BACKGROUND: Knee osteoarthritis (OA) is still challenging to prevent or treat. Enhanced endoplasmic reticulum (ER) stress and increased pyroptosis in chondrocytes may be responsible for cartilage degeneration. This study aims to investigate the effect of ER stress on chondrocyte pyroptosis and the upstream regulatory mechanisms, which have rarely been reported. METHODS: The expression of the histone methyltransferase enhancer of zeste homolog 2 (EZH2), microRNA-142-3p (miR-142-3p), and high mobility group box 1 (HMGB1) and the levels of ER stress, pyroptosis, and metabolic markers in normal and OA chondrocytes were investigated by western blotting, quantitative polymerase chain reaction, immunohistochemistry, fluorescence in situ hybridization, fluorescein amidite-tyrosine-valine-alanine-aspartic acid-fluoromethyl ketone (FAM-YVAD-FMK)/Hoechst 33342/propidium iodide (PI) staining, lactate dehydrogenase (LDH) release assays, and cell viability assessments. The effects of EZH2, miR-142-3p, and HMGB1 on ER stress and pyroptosis and the hierarchical regulatory relationship between them were analyzed by chromatin immunoprecipitation, luciferase reporters, gain/loss-of-function assays, and rescue assays in interleukin (IL)-1β-induced OA chondrocytes. The mechanistic contribution of EZH2, miR-142-3p, and HMGB1 to chondrocyte ER stress and pyroptosis and therapeutic prospects were validated radiologically, histologically, and immunohistochemically in surgically induced OA rats. RESULTS: Increased EZH2 and HMGB1, decreased miR-142-3p, enhanced ER stress, and activated pyroptosis in chondrocytes were associated with OA occurrence and progression. EZH2 and HMGB1 exacerbated and miR-142-3p alleviated ER stress and pyroptosis in OA chondrocytes. EZH2 transcriptionally silenced miR-142-3p via H3K27 trimethylation, and miR-142-3p posttranscriptionally silenced HMGB1 by targeting the 3'-UTR of the HMGB1 gene. Moreover, ER stress mediated the effects of EZH2, miR-142-3p, and HMGB1 on chondrocyte pyroptosis. In vivo experiments mechanistically validated the hierarchical regulatory relationship between EZH2, miR-142-3p, and HMGB1 and their effects on chondrocyte ER stress and pyroptosis. CONCLUSIONS A novel EZH2/miR-142-3p/HMGB1 axis mediates chondrocyte pyroptosis and cartilage degeneration by regulating ER stress in OA, contributing novel mechanistic insights into OA pathogenesis and providing potential targets for future therapeutic research.
Enhancer of Zeste Homolog 2 Protein/genetics* ; Osteoarthritis, Knee/pathology* ; Chondrocytes/metabolism* ; Pyroptosis/physiology* ; HMGB1 Protein/genetics* ; MicroRNAs/metabolism* ; Endoplasmic Reticulum Stress/genetics* ; Humans ; Animals ; Rats ; Male ; Rats, Sprague-Dawley ; Middle Aged

Objective To explore the effect of miRNA-222-3p in endothelial progenitor cell-derived exosomes(EPCs-Exo)on skin wound healing in diabetic mice.Methods Endothelial progenitor cell(EPCs)derived from C57BL/6 mouse bone marrow were identified by fluorescence staining.Subsequently,EPCs-Exo isolated from the media of EPCs were identified,and high-throughput sequencing of EPCs-Exo miRNA was completed.The skin injury model of diabetic mice was established.According to different groups,the wounds were treated with externally ap-plied phosphate buffer solution(PBS)and EPCs-Exo;Subcutaneous injection of PBS,agomiR-222-3p,and an-tagomiR-222-3p at the edge of the wound was performed continuously for 14 days,and the wound healing rate was observed.Meanwhile,immunofluorescence methods were used to investigate the changes in the expression levels of ROS,CD31,and VEGF in the wound margin tissue before and after treatment.Results EPCs-Exo significantly ac-celerated skin wound healing in diabetic mice,reduced the level of ROS,and increased the expression level of VEGF and CD31 in the wound margin tissue(P＜0.05).High-throughput sequencing showed that miRNA-222-3p was highly expressed in EPCs-Exo.Local subcutaneous injection of miRNA-222-3p into wound margin tissue signifi-cantly promoted the skin wound healing of diabetic mice,reduced the level of ROS,and increased the expression level of VEGF and CD31 in the wound margin tissue(P＜0.05).Conclusion MiRNA-222-3p promotes wound healing in diabetic mice and plays an important role in EPCs-Exo promoting wound healing.

Objective: To explore the correlation between Diabetes Complication Severity Index(DCSI), C-reactive protein/albumin ratio(CAR) and death in patients with diabetic foot ulcer(DFU) and to clarify their predictive value for all-cause death in DFU patients. Methods: Retrospectively analyzed the clinical data of 354 DFU patients who were treated in the Endocrinology Department of the First Affiliated Hospital of Anhui Medical University from July 2019 to December 2022. Based on survival status during follow-up, patients were divided into a survival group(n=268) and a death group(n=86). Univariate and multivariate Cox regression analyses were used to identify risk factors for all-cause death in DFU patients. Receiver operating characteristic(ROC) curves were plotted to evaluate the predictive value of DCSI, CAR, and their combination for all-cause death in DFU patients. Kaplan-Meier curves were used to explore the impact of different DCSI and CAR levels on survival in DFU patients. Results: Univariate Cox regression analysis showed that older age, history of hypertension, higher Wagner classification levels, and elevated levels of CRP, Scr, FDP, DCSI score, and CAR were associated with a higher risk of death in DFU patients(P<0.05). Higher levels of HGB, HCT, ALB, or eGFR were associated with a lower risk of death. Patients receiving combined insulin and oral hypoglycemic medication had a lower risk of death compared to those receiving only insulin therapy(P<0.05). Multivariate Cox regression analysis indicated that older age, higher levels of Scr, DCSI, and CAR were independent risk factors for all-cause death in DFU patients, while higher levels of ALB and combined insulin and oral hypoglycemic therapy were protective factors. ROC curve analysis showed that the AUC values for DCSI, CAR, and their combination were 0.652, 0.633, and 0.686, respectively. Kaplan-Meier curve analysis revealed that patients with high DCSI scores(≥4.5) had a lower survival rate compared to those with lower DCSI scores(<4.5). Similarly, patients with high CAR levels(≥0.124) had a lower survival rate compared to those with lower CAR levels(<0.124). Conclusion High levels of DCSI and CAR are independent risk factors for all-cause death in DFU patients. DCSI, CAR, and their combination have predictive value for all-cause mortality in DFU patients.

Objectives:To investigate the effect of body mass index(BMI)on perioperative and long-term prognosis of patients with severe aortic stenosis(AS)after transcatheter aortic valve replacement(TAVR). Methods:This retrospective study imcluded 180 patients with severe AS who received TAVR in Fujian Provincial Hospital from January 2019 to January 2022.According to the BMI,patients were divided into four groups:low weight group(BMI<18.5 kg/m2,n=23),normal weight group(18.5 kg/m2≤BMI<24.0 kg/m2,n=65),overweight group(24.0 kg/m2≤BMI<28.0 kg/m2,n=57),obesity group(BMI≥28.0 kg/m2,n=35).The general clinical characteristics,imaging parameters,perioperative indexes,all-cause death and the incidence of other adverse cardiac events during(18.0±6.8)months follow-up were compared among different groups.Risk factors for the perioperative complications and long-term outcomes of TAVR were evaluated. Results:The prevalence of hypertension and diabetes,left ventricular end-diastolic diameter,ventricular septal thickness and left ventricular posterior wall thickness were significantly higher in the obese group than in normal weight group(all P<0.05).The level of prealbumin in low weight group was lower than in normal weight group(P<0.05).The total perioperative complications in low weight group were higher than in normal weight group(60.9%vs.12.3%,P=0.042).During(18.0±6.8)months follow-up,the incidence of all-cause death in the low weight group was significantly higher than that in normal weight group,overweight group and obese group(17.4%vs.4.6%vs.3.5%vs.5.7%,P=0.003).Kaplan-Meier survival analysis evidenced higher mortality rate in low weight group at 18 months after TAVR(log-rank P<0.01).Multivariate Cox regression analysis showed that the risk of long-term adverse cardiovascular events was significantly higher in low weight group than in normal weight group(HR=7.633,95%CI:1.012-57.564,P=0.049). Conclusions:Low weight patients with severe AS have a higher incidence of perioperative complications and a poor long-term prognosis.Such patients should appropriately strengthen their nutritional intake and adjust their body weight to normal levels before performing TAVR.

Objective:To evaluate the clinical efficacy and safety of secukinumab in the treatment of moderate to severe the adults with plaque psoriasis.Methods:The clinical data from 183 adult patients with moderate to severe plaque psoriasis treated with secukinumab were collected.The patients received subcutaneous injections of secukinumab once a week at weeks 0,1,2,3,and 4,followed by an injection every 4 weeks,with each dose of 300 mg.The follow-up period was 52 weeks.The psoriasis area and severity index(PASI),body surface area(BSA),investigator global assessment(IGA),and dermatology life quality index(DLQI)scores of the patients with psoriasis were caculated.The clinical efficacy and safety of secukinumab in the treatment of moderate to severe plaque psoriasis were evaluated,and the influencing factors were analyzed.Results:Compared with week 0,the PASI、BSA、IGA and DLQI scores of the patients were significantly decreased at weeks 4,12,24,and 52 of secukinumab treatment(P<0.05).After treated with secukinumab,the percentages of the patients achieving PASI 75,PASI 90,and PASI 100 at week 4 were 95.6%,84.2%,and 47.5%,respectively;at week 12,they were 97.3%,95.6%,and 78.7%,respectively;at week 24,they were 97.8%,96.7%,and 84.2%,respectively;and at week 52,they were 98.4%,97.8%,and 83.6%,respectively.The percentages of the patients with BSA≤1%at weeks 4,12,24,and 52 were 80.9%,94.5%,95.6%,and 94.0%,respectively.The percentages of the patients with IGA score of 0/1 at week 4,12,24,and 52 were 86.3%,97.3%,96.7%,and 95.6%,respectively.The percentages of the patients with DLQI score of 0/1 at weeks 4,12,24,and 52 were 76.6%,89.1%,92.9%,and 91.8%,respectively.At week 4 of secukinumab treatment,there were significant differences in age,body mass index(BMI),disease duration,baseline PASI score,and history of previous biologic treatment between the patients in two groups(P<0.05).At week 24 of secukinumab treatment,there were significant differences in age and BMI between the patients in two groups(P<0.05).At week 4,BMI≥25 kg·m-2,disease duration≥10 years,baseline PASI score≥10,and a history of previous biologic treatment were risk factors affecting the recovery of the patient(P<0.05).At week 24,age≥40 years was a risk factor affecting the recovery of the patient(P<0.05).During the treatment period,44 out of 183 psoriasis patients reported 49 adverse reactions,and the adverse reaction rate was 24.0%.No serious adverse events or fatal adverse reactions occurred.The adverse reactions included upper respiratory tract infections in 23 cases,eczema-like skin lesions in 10 cases,skin fungal infections in 6 cases,urticaria in 3 cases,mild liver function abnormalities in 2 cases,folliculitis in 2 cases,conjunctivitis in 2 cases,and otitis media in 1 case.Conclusion:Secukinumab treatment for the adult patients with moderate to severe plaque psoriasis is rapid-acting and has lasting efficacy.The BMI,disease duration,baseline PASI score,history of previous biologic treatment,and age are the factors influencing the clinical efficacy of secukinumab.The overall safety is good,and secukinumab may be used as a first-line treatment option for moderate to severe plaque psoriasis.

Objective:To investigate the relationship between positive asthma prediction index (API) and single nucleotide polymorphisms (SNPs) of interleukin (IL-13), IL-4, β 2 adrenergic receptor (ADRB2), and type I Fc ε receptor β (FcER1B) genes in asthmatic children.Methods:A prospective study was conducted on 102 asthmatic children under 5 years old admitted to Zhongshan Boai Hospital and Foshan First People′s Hospital (51 cases were API positive and 51 cases were API negative) from January 2020 to August 2023. Oral and buccal mucosal exfoliated cells were collected from the children, and genomic DNA was extracted using magnetic bead method. Four gene loci (IL-13 rs20541, IL-4 rs2243250, ADRB2 rs1042713, FcER1B rs569108) were genotyped using a matrix assisted laser desorption ionization time-of-flight mass spectrometer. Logistic regression analysis was used to evaluate the correlation between SNP typing at these four gene loci and API positivity in asthmatic children.Results:There was a statistically significant difference in the SNP typing and allele distribution frequency of IL-13 rs20541, IL-4 rs2243250, ADRB2 rs1042713, FcER1B rs569108 between the API positive and API negative groups of wheezing children (all P<0.05). Among API positive children, the proportion of IL-13 rs20541 site was higher in GG type, the proportion of IL-4 rs2243250 site was higher in TT type, the proportion of ADRB2 rs1042713 site was higher in AG type, and the proportion of FcER1B rs569108 site was higher in AA type; The results of logistic regression analysis showed that IL-13 rs20541 GG type, IL-4 rs2243250 TT type, FcER1B rs569108 AA type were associated with the risk of API positivity in asthmatic children (all P<0.05). Conclusions:IL-13, IL-4, and FcER1B genes are risk genes for the development of API positive wheezing in children under 5 years old. SNP typing of these genes can be used to evaluate the risk of API positivity in clinical practice.

Objective:To investigate the clinical effect of artificial intelligence(AI)technique in delineating target volume for patients with lung cancer during radiotherapy.Methods:A total of 60 patients with lung cancer who received radiotherapy in Pingxiang People's Hospital from September 2021 to March 2023 were selected,and they were divided into control group and observation group by random envelope method,with 30 cases in each group.The control group outlined target volume as conventional method.The observation group adopted deep learning technique to conduct train,and then,UNet network model was output and was used to complete automatic delineation for the target volume of radiotherapy for patients.The near-term efficacy,planning target region volume,radiation dose of target volume,volume and dose of organ at risk(OAR),survival time and incidence of adverse reactions were compared between two groups.Results:The objective relief rate(ORR)of observation group was 70.0％(21/30)after intervention,which was higher than that[46.67％(14/30)]of control group,and the difference was statistically significant(x2=5.691,P＜0.05).The radiation doses of internal target volume(ITV)and planning target volume in observation group were lower respectively than those in control group(t=4.591,4.934,P＜0.05),and the differences of them were significant,respectively.The volume percentages(V20,V5)of the exposed radiation dose that were higher than 20 Gy and 5 Gy in normal lung tissue,the exposed mean lung dose(MLD)of bilateral lungs and the exposed dose of 1cc volume(D1cc)of bilateral lungs in observation group were all lower than those in control group,the differences were statistically significant(t=5.249,4.571,6.092,5.339,P＜0.05),respectively.There was no statistical significance in the incidence of adverse reaction between two groups(P＞0.05).Conclusion:The application of AI technique in delineating target volume of radiotherapy for lung cancer can improve ORR,which is helpful to decrease the planning target volume,D95 and conformal index,and reduce the volume and dose of OAR.It does not increase the incidence of adverse reactions.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective:To evaluate the effects of different imaging frequencies and matching strategies of cone-beam computed tomography (CBCT) on dose-volume parameters in target and organs at risk (OAR) during image-guided radiotherapy for prostate cancer.Methods:A total of 561 sets of CBCT images from 21 patients treated with radical prostate radiotherapy who were admitted to Peking University First Hospital from June 2022 to May 2023 were retrospectively analyzed. All patients received volumetric intensity modulated arc therapy (VMAT) at a prescribed dose of 70 Gy divided into 25 times, 2.8 Gy per time. Clinical target volume (CTV) and OAR were delineated by the same oncologist on each CBCT image. The planned CT (pCT) was rigorously registered to CBCT after calibration of positioning errors according to different image guidance modes and frequencies, and CT values and structures were propagated to CBCT through deformable image registration (DIR). The daily dose was mapped to pCT according to the deformation vector field (DVF) for dose accumulation. The actual cumulative dose of daily online CBCT validation was compared with the weekly CBCT validation regimen (days 1, 2, 3, 6, 11, 16 and 21 online imaging). The dosimetric comparison was also made between bone-based matching and soft tissue-based matching (after automatic bone-based matching, manual prostate-based matching was performed and fine-tuning was made regarding the anterior wall of rectum). Wilcoxon signed rank-sum test was utilized to analyze dose-volume parameters between planned and cumulative doses that exhibited non-normal distribution, while paired t-test was employed for assessing shift values and average dose parameters that demonstrated normal distribution. Results:Compared with daily CBCT image guidance, the CTV_D 98% in weekly CBCT was significantly reduced [(69.08±1.58) vs. (65.24±3.64) Gy, P<0.001]. The CTV_D 98% of bone-based matching was (69.27±2.14) Gy, but the high-dose volume of the rectum were significantly increased: V 60 Gy was 3.18%±3.10%, V 65 Gy was 0.77%±1.23%. The target area coverage using soft tissue-based matching is sufficient, with a CTV_D 98% of (69.08±1.58) Gy. And the percentage volume of high-dose volume of the rectum was significantly reduced, with V 60 Gy being 2.02%±2.42% and V 65 Gy being 0.34%±0.68%. Conclusions:In prostate cancer patients undergoing moderately-fractionated radiotherapy, daily CBCT image guidance demonstrates superior target coverage compared to a weekly scheme. Soft tissue-based matching, which is automatic bone-based matching followed by manual soft tissue-based matching and fine-tuning according to the anterior rectal wall, offers better rectal protection while maintaining target coverage.

In March 2024, organized by Chinese Society of Parenteral and Enteral Nutrition (CSPEN), experts in the fields of general surgery, critical care medicine, gastroenterology, geriatrics, clinical nutrition, clinical pharmacy and evidence-based medicine developed the guidelines for the clinical application of micronutrients in Chinese adult patients (2024 edition) on the basis of latest clinical evidence. The guidelines is of great value in guiding the clinical application of micronutrients. Here, we intended to interpret the guidelines, summarize the differences between domestic and foreign guidelines, and thus enhance our understanding.