Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

[Objective]To study the formation,change and propagation of Liuwei Dihuang Pill.[Methods]The medical literature and other historical records about Liuwei Dihuang Pill were collected and analyzed,and the formation process,effect change,influencing factors behind the change and application of this prescription and the transmission path were discussed.[Results]Liuwei Dihuang Pill was developed by QIAN Yi,a doctor in Song Dynasty,based on the decoction of Shengqi Pill.It was used to treat kidney deficiency syndrome in children.Because the cooked Rehmannia can nourish Yin and blood,Song and Yuan Dynasties doctors also used the prescription for Yin blood deficiency.In the Ming Dynasty,with the elucidations of the Mingmen theory by the doctors of the warm-tonifying faction,this prescription became the representative formula for tonifying kidney Yin.At the same time,the spreading and population of this prescription was not only in the elite medical group,but also through the medical heritage of GAO Doukui,LYU Liuliang and FANG Yizhi,in the form of medical books,prescription books and health books in the folk.By the Qing Dynasty,the spreading of this formula had shown the characteristics of"secularization",and the literature,literati's notes,novels and other materials can reflect the use of Liuwei Dihuang Pill in the folk.[Conclusion]This paper discusses the origin and development of Liuwei Dihuang Pill,which is of great significance for the study of the rise and formation of the warm-tonifying thought in the Ming and Qing Dynasties.

Objective:To analyze clinical data from patients with chronic spontaneous urticaria (CSU) , and to explore their disease burden.Methods:Clinical data were retrospectively collected from CSU outpatients who visited the Tianjin Medical University General Hospital from November 2021 to October 2023. The primary evaluation indicators included the 7-day urticaria activity score (UAS7) , chronic urticaria quality of life questionnaire (CU-Q2oL) , urticaria control test (UCT) , medication use in the past 6 months, number of outpatient visits and medical expenses, CSU disease duration, and the presence of comorbid atopic diseases and autoimmune diseases. For quantitative data, results were expressed as mean ± standard deviation when normally distributed, or as median (lower quartile, upper quartile) when not normally distributed. Correlation analysis was performed using Pearson correlation coefficients, false discovery rate (FDR) correction, multivariate linear regression, and collinearity diagnostics.Results:A total of 489 CSU patients were included, comprising 303 females (62.0%) and 186 males (38.0%) , with the ages being 39.3 ± 15.0 years and disease duration being 0.75 (0.17, 3) years. The number of outpatient visits was 5.1 ± 1.9, and the medical costs were 396.4 ± 116.0 yuan. Baseline UAS7, UCT, and CU-Q2oL scores were 16.9 ± 11.0 points, 7.0 ± 3.8 points, and 51.9 ± 16.3 points, respectively. Seventy-two patients (14.7%) had a family history of atopic diseases, and 144 patients (29.4%) had comorbid atopic conditions, including atopic dermatitis ( n = 29) , allergic rhinitis ( n = 89) , allergic conjunctivitis ( n = 13) , allergic asthma ( n = 7) , and allergic sinusitis ( n = 6) . Forty-one patients (8.4%) had comorbid autoimmune diseases, including connective tissue diseases ( n = 2) and autoimmune thyroid diseases ( n = 39) . In the past 6 months, 419 patients (85.7%) received first-line or second-line therapies (antihistamines alone or in combination) , while 70 patients (14.3%) received third-line therapies, including omalizumab ( n = 35, 7.1%) , glucocorticoids ( n = 22, 4.5%) , cyclosporine ( n = 7, 1.4%) , and Tripterygium wilfordii preparations ( n = 7, 1.4%) . According to the UAS7 scores, 98 patients (20.0%) were in good control, 153 (31.3%) exhibited mild disease activity, 138 (28.2%) showed moderate activity, and 100 (20.5%) exhibited severe activity; outpatient visits and medical costs increased with disease activity (both P < 0.05) . The CU-Q2oL scores were positively correlated with the UAS7 scores ( r = 0.520, P < 0.001, FDR < 0.001) , and negatively correlated with the UCT scores ( r = -0.597, P < 0.001, FDR < 0.001) . Disease duration was positively associated with the UAS7 scores ( β = 0.223, P = 0.023) . The patients with autoimmune diseases had significantly longer disease duration ( P = 0.049) , but there was no significant difference in the UAS7 score between the patients with and without autoimmune diseases ( P = 0.340) ; there were no significant differences in disease duration or UAS7 scores between patients with and without atopic diseases (both P > 0.05) . Conclusion:Higher disease activity in CSU patients was significantly correlated with worse quality of life, increased outpatient visits, and greater economic burden.

Objective:To investigate the efficacy and safety of omalizumab in the treatment of chronic spontaneous urticaria (CSU) during pregnancy and lactation.Methods:A single-center retrospective study was conducted. From February 2022 to December 2024, 8 pregnant or lactating patients with CSU who received omalizumab treatment were collected from the Departments of Dermatovenereology and Allergy, Tianjin Medical University General Hospital, including 3 pregnant and 5 lactating patients. Clinical data were analyzed, including the patients' ages, disease duration of CSU, timing of omalizumab initiation, dosage and treatment intervals of omalizumab. During the treatment and follow-up, the 7-day urticaria activity score (UAS7) was used to evaluate disease activity of CSU patients, and adverse events were recorded.Results:The ages of the 8 patients ranged from 29 to 40 (33.25 ± 3.81) years, and the disease duration of CSU ( M[ Q1, Q3]) was 2.8 (1.6, 5.2) years. Three patients began omalizumab treatment before conception, with a dose of 300 mg every 3 - 4 weeks; after 3 - 8 sessions of treatment, pregnancy was confirmed, followed finally by successful deliveries. Five patients started omalizumab treatment at doses of 150 - 300 mg/4 weeks during lactation. All the 8 patients received omalizumab injections for 3 - 24 sessions, with an average of 10.38 sessions. Before omalizumab treatment, the UAS7 scores were 6.0 (2.8, 23.5) points; during the treatment, UAS7 scores decreased to 0 - 6 points, and CSU symptoms were completely controlled or well controlled. None of the 3 pregnant patients reported maternal adverse events, small-for-gestational-age or low-birth-weight infant outcomes, premature delivery (< 37 weeks) , spontaneous abortion (< 28 weeks) , congenital malformations in infants, or infant adverse events. One lactating patient developed a mild fever and fatigue 6 hours after the first omalizumab injection, which resolved spontaneously within 48 hours; the other 4 lactating patients did not experience any maternal or infant adverse events. Conclusion:Omalizumab may be an effective and safe treatment option for CSU patients during pregnancy and lactation.

Objective:To analyze the epidemiologic characteristics of avian influenza virus and the molecular characteristics and genetic evolution of H9N2 subtype avian influenza viruses in the live poultry markets in Fujian province in 2021-2023.Methods:Six types of specimens were collected from five cities in Fujian province. The specimens were subjected to nucleic acid detection for influenza A viruses, subtypes H5, H7, and H9 by fluorescence quantitative PCR, and the results were analyzed statistically with χ2 test. Specimens with Ct value less than 31 were screened for targeted amplification and next-generation sequencing of the hemagglutinin (HA) and neuraminidase (NA) genes. Reference sequences were downloaded from the databases, and the characteristics of molecular variation and genetic evolution were analyzed by using bioinformatics softwares. Results:From 2021 to 2023, a total of 1 853 specimens were collected from five cities, with a positive rate of 50.94% for influenza A viruses, including 684 specimens of H9 subtype, 23 specimens of H5 subtype, 1 specimen of H7 subtype, 28 specimens of H5 and H9 subtype, 1 specimen of H7 and H9 subtype, and 207 specimens of unclassified A-type. There were significant differences in the positive detection rates of influenza A viruses in different cities( χ2=461.82, P<0.001). Statistically significant differences in influenza A virus positivity rates across years and quarters( χ2=12.26, P=0.002; χ2=30.12, P<0.001), with higher rates of 56.39% and 55.34% in the first and third quarters, respectively. And the differences in the positive rates of influenza A viruses in different types of specimens were statistically significant( χ2=23.05, P<0.001), with specimens on the cage surface having a positivity rate of 56.09%, which was the highest of all types of specimens. A total of 24 strains of HA and NA genes of H9N2 subtype were fully sequenced. Compared with the sequence of NCBI database, the highest identity of HA gene nucleotide sequences ranged from 97.03% to 99.87%, and the highest identity of NA gene nucleotide sequences ranged from 97.50% to 99.78%.Twenty-three strains with both HA and NA genes belonged to the G57 genotype in the Y280-like evolutionary branch of the Eurasian lineage, and one strain belonged to the Y439-like evolutionary branch of the Eurasian lineage. The cleavage sites of all the strains showed the characteristic of low pathogenicity, and most strains had receptor binding sites characterized by avian-derived and human receptors. Conclusions:The overall positive rate of avian influenza viruses in live poultry markets in Fujian province was relatively high, especially in the first and third quarters, with H9 subtype accounting for the main proportion. Most of H9N2 subtype belonged to the Y280-like G57 genotype with a small number of Y439-like evolutionary branches, suggesting the possibility of genetic recombination and the risk of human infection. Thus, surveillance of avian influenza viruses in the live poultry markets as well as mutation analysis should continue to be strengthened.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Objective:Bidirectional causal associations of 41 cytokines with atopic dermatitis(AD)were explored based on a Mendelian randomization(MR)approach.Methods:Pooled data from genome wide association study(GWAS)of 41 cytokines and AD were utilized for instrumental variable(IV)screening,and single nucleotide polymorphism(SNP)affecting the results of MR analyses was excluded by the MR-PRESSO outlier test as well as by the MR Steiger filtering method.Two-sample bidirectional MR analyses were performed using inverse variance weighting(IVW),MR-Egger regression,and weighted median methods(WM).MR-Egger intercept term test and Cochran's Q test were performed to test the pleiotropy and heterogeneity of IV,and MR results were visu-alized by scatterplots,funnel plots,and leave-one-out plots.Results:Forward MR analysis showed that MIG(IVW:OR=0.89;95%CI:0.81～0.97;P=0.006)reduced the risk of AD development.In contrast,IL-5(IVW:OR=1.17;95%CI:1.01～1.36;P=0.042)and IL-18(MR Egger:OR=1.17;95%CI:1.03～1.33;P=0.030)increased the risk of AD development.Inverse MR analysis showed a potential causal association between AD and increased MIG(IVW:Beta=0.10;95%CI:0.02～0.17;P=0.014).None of the sensitivity analyses indicated pleiotropy and heterogeneity of the included IV.Conclusion:MIG may be an important marker in the progression of AD with a potential bidirectional causal association with risk of morbidity.IL-5 and IL-18 have a potential positive causal association for AD.

Objective:To analyze clinical data from patients with chronic spontaneous urticaria (CSU) , and to explore their disease burden.Methods:Clinical data were retrospectively collected from CSU outpatients who visited the Tianjin Medical University General Hospital from November 2021 to October 2023. The primary evaluation indicators included the 7-day urticaria activity score (UAS7) , chronic urticaria quality of life questionnaire (CU-Q2oL) , urticaria control test (UCT) , medication use in the past 6 months, number of outpatient visits and medical expenses, CSU disease duration, and the presence of comorbid atopic diseases and autoimmune diseases. For quantitative data, results were expressed as mean ± standard deviation when normally distributed, or as median (lower quartile, upper quartile) when not normally distributed. Correlation analysis was performed using Pearson correlation coefficients, false discovery rate (FDR) correction, multivariate linear regression, and collinearity diagnostics.Results:A total of 489 CSU patients were included, comprising 303 females (62.0%) and 186 males (38.0%) , with the ages being 39.3 ± 15.0 years and disease duration being 0.75 (0.17, 3) years. The number of outpatient visits was 5.1 ± 1.9, and the medical costs were 396.4 ± 116.0 yuan. Baseline UAS7, UCT, and CU-Q2oL scores were 16.9 ± 11.0 points, 7.0 ± 3.8 points, and 51.9 ± 16.3 points, respectively. Seventy-two patients (14.7%) had a family history of atopic diseases, and 144 patients (29.4%) had comorbid atopic conditions, including atopic dermatitis ( n = 29) , allergic rhinitis ( n = 89) , allergic conjunctivitis ( n = 13) , allergic asthma ( n = 7) , and allergic sinusitis ( n = 6) . Forty-one patients (8.4%) had comorbid autoimmune diseases, including connective tissue diseases ( n = 2) and autoimmune thyroid diseases ( n = 39) . In the past 6 months, 419 patients (85.7%) received first-line or second-line therapies (antihistamines alone or in combination) , while 70 patients (14.3%) received third-line therapies, including omalizumab ( n = 35, 7.1%) , glucocorticoids ( n = 22, 4.5%) , cyclosporine ( n = 7, 1.4%) , and Tripterygium wilfordii preparations ( n = 7, 1.4%) . According to the UAS7 scores, 98 patients (20.0%) were in good control, 153 (31.3%) exhibited mild disease activity, 138 (28.2%) showed moderate activity, and 100 (20.5%) exhibited severe activity; outpatient visits and medical costs increased with disease activity (both P < 0.05) . The CU-Q2oL scores were positively correlated with the UAS7 scores ( r = 0.520, P < 0.001, FDR < 0.001) , and negatively correlated with the UCT scores ( r = -0.597, P < 0.001, FDR < 0.001) . Disease duration was positively associated with the UAS7 scores ( β = 0.223, P = 0.023) . The patients with autoimmune diseases had significantly longer disease duration ( P = 0.049) , but there was no significant difference in the UAS7 score between the patients with and without autoimmune diseases ( P = 0.340) ; there were no significant differences in disease duration or UAS7 scores between patients with and without atopic diseases (both P > 0.05) . Conclusion:Higher disease activity in CSU patients was significantly correlated with worse quality of life, increased outpatient visits, and greater economic burden.