BACKGROUND:Rheumatoid arthritis is influenced by complex genetic and environmental factors.Although observational studies have found some correlation between plasma proteins and rheumatoid arthritis,the susceptibility to confounding and reverse causation makes it difficult to clarify whether these proteins are pathogenic factors of rheumatoid arthritis.OBJECTIVE:To explore the potential of plasma proteins as biomarkers and therapeutic targets in rheumatoid arthritis through Mendelian randomization analysis of plasma proteins in the onset and progression of rheumatoid arthritis.METHODS:A large-scale two-sample Mendelian randomization analysis was conducted to comprehensively assess the causal relationships between 1 553 circulating proteins and rheumatoid arthritis based on the Decode database(developed by Decode Genetics in Iceland,which contains genomic data from the Icelandic population),the MR-Base platform(developed by a team of researchers at the University of Oxford in the United Kingdom,specifically designed to provide genetic and phenotypic data for Mendelian randomization analyses),and the GWAS Catalog platform(developed by the European Institute of Bioinformatics,which provides data for genome wide association studies worldwide).The causal effects were estimated using the Wald ratio and inverse variance weighting methods,with Bonferroni correction applied to control for false positives caused by multiple testing.To ensure the robustness of the results,sensitivity analyses were performed to validate the positive causal relationship between circulating proteins and rheumatoid arthritis,and Bayesian colocalization and phenome scanning were used to exclude confounding effects and horizontal pleiotropy.Additionally,external validation was carried out using new plasma protein datasets to reduce the likelihood of false discoveries.Finally,small-molecule compounds associated with candidate proteins were identified using the Drug Signatures Database(DsigDB),and molecular docking was performed to predict the binding patterns and energies between proteins and compounds,identifying the most stable and likely binding molecules and mechanisms.RESULTS AND CONCLUSION:(1)Sensitivity analyses,including Bayesian colocalization and phenome scanning,identified four plasma proteins with reliable causal relationships with rheumatoid arthritis:FCRL3,IL6R,ICOSLG,and TNFAIP3.Their genetic effects were estimated as follows:FCRL3[odds ratio(OR)=1.12,95％confidence interval(CI):1.07-1.17],IL6R(OR=0.94,95％CI:0.91-0.96),ICOSLG(OR=2.42,95％CI:1.67-3.52),and TNFAIP3(OR=2.19,95％CI:1.88-2.56).Furthermore,molecular docking analysis revealed that the small-molecule compound benzo[a]pyrene exhibited favorable binding with these candidate proteins,suggesting its potential as a therapeutic agent for rheumatoid arthritis.(2)This study provides a comprehensive analysis of the genetic causal relationships of FCRL3,IL6R,ICOSLG,and TNFAIP3 in rheumatoid arthritis.These proteins not only serve as potential molecular biomarkers for rheumatoid arthritis risk screening and disease prevention,but also offer key candidate targets for further understanding the pathogenic mechanisms of rheumatoid arthritis and developing targeted therapies.Although the study is based on European populations,its findings offer important insights for biomedical research in China.By incorporating Mendelian randomization methods to analyze genetic causality,future research on rheumatoid arthritis in the Chinese population could provide more accurate causal inferences,offering theoretical support for localized risk assessment and treatment strategies.

ObjectiveTo establish a mouse model of rheumatoid arthritis with interstitial lung disease （RA-ILD） in DBA/1 mice using Porphyromonas gingivalis （Pg） infection combined with collagen-induced arthritis （CIA）， and to comprehensively evaluate pathological characteristics in joints， lungs， and serum. MethodsForty DBA/1 mice were randomly divided into four groups， i.e.， Control， Pg infection （Pg）， CIA， and Pg infection combined with CIA （Pg+CIA）， with 10 mice in each group. Arthritis clinical symptoms were evaluated by recording arthritis incidence and clinical scores. Micro-CT scanning was used to assess knee joint pathology. Histopathological changes and collagen deposition in knee joints and lung tissues were analyzed using hematoxylin-eosin （HE） and Masson staining. Immunohistochemistry was performed to detect protein expression of α-smooth muscle actin （α-SMA）， typeⅠ collagen （ColⅠ）， and fibronectin （FN） in lung tissues. Real-time quantitative polymerase chain reaction（Real-time PCR）was used to measure mRNA expression levels of α-SMA， ColⅠ， FN， tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and IL-1β in lung tissues. Enzyme-linked immunosorbent assay （ELISA） was used to detect serum levels of Pg， cyclic citrullinated peptide （CCP）， and immunoglobulin G （IgG）. ResultsJoint lesions： The CIA and Pg+CIA groups showed 100% arthritis incidence， with evident joint redness， swelling， and deformity. The number of affected limbs was 27 and 28， and clinical scores were 68 and 70， respectively. No obvious clinical symptoms were observed in the Pg group. Histopathological and imaging analyses showed severe joint lesions in the CIA and Pg+CIA groups， with significantly increased histopathological scores， bone mineral density， bone volume fraction， trabecular thickness， and trabecular number compared to the Control group （P<0.01）. No obvious joint pathology was observed in the Pg group. Lung lesions： The Pg+CIA group exhibited marked alveolar inflammation， interstitial inflammatory cell infiltration， and alveolar wall thickening， with pronounced blue staining of collagen fibers. Histopathological scores and collagen area ratios were significantly higher than those of the Control， Pg， and CIA groups （P<0.05）. Lung protein and mRNA expression levels of α-SMA， ColⅠ， and FN were markedly increased， and mRNA levels of IL-6， TNF-α， and IL-1β were significantly elevated compared to the Control group （P<0.05）. Serology： The Pg+CIA group showed significantly higher levels of CCP， Pg， and IgG compared with the Control， Pg， and CIA groups （P<0.05）. ConclusionDBA/1 mice subjected to Pg infection combined with CIA exhibited pronounced symptoms and pathological features of RA-ILD， along with elevated serum anti-CCP antibody levels. This model represents a novel RA-ILD mouse model， providing a valuable experimental tool for investigating RA-ILD pathogenesis and developing new therapeutics， and serves as a basis for establishing anti-cyclic citrullinated peptide antibody （ACPA）-positive RA-ILD animal models.

BACKGROUND:Rheumatoid arthritis is influenced by complex genetic and environmental factors.Although observational studies have found some correlation between plasma proteins and rheumatoid arthritis,the susceptibility to confounding and reverse causation makes it difficult to clarify whether these proteins are pathogenic factors of rheumatoid arthritis.OBJECTIVE:To explore the potential of plasma proteins as biomarkers and therapeutic targets in rheumatoid arthritis through Mendelian randomization analysis of plasma proteins in the onset and progression of rheumatoid arthritis.METHODS:A large-scale two-sample Mendelian randomization analysis was conducted to comprehensively assess the causal relationships between 1 553 circulating proteins and rheumatoid arthritis based on the Decode database(developed by Decode Genetics in Iceland,which contains genomic data from the Icelandic population),the MR-Base platform(developed by a team of researchers at the University of Oxford in the United Kingdom,specifically designed to provide genetic and phenotypic data for Mendelian randomization analyses),and the GWAS Catalog platform(developed by the European Institute of Bioinformatics,which provides data for genome wide association studies worldwide).The causal effects were estimated using the Wald ratio and inverse variance weighting methods,with Bonferroni correction applied to control for false positives caused by multiple testing.To ensure the robustness of the results,sensitivity analyses were performed to validate the positive causal relationship between circulating proteins and rheumatoid arthritis,and Bayesian colocalization and phenome scanning were used to exclude confounding effects and horizontal pleiotropy.Additionally,external validation was carried out using new plasma protein datasets to reduce the likelihood of false discoveries.Finally,small-molecule compounds associated with candidate proteins were identified using the Drug Signatures Database(DsigDB),and molecular docking was performed to predict the binding patterns and energies between proteins and compounds,identifying the most stable and likely binding molecules and mechanisms.RESULTS AND CONCLUSION:(1)Sensitivity analyses,including Bayesian colocalization and phenome scanning,identified four plasma proteins with reliable causal relationships with rheumatoid arthritis:FCRL3,IL6R,ICOSLG,and TNFAIP3.Their genetic effects were estimated as follows:FCRL3[odds ratio(OR)=1.12,95％confidence interval(CI):1.07-1.17],IL6R(OR=0.94,95％CI:0.91-0.96),ICOSLG(OR=2.42,95％CI:1.67-3.52),and TNFAIP3(OR=2.19,95％CI:1.88-2.56).Furthermore,molecular docking analysis revealed that the small-molecule compound benzo[a]pyrene exhibited favorable binding with these candidate proteins,suggesting its potential as a therapeutic agent for rheumatoid arthritis.(2)This study provides a comprehensive analysis of the genetic causal relationships of FCRL3,IL6R,ICOSLG,and TNFAIP3 in rheumatoid arthritis.These proteins not only serve as potential molecular biomarkers for rheumatoid arthritis risk screening and disease prevention,but also offer key candidate targets for further understanding the pathogenic mechanisms of rheumatoid arthritis and developing targeted therapies.Although the study is based on European populations,its findings offer important insights for biomedical research in China.By incorporating Mendelian randomization methods to analyze genetic causality,future research on rheumatoid arthritis in the Chinese population could provide more accurate causal inferences,offering theoretical support for localized risk assessment and treatment strategies.

Purpose: Approximately 50%-74% of patients with metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients. Materials and Methods: In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400 mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cutoff date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% confidence interval [CI], 8.3 to 18.5). With all patients evaluated, an ORR of 38.9% (95% CI, 23.1 to 56.5) and a DCR of 83.3% (95% CI, 67.2 to 93.6) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs. Conclusion Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.

Purpose: Approximately 50%-74% of patients with metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients. Materials and Methods: In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400 mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cutoff date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% confidence interval [CI], 8.3 to 18.5). With all patients evaluated, an ORR of 38.9% (95% CI, 23.1 to 56.5) and a DCR of 83.3% (95% CI, 67.2 to 93.6) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs. Conclusion Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.

Objective:To analyze the epidemiological characteristics of the population receiving assisted reproductive technology (ART) therapy and the health status of their offspring in Shanghai from 2011 to 2020.Methods:Based on the birth cohort of the entire population in Shanghai, the proportion and trend changes of ART offspring in the birth cohort were analyzed. The characteristics of ART and naturally conceived populations, including household registration, education level, maternal age, and reproductive history, were examined. Additionally, the health status between ART offspring and naturally conceived offspring were compared.Results:From 2011 to 2020, a total of 70 729 ART offspring were born in Shanghai, accounting for 3.69% of the total births. In 2020, this proportion reached 7.79%. The ART conception rate for primiparous women was higher than that for multiparous women, with both showing upward trends and reaching 9.87% and 2.36%, respectively, in 2020. The ART conception rate was higher in women with higher education levels and local household registration than in those with lower education levels and non-local household registration. The incidence rates of preterm birth and low birth weight in ART singleton offspring were 7.76% and 4.82%, respectively, higher than the 4.69% and 2.87% in naturally conceived offspring, but no increasing trend was observed in naturally conceived offspring. Among twin and multiple newborns, the incidence rates of preterm birth and low birth weight were 56.98% and 46.82% for ART, lower than the 58.51% and 51.32% for natural conception.Conclusions:The difference in social and demographic characteristics was obvious in population receiving ART, suggesting that the differed demand of some people for ART therapy, and it is necessary to strengthen the construction of public health services and further expand the coverage and accessibility of ART services. With technological advancements, the rates of preterm birth and low birth weight remain relatively stable, and even decrease in twin and multiple newborns.

Background: Rheumatoid arthritis (RA) is a systemic inflammatory disease primarily affecting the joints of the limbs. As the disease progresses, it can involve multiple organ systems. Interstitial lung disease (ILD) is the most common pulmonary manifestation of RA. Reported animal models of RA-ILD include adjuvant-induced arthritis (AA), collagen-induced arthritis (CIA), and transgenic mouse arthritis. However, the establishment criteria and evaluation methods for these models lack uniform standards, and they fail to fully replicate the clinicopathological characteristics of RA-ILD. This limitation significantly hinders research into the pathogenesis and development of therapeutic drugs for RA-ILD. Objective: The aim of the study was to review literature in China and abroad on RA-ILD animal models, analyze current research progress, identify existing issues, and propose research recommendations. Methods: Literature searches were conducted using the English keywords “rheumatoid arthritis, interstitial lung disease, model” and the Chinese keywords “(rheumatoid arthritis), (interstitial lung disease), (model)” or “(rheumatoid arthritis), (lung interstitial lesions), (model).” The search was performed in PubMed, Web of Science, CNKI, Wanfang Data, and VIP (China Science and Technology Journal Database) for articles published before November 2024. A total of 41 articles were included. Results and conclusions: The CIA model and the CIA model combined with bleomycin are commonly used due to their similarities to the histopathology and disease manifestations of human RA-ILD. Additionally, these models have appropriate cost and modeling duration, along with a high success rate, making them preferable choices. Transgenic animal models exhibit pathological features similar to the nonspecific interstitial pneumonia subtype of human RA-ILD and are useful for studying the genetic effects on RA-ILD. However, they have drawbacks such as high economic costs, long modeling durations, and a low success rate in some cases. The AA model is easy to establish, requires a short modeling period, and has low experimental costs. However, it lacks the chronic pathological development characteristic of human RA and exhibits a degree of self-limitation in lesion progression. Among other models, the comprehensive HLA-DQ8 transgenic mouse model can be used to study the combined effects of genetic and environmental factors on RA-ILD. The collagen autoantibody-induced arthritis model combined with bleomycin has a short modeling period, but it does not align well with the disease course of RA-ILD. These established animal models provide valuable insights into the pathogenesis of RA-ILD, the identification of novel biomarkers, and the development of new therapeutic approaches. Future research should focus on identifying an animal model that better replicates the physiological and pathological changes of clinical RA-ILD while being more convenient, cost-effective, and comprehensive in reflecting disease progression.

Objective:To compare the effect of transcranial magnetic stimulation (rTMS) of the contralesional hemisphere at different frequencies on the recovery of upper limb motor function after a moderate-to-severe ischemic stroke.Methods:The inter-hemisphere compensation model was applied along with electroencephalogram (EEG) power spectrum density measurements. Thirty stroke survivors were randomly assigned to a sham stimulation group ( n=9), a high-frequency stimulation group ( n=11) or a low-frequency stimulation group ( n=10). In addition to physical and pharmacological therapy, the low-frequency and high-frequency groups received 1Hz or 5Hz rTMS, while the sham group received sham stimulation. The rTMS was delivered over the contralesional (unaffected) hemisphere once daily for 20 minutes over 15 consecutive days. Before, as well as 7 and 15 days after the treatment, all of the subjects′ motor functioning was assessed using the Fugl-Meyer Assessment for the upper extremity (FMA-UE) and their ability in the activities of daily living was assessed using the modified Barthel Index (MBI). Resting-state EEGs with the eyes closed were also recorded, and absolute alpha power across the whole brain was calculated. Changes from baseline FMA-UE and MBI scores and absolute alpha power were analyzed using one-way and repeated-measures analysis of variance. Results:After the treatment, significant within-group improvements from baseline were observed in the FMA-UE scores, MBIs and absolute alpha power, except for absolute alpha power in the low-frequency and sham groups. The repeated-measures analysis of variance revealed significant time × group interactions for FMA-UE ( F=9.926, P≤0.001), MBI ( F=8.789, P≤0.001) and absolute alpha power ( F=4.511, P≤0.05). So the treatment effects varied among the groups. Post hoc Bonferroni-corrected comparisons showed that the high-frequency group exhibited significantly greater improvements from baseline in terms of all three indicators compared with the other two groups. Conclusions:High-frequency (5Hz) rTMS applied to the contralesional hemisphere produced greater improvement than low-frequency (1Hz) stimulation in the upper limb motor function of patients with moderate-to-severe stroke. These findings support the use of the interhemispheric compensation model to guide rTMS therapy, particularly for patients with FMA-UE scores below 43.

Objective:To analyze the epidemiological characteristics of the population receiving assisted reproductive technology (ART) therapy and the health status of their offspring in Shanghai from 2011 to 2020.Methods:Based on the birth cohort of the entire population in Shanghai, the proportion and trend changes of ART offspring in the birth cohort were analyzed. The characteristics of ART and naturally conceived populations, including household registration, education level, maternal age, and reproductive history, were examined. Additionally, the health status between ART offspring and naturally conceived offspring were compared.Results:From 2011 to 2020, a total of 70 729 ART offspring were born in Shanghai, accounting for 3.69% of the total births. In 2020, this proportion reached 7.79%. The ART conception rate for primiparous women was higher than that for multiparous women, with both showing upward trends and reaching 9.87% and 2.36%, respectively, in 2020. The ART conception rate was higher in women with higher education levels and local household registration than in those with lower education levels and non-local household registration. The incidence rates of preterm birth and low birth weight in ART singleton offspring were 7.76% and 4.82%, respectively, higher than the 4.69% and 2.87% in naturally conceived offspring, but no increasing trend was observed in naturally conceived offspring. Among twin and multiple newborns, the incidence rates of preterm birth and low birth weight were 56.98% and 46.82% for ART, lower than the 58.51% and 51.32% for natural conception.Conclusions:The difference in social and demographic characteristics was obvious in population receiving ART, suggesting that the differed demand of some people for ART therapy, and it is necessary to strengthen the construction of public health services and further expand the coverage and accessibility of ART services. With technological advancements, the rates of preterm birth and low birth weight remain relatively stable, and even decrease in twin and multiple newborns.

This study aims to compare the vaccination rates and incidence of adverse reaction rates following administration of two domestically produced human papillomavirus (HPV) vaccines in individuals aged 9-30 years,investigate the impact of distinct manufacturing processes and vaccination schedules on adverse reaction rates. From November 2023 to June 2024, the Immunization Planning Department of Liuzhou Center for Disease Control and Prevention conducted a single-center, randomized, open-label, parallel-group trial using community-based recruitment of eligible participants aged 9 to 30 years. Participants were randomly assigned to receive either of two domestically produced HPV vaccines (Walrinvax or Cecolin). As specified in the vaccine package inserts, subjects were stratified into a two-dose regimen group (aged 9-14 years) and a three-dose regimen group (aged 15-30 years). Vaccination rates were recorded, and adverse reactions within 0-30 days post-vaccination were monitored. The results showed that a total of 400 participants were enrolled. Both the full vaccination rate and the timely completion rate were significantly higher in the two-dose regimen group compared to the three-dose regimen group (Fisher′s exact test, P<0.01; χ2=7.06, P<0.01). A total of 985 doses were administered. The overall adverse reaction rate was 18.78% (185/985), with local and systemic reactions occurring at 8.02% (79/985) and 10.76% (106/985), respectively. The most frequent adverse reactions were injection site pain (4.97%, 49/985) and fever (4.47%, 44/985). No grade 4 or special-interest adverse events were reported.The incidence of adverse reactions for the two domestic HPV vaccines with different production processes (at 0/6 months) was 13.96% (55/394) and 17.46% (69/395) respectively, with no statistically significant difference (χ2=1.83, P>0.05).The adverse reaction rate was significantly lower in the 9-14 years group (9.77%) compared the 15-30 years group (24.91%)(χ 2=35.67, P<0.01). In conclusion, both domestic HPV vaccines demonstrated a favorable safety profile in the 9-30 years age group, with mostly mild adverse reactions. Compared to the three-dose schedule (15-30 years group), the two-dose HPV vaccination schedule (9-14 years group) significantly reduced the incidence of adverse reactions and improved vaccination compliance.