Objective To investigate the effect of field angle on the results of in vivo dose validation of electronic portal imaging device(EPID)in patients.Methods Design the mold test and analyze the influence of different mold thicknesses and different frame angles on the 2D γ pass rate.Twenty-three patients who un-derwent radiotherapy in the Department of Radiotherapy of Jinhua Municipal Central Hospital from January to June 2023 were selected as the research object.In vivo dose verification was carried out during treatment to obtain 2D γ pass rate using same-day sector beam CT(FBCT)of planned CT and executive image guided(IG-RT)as reference images,and the influence of field angle on pass rate was analyzed.Results When the frame angle was unchanged,the area of the shooting field was larger than 17 cm×17 cm,and the 2D γ passing rate decreased with the increase of the thickness.The frame angle had no effect on the 2D γ pass rate when the mold thickness was constant.In clinical treatment data,the passage rate of 2D γ near 0°/180° was higher than that near 90°/270°(P＜0.05),and the passage rate near 90°/270° in the FBCT group was higher than that in the IGRT group(P＜0.05).The median passing rate of 3 mm 2D γ was 97.97％in 3％of the 23 patients.The non-IGRT group was 96.81％,the IGRT group was 97.89％,the FBCT group was 98.94％.There was a statistically significant difference in 2D γ passing rate between the non-IGRT group and the IGRT group(Z=-5.083,P＜0.05),and there was a statistically significant difference in 2D γ passing rate between the IGRT group and the FBCT group(Z=-10.657,P＜0.05).Conclusion Clinically,the difference of pass rate in vi-vo dose verification at different rack angles is mainly due to the difference of images within and between ses-sions.Using same-day FBCT as the reference image for in-vivo dose verification can improve the accuracy of pass rate and eliminate the influence of image difference between sessions.

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

OBJECTIVE: To investigate the relationship between physical activity and genetic risk and their combined effects on the risk of developing chronic obstructive pulmonary disease. METHODS: This prospective cohort study included 318,085 biobank participants from the UK. Physical activity was assessed using the short form of the International Physical Activity Questionnaire. The participants were stratified into low-, intermediate-, and high-genetic-risk groups based on their polygenic risk scores. Multivariate Cox regression models and multiplicative interaction analyses were used. RESULTS: During a median follow-up period of 13 years, 9,209 participants were diagnosed with chronic obstructive pulmonary disease. For low genetic risk, compared to low physical activity, the hazard ratios ( HRs) for moderate and high physical activity were 0.853 (95% confidence interval [ CI]: 0.748-0.972) and 0.831 (95% CI: 0.727-0.950), respectively. For intermediate genetic risk, the HRs were 0.829 (95% CI: 0.758-0.905) and 0.835 (95% CI: 0.764-0.914), respectively. For participants with high genetic risk, the HRs were 0.809 (95% CI: 0.746-0.877) and 0.818 (95% CI: 0.754-0.888), respectively. A significant interaction was observed between genetic risk and physical activity. CONCLUSION Moderate or high levels of physical activity were associated with a lower risk of developing chronic obstructive pulmonary disease across all genetic risk groups, highlighting the need to tailor activity interventions for genetically susceptible individuals.
Humans ; Pulmonary Disease, Chronic Obstructive/epidemiology* ; Exercise ; Male ; Female ; Middle Aged ; Prospective Studies ; Aged ; Genetic Predisposition to Disease ; Risk Factors ; United Kingdom/epidemiology* ; Incidence ; Adult

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

OBJECTIVES: Anxiety is a common negative emotion. Under current social circumstances, university young teachers face multiple stressors and are more prone to anxiety, seriously threatening their physical and mental health. This study aims to investigate the impact of job insecurity on anxiety of university young teachers, while exploring the mediating roles of perceived stress and insomnia on this relationship. METHODS: Using convenience sampling, young teachers from a general university in a Chinese province were surveyed online. Scores of the Job Insecurity Scale, Perceived Stress Scale, Athens Insomnia Scale-Short Form, and Generalized Anxiety Disorder Scale were collected. A chain mediation analysis was conducted using the PROCESS macro. RESULTS: A total of 798 subjects were finally included. The detection rate of anxiety among university young teachers was 36.47%. Mediation analysis showed that job insecurity not only had a direct effect on anxiety, but also indirectly affected anxiety via perceived stress (46.42% of the total effect) and insomnia (7.45%), as well as through the chain-mediating path of perceived stress→ insomnia (13.18%; all P<0.05). CONCLUSIONS Job insecurity is a significant predictor of anxiety in young university faculty. Perceived stress and insomnia serve as sequential mediators in this relationship. Targeted interventions addressing job insecurity, stress perception, and sleep disturbances, alongside efforts to improve mental health literacy and the working environment, may help promote the overall well-being of university young teachers.
Humans ; Sleep Initiation and Maintenance Disorders/epidemiology* ; Universities ; Female ; Anxiety/psychology* ; Male ; Stress, Psychological/psychology* ; Adult ; Faculty/psychology* ; Surveys and Questionnaires ; China/epidemiology* ; Occupational Stress ; Job Security

To investigate the molecular mechanisms underlying the mechanosensitive ion channel PI-EZO2 in osteoarthritis(OA),we developed a lentiviral vector for endogenous PIEZO2 overexpression and established a stable PIEZO2-high-expressing immortalized human primary chondrocyte line.By map-ping the open reading frame of the PIEZO2 locus and designing sequence-specific sgRNA,we employed the CRISPR/Cas9 synergistic activation mediator(SAM)system to precisely integrate transcriptional ac-tivation elements into the PIEZO2 promoter region.Lentiviral-mediated targeted genomic integration en-sured endogenous PIEZO2 overexpression,confirmed by mCherry fluorescence tracing coupled with flow cytometric sorting,which revealed membrane-specific localization of PIEZO2 protein(localization effi-ciency:78.49％).Quantitative PCR demonstrated a 17-fold upregulation of PIEZO2 mRNA,while Western blotting validated enhanced membrane-localized protein expression.Strikingly,PIEZO2-overex-pressing chondrocytes exhibited hallmark OA metabolic phenotypes compared to wild-type controls:typeⅡ collagen mRNA expression decreased to 50％of baseline levels,whereas matrix metalloproteinase 13(MMP13)mRNA surged by 20-fold.These alterations recapitulated the pathological matrix metabolic phenotype observed in biomechanical OA models induced by cyclic mechanical stress(10％strain,0.5 Hz,8 h/day for 2 consecutive days).Collectively,we successfully generated a human chondrocyte model with stable PIEZO2 overexpression,which faithfully mirrors mechanotransduction-driven OA progression.This engineered cellular system provides a robust platform for dissecting PIEZO2-mediated mechanosig-naling networks and advancing targeted therapeutic discovery.

Objective To analyze the efficacy and safety of ustekinumab(UST)in patients with moderate-to-severe Crohn's disease(CD),and to identify factors influencing clinical outcomes.Methods Data were retrospectively collected from patients with moderate-to-severe CD treated with UST in the First Affiliated Hospital of Zhejiang Chinese Medical University and Hangzhou Hospital of Traditional Chinese Medicine between November 2020 and May 2023.Patients were categorized into first-line(not treated with biologic agents,n=68)and second-line(treated with biologic agents,n=66)treatment groups based on prior use of biologic agents.Baseline characteristics,including age,sex,smoking status,disease duration,age at diagnosis,lesion site,disease behavior,perianal disease,history of intestinal surgery,and CD-related drug use,were compared between the two groups.Crohn's disease activity indices(CDAI)were recorded at baseline,week 14,and week 52 to assess the clinical efficacy at weeks 14 and 52.Endoscopic evaluations were performed at baseline and week 52 to evaluate endoscopic efficacy at week 52.The 52-week drug persistence rate and safety profile were also analyzed.Influencing factors related to clinical outcomes were evaluated using univariate and multivariate logistic regression.Results A total of 134 patients with moderate-to-severe CD treated with UST were included.At week 14,clinical response and remission rates were 75.4%(101/134)and 33.6%(45/134),respectively,with no significant difference in clinical efficacy between first-line and second-line groups(clinical response rate:77.9%vs.72.7%,P=0.484;clinical remission rate:38.2%vs.28.8%,P=0.247).At week 52,clinical response and remission rates were 79.9%(107/134)and 56.0%(75/134),respectively.The rates of endoscopic response and remission were 70.9%(95/134)and 38.8%(52/134),respectively.There were no significant differences in clinical efficacy(clinical response rate:80.9%vs.78.8%,P=0.763;clinical remission rate:60.3%vs.51.5%,P=0.306)and endoscopic efficacy(endoscopic response rate:76.5%vs.65.2%,P=0.149;endoscopic remission rate:42.6%vs.34.8%,P=0.354)between the two groups.The 52-week drug persistence rate was 85.8%(115/134),and the adverse reaction rate was 4.5%(6/134).Compared with first-line treatment group,biologic-experienced patients had a significantly higher proportion of dose-optimized therapy in second-line treatment group(45.5%vs.22.1%,P=0.004).Multivariate logistic regression showed that the 14-week clinical response was a significant predictor of 52-week clinical remission,while perianal disease and intestinal surgery history were significant factors associated with treatment failure(P<0.05).Conclusions UST demonstrates significant efficacy in improving clinical and endoscopic outcomes for moderate-to-severe CD patients,with a favorable safety profile.Clinical response at 14 weeks is strongly predictive of clinical remission at 52 weeks.Patients with perianal disease or a history of intestinal surgery were at higher risk of treatment failure.

To investigate the molecular mechanisms underlying the mechanosensitive ion channel PI-EZO2 in osteoarthritis(OA),we developed a lentiviral vector for endogenous PIEZO2 overexpression and established a stable PIEZO2-high-expressing immortalized human primary chondrocyte line.By map-ping the open reading frame of the PIEZO2 locus and designing sequence-specific sgRNA,we employed the CRISPR/Cas9 synergistic activation mediator(SAM)system to precisely integrate transcriptional ac-tivation elements into the PIEZO2 promoter region.Lentiviral-mediated targeted genomic integration en-sured endogenous PIEZO2 overexpression,confirmed by mCherry fluorescence tracing coupled with flow cytometric sorting,which revealed membrane-specific localization of PIEZO2 protein(localization effi-ciency:78.49％).Quantitative PCR demonstrated a 17-fold upregulation of PIEZO2 mRNA,while Western blotting validated enhanced membrane-localized protein expression.Strikingly,PIEZO2-overex-pressing chondrocytes exhibited hallmark OA metabolic phenotypes compared to wild-type controls:typeⅡ collagen mRNA expression decreased to 50％of baseline levels,whereas matrix metalloproteinase 13(MMP13)mRNA surged by 20-fold.These alterations recapitulated the pathological matrix metabolic phenotype observed in biomechanical OA models induced by cyclic mechanical stress(10％strain,0.5 Hz,8 h/day for 2 consecutive days).Collectively,we successfully generated a human chondrocyte model with stable PIEZO2 overexpression,which faithfully mirrors mechanotransduction-driven OA progression.This engineered cellular system provides a robust platform for dissecting PIEZO2-mediated mechanosig-naling networks and advancing targeted therapeutic discovery.

Objective:To explore the construction method of a resistant multiple myeloma(MM)patient-derived xenotransplantation(PDX)model.Methods:1.0 × 107 MM patient-derived mononuclear cells(MNCs),2.0 × 106 MM.1S cells and 2.0 × 106 NCI-H929 cells were respectively subcutaneously inoculated into NOD.CB17-Prkdcscid Il2rgtml/Bcgen(B-NDG)mice with a volume of 100 p1 per mouse to establish mouse model.The morphologic,phenotypic,proliferative and genetic characteristics of PDX tumor were studied by hematoxylin-eosin staining,immunohistochemical staining(IHC),cell cycle analysis,flow cytometry and fluorescence in situ hybridization(FISH).The sensitivity of PDX tumor to bortezomib and anlotinib monotherapy or in combination was investigated through cell proliferation,apoptosis and in vitro and in vivo experiments.The effects of anlotinib therapy on tumor blood vessel and cell apoptosis were analyzed by IHC,TUNEL staining and confocal fluorescence microscope.Results:MM PDX model was successfully established by subcutaneously inoculating primary MNCs.The morphologic features of tumor cells from MM PDX model were similar to those of mature plasma cells.MM PDX tumor cells positively expressed CD138 and CD38,which presented 1q21 amplification,deletion of Rb1 and IgH rearrangement,and had a lower proliferative activity than MM cell lines.In vitro,PDX,MM.1S and NCI-H929 cells were treated by bortezomib and anlotinib for 24 hours,respectively.Cell viability assay showed that the IC50 value of bortezomib were 5 716.486,1.025 and 2.775 nmol/L,and IC50 value of anlotinib were 5 5107.337,0.706 and 5.13 μmol/L,respectively.Anlotinib treatment increased the apoptosis of MM.1S cells(P＜0.01),but did not affect PDX tumor cells(P＞0.05).In vivo,there was no significant difference in PDX tumor growth between bortezomib monotherapy group and control group(P＞0.05),while both anlotinib monotherapy and anlotinib combined with bortezomib effectively inhibited PDX tumor growth(both P＜0.05).The vascular perfusion and vascular density of PDX tumor were decreased in anlotinib treatment group(both P＜0.01).The apoptotic cells in anlotinib treatment group were increased compared with those in control group(P＜0.05).Conclusion:Bortezomib-resistant MM PDX model can be successfully established by subcutaneous inoculation of MNCs from MM patients in B-NDG mice.This PDX model,which retains the basic biological characteristics of MM cells,can be used to study the novel therapies.

Human mass balance study is a pivotal research in the field of clinical pharmacology, aiming at elucidating the metabolic and excretion pathways of drugs in humans. Currently, human mass balance studies predominantly employ radiolabeling techniques. Recently, both the U.S. Food and Drug Administration (FDA) and the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) issued related research drafts and guidelines to encourage and guide the pharmaceutical industry to conduct research in compliance with established standards. The selection of radiolabeling sites is crucial for obtaining critical information on drug metabolism. However, in vivo biotransformation may lead to partial disintegration of the molecular structure, thereby resulting in the loss of metabolic product information of the unlabeled moiety. Administering drugs with different radiolabeling sites separately or in combination, or labeling multiple radioactive isotopes within one molecule, can effectively solve this problem. This article reviews relevant technological progress, analyzes radiolabeling strategies, and discusses the application of drugs with multiple radiolabeling sites in human mass balance studies.