BACKGROUND: This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate. RESULTS: A total of 409 patients, 65.0% ( n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% ( n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 10 9 /L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 10 9 /L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs. CONCLUSIONS A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.
Humans ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Male ; Female ; Retrospective Studies ; Middle Aged ; Lung Neoplasms/metabolism* ; Aged ; B7-H1 Antigen/metabolism* ; Programmed Cell Death 1 Receptor/metabolism* ; Adult ; Aged, 80 and over ; Immune Checkpoint Inhibitors/therapeutic use*

OBJECTIVE To explore whether pachymic acid （Pac） regulates mitochondrial autophagy mediated by the PTEN- induced kinase 1 （PINK1）/Parkin RBR E3 ubiquitin-protein ligase （Parkin） signaling pathway to alleviate myocardial injury in coronary heart disease （CHD） rats. METHODS SD rats were divided into control （Con） group， CHD group， Pac low-dose group （Pac-L group）， Pac high-dose group （Pac-H group）， Pac-H+PINK1/Parkin signaling pathway inhibitor group （Pac-H+3-MA group）， with 10 rats in each group. Except for the Con group， CHD models were established in the remaining groups of rats. After successful modeling， the rats in each group were intraperitoneally injected with the corresponding drugs or normal saline. After continuous intervention for 4 weeks， the left ventricular ejection fraction （LVEF）， left ventricular end-diastolic volume （LVEDV）， left ventricular end-systolic volume （LVESV）， and mean arterial pressure （MAP） of the rats were detected. The levels of creatine kinase isoenzyme （CK-MB）， lactate dehydrogenase （LDH）， cardiac troponin I （cTnI）， and cardiac troponin T （cTnT） in the serum， as well as the levels of tumor necrosis factor-α （TNF-α）， interleukin-10 （IL-10）， IL-1β， reactive oxygen species （ROS）， malondialdehyde （MDA） in the myocardial tissue， and the activities of catalase （CAT） and superoxide dismutase （SOD）， as well as the expression levels of p62， cleaved caspase-3， Parkin， PINK1 proteins and the ratio of microtubule-associated protein 1 light chain 3 Ⅱ （LC3Ⅱ）/LC3Ⅰ ratio were measured. The morphology of myocardial tissue and mitochondrial autophagic vesicles were observed， and the number of mitochondrial autophagic vesicles per unit area and the rate of cardiomyocyte apoptosis were counted. RESULTS Compared with CHD group， LVEF， MAP， IL-10 levels， CAT and SOD activities， p62， Parkin， PINK1 protein expressions， LC3Ⅱ/LC3Ⅰ ratio， the numbers of mitochondrial autophagic vesicles per unit area in the Pac-L and Pac-H E-mail：hzdpft@163.com groups were increased significantly （P＜0.05）； the levels of LVEDV， LVESV， CK-MB， LDH， cTnI， cTnT， TNF-α， IL-1β， ROS and MDA， cell apoptosis rates， and protein expression of cleaved caspase-3 were all decreased significantly （P＜0.05）； and the changes in various indicators were more pronounced in the Pac-H group （P＜0.05）； both groups showed varying degree of improvement in myocardial histopathological morphology. Compared with the Pac-H group， the aforementioned indicators in rats from the Pac-H+3-MA group were all significantly reversed （P＜0.05）. CONCLUSIONS Pac may promote mitochondrial autophagy in cardiomyocytes of CHD rats by activating the PINK1/ Parkin signaling pathway， thereby reducing inflammatory responses and oxidative stress and improving myocardial injury.

In this study, the pharmacodynamic components and potential pharmacological functions of Danzhi Xiaoyao Formula in treating nervous system diseases were investigated by hippocampal component characterization and network pharmacology. After rats were administrated with Danzhi Xiaoyao Formula by gavage, high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(HPLC-Q-TOF-MS/MS) was employed to explore the components in the hippocampus of rats. Fifty-seven components were identified in the hippocampus of rats by comparing the extract of Danzhi Xiaoyao Formula, herbal components in the hippocampus after administration, and blank samples. KEGG and GO analyses predicted 74 core targets including GSK3B, MAPK1, AKT, IL6. These targets were involved in PI3K/Akt, NF-κB, MAPK, JAK/STAT, Wnt, and other signaling pathways. The results indicated that Danzhi Xiaoyao Formula may ameliorate other nervous system diseases enriched in DO, such as neurodegenerative diseases, cerebrovascular diseases, and mental and emotional disorders by mediating target pathways, inhibiting inflammation, reducing neuronal damage, and alleviating hippocampal atrophy. The relevant activities exhibited by this formula in nervous system diseases such as Alzheimer's disease, Parkinson's disease, and diabetic neuropathy have extremely high development value and are worthy of further in-depth research. This study provides a theoretical basis and practical guidance for expanding the application of Danzhi Xiaoyao Formula in the treatment of nervous system diseases.
Drugs, Chinese Herbal/administration & dosage* ; Animals ; Rats ; Hippocampus/metabolism* ; Network Pharmacology ; Chromatography, High Pressure Liquid ; Tandem Mass Spectrometry ; Rats, Sprague-Dawley ; Male ; Nervous System Diseases/genetics* ; Humans ; Signal Transduction/drug effects*

BACKGROUND: Based on the China-VHD database, this study sought to develop and validate a Valvular Heart Disease- specific Age-adjusted Comorbidity Index (VHD-ACI) for predicting mortality risk in patients with VHD. METHODS & RESULTS: The China-VHD study was a nationwide, multi-centre multi-centre cohort study enrolling 13,917 patients with moderate or severe VHD across 46 medical centres in China between April-June 2018. After excluding cases with missing key variables, 11,459 patients were retained for final analysis. The primary endpoint was 2-year all-cause mortality, with 941 deaths (10.0%) observed during follow-up. The VHD-ACI was derived after identifying 13 independent mortality predictors: cardiomyopathy, myocardial infarction, chronic obstructive pulmonary disease, pulmonary artery hypertension, low body weight, anaemia, hypoalbuminaemia, renal insufficiency, moderate/severe hepatic dysfunction, heart failure, cancer, NYHA functional class and age. The index exhibited good discrimination (AUC, 0.79) and calibration (Brier score, 0.062) in the total cohort, outperforming both EuroSCORE II and ACCI (P < 0.001 for comparison). Internal validation through 100 bootstrap iterations yielded a C statistic of 0.694 (95% CI: 0.665-0.723) for 2-year mortality prediction. VHD-ACI scores, as a continuous variable (VHD-ACI score: adjusted HR (95% CI): 1.263 (1.245-1.282), P < 0.001) or categorized using thresholds determined by the Yoden index (VHD-ACI ≥ 9 vs. < 9, adjusted HR (95% CI): 6.216 (5.378-7.184), P < 0.001), were independently associated with mortality. The prognostic performance remained consistent across all VHD subtypes (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid valve disease, mixed aortic/mitral valve disease and multiple VHD), and clinical subgroups stratified by therapeutic strategy, LVEF status (preserved vs. reduced), disease severity and etiology. CONCLUSION The VHD-ACI is a simple 13-comorbidity algorithm for the prediction of mortality in VHD patients and providing a simple and rapid tool for risk stratification.

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

With the rapid development of competitive sports, the incidence of anterior cruciate ligament (ACL) injury is on the rise. Such injuries may shorten athletes′ career and lead to other long-term adverse consequences. Although athletes generally recover well after ACL reconstruction, many still struggle to return to their pre-injury performance levels. Advances in the understanding of ACL anatomy and injury mechanisms, along with the evolution of surgical techniques and rehabilitation methods, have provided more individualized and tailored options for athletes following ACL injuries. However, there is currently no consensus in China regarding surgical and rehabilitation strategies for competitive athletes aiming to return to sports after ACL injuries. To this end, the Sports Medicine Committee of the Chinese Research Hospital Association and the Editorial Board of the Chinese Journal of Trauma jointly formulated the Expert consensus on surgical treatment and rehabilitation for competitive sports athletes returning to sports after anterior cruciate ligament injury ( version 2025), and presented 14 recommendations covering surgical indications, preoperative rehabilitation, surgical timing, surgical strategies and postoperative rehabilitation strategies, aiming to improve the surgical treatment and rehabilitation system for ACL injuries in competitive athletes and facilitate their return to high-level sports performance after injury.

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

Fe/Mn/Gd polymetallic nanooxide(FMGN)were prepared by one-step solvent thermal reaction by using Fe(acac)3,Mn(acac)2 and Gd(acac)3 as reaction precursors.Next,hyaluronic acid(HA)was used to modify FMGN to fabricate tumor-targeting T 1-T 2 dual-mode magnetic resonance imaging(MRI)contrast agent(HA-FMGN)for accurate diagnosis of prostate cancer.The structure and morphology of FMGN were observed by transmission electron microscope(TEM).It was found that FMGN exhibited a uniform nanocluster spherical structure when the feeding ratio of iron acetylacetonate,manganese acetylacetonate,and gadolinium acetylacetonate was 3:2:1.X-ray diffraction(XRD)analysis showed that FMGN had a typical inverse spinel structure of Mn doped Fe 3O 4,with Gd existing in the form of amorphous gadolinium oxide.The longitudinal relaxivity(r 1)and transverse relaxivity(r 2)of FMGN were 13.395 and 428.535 L/(mmol·s),respectively,measured by 0.5 T MRI analyzer,which proved that FMGN had excellent T 1-T 2 dual-mode MRI contrast capability.The cytotoxicity and hemolysis test found that HA-FMGN didn't damage red cells and induce toxicity for normal cells,indicating that HA-FMGN had excellent cell biocompatibility.The internalization efficacy of HA-FMGN was observed by CLSM,and the results showed that HA-FMGN possessed excellent prostate tumor-targeting ability.In vivo MRI experiment showed that HA-FMGN significantly enhanced T 1 and T 2 weighted MRI signal to noise ratio(SNR)of prostate tumor,which promoted the accurate diagnosis of orthotopic prostate cancer.

Objective To explore the relationship between dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI)and clinical pathological features of invasive breast cancer and lymphovascular invasion(LVI).Methods Imaging and clinical pathological data were retrospectively collected from 508 patients with invasive breast cancer who underwent breast DCE-MRI at the First Medical Center of Chinese PLA General Hospital from January 2019 to August 2021.Patients were divided into the LVI-positive(LVI+)group(n=79)and LVI-negative(LVI-)group(n=429)based on postoperative pathological results.Univariate and multivariate logistic regression analyses were used to identify risk factors for LVI.Results Compared with LVI-group,LVI+group had a higher proportion of patients aged<45 years(44.3%vs.27.0%,P=0.002),non-mass-like enhancement(NME)(31.7%vs.17.7%,P=0.004),Ki-67 expression rate(40.0%vs.30.0%,P<0.001),high Ki-67 expression(94.9%vs.78.1%,P=0.001),Luminal B subtype(76.0%vs.60.1%,P=0.008),and positive axillary lymph nodes rate(72.2%vs.31.5%,P<0.001),while the proportion of Luminal A subtype was lower(2.5%vs.21.5%,P<0.001).Univariate and multivariate logistic regression analyses showed that age≥45 years(OR=0.468,95%CI 0.280-0.783,P=0.004)was an independent protective factor for LVI,while NME(OR=1.987,95%CI 1.126-3.444,P=0.016)was an independent risk factor.Compared with Luminal A subtype,patients with Luminal B subtype(OR=10.482,95%CI 3.164-64.923,P=0.001),HER-2 overexpression subtype(OR=11.571,95%CI 2.755-79.341,P=0.003)and triple-negative subtypes(OR=8.433,95%CI 1.985-57.908,P=0.009)had a higher risk of LVI.Conclusions Age≥45 years is an independent protective factor for LVI,while NME is an independent risk factor.Among molecular subtypes,patients with Luminal B,HER-2 overexpression and triple-negative subtypes have a higher risk of LVI compared with the Luminal A subtype.

Objective To compare the effect of different intensity of neuromuscular training(NMT)on muscle strength and knee joint function of patients after anterior cruciate ligament reconstruction(ACLR).Methods From January,2023 to January,2024,60 ACLR patients in Changhai Hospital were selected,and they received the same intensity of NMT from one to eight weeks after surgery.Eight weeks after surgery,they were randomly divided into low intensity group(n=30)and high intensity group(n=30),and then they received different inten-sities of NMT from nine to 16 weeks after surgery,each training session lasted one hour,with three sessions per week,totaly 48 sessions.The Lysholm score,knee flexor and extensor muscle strength and muscle endurance-were compared at eight weeks and 16 weeks after surgery.Results After group training,the Lysholm score significantly increased in both groups(|t|>13.739,P<0.001),and was higher in the high intensity group than in the low intensity group(t=-2.574,P<0.05);in the high intensity group,the relative peak torque and endurance of the extensor and flexor muscles improved at angular velocities of 60°/s,120°/s and 180 °/s(|t|>2.320,P<0.05);in the low intensity group,the flexor peak torque improved at all the three angular velocities(t>2.177,P<0.05),the extensor peak torque improved at angular velocities of 60°/s and 180°/s(|t|>1.715,P<0.05),and the extensor endurance improved at angular velocity of 60°/s(t=-2.293,P<0.05).However,there was no significant difference in the relative peak torque and endurance of the extensor and flexor muscles at all the three angular velocities(P>0.05).Conclusion Both high and low intensity NMT could improve the muscle strength,muscle endurance and knee joint func-tion.Maybe,high intensity is superior to low intensity.Further verification is still needed.