During sudden outbreaks of major infectious diseases,traditional vaccine clinical trials often fail to deliver timely and meaningful outcomes.To address this,innovative trial designs are essential to accelerate or restructure the traditional three-phase clinical trial process while maintaining adherence to scientific principles of drug candidate safety and efficacy.This paper presents various innovative vaccine clinical trial designs and concepts,along with critical considerations for their application,to serve as a methodological reference for related research.Adaptive designs provide flexibility by dynamically adjusting trial parameters—such as dose selection,population stratification,and sample size reestimation—based on interim analysis results.Bayesian designs incorporate historical data and prior information,reducing sample size requirements.Master protocol designs enable the evaluation of multiple treatments or target populations within a unified framework,significantly improving efficiency.Additionally,real-world data(RWD),including electronic health records vaccination records and insurance claims,supports the creation of virtual control groups,addressing ethical concerns while enhancing trial feasibility.A hybrid design combining randomized controlled trials(RCTs)with RWD is also proposed to leverage the strengths of both methodologies.These innovative designs optimize the research process,accelerating vaccine development and regulatory approval.By integrating these approaches,robust evidence-based insights can be generated,advancing precision medicine goals and strengthening public health responses to emerging infectious diseases.

Aim To explore the MST1 knockdown at-tenuates the inhibitory effect of salvianolic acid B(Sal B)on pERK anti-renal fibrosis.Methods In vitro experiments stimulated human renal cortical proximal tubular epithelial cells(HK-2)with XMU-XP-1(10μmol·L-1)inhibitor;in vivo experiments induced wild-type(WT)and MST1 systemic knockout mouse(MST1-/-)renal fibrosis models with DEN/CCl4/C2H5OH(DCC)and interfered with Sal B(15 mg·kg-1·d-1,ig)intervention.Renal histopathology was observed by HE and Masson staining;α-SMA and pERK protein expression was detected by Western blot;and pERK protein expression was detected by im-munofluorescence.Results In vitro results showed that Sal B could inhibit pERK protein expression.In vivo results showed that Sal B could improve DCC-in-duced renal tissue pathological injury and inhibit α-SMA and pERK protein expression;MST1-/-aggrava-ted pathological injury and significantly up-regulated α-SMA and pERK protein expression.Conclusion Sal B reduces the stimulatory effect of XMU-MP-1 on HK-2 cells by inhibiting the phosphorylation of ERK protein;Sal B exerts its anti-renal fibrosis effect by inhibiting the phosphorylation of α-SMA protein and ERK pro-tein;and MST1-/-,aggravating the pathological inju-ry of renal tissue,significantly up-regulated the expres-sion of α-SMA and pERK protein,which in turn atten-uated the antirenal fibrosis effect of Sal B.

Aim To explore the MST1 knockdown at-tenuates the inhibitory effect of salvianolic acid B(Sal B)on pERK anti-renal fibrosis.Methods In vitro experiments stimulated human renal cortical proximal tubular epithelial cells(HK-2)with XMU-XP-1(10μmol·L-1)inhibitor;in vivo experiments induced wild-type(WT)and MST1 systemic knockout mouse(MST1-/-)renal fibrosis models with DEN/CCl4/C2H5OH(DCC)and interfered with Sal B(15 mg·kg-1·d-1,ig)intervention.Renal histopathology was observed by HE and Masson staining;α-SMA and pERK protein expression was detected by Western blot;and pERK protein expression was detected by im-munofluorescence.Results In vitro results showed that Sal B could inhibit pERK protein expression.In vivo results showed that Sal B could improve DCC-in-duced renal tissue pathological injury and inhibit α-SMA and pERK protein expression;MST1-/-aggrava-ted pathological injury and significantly up-regulated α-SMA and pERK protein expression.Conclusion Sal B reduces the stimulatory effect of XMU-MP-1 on HK-2 cells by inhibiting the phosphorylation of ERK protein;Sal B exerts its anti-renal fibrosis effect by inhibiting the phosphorylation of α-SMA protein and ERK pro-tein;and MST1-/-,aggravating the pathological inju-ry of renal tissue,significantly up-regulated the expres-sion of α-SMA and pERK protein,which in turn atten-uated the antirenal fibrosis effect of Sal B.

Objective To compare the effects of different doses of budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet in the treatment of cough variant asthma(CVA)and the improvement of airway function and inflammatory factors.Methods Elderly patients with cough variant asthma were randomly divided into group A and group B.Both groups of patients received budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet.Group A was given budesonide and formoterol fumarate powder for inhalation(Ⅱ),2 inhalation per time,twice a day;Group B was given budesonide and formoterol fumarate powder for inhalation,4 inhalation per time,twice a day;budesonide fumatrol inhalation powder mist for continuous treatment for 6 months,and montelukast sodium tablet 10 mg once a day for at least 3 months.The nighttime cough scores of the two groups were compared before treatment and after treatment.The percentage of forced expiratory volume in one second(FEV1)in the predicted value,the maximum mid expiratory flow(MMEF),the fractional exhaled nitric oxide(FeNO),interleukin-5(IL-5)and eosinophils were compared between the two groups.The incidence of adverse drug reactions and the recurrence rate within 1 year were compared between the two groups.Results A total of 45 cases were enrolled in both the group A and the group B.At 9 months after treatment,the nocturnal cough scores of the group A and the group B were(0.93±0.42)and(0.65±0.29)points,respectively;the percentage of FEV1 in the predicted value were(97.75±9.67)％and(100.93±11.06)％,respectively;the MMEF values were(2.81±1.04)and(3.08±1.09)L·s-1,respectively;the FeNO values were(18.94±9.75)and(15.94±7.96)ppb,respectively;the IL-5 levels were(10.88±7.06)and(8.11±5.56)pg·mL-1,respectively.The above indicators in group B showed statistically significant differences compared to group A(all P＜0.05).The total incidence of adverse drug reactions in group A and group B were 8.89％(5 cases/45 cases)and 13.33％(6 cases/45 cases),respectively.The recurrence rates was 15.56％(7 cases/45 cases)and 13.33％(6 cases/45 cases),respectively.There was no statistically significant difference in the above indicators between group B and group A(all P＞0.05).Conclusion For elderly patients with CVA,higher dose of budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet can better improve cough symptoms,reduce the level of airway hyperresponsiveness and inflammatory factors,reduce the recurrence rate,and the patients are well tolerated.

Objective To compare the effects of different doses of budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet in the treatment of cough variant asthma(CVA)and the improvement of airway function and inflammatory factors.Methods Elderly patients with cough variant asthma were randomly divided into group A and group B.Both groups of patients received budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet.Group A was given budesonide and formoterol fumarate powder for inhalation(Ⅱ),2 inhalation per time,twice a day;Group B was given budesonide and formoterol fumarate powder for inhalation,4 inhalation per time,twice a day;budesonide fumatrol inhalation powder mist for continuous treatment for 6 months,and montelukast sodium tablet 10 mg once a day for at least 3 months.The nighttime cough scores of the two groups were compared before treatment and after treatment.The percentage of forced expiratory volume in one second(FEV1)in the predicted value,the maximum mid expiratory flow(MMEF),the fractional exhaled nitric oxide(FeNO),interleukin-5(IL-5)and eosinophils were compared between the two groups.The incidence of adverse drug reactions and the recurrence rate within 1 year were compared between the two groups.Results A total of 45 cases were enrolled in both the group A and the group B.At 9 months after treatment,the nocturnal cough scores of the group A and the group B were(0.93±0.42)and(0.65±0.29)points,respectively;the percentage of FEV1 in the predicted value were(97.75±9.67)％and(100.93±11.06)％,respectively;the MMEF values were(2.81±1.04)and(3.08±1.09)L·s-1,respectively;the FeNO values were(18.94±9.75)and(15.94±7.96)ppb,respectively;the IL-5 levels were(10.88±7.06)and(8.11±5.56)pg·mL-1,respectively.The above indicators in group B showed statistically significant differences compared to group A(all P＜0.05).The total incidence of adverse drug reactions in group A and group B were 8.89％(5 cases/45 cases)and 13.33％(6 cases/45 cases),respectively.The recurrence rates was 15.56％(7 cases/45 cases)and 13.33％(6 cases/45 cases),respectively.There was no statistically significant difference in the above indicators between group B and group A(all P＞0.05).Conclusion For elderly patients with CVA,higher dose of budesonide and formoterol fumarate powder for inhalation combined with montelukast sodium tablet can better improve cough symptoms,reduce the level of airway hyperresponsiveness and inflammatory factors,reduce the recurrence rate,and the patients are well tolerated.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

This article aims to explore the effect and mechanism of Liujunzi Pills on the intestinal microbiota of rats with spleen Qi deficiency syndrome. The raw Rhei Radix et Rhizoma water extract(1 g·mL~(-1)) was used to prepare spleen Qi deficiency rat models. A total of 44 SD male rats were randomly divided into a control group, a model group, Liujunzi Pills groups at high(3.24 g·kg~(-1)), medium(1.62 g·kg~(-1)), low(0.81 g·kg~(-1)) doses, and Shenling Baizhu San(2.50 g·kg~(-1)) group. The drug effect was evaluated by observing the following aspects: spleen index, fecal water content, body weight, and intestinal propulsion index. Gut microbiota analysis and 16S rRNA gene sequencing were conducted on feces. Enzyme-linked immunosorbent assay(ELISA) and UV spectrophotometry were used to detect interleukin-1β(IL-1β) and adenosine triphosphate(ATP) levels in small intestine tissues. Hematoxylin-eosin staining and transmission electron microscopy were employed to observe changes in intestinal pathology and microstructure. The results show that, compared with the control group, fecal moisture content is significantly increased while spleen index, body weight, and intestinal propulsion index are significantly reduced in rats of the model group, indicating the successful establishment of the model. The above symptoms can be improved by both Shenling Baizhu San and Liujunzi Pills. Compared with the control group, in the model group, the gut microbiota abundance is changed with an unbalanced development: the abundance of beneficial bacteria within the Bacteroidetes phylum is reduced, accompanied by a significantly decreased Shannon index, and reduced signal levels of nicotinamide adenine dinucleotide phosphate(NADPH)-related enzymes relevant to mitochondria. However, Liujunzi Pills and Shenling Baizhu San can significantly improve the Bacteroidetes phylum abundance in gut microbiota, microbial diversity, and NADPH activity in the model group. Additionally, compared with the control group, the ATP level is decreased and the IL-1β level is increased in small intestinal tissues of the model group, with shorter small intestinal epithelial villi and decreased mitochondrial number. The above symptoms can be improved by Liujunzi Pills and Shenling Baizhu San. In conclusion, Liujunzi Pills can treat spleen Qi deficiency syndrome by enhancing mitochondrial function to regulate gut microbiota balance and diversity.
Animals ; Gastrointestinal Microbiome/drug effects* ; Drugs, Chinese Herbal/pharmacology* ; Male ; Rats, Sprague-Dawley ; Rats ; Qi ; Spleen/metabolism* ; Splenic Diseases/metabolism* ; Humans ; Interleukin-1beta/genetics* ; Bacteria/drug effects* ; Feces/microbiology* ; Adenosine Triphosphate/metabolism*

OBJECTIVE: To investigate the role of extracellular vesicles (EVs) derived from placental tissue and placental mesenchymal stem cells in supporting the growth and function of adult hematopoietic stem and progenitor cells (HSPCs), so as to optimize their culture system. METHODS: EVs were isolated from mouse placental tissue (PL-EV) and placental mesenchymal stem cells (PL-MSC-EV). These EVs were co-cultured with 3 000 adult bone marrow LKS⁺ (lineage^- c-Kit⁺ Sca-1⁺ ) cells for 72 hours at concentrations of 0, 1, 10, 50, 100, and 200 μg/ml. The proportion and absolute count of LKS⁺ cells after co-culture were analyzed by flow cytometry, while their self-renewal and multi-lineage differentiation potential were evaluated using colony-forming unit (CFU) assays. RESULTS: Compared to the blank control group, the proportion of LKS⁺ cells were significantly increased in PL-EV groups at concentrations ≥10 μg/ml after 72 hours of co-culture. Notably, LKS⁺ cells co-cultured at the concentration of 10 μg/ml exhibited the highest absolute count (899±171) and the highest proportion of LT-HSCs (LKS⁺ CD135^- CD34^-) (0.67%±0.07%). In the PL-MSC-EV co-culture system, the absolute count of LKS⁺ cells peaked at the concentration of 1 μg/ml (1011±99 cells), though the proportion of LT-HSCs was relatively low (0.15%±0.05%). The comparison between these two culture systems revealed that PL-EV at 10 μg/ml and PL-MSC-EV at 1 μg/ml displayed the most pronounced effects on LKS⁺ cell proliferation, but with no significant difference between them. CFU assays showed that, in the PL-EV culture system, the number of LKS⁺ colony formed in 1 and 10 μg/ml groups was not significantly different compared with the blank control group. In contrast, in the PL-MSC-EV system, the highest LKS⁺ colony-forming capacity was observed when co-cultured with 1 μg/ml PL-MSC-EV, while a significant reduction was noted at concentrations above 10 μg/ml. CONCLUSION PL-EV and PL-MSC-EV effectively support the growth and function of HSPCs. And PL-MSC-EV exhibits a superior efficacy in preserving the stemness of LKS⁺ cells, thus suggesting its potential for optimizing culture systems of HSPCs.
Mesenchymal Stem Cells/cytology* ; Extracellular Vesicles ; Placenta/cytology* ; Female ; Animals ; Mice ; Pregnancy ; Hematopoietic Stem Cells/cytology* ; Coculture Techniques ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured

Objective:To investigate the characteristics of hand dysfunction and its associated factors in patients with rheumatoid arthritis (RA).Methods:A cross-sectional study. Patients with RA were recruited from January 2019 to April 2024 at the Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University. Demographic and clinical data were collected, including age, gender, active smoking, disease duration, time of morning stiffness, rheumatoid factor and anti-cyclic citrullinated peptide antibody, disease activity, radiographic indicators, and hand function assessment. Hand function was assessed by grip strength measures and self-reported items related to hand function in the Stanford Health Assessment Questionnaire. Factors related to hand function were analyzed by logistic regression analyses.Results:A total of 1 079 RA patients were recruited [mean age: (53.0±12.6) years]. Overall, 72.6% (783/1 079) patients experienced a decrease in grip strength, 57.2% (617/1 079) patients experienced a decreased grip strength in both hands, with the average grip strength of the left and right hands decreasing by 16.3% and 14.1%, respectively, compared to normal values; 39.9% (430/1 079) patients had self-reported hand dysfunction. There were 185 (17.1%) older RA patients (age ≥65 years). The proportion of older RA patients with decreased grip strength [89.7% (166/185) vs. 69.0% (617/894)] and degree of decrease in grip strength compared to normal values (left hand:-35.3%±30.6% vs. -12.3%±38.6%; right hand:-32.6%±32.3% vs. -10.3%±42.1%) were significantly higher than that in young patients, and the proportion of older patients with self-reported hand dysfunction was also significantly higher [53.0% (98/185) vs. 37.1% (332/894), all P<0.001]. Multivariate logistic regression analysis showed that pain visual analogue scale ( OR=1.375, 95% CI 1.020-1.854) was independently associated with grip strength decrease in older RA patients, while the 28-joint tender joint count ( OR=1.151, 95% CI 1.063-1.246) and provider global assessment of disease activity ( OR=1.381, 95% CI 1.171-1.628) were associated with self-reported hand dysfunction. Conclusions:Hand dysfunction is common in RA patients, especially among older RA patients, which is related to pain, joint tenderness and provider global assessment of disease activity. This result implies the importance of pain management in RA patients.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.