Clinical outcomes of treatment-naïve HBeAg-negative patients with chronic hepatitis B virus infection with low serum HBsAg and undetectable HBV DNA.

Serum hepatitis B surface antigen (HBsAg) level < 100 IU/ml and undetectable hepatitis B virus (HBV) DNA have been recently proposed as an alternate endpoint of "partial cure" in chronic hepatitis B (CHB). We investigated clinical outcomes of hepatitis B e antigen (HBeAg)-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA. Treatment-naïve HBeAg-negative CHB patients with undetectable HBV DNA and normal alanine aminotransferase were retrospectively included from three institutions. Patients were classified into the low HBsAg group (<100 IU/ml) and the high HBsAg group (≥100 IU/ml). Liver fibrosis was evaluated by noninvasive tests (NITs). A total of 1218 patients were included and the median age was 41.5 years. Patients with low HBsAg were older (45.0 vs. 40.0 years, P < 0.001) than those in the high HBsAg group, while the NIT parameters were comparable between groups. During a median follow-up of 25.7 months, patients with low HBsAg achieved a higher HBsAg clearance rate (13.0% vs. 0%, P < 0.001) and a lower rate of significant fibrosis development (2.2% vs. 7.0%, P = 0.049) compared to patients with high HBsAg. No patient developed HCC in either group. HBsAg level was negatively associated with HBsAg clearance (HR 0.213, P < 0.001) and patients with HBsAg < 100 IU/ml had a low risk of significant fibrosis development (HR 0.010, P = 0.002). The optimal cutoff value of HBsAg for predicting HBsAg clearance was 1.1 Log10 IU/ml. Treatment-naïve HBeAg-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA had favourable outcomes with a high rate of HBsAg clearance and a low risk of fibrosis progression.

Preoperative assessment of fistula-in-ano using SonoVue enhancement during three-dimensional transperineal ultrasound.

Background: Accurate preoperative evaluation of fistula-in-ano can guide the choice of surgical procedure and may improve healing rates. This prospective study aimed to evaluate the accuracy of conventional 3D transperineal ultrasound (3D-TPUS) compared with SonoVue (SVE)-enhanced 3D-TPUS for the detection and classification of anal fistula. Methods: In this prospective study, 3D-TPUS reconstructions were performed before and after SVE enhancement in 60 patients with fistula-in-ano who intended to undergo surgery at the Department of Anorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University (P. R. China) between January 2021 and October 2021. Accuracies of anal fistula classification, complexity classification, detection of anal fistula branches, and detection of internal opening between 3D-TPUS and SVE 3D-TPUS were compared based on a reference standard-intraoperative findings. Results: This study enrolled 60 patients (mean age, 37.1 ± 11.4 years; mean follow-up, 9 ± 3 months). Intraoperative findings showed that the fistula type was intersphincteric in 23 patients (38.3%), trans-sphincteric in 35 (58.3%; 12 high and 23 low), and suprasphincteric in 2 (3.3%). Moreover, 68 internal openings were found. Compared with the accuracy of 3D-TPUS, that of SVE 3D-TPUS was similar in fistula classification [95.0% (57/60) vs 96.7% (58/60), P = 0.392], but significantly higher in internal opening evaluation [80.9% (55/68) vs 97.1% (66/68), P = 0.001], complexity classification [85.0% (51/60) vs 98.3% (59/60), P = 0.018], and detection of fistula branches [70.4% (19/27) vs 92.6% (25/27), P = 0.031]. Conclusions: SVE 3D-TPUS may be a useful examination for patients with perianal fistulae because of its high accuracy and consistency with intraoperative findings, especially in complex fistula-in-ano and difficult cases.

Association of survival with adjuvant chemotherapy in patients with stage IB gastric cancer: a multicentre, observational, cohort study.

Background: Recurrence following radical resection in patients with stage IB gastric cancer (GC) is not uncommon. However, whether postoperative adjuvant chemotherapy could reduce the risk of recurrence in stage IB GC remains contentious. Methods: We collected data on 2110 consecutive patients with pathologic stage IB (T1N1M0 or T2N0M0) GC who were admitted to 8 hospitals in China from 2009 to 2018. The survival of patients who received adjuvant chemotherapy was compared with that of postoperative observation patients using propensity score matching (PSM). Two survival prediction models were constructed to estimate the predicted net survival gain attributable to adjuvant chemotherapy. Findings: Of the 2110 patients, 1344 received adjuvant chemotherapy and 766 received postoperative observation. Following the 1-to-1 matching, PSM yielded 637 matched pairs. Among matched pairs, adjuvant chemotherapy was not associated with improved survival compared with postoperative observation (OS: hazard ratio [HR], 0.72; 95% CI, 0.52-1.00; DFS: HR, 0.91; 95% CI, 0.64-1.29). Interestingly, in the subgroup analysis, reduced mortality after adjuvant chemotherapy was observed in the subgroups with elevated serum CA19-9 (HR, 0.22; 95% CI, 0.08-0.57; P = 0.001 for multiplicative interaction), positive lymphovascular invasion (HR, 0.32; 95% CI, 0.17-0.62; P < 0.001 for multiplicative interaction), or positive lymph nodes (HR, 0.17; 95% CI, 0.07-0.38; P < 0.001 for multiplicative interaction). The survival prediction models mainly based on variables associated with chemotherapy benefits in the subgroup analysis demonstrated good calibration and discrimination, with relatively high C-indexes. The C-indexes for OS were 0.74 for patients treated with adjuvant chemotherapy and 0.70 for patients treated with postoperative observation. Two nomograms were built from the models that can calculate individualized estimates of expected net survival gain attributable to adjuvant chemotherapy. Interpretation: In this cohort study, pathologic stage IB alone was not associated with survival benefits from adjuvant chemotherapy compared with postoperative observation in patients with early-stage GC. High-risk clinicopathologic features should be considered simultaneously when evaluating patients with stage IB GC for adjuvant chemotherapy. Funding: National Natural Science Foundation of China; the National Key R&D Program of China.

Naringin-induced M2 macrophage polarization facilitates osteogenesis of BMSCs and improves cranial bone defect healing in rat.

Osteoimmunology has uncovered the critical role of the immune microenvironment in the bone healing process, with macrophages playing a central part in generating immune responses via chemokine production. Naringin, a flavanone glycoside extracted from various plants, has been shown to promote osteoblast differentiation, thereby enhancing bone formation and mitigating osteoporosis progression. Current research on the osteogenic mechanism primarily focuses on the direct impact of naringin on mesenchymal stem cells, while its indirect immunoregulatory effects remain elusive. In this study, we investigated the bone defect-enhancing effects of varying naringin concentrations in vivo using a cranial bone defect model in Sprague-Dawley rats. We assessed the osteoimmune modulation capacity of naringin by exposing lipopolysaccharide (LPS)-induced RAW 264.7 macrophages to different doses of naringin. To further elucidate the underlying osteogenic enhancement mechanism, Bone Marrow Stromal Cells (BMSCs) derived from mice were treated with conditioned media from naringin-treated macrophages. Our findings indicated that naringin promotes M2 phenotype polarization in macrophages, as evidenced by the downregulation of pro-inflammatory cytokines Inducible Nitric Oxide Synthase (iNOS), interleukin (IL)-1ß, and Tumor Necrosis Factor (TNF)-α, and the upregulation of anti-inflammatory cytokine Transforming growth factor (TGF)-ß. Transcriptome analysis revealed that differentially expressed genes were significantly enriched in osteoblast differentiation and anti-inflammatory response pathways in naringin-pretreated macrophages, with the cytokines signaling pathway being upregulated. The conditioned media from naringin-treated macrophages stimulated the expression of osteogenic-related genes Alkaline phosphatase (Alp), osteocalcin (Ocn), osteopontin (Opn), and Runt-related transcription factor (Runx) 2, as well as protein expression in BMSCs. In conclusion, naringin alleviates macrophage inflammation by promoting M2 phenotype polarization, which in turn enhances the osteogenic differentiation of BMSCs, contributing to its bone healing effects in vivo. These results suggest that naringin holds significant potential for improving bone defect healing through osteoimmune modulation.

Liver inflammation activity in patients with autoimmune hepatitis with normal alanine aminotransferase and immunoglobulin G levels.

Background and aims: Normal serum transaminases and immunoglobulin G (IgG) levels are surrogate markers for hepatic histologic disease activity in autoimmune hepatitis (AIH). This study aimed to evaluate liver inflammation in patients with AIH with normal serum alanine aminotransferase (ALT) and IgG levels. Methods: Two hundred and five AIH patients who underwent liver biopsy in four medical centers were included. Logistic regression analysis was used to identify risk factors associated with advanced inflammation. Results: One hundred and thirty-one (63.9 %) AIH patients had advanced liver inflammation, and 108 (52.7 %) patients had advanced liver fibrosis. 60.0 % of patients with normal ALT and 51.7 % of patients with normal ALT and IgG had advanced inflammation. However, 76.7 % and 35.0 % of patients with or without advanced fibrosis with normal ALT had advanced inflammation, while the corresponding proportions of advanced inflammation were 78.6 % and 26.7 % in patients with normal ALT and IgG, respectively. Moreover, 81.0 % and 44.8 % of patients with and without cirrhosis with normal ALT had advanced inflammation, while the corresponding proportions were 83.3 % and 29.4 % in patients with normal ALT and IgG, respectively. Red cell distribution width (OR = 1.325, 95%CI 1.045-1.681, P = 0.020) and PT (OR = 1.514, 95%CI 1.138-2.014, P = 0.004) were independent factors associated with advanced inflammation. Conclusions: High proportion of advanced inflammation was found in AIH patients with normal ALT and IgG levels despite without advanced fibrosis. Although using non-invasive methods may contribute to rule out liver fibrosis in AIH patients with normal ALT and IgG levels, liver biopsy is encouraged to assess liver inflammation.

Advances in the relationship between periodontopathogens and respiratory diseases (Review).

Periodontitis is a common chronic inflammatory and destructive disease in the mouth and is considered to be associated with systemic diseases. Accumulating evidence has suggested that periodontitis is a risk factor for pulmonary diseases such as pneumonia, chronic obstructive pulmonary disease (COPD), asthma, coronavirus disease 2019 (COVID­19) and lung cancer. The presence of common periodontal pathogens has been detected in samples from a variety of pulmonary diseases. Periodontal pathogens can be involved in lung diseases by promoting the adhesion and invasion of respiratory pathogens, regulating the apoptosis of respiratory epithelium and inducing overexpression of mucin and disrupting the balance of immune systemin respiratory epithelium cells. Additionally, measures to control plaque and maintain the health of periodontal tissue can decrease the incidence of respiratory adverse events. This evidence suggests a close association between periodontitis and pulmonary diseases. The present study aimed to review the clinical association between periodontitis and pneumonia, COPD, asthma, COVID­19 and lung cancer, and propose a possible mechanism and potential role of periodontal pathogens in linking periodontal disease and lung disease. This could provide a direction for further research on the association between periodontitis and lung disease and provide novel ideas for the clinical diagnosis and treatment management of these two diseases.

Extraction, structure, pharmacological activities and applications of polysaccharides and proteins isolated from snail mucus.

Snail mucus had medical applications for wound healing as early as ancient Greece and the late Han Dynasty (China). A literature search found 165 modern research papers discussing the extraction methods, chemical compositions, pharmacological activities, and applications of snail mucus. Thus, this review summarized the research progress on the extraction, structure, pharmacological activities, and applications of polysaccharides and proteins isolated from snail mucus. The extraction methods of snail mucus include natural secretion and stimulation with blunt force, spray, electricity, un-shelling, ultrasonic-assisted, and ozone-assisted. As a natural product, snail mucus mainly comprises two polysaccharides (glycosaminoglycan, dextran), seven glycoproteins (mucin, lectin), various antibacterial peptides, allantoin, glycolic acid, etc. It has pharmacological activities that encourage cell migration and proliferation, and promote angiogenesis and have antibacterial, anti-oxidative and anticancer properties. The mechanism of snail mucus' chemicals performing antibacterial and wound-healing was proposed. Snail mucus is a promising bioactive product with multiple medical applications and has great potential in the pharmaceutical and healthcare industries. Therefore, this review provides a valuable reference for researching and developing snail mucus.

Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2.

Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2-Gi1 complexes with or without agonists, including the drugs niacin (2.69 Å) and acipimox (3.23 Å), the highly subtype-specific agonist MK-6892 (3.25 Å), and apo form (3.28 Å). Combined with molecular dynamics simulation and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R1113.36, S17945.52, and Y2847.43. Notably, the MK-6892-HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which shed light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.

Noninvasive diagnosis of significant liver inflammation in patients with chronic hepatitis B in the indeterminate phase.

The presence of significant liver inflammation is an important indication for antiviral treatment in patients with chronic hepatitis B (CHB) in the indeterminate phase. We aimed to establish a non-invasive nomogram to predict significant liver inflammation in these patients. A total of 195 CHB patients in the indeterminate phase were randomly split into training and validation sets. The least absolute shrinkage and selection operator and logistic regression were applied to identify risk factors and establish a predictive model. A calibration curve, decision curve analysis (DCA), and receiver operating characteristic (ROC) curve were applied to assess the performance of the nomogram. The median age was 42.0 y and 59.5% of the patients were male. Alkaline phosphatase, γ-glutamyl transpeptidase, and prothrombin time were independent predictors for significant liver inflammation and selected to establish the AGP-nomogram. The calibration plot demonstrated that the predicted results matched the actual values. The DCA showed a high net benefit when the threshold probability was 25-83% in the training set and 31-100% in the validation set. The areas under ROC curves of AGP-nomogram in predicting significant inflammation were significantly higher than ALT in the training set (0.744 vs. 0.642, P = 0.049) and validation set (0.766 vs. 0.660, P = 0.047). The ability of AGP-nomogram in predicting advanced inflammation was also superior to ALT. The AGP-nomogram can accurately identify significant inflammation in CHB patients in the indeterminate phase, and its application may reduce the need for liver biopsy and help identify candidates for antiviral treatment.Abbreviations: AASLD: American Association for the Study of Liver Diseases; ALB: albumin; ALP: alkaline phosphatase; ALT: alanine aminotransferase; APRI: aspartate aminotransferase-to-platelet ratio index; AST: aspartate aminotransferase; AUROC: area under the receiver operating characteristic curve; CHB: chronic hepatitis B; CI: confidence interval; DCA: decision curve analysis; FIB-4: fibrosis index based on the four factors; GLB: globulin; GGT: γ-glutamyl transpeptidase; HBcAb: hepatitis B core antibody; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HIV: human immunodeficiency virus; INR: international-normalized ratio; IQR: interquartile range; LASSO: least absolute shrinkage and selection operator; LB: liver biopsy; LR: Likelihood ratio; NAFLD: non-alcoholic fatty liver disease; NPV: negative predictive value; PLT: platelets; PPV: positive predictive value; PT: prothrombin time; ROC: receiver operating characteristic; TB: total bilirubin; TE: transient elastography; ULN: upper limit of normal.

A novel web-based online nomogram to predict advanced liver fibrosis in patients with autoimmune hepatitis-primary biliary cholangitis overlap syndrome.

Background: Patients with autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome have a worse prognosis compared to AIH or PBC alone and accurately predicting the severity and dynamically monitoring the progression of disease are therefore essential. We aimed to develop a nomogram-based model to predict advanced liver fibrosis in patients with AIH-PBC overlap syndrome. Methods: A total of 121 patients with AIH-PBC overlap syndrome were retrospectively included and randomly assigned to a development set and a validation set. Backward stepwise regression's best model with the lowest AIC was employed to create a nomogram. Diagnose accuracy was evaluated using the area under the receiver operator characteristic curve (AUROC), calibration analysis, and decision curve analysis (DCA) and was compared with aspartate aminotransferase-to-platelet ratio (APRI) and fibrosis index based on four factors-4 (FIB-4) score. Results: The median age of patients was 53.0 years (IQR: 46.0-63.0), and female patients accounted for 95.0 %. Platelets, globulin, total bilirubin, and prothrombin time were associated with advanced fibrosis (≥S3) and used to construct an AIH-PBC overlap syndrome fibrosis (APOSF)-nomogram (available online at https://ndth-zzy.shinyapps.io/APOSF-nomogram/). The AUROCs of APOSF-nomogram were 0.845 (95 % CI: 0.754-0.936) and 0.843 (95 % CI: 0.705-0.982) in development set and validation set respectively, which was significantly better than APRI and FIB-4. Calibration revealed that the estimated risk fits well with biopsy-proven observation. DCA outperformed APRI and FIB4 in terms of net benefit, demonstrating clinical utility. Conclusion: This novel non-invasive web-based online APOSF-nomogram provided a convenient tool for identifying advanced fibrosis in patients with AIH-PBC overlap syndrome. Further prospective, multicenter studies with large sample size are necessary to validate the applicability of APOSF-nomogram.

Computed tomography in measuring electrode insertion angle and depth for cricopharyngeal muscle electromyography.

Background: Electromyography of the cricopharyngeal muscle (CP-EMG) is one of many assessment tools for dysphagia. The key to performing EMG and BTX injections is to precisely locate the cricopharyngeal muscle with an electrode. One of the main difficulties of electrode insertion is the fact that the CP muscle is located deep within the neck. Since a neck computed tomography (CT) can clearly display the CP muscle, thyroid, and blood vessels in the neck, we speculate that a safe concentric needle electrode insertion path to the cricopharyngeal muscle can be simulated with the assistance of the patient's neck CT which clearly marks the angle and depth of concentric needle electrode insertion. The purpose of this study was to explore simulated electrode insertion angles and insertion depths for cricopharyngeal electromyography based on retrospective CT data and present a method of percutaneous localization of the cricopharyngeal muscle based on CT images of the neck. Methods: One hundred and forty-three neck CT scans performed between January 2019 and November 2020 were included in this study. With the assistance of the angle and straight-line tools found in the Advantage Workstation 4.4 (GE, HealthCare), simulated insertion angles and depths from the anterior border of the sternocleidomastoid muscle to the cricopharyngeal muscle were obtained. Results: The 143 CT images originated from participants that included 63 males (44.1%) with an average age of 46.2±13.9 years old. The insertion angle, insertion depth, and neck thickness measured on the CT images were 53.2±10.7˚, 24.2±4.1 mm, and 130.1±17.7 mm, respectively. The insertion angle and depth were significantly greater in males than in females (P<0.05), and the insertion angle increased with the age of participants (P<0.05). A generalized linear model (GLM) showed that insertion angle was positively correlated with neck thickness (ß=0.14; 95% CI: 0.03 to 0.25) and gender (ß=5.08; 95% CI: 1.31 to 8.85), and negatively correlated with age (ß=-5.88; 95% CI: -9.54 to -1.62). Insertion depth was only positively correlated with the neck thickness (ß=0.11; 95% CI: 0.07 to 0.15). Conclusions: This study indicates that age, gender, and neck thickness are influencing factors for insertion angle, while neck thickness is the influencing factor for insertion depth. The simulated concentric needle electrode insertion method based on CT can assist clinical operation to ensure safety and effectiveness of cricopharyngeal electromyography.

Development and Validation of a Nomogram to Predict Significant Liver Inflammation in Patients with Chronic Hepatitis B.

Background: Noninvasive diagnosis of liver inflammation is important for patients with chronic hepatitis B (CHB). This study aimed to develop a nomogram to predict significant liver inflammation for CHB patients. Methods: CHB patients who underwent liver biopsy were retrospectively collected and randomly divided into a development set and a validation set. The least absolute shrinkage and selection operator regression and logistic regression analysis were used to select independent predictors of significant liver inflammation, and a nomogram was developed. The performance of nomogram was assessed by receiver operating characteristic (ROC) curves, calibration curves and decision curve analysis (DCA). Results: A total of 1019 CHB patients with a median age of 39.0 years were included. Alanine aminotransaminase (ALT, P = 0.018), gamma-glutamyl transpeptidase (P = 0.013), prothrombin time (P < 0.001), and HBV DNA level (P = 0.030) were identified as independent predictors of significant liver inflammation in the development set. A model namely AGPD-nomogram was developed based on the above parameters. The area under the ROC curve in predicting significant inflammation was 0.765 (95% CI: 0.727-0.803) and 0.766 (95% CI: 0.711-0.821) in the development and validation sets, which were significantly higher than other indexes. The AGPD-nomogram had a high predictive value in patients with normal ALT. Moreover, the nomogram was proven to be clinically useful by DCA. Conclusion: A visualized AGPD-nomogram which incorporated routine clinical parameters was proposed to facilitate the prediction of significant liver inflammation in CHB patients. This nomogram had high accuracy in the identification of significant liver inflammation and would be a useful tool for the better management of CHB patients, especially for those with normal ALT.

Walnut Protein: A Rising Source of High-Quality Protein and Its Updated Comprehensive Review.

Recently, plant protein as a necessary nutrient source for human beings, a common ingredient of traditional processed food, and an important element of new functional food has gained prominence due to the increasing demand for healthy food. Walnut protein (WP) is obtained from walnut kernels and walnut oil-pressing waste and has better nutritional, functional, and essential amino acids in comparison with other vegetable and grain proteins. WP can be conveniently obtained by various extraction techniques, including alkali-soluble acid precipitation, salting-out, and ultrasonic-assisted extraction, among others. The functional properties of WP can be modified for desired purposes by using some novel methods, including free radical oxidation, enzymatic modification, high hydrostatic pressure, etc. Moreover, walnut peptides play an important biological role both in vitro and in vivo. The main activities of the walnut peptides are antihypertensive, antioxidant, learning improvement, and anticancer, among others. Furthermore, WP could be applied in the development of functional foods or dietary supplements, such as delivery systems and food additives, among others. This review summarizes recent knowledge on the nutritional, functional, and bioactive peptide aspects of WP and possible future products, providing a theoretical reference for the utilization and development of oil crop waste.

Relationship between IgE-mediated allergy and complicated appendicitis in children.

PURPOSE: To investigate the relationship of IgE-mediated allergy and complicated appendicitis (CA) and overall prognosis. METHODS: We retrospectively analyzed a consecutive series of patients with acute appendicitis (AA) who received appendectomy at Beijing Children's Hospital between July 1, 2018 and June 30, 2020. Patients were classified into two groups, with or without IgE-mediated allergies. Logistic regression adjusting for age, duration of symptoms, WBC count, neutrophil count, C-reactive protein (CRP), Appendicolith and presence of allergy was used to evaluate the association between CA and IgE-mediated allergy. RESULTS: In total, 1156 patients were included. 162 (14.0%) of the patients had IgE-mediated allergy while 994 (86.0%) did not. Children with allergies had a decreased chance of developing CA after adjustment for age, duration of symptoms, WBC count, Neutrophil count, CRP, and appendicolith present rate (adjusted OR = 0.582, 0.364-0.929, P = 0.023). There were no significant differences in operative time, length of hospital stay (LOS), readmission, or adhesive intestinal obstruction rate between allergy and non-allergy patients. CONCLUSIONS: IgE-mediated allergy is related to a reduction risk of CA in the pediatric population and may not affect the prognosis of patients received appendectomy.

SMSCs-derived sEV overexpressing miR-433-3p inhibits angiogenesis induced by sEV released from synoviocytes under triggering of ferroptosis.

BACKGROUND: Ferroptosis is characterized by accumulation of lipid peroxides that leads to oxidative stress. In progressive rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) suffered from oxidative stress induced by generation of excess reactive oxygen species (ROS) and survived from elevated lipid oxidation. However the phenomenon of abnormal synovial fibroblasts proliferation under ferroptotic stress remain to be explained and the effects of this event on disease progression of RA need to be investigated. METHODS: FLS from RA patients (RA-FLS) were stimulated with LPS as an inflammatory model in vitro, and simultaneously treated with ferroptosis inducer Erastin/RSL3 or inhibitor ferrostatin-1. Besides, small extracellular vesicles (sEV) from the supernatant of RA-FLS culture under Erastin/RSL3 management were isolated. The degree of ferroptosis in cells were evaluated by Lipid-ROS detection via flowcytometry and ferroptosis marker protein expression determined by western bloting. The expression of core component of ESCRT-III CHMP4A and CHMP5 was determined by western bloting, and knockdown of CHMP4A was further performed to detect the influence of ESCRT-III complex on ferroptosis as well as LPS/Erastin induced sEV (LPS/Erastin-sEV) releasing. Moreover, miR-433-3p level in the isolated sEV was evaluated by RT-qPCR and interaction of miR-433-3p with FOXO1/VEGF axis were evaluated. MiR-433-3p was overexpressed in synovial mesenchymal stem cells (SMSCs) via miR-433-3p mimics transfection. RA-FLS was co-cultured with human dermal microvascular endothelial cells (HDMECs). LPS/Erastin-sEV or sEV derived from miR-433-3p-overexpressing SMSCs (miR-433-3p-SMSCs-sEV) were added to the co-culture system, and supernatants from co-culture without sEV were given to HDMECs. Angiogenic activity of HDMECs were identified by transwell test and endothelial tube formation analysis. Erastin-sEV and miR-433-3p-SMSCs-sEV were also administrated in collagen-induced arthritis (CIA) mouse model respectively, and progression of arthritis were evaluated. RESULTS: Ferroptosis of RA-FLS was triggered by LPS/Erastin and accompanied with increased expression of ESCRT-III core components as well as elevated release of sEV from RA-FLS. HDMECs' migration and tube formation in vitro was significantly induced/suppressed by supernatants from co-culture under management of Erastin-sEV/miR-433-3p-SMSCs-sEV due to varied VEGF expression regulated by miR-433-3p targeting FOXO1. MiR-433-3p-SMSCs-sEV could inhibit the Erastin-sEV promoted VEGF expression and mitigated arthritis severity. CONCLUSION: Erastin-sEV could aggravate synovial angiogenesis and promote arthritis progression. Administration of miR-433-3p-SMSCs-sEV may be a potential novel therapeutic method as significant antagonism to Erastin-sEV for RA treatment.

The effect of light therapy on sleep quality in cancer patients: a systematic review and meta-analysis of randomized controlled trials.

Background: Sleep problem is one of the major issues of cancer patients and may have detrimental effects on the ongoing treatment and recovery of patients. However, the evidence for the effect of light therapy on sleep problems in this population remained scarce. This study aimed to examine the effect of light therapy on self-reported and physiological measures of sleep quality of cancer patients. It also aimed to quantify the magnitude of the effect using a meta-analytical approach. Methods: Six databases were searched for randomized control trials (RCTs). The primary outcome was the sleep quality using the Pittsburgh sleep quality index (PSQI) measurement of self-reported scores, and the secondary outcomes included total sleep time and sleep efficiency measured by actigraphy. Meta-analyses were performed with the random effects model using the RevMan software. The standardized mean difference (SMD) of the PSQI scores and other measures with their 95% confidence intervals (CIs) were used for assessing the treatment effect (CRD42023370947). Results: Nine RCTs were identified and included in the study. Light therapy significantly improved the self-reported sleep quality with a reduction of the pooled PSQI score (SMD = -0.72; 95% CI: -1.24 to -0.21; p = 0.006). Regarding total sleep time (p = 0.72) and sleep efficiency (p = 0.47), no significant effects of light therapy were found. Conclusion: Light therapy could improve self-reported sleep quality in cancer patients. However, due to the heterogeneity and small sample size of the included trials, the results should be interpreted cautiously. Trials with better designs and larger sample sizes are suggested to be conducted for a more definitive conclusion.Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=370947.

Develop and validate a novel online AIHI-nomogram to predict severe liver inflammation in patients with autoimmune hepatitis.

INTRODUCTION AND OBJECTIVES: Assessment of liver inflammation plays a vital role in the management of patients with autoimmune hepatitis (AIH). We aimed to establish and validate a nomogram to predict severe liver inflammation in AIH patients. PATIENTS AND METHODS: AIH patients who underwent liver biopsy were included and randomly divided into a training set and a validation set. Independent predictors of severe liver inflammation were selected by the least absolute shrinkage and selection operator regression from the training set and used to conduct a nomogram. Receiver characteristic curves (ROC), calibration curves, and decision curve analysis (DCA) were adopted to evaluate the performance of nomogram. RESULTS: Of the 213 patients, female patients accounted for 83.1% and the median age was 53.0 years. The albumin, gamma-glutamyl transpeptidase, total bilirubin, red cell distribution width, prothrombin time, and platelets were independent predictors of severe inflammation. An online AIHI-nomogram was established and was available at https://ndth-zzy.shinyapps.io/AIHI-nomogram/. The calibration curve revealed that the AIHI-nomogram had a good agreement with actual observation in the training and validation sets. The area under the ROCs of AIHI-nomogram were 0.795 in the training set and 0.759 in the validation set, showing significantly better performance than alanine aminotransferase and immunoglobulin G in the training and validation sets, as well in AIH patients with normal ALT in the training set. DCA indicated that the AIHI-nomogram was clinically useful. CONCLUSIONS: This novel AIHI-nomogram provided an excellent prediction of severe liver inflammation in AIH patients and could be used for the better management of AIH.

An easy-to-use AIHF-nomogram to predict advanced liver fibrosis in patients with autoimmune hepatitis.

Background: The evaluation of liver fibrosis is essential in the management of patients with autoimmune hepatitis (AIH). We aimed to establish and validate an easy-to-use nomogram to identify AIH patients with advanced liver fibrosis. Methods: AIH patients who underwent liver biopsies were included and randomly divided into a training set and a validation set. The least absolute shrinkage and selection operator (LASSO) regression was used to select independent predictors of advanced liver fibrosis from the training set, which were utilized to establish a nomogram. The performance of the nomogram was evaluated using the receiver characteristic curve (ROC), calibration curve, and decision curve analysis (DCA). Results: The median age of 235 patients with AIH was 54 years old, with 83.0% of them being female. Six independent factors associated with advanced fibrosis, including sex, age, red cell distribution width, platelets, alkaline phosphatase, and prothrombin time, were combined to construct a predictive AIH fibrosis (AIHF)-nomogram. The AIHF-nomogram showed good agreement with real observations in the training and validation sets, according to the calibration curve. The AIHF-nomogram performed significantly better than the fibrosis-4 and aminotransferase-to-platelet ratio scores in the training and validation sets, with an area under the ROCs for predicting advanced fibrosis of 0.804 in the training set and 0.781 in the validation set. DCA indicated that the AIHFI-nomogram was clinically useful. The nomogram will be available at http://ndth-zzy.shinyapps.io/AIHF-nomogram/as a web-based calculator. Conclusions: The novel, easy-to-use web-based AIHF-nomogram model provides an insightful and applicable tool to identify AIH patients with advanced liver fibrosis.

Dietary palmitoleic acid reprograms gut microbiota and improves biological therapy against colitis.

Magnitude and diversity of gut microbiota and metabolic systems are critical in shaping human health and diseases, but it remains largely unclear how complex metabolites may selectively regulate gut microbiota and determine health and diseases. Here, we show that failures or compromised effects of anti-TNF-α therapy in inflammatory bowel diseases (IBD) patients were correlated with intestinal dysbacteriosis with more pro-inflammatory bacteria, extensive unresolved inflammation, failed mucosal repairment, and aberrant lipid metabolism, particularly lower levels of palmitoleic acid (POA). Dietary POA repaired gut mucosal barriers, reduced inflammatory cell infiltrations and expressions of TNF-α and IL-6, and improved efficacy of anti-TNF-α therapy in both acute and chronic IBD mouse models. Ex vivo treatment with POA in cultured inflamed colon tissues derived from Crohn's disease (CD) patients reduced pro-inflammatory signaling/cytokines and conferred appreciable tissue repairment. Mechanistically, POA significantly upregulated the transcriptional signatures of cell division and biosynthetic process of Akkermansia muciniphila, selectively increased the growth and abundance of Akkermansia muciniphila in gut microbiota, and further reprogrammed the composition and structures of gut microbiota. Oral transfer of such POA-reprogrammed, but not control, gut microbiota induced better protection against colitis in anti-TNF-α mAb-treated recipient mice, and co-administration of POA with Akkermansia muciniphila showed significant synergistic protections against colitis in mice. Collectively, this work not only reveals the critical importance of POA as a polyfunctional molecular force to shape the magnitude and diversity of gut microbiota and therefore promote the intestinal homeostasis, but also implicates a new potential therapeutic strategy against intestinal or abenteric inflammatory diseases.