 % conficence interval: 0.388-0.891), whereas no benefit was observed in low-risk patients. Additionally, no significant interactions were found in subgroup analyses. Restricted cubic spline analysis suggested a downward trend in mortality risk with increasing energy delivery in high-risk patients (P-nonlinear = 0.063). CONCLUSIONS:Early energy delivery ≥60 % of target is linked to lower 28-day mortality in high-risk sepsis patients, with no clear benefit in low-risk groups. These results support risk-based nutritional strategies in sepsis care. TRIALS REGISTRATION:ISRCTN 12233792, registered on November 24, 2017.

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is a newly emerging infectious disease. Given its rapid disease progression and high mortality rate, early warning is crucial in improving the outcomes, However, to date, relevant comprehensive predictors or an effective prediction model are still poorly explored.MethodsA plasma proteomic profile was performed at early stages in patients with SFTS. Functional clustering analysis was used to select the candidate proteins and then validate their expression by ELISA. A cohort consisting of 190 patients with SFTS was used to develop the predictive model for severe illness and subsequently validate it in a new cohort consisting of 93 patients with SFTS.ResultsA significant increase in plasma proteins associated with various functional clusters, such as the proteasomal protein catabolic process, phagocytosis, and humoral immune response, was observed in severe SFTS patients. High levels of four proteins including NID1, HSP90α, PSMA1, and VCAM1 were strongly correlated with multi-organ damage and disease progression. A prediction model was developed at the early stage to accurately predict severe conditions with the area under the curve of 0.931 (95% CI, 0.885, 0.963).ConclusionThe proteomic signatures identified in this study provide insights into the potential pathogenesis of SFTS. The predictive models have substantial clinical implications for the early identification of SFTS patients who may progress to severe conditions.

Background: The concept of cardiovascular-kidney-metabolic syndrome (CKM) was recently proposed by the American Heart Association. Insulin resistance (IR) is closely linked to metabolic disorders, chronic kidney disease, and cardiovascular disease, which are the key components of CKM. As a surrogate IR marker, estimated glucose disposal rate (eGDR) may help identify high-risk patients. However, the specific role of eGDR in CKM progression and outcomes remains undefined. We aimed to evaluate the associations between eGDR and CKM progression, as well as its association with death in patients with CKM. Methods: Data was obtained from the National Health and Nutrition Examination Survey 1999-2018. Adults aged ≥ 20 years with complete data on CKM components and eGDR were included. Study outcomes were CKM progression and death outcomes. Multinomial logistic regression was used to evaluate the association between eGDR and CKM staging. Kaplan-Meier curves and Cox proportional hazard models assessed death outcomes, with restricted cubic splines exploring non-linear relationships. Stratified and sensitivity analyses tested the robustness of results. The predictive performance of eGDR was compared with the Homeostasis Model Assessment of Insulin Resistance and triglyceride-glucose index for death outcomes. Results: 29,290 participants were included (median age: 53.00 years, 51.96% males), with 27,769 classified as having CKM. Higher eGDR was also associated with lower odds of progression to advanced CKM stages. In CKM patients, over a median follow-up of 8.92 years, 4,926 deaths occurred (17.7%), with 1,330 (4.8%) cardiovascular deaths and 3,596 (12.9%) non-cardiovascular deaths. Compared with the lowest eGDR quartile, CKM patients in the highest quartile had lower risk of all-cause death (HR=0.59, 95%CI: 0.52-0.66), cardiovascular death (HR=0.52, 95%CI: 0.41-0.66), and non-cardiovascular death (HR=0.60, 95%CI: 0.53-0.69) (all P<0.001). Non-linear relationships between eGDR and death outcomes were observed (all P for nonlinear<0.001). Subgroup and sensitivity analyses confirmed the robustness of these associations. Additionally, eGDR predicted death in CKM patients better than other IR markers. Conclusions: Our findings support the utility of eGDR as a risk stratification tool in CKM populations. Lower eGDR levels were associated with more advanced CKM stages and higher long-term mortality, suggesting its potential role in identifying high-risk individuals.

BACKGROUND:Severe fever with thrombocytopenia syndrome (SFTS), caused by Dabie bandavirus (DBV) infection, is characterized by early cytokine storm as a primary pathological feature, although the precise mechanisms remain unclear. Low-density neutrophils (LDNs) are elevated in the peripheral blood of patients with autoimmune or infectious diseases and are closely associated with inflammatory damage and disease severity. However, the pathogenic contribution of LDNs to the progression of SFTS is largely unexplored. This study employed single-cell RNA sequencing (scRNA-seq) to profile the transcriptomic characteristics of LDNs during the acute phase of SFTS, aiming to reveal their compositional and functional heterogeneity following DBV infection, explore their role in the cytokine storm, and further understand their impact on disease progression. METHODS:Cells were isolated from 13 acute-phase SFTS patients with varying disease severity and 3 healthy controls using density gradient centrifugation, followed by preparation of single-cell suspensions for 3'-end scRNA-seq. Sequencing data were processed using the Seurat pipeline, including dimensionality reduction, clustering, cell-type annotation, and visualization with Uniform Manifold Approximation and Projection (UMAP). Low-density granulocytes (LDGs) and their subclusters were identified using canonical gene markers. Functional enrichment of differentially expressed genes (DEGs) was analyzed by high-dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA), Gene Ontology (GO), AddModuleScore, single-sample Gene Set Enrichment Analysis (ssGSEA), and immune-related Gene Set Enrichment Analysis (irGSEA), while cellular interactions were explored using CellCall. RESULTS:1. Compositional heterogeneity: The proportion of LDNs in peripheral blood increased in SFTS patients with greater disease severity during the acute phase. 2. Functional heterogeneity: (1) LDN subclusters showed functional diversity but consistently displayed pro-inflammatory or anti-infective properties. (2) With intensification of the systemic inflammatory response, the expression of multiple cytokine genes (e.g., IL6, IL8, TNFA) and gene sets of the inflammatory pathway (e.g., TNFA-SIGNALING-VIA-NFKB, INFLAMMATORY-RESPONSE) were significantly upregulated in LDNs. Concurrently, the expression of gene sets of type I interferon response pathway (e.g., INTERFERON-ALPHA-RESPONSE, INTERFERON-GAMMA-RESPONSE) and genes of interferon-induced antiviral proteins (e.g., EIF2AK2, OAS1, MX1) were also elevated. (3) In severe cases, glucocorticoid therapy downregulated expression of these inflammatory genes, demonstrating anti-inflammatory effects but potentially increasing infection risk. CONCLUSIONS:This study revealed an increased proportion and heightened pro-inflammatory activity of LDNs during the acute phase of SFTS, closely correlating with disease severity. These findings suggest that LDNs may serve as potential early-warning biomarkers for predicting severe progression in patients with SFTS.

Previous observational inquiries have revealed a correlation between depression and infectious maladies. This study seeks to elucidate the causal linkages between depression, specifically Major Depressive Disorder (MDD), and infectious diseases. Nevertheless, the causative nature of the association between MDD and infectious diseases remains elusive. Two-sample Mendelian Randomization (MR) analyses was executed utilizing single nucleotide polymorphisms (SNPs) significantly connected with MDD and infectious diseases as instrumental variables (IVs). A series of sensitivity analyses were subsequently conducted. Genetic variants linked to MDD were employed as instrumental variables sourced from a genome-wide meta-analyses comprising 500,199 individuals. Summary-level data on five infectious diseases, including candidiasis, pneumonia, skin and soft tissue infections (SSTI), upper respiratory tract infections (URTI), and urinary tract infections (UTI), were acquired from the UK Biobank and FinnGen study. Our findings evinced that genetically predicted MDD exhibited a heightened risk of candidiasis (OR = 1.52, 95% CI 1.06-2.17; P = 2.38E-02), pneumonia (OR = 1.14, 95% CI 1.01-1.29; P = 3.16E-02), URTI (OR = 1.23, 95% CI 1.12-1.36; P = 3.71E-05), and UTI (OR = 1.26, 95% CI 1.12-1.42; P = 8.90E-05). Additionally, we identified bidirectional causal relationships between UTI and MDD. The associations between MDD and the risk of URTI and UTI remained consistent in multivariable MR analyses, accounting for genetically predicted smoking and body mass index. In conclusion, this investigation ascertained a causal connection between MDD and the susceptibility to infectious diseases, particularly URTI and UTI.

Epstein-Barr virus (EBV) can be reactivated and proliferated with fatal outcome in immuno-compromised people, but the clinical consequences of EBV infection in patients with severe fever with thrombocytopenia syndrome (SFTS) remain uncertain. In this study, we investigated the infection rate, the influence and the early predictors of EBV infection in SFTS patients. In this retrospective study, SFTS patients who were treated in the First Affiliated Hospital of Nanjing Medical University from May 2011 to August 2021 were enrolled and divided into infected and non-infected groups. We compared the demographic characteristics, clinical manifestations and signs, laboratory tests and prognosis, and explored the risk factors of EBV infection by receiver operating characteristic (ROC) curve and logistic regression. A total of 120 hospitalized SFTS patients with EBV-DNA testing were enrolled in this study. Patients with EBV infection had statistically significant higher mortality rate (32.0

Background:Since 2020, global attention has heightened towards epidemics caused by avian influenza A H5N1 virus of clade 2.3.4.4b in birds and mammals. This study presents the epidemiological history, clinical manifestations, and prognosis of a unique case infected with avian influenza A H5N1 clade 2.3.4.4b, along with the continuation of SARS-CoV-2 viral RNAs, in Eastern China. Methods:We collected and analysed the patient's clinical, epidemiological, and virological data. Both sputum and bronchoalveolar lavage fluid (BALF) samples were subjected to real-time RT-PCR to test for respiratory pathogens of interests, including SARS-CoV-2 and influenza virus. Influenza virus isolation and propagation were performed on embryonated eggs. Serological tests were used to determine the presence of SARS-CoV-2 antibodies. Phylogenetic analysis was constructed to explore viral evolution and origin of A/H5N1 virus. Results:A 53-year-old female farmer with chronic bronchiectasis was hospitalized with severe pneumonia. Real-time RT-PCR revealed the presence of avian influenza A H5N1 and SARS-CoV-2 in BALF and sputum samples. Sequence analyses classified the human isolate as clade 2.3.4.4b of avian influenza A H5N1. The amino acid motif GlnSerGly at residues 226-228 of the haemagglutinin protein indicated avian-like receptor binding preference. Epidemiological investigation established that the patient had exposure to sick or dead poultry 3 days before illness onset, while no cases of human-to-human H5N1 virus transmission were identified in 31 close contacts. Conclusion:We presented that the clade 2.3.4.4b H5N1 avian influenza virus has the potential to cross-infect humans with serious symptoms, especially in individuals already affected by COVID-19. It is indeed crucial to closely monitor the virus's evolution in both avian populations and humans. Continued research and surveillance efforts are vital to monitor any potential changes in the virus, as well as to inform public health policies and interventions.

Background The H5N1 influenza virus is a cause of severe pneumonia. Co-infection of influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to poor prognosis of patients during the COVID-19 epidemic. However, reports on patients co-infected with avian influenza virus and SARS-CoV-2 are scarce. Case presentation A 52-year-old woman presented with a fever, which has persisted for the past eight days, along with worsening shortness of breath and decreased blood pressure. Computed tomography (CT) revealed an air bronchogram, lung consolidation, and bilateral pleural effusion. The subsequent polymerase chain reaction (PCR) of the bronchoalveolar lavage fluid (BALF) revealed positivity for H5N1 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Conclusion The H5N1 influenza virus is a cause of severe pneumonia. The clinical presentation of the patient had a predomination of H5N1 influenza rather than COVID-19. A PCR analysis for the identification of the virus is necessary to reveal the pathogen causing the severe pneumonia. The patient exhibited an excellent prognosis upon the use of the appropriate antiviral medicine.

Background Lung transplantation is the optimal treatment choice, while extracorporeal membrane oxygenation (ECMO) provides cardiopulmonary support during the perioperative period of lung transplantation. Currently, there is no reported research on the ECMO withdrawal and duration of mechanical ventilation in idiopathic pulmonary fibrosis (IPF) patients undergoing lung transplantation. Therefore, this study aims to evaluate the impact of ECMO duration on prolonged mechanical ventilation (MV) time in patients, attempting to explore the relationship between the two. Methods This study included 170 patients with IPF who underwent lung transplantation under ECMO technology. The patients were divided into normal and delayed groups based on the ECMO application time of 72 hours. A multifactor logistic regression analysis was conducted to explore the independent risk factors for prolonged mechanical ventilation time (more than 3 days), and restricted cubic spline was used to investigate the relationship between ECMO application time and MV time. Receiver operating characteristic (ROC) was further utilized to assess the performance of ECMO application time in predicting prolonged mechanical ventilation time for patients. Results The gender and ECMO application time of patients with IPF are independent risk factors for prolonged MV time. In post-lung transplant patients, for each additional hour of ECMO application time, the risk of MV exceeding 3 days increases by 0.15 times. A restrictive cubic spline plot of ECMO application time and MV time shows a nonlinear relationship between the two groups, with an area under the ROC curve of 0.854 (95% CI 0.796–0.913, P < 0.05). Conclusion After lung transplantation, there is a nonlinear relationship between the application time of ECMO and MV time in patients with IPF. The application time of ECMO can predict well the extension of MV in patients during ICU stay. Therefore, clinicians can assess the duration of MV in patients with IPF based on the application time of ECMO, further avoiding complications related to MV.

Previous studies have shown that the obesity paradox exists in cardiovascular disease (CVD), giving patients a survival advantage, but controversy remains as to whether it applies to patients with cardiogenic shock (CS), especially in the elderly. We therefore aimed to determine whether obesity affects 28-day prognosis in elderly patients with CS. We used clinical data from the Medical Information Market in Critical Care IV (MIMIC-IV) database. Critical patients with CS were categorized into two groups based on age; age < 65 years and ≥ 65 years were classified as young adult patients and elderly patients, respectively. Patients were then categorized into two subgroups based on their body mass index (BMI), one with a BMI ≥ 30 kg/m2 and the other with a BMI < 30 kg/m2. The primary outcome was a 28-day prognosis. Secondary outcomes were mechanical ventilation status, length of hospitalization, and length of ICU stay. 1827 patients from the MIMIC-IV ICU database were analyzed, of which 571 patients were < 65 years old and 1256 patients were ≥ 65 years old. According to multifactorial logistic analysis, BMI > 30 kg/m2 was not a 28-day risk factor for death in elderly patients critically ill with CS (Overweight OR 1.28, P = 0.221; Obesity OR 1.15, P = 0.709; Severe obesity OR 1.46, P = 0.521; using normal weight as a reference). In contrast, underweight was a risk factor (OR 2.42, P = 0.039). Kaplan–Meier curves showed that in the older age group, 28-day survival was significantly higher in patients with BMI ≥ 30 kg/m2 compared to those with BMI < 30 kg/m2 [261 (66.75

Severe fever with thrombocytopenia syndrome (SFTS) is a severe emerging infectious disease caused by Dabie bandavirus (DBV). Tectorigenin has been demonstrated to exert anti-inflammatory effect. Here, we aimed to investigate the effects of tectorigenin on DBV-induced cytokine storm. Effects of tectorigenin on cytokines in DBV-infected THP-1 cells and plasma samples of Type I interferon receptor (IFNAR)-/- mice infected with DBV were detected. The changes in body weight and survival time of mice were recorded. The liver, spleen, kidney, and lymph node tissues were collected for hematoxylin-eosin staining. We demonstrated that tectorigenin reduced the expression levels of inflammatory cytokines in both DBV-infected THP-1 cells and plasma samples of IFNAR-/- mice infected with DBV. Tectorigenin attenuated DBV-induced histopathological changes in mice. Mechanistically, tectorigenin attenuated DBV-induced phosphorylation of inhibitor of kappa-B kinase alpha/beta (IKKα/β) of the nuclear factor-κB (NF-κB) signaling pathway, extracellular signal-regulated kinase (ERK) of the mitogen-activated protein kinase (MAPK) signaling pathway and might function by downregulation of Toll-like receptor. The result of this study suggested that tectorigenin exerted anti-inflammatory effects in vivo and in vitro and could serve as a novel potential therapeutic strategy for SFTS.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a common chronic liver disease worldwide. No effective pharmacologic therapies for MASH have been developed; to develop such promising drugs, the underlying mechanisms regulating MASH need to be elucidated. Here, we aimed to determine the role of ovarian tumor domaincontaining protein 5 (OTUD5) in MASH progression and identify a specific mechanism. METHODS: The expression levels of OTUD subfamily under palmitic acid/oleic acid (PAOA) stimulation were screened. OTUD5 expression was assessed in human liver tissues withoutsteatosis, those with simple steatosis, and those with MASH. MASH models were developed in hepatocyte-specific Otud5- knockout mice that were fed high -fat high -cholesterol and highfat high -cholesterol plus high-fructose/sucrose diet for 16 weeks. RESULTS: The expression of OTUD5 was down -regulated in fatty liver and was negatively related to the progression of MASH. Lipid accumulation and inflammation were exacerbated by Otud5 knockdown but attenuated by Otud5 overexpression under PAOA treatment. Hepatocyte-specific Otud5 deletion markedly exacerbated steatosis, inflammation, and fibrosis in the livers of 2 MASH mouse models. We identified voltagedependent anion channel 2 (VDAC2) as an OTUD5-interacting partner; OTUD5 cleaved the K48 -linked polyubiquitin chains from VDAC2, and it inhibited subsequent proteasomal degradation. The anabolic effects of OTUD5 knockdown on PAOAinduced lipid accumulation were effectively reversed by VDAC2 overexpression in primary hepatocytes. Metabolomic results revealed that VDAC2 is required for OTUD5-mediated protection against hepatic steatosis by maintaining mitochondrial function. CONCLUSIONS: OTUD5 may ameliorate MASH progression via VDAC2-maintained mitochondrial homeostasis. Targeting OTUD5 may be a viable MASH -treatment strategy. (Cell Mol Gastroenterol Hepatol 2024;17:399-421; https://doi.org/ 10.1016/j.jcmgh.2023.11.014)

Objectives Invasive pulmonary aspergillosis (IPA) is common in immuno-compromised people, and a high incidence of IPA has been found in patients with severe fever with thrombocytopenia syndrome (SFTS). Our study aimed to determine the independent risk factors for IPA and the relationship between smoking status and the risk of IPA in SFTS patients. Methods A retrospective analysis of SFTS patients in the First Affiliated Hospital of Nanjing Medical University from May 2011 to December 2021 was reviewed. The patients were divided into two groups: IPA and non-IPA groups. We compared demographic characteristics, clinical manifestation, laboratory parameters, treatment, and prognosis, and explored the risk factors of IPA using logistic regression and ROC curve. The dose-dependent effect of smoking on the risk of IPA was further estimated, including the age of smoking initiation, daily smoking amount, smoking duration, and pack-years of smoking. Results In total, 189 individuals were included. Compared with the non-IPA group, the IPA group had higher levels of smoking, drinking, cough, dyspnea, aCCI scores, Dabie bandavirus (DBV) RNA load, ferritin, PCT, IL-6, APTT, LDH, BUN, creatinine, and lower levels of FT4 and TSH. The incidences of MODS, admission to ICU, ventilation, and broad-spectrum antibiotic treatment were significantly higher in the IPA group than in the non-IPA group. Multivariable logistic analysis showed that smoking history, cough, creatinine, admission to ICU, broad-spectrum, and corticosteroid therapies were the independent risk factors for IPA in SFTS patients. We further confirmed that the age of smoking initiation <30 years, smoking at least one pack per day, smoking for at least 40 years, and having at least 40 pack-years of smoking exposure were the independent risk factors for IPA among smokers. Conclusion The prognosis of SFTS patients in the IPA group is worse than that of the non-IPA group. Attention should be paid to SFTS patients with a smoking history, cough, creatinine, admission to ICU, and broad-spectrum and corticosteroid therapies. There is a strong dose-dependent association between smoking and IPA development in SFTS patients. Prophylactic antifungal therapy should be considered for SFTS patients with these risk factors, but further studies are necessary to determine if it is beneficial for the prognosis of these patients.

Objectives: To investigate the changes and mechanism of Siglec-9 on NK cells in peripheral blood of patients with severe fever with thrombocytopenia syndrome (SFTS). Methods: First, we used single-cell RNA sequencing to analyze the frequency of NK cells in Peripheral Blood Mononuclear Cells (PBMCs) of SFTS patients and healthy controls (HCs), as well as the differences in the genes on NK cells. Secondly, we analyzed the expression of Siglec-9 and other receptors on NK cells by flow cytometry. Thirdly, we analyzed the correlation between Siglec-9 on NK cells and DBV viral load in plasma. Results: Compared with HCs, the frequency of NK cells in peripheral blood of SFTS patients was significantly decreased, and the activating receptors on NK cells were reduced. The expression of Siglec-9 on NK cells and the frequency of Siglec-9+NK cells decreased significantly in SFTS patients. The expression of Siglec-9 on CD16+CD56dim NK cells was negatively correlated with DBV viral load. In addition, Siglec-9+NK cells expressed higher levels of activating receptors and exhibited stronger effector functions than Siglec-9-NK cells. Conclusions: The decreased expression of Siglec-9 on NK cells predicts NK cell dysfunction in SFTS patients, suggesting that Siglec-9 may be a potential marker for functional NK cell subsets in SFTS patients.

目的 探讨系统免疫炎症指数(SII)与单核细胞-淋巴细胞计数比(MLR)对接受前列腺切除术的非转移性前列腺癌患者术后生化复发(BCR)的预测价值.方法 选取2016年1月至2019年12月于本院接受前列腺切除术的150例前列腺癌患者为研究对象,回顾性收集其临床病理资料与术前血常规检测结果.基于受试者工作特征(ROC)曲线确定SII和MLR预测患者无生化复发生存率(BFS)的最佳临界值,并以此将患者分为高SII组(＞402.48,71例)和低 SII 组(≤402.48,79 例)以及高 MLR 组(＞0.166,78 例)与低 MLR 组(≤0.166,72 例).采用Kaplan-Meier方法估算并比较两组患者的5年BFS,评估SII、MLR与前列腺癌患者BFS的关系.通过单、多变量Cox回归分析确定影响术后BCR的独立影响因素.结果 SII预测BFS的最佳临界值为402.48,曲线下面积(AUC)为0.694(95％CI:0.601～0.786),灵敏度为72.0％,特异度为 58.0％;MLR 的最佳临界值为 0.166,AUC 值为 0.687(95％CI:0.596～0.778),灵敏度与特异度分别为68.0％和61.0％.高SII组的Gleason评分≥8分的比例高于低SII组,差异有统计学意义(P=0.014);高MLR患者术前前列腺特异性抗原(PSA)≥20 ng/mL和Gleason评分≥8分的比例显著高于低MLR组,差异均有统计学意义(P=0.025、0.032).Kaplan-Meier生存分析结果显示,高SII组的5年BFS低于低SII组,差异有统计学意义(25.5％vs.63.4％,P=0.003).高、低 MLR组患者的5 年 BFS分别为 17.2％与57.2％,差异有统计学意义(x2=11.898,P=0.001).多变量Cox回归模型结果显示,术前PSA≥20 ng/mL、Gleason 评分≥8 分、T3b～T4a 期、SII＞402.48 和 MLR＞0.166 是前列腺癌患者 BFS的独立预测因子.结论 术前高SII(＞402.48)、MLR(＞0.166)是预测前列腺癌患者术后发生BCR的两项廉价、敏感的血液学参数,有助于准确识别高风险个体并早期指导临床治疗.

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was caused by the Dabie bandavirus (DBV), and it has become a global public health threat. Cytokine storm is considered to be an important pathogenesis of critical SFTS. Tripartite motif-containing 3 (TRIM3), as a member of the TRIM protein family, may contribute to the regulation of the immune and inflammatory responses after viral infection. However, whether TRIM3 plays a major role in the pathogenesis of SFTS has not yet been investigated.MethodsTRIM3 mRNA levels were detected in PBMCs between 29 SFTS patients and 29 healthy controls by qRT-PCR. We established the pathogenic IFNAR−/− SFTS mouse model successfully by inoculating subcutaneously with DBV and testing the expression levels of TRIM3 mRNA and protein by qRT-PCR and immunofluorescence in the livers, spleens, lungs, and kidneys. TRIM3OE THP-1 cells and peritoneal macrophages extracted from TRIM3−/− mice were infected with DBV. The effect of TRIM3 on cytokines was detected by qRT-PCR and ELISA. Then we examined Toll-like receptor 3 (TLR3) and protein phosphorylation in the MAPK pathway after DBV infection using Western blot. Flow cytometry was used to verify TLR3 expression on peripheral blood monocytes in SFTS patients. We further explored the interaction between TRIM3 and TLR3 using CO-IP and Western blot.ResultsCompared to healthy controls, TRIM3 mRNA expression in PBMCs is decreased in SFTS patients, especially in severe cases. TRIM3 mRNA and protein were synchronously reduced in the livers, spleens, lungs, and kidney tissues of the IFNAR−/− SFTS mice model. In the DBV-infected cell model, TRIM3 overexpression can inhibit the DBV-induced release of IL-1β, IL-6, and TNF-α, the expression of TLR3, and protein phosphorylation in the MAPK pathway, which plays an anti-inflammatory role, while TRIM3 deficiency exacerbates the pro-inflammatory effects. We further found that TRIM3 can promote TLR3 degradation through K48-linked ubiquitination.ConclusionTRIM3 can inhibit the production of cytokines by regulating the degradation of TLR3 through K48-linked ubiquitination, which can be a therapeutic target for improving the prognosis of SFTS.