Recent data suggest that vascular endothelial growth factor receptor inhibitor (VEGFRi) can enhance the anti-tumor activity of the anti-programmed cell death-1 (anti-PD-1) antibody in colorectal cancer (CRC) with microsatellite stability (MSS). However, the comparison between this combination and standard third-line VEGFRi treatment is not performed, and reliable biomarkers are still lacking. We retrospectively enrolled MSS CRC patients receiving anti-PD-1 antibody plus VEGFRi (combination group, n=54) or VEGFRi alone (VEGFRi group, n=32), and their efficacy and safety were evaluated. We additionally examined the immune characteristics of the MSS CRC tumor microenvironment (TME) through single-cell and spatial transcriptomic data, and an MSS CRC immune cell-related signature (MCICRS) that can be used to predict the clinical outcomes of MSS CRC patients receiving immunotherapy was developed and validated in our in-house cohort. Compared with VEGFRi alone, the combination of anti-PD-1 antibody and VEGFRi exhibited a prolonged survival benefit (median progression-free survival: 4.4 vs. 2.0 months, P=0.0024; median overall survival: 10.2 vs. 5.2 months, P=0.0038) and a similar adverse event incidence. Through single-cell and spatial transcriptomic analysis, we determined ten MSS CRC-enriched immune cell types and their spatial distribution, including naive CD4⁺ T, regulatory CD4⁺ T, CD4⁺ Th17, exhausted CD8⁺ T, cytotoxic CD8⁺ T, proliferated CD8⁺ T, natural killer (NK) cells, plasma, and classical and intermediate monocytes. Based on a systemic meta-analysis and ten machine learning algorithms, we obtained MCICRS, an independent risk factor for the prognosis of MSS CRC patients. Further analyses demonstrated that the low-MCICRS group presented a higher immune cell infiltration and immune-related pathway activation, and hence a significant relation with the superior efficacy of pan-cancer immunotherapy. More importantly, the predictive value of MCICRS in MSS CRC patients receiving immunotherapy was also validated with an in-house cohort. Anti-PD-1 antibody combined with VEGFRi presented an improved clinical benefit in MSS CRC with manageable toxicity. MCICRS could serve as a robust and promising tool to predict clinical outcomes for individual MSS CRC patients receiving immunotherapy.
Humans ; Colorectal Neoplasms/drug therapy* ; Male ; Female ; Immunotherapy ; Middle Aged ; Aged ; Tumor Microenvironment/immunology* ; Retrospective Studies ; Microsatellite Instability ; Transcriptome ; Single-Cell Analysis ; Programmed Cell Death 1 Receptor/immunology* ; Gene Expression Profiling ; Immune Checkpoint Inhibitors/therapeutic use* ; Adult ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors*

OBJECTIVE To explore the effect of the comprehensive unit-based safety program(CUSP)collaborative action strategy on reducing the incidence of catheter-associated urinary tract infection(CAUTI)in elderly patients.METHODS From Jun.to Nov.2024,the Seventh Medical Center of the PLA General Hospital implemented the CUSP collaborative action strategy for intervention.Comparisons were made between pre-intervention(from Dec.2023 to May 2024)and post-intervention(from Jun.to Nov.2024)regarding nurses' know ledge-attitude-practice(KAP)scores on CAUTI prevention,implementation rates of key nursing measures for elderly CAUTI prevention and CAUTI incidence rates among elderly patients.RESULTS The pre-intervention KAP score of nurses from geriatric de-partment on CAUTI prevention was(83.44±6.67),significantly lower than the post-intervention score(108.19±16.27)(P＜0.001).The implementation rates of 10 key nursing measures for elderly CAUTI prevention improved(P＜0.05).The incidence rate of CAUTI was 2.88‰(16/5 546)among 5 546 catheter days before the intervention,and the incidence rate of CAUTI was 0.73‰(4/5 496)among 5 496 catheter days after the intervention(P=0.008).CONCLUSIONS The CUSP collaborative action strategy effectively enhances the KAP levels of nurses from geriatric department on CAUTI prevention,improves the implementation rates of key nursing measures,and reduces CAUTI incidence rates among elderly patients.

OBJECTIVE To explore the effect of the comprehensive unit-based safety program(CUSP)collaborative action strategy on reducing the incidence of catheter-associated urinary tract infection(CAUTI)in elderly patients.METHODS From Jun.to Nov.2024,the Seventh Medical Center of the PLA General Hospital implemented the CUSP collaborative action strategy for intervention.Comparisons were made between pre-intervention(from Dec.2023 to May 2024)and post-intervention(from Jun.to Nov.2024)regarding nurses' know ledge-attitude-practice(KAP)scores on CAUTI prevention,implementation rates of key nursing measures for elderly CAUTI prevention and CAUTI incidence rates among elderly patients.RESULTS The pre-intervention KAP score of nurses from geriatric de-partment on CAUTI prevention was(83.44±6.67),significantly lower than the post-intervention score(108.19±16.27)(P＜0.001).The implementation rates of 10 key nursing measures for elderly CAUTI prevention improved(P＜0.05).The incidence rate of CAUTI was 2.88‰(16/5 546)among 5 546 catheter days before the intervention,and the incidence rate of CAUTI was 0.73‰(4/5 496)among 5 496 catheter days after the intervention(P=0.008).CONCLUSIONS The CUSP collaborative action strategy effectively enhances the KAP levels of nurses from geriatric department on CAUTI prevention,improves the implementation rates of key nursing measures,and reduces CAUTI incidence rates among elderly patients.

Objective To investigate the risk factors for bronchopulmonary dysplasia(BPD)in twin preterm infants with a gestational age of<34 weeks,and to provide a basis for early identification of BPD in twin preterm infants in clinical practice.Methods A retrospective analysis was performed for the twin preterm infants with a gestational age of<34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020.According to their conditions,they were divided into group A(both twins had BPD),group B(only one twin had BPD),and group C(neither twin had BPD).The risk factors for BPD in twin preterm infants were analyzed.Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins.Results A total of 904 pairs of twins with a gestational age of<34 weeks were included in this study.The multivariate logistic regression analysis showed that compared with group C,birth weight discordance of>25%between the twins was an independent risk factor for BPD in one of the twins(OR=3.370,95%CI:1.500-7.568,P<0.05),and high gestational age at birth was a protective factor against BPD(P<0.05).The conditional logistic regression analysis of group B showed that small-for-gestational-age(SGA)birth was an independent risk factor for BPD in individual twins(OR=5.017,95%CI:1.040-24.190,P<0.05).Conclusions The development of BPD in twin preterm infants is associated with gestational age,birth weight discordance between the twins,and SGA birth.

Objective:To explore the therapeutic effect and safety of dexamethasone combined with ulinastatin in pa-tients with acute severe viral myocarditis(ASVMC).Methods:Clinical data of 92 ASVMC patients treated in our hospital from August 2018 to November 2020 were retrospectively collected,and divided into dexamethasone group(n=46)and combined treatment group(n=46,dexamethasone combined with ulinastatin)according to different treatment program.Each group received corresponding medication based on routine therapy for four weeks.Thera-peutic effect,levels of myocardial enzyme spectrum indexes[cardiac troponin Ⅰ(cTnⅠ),creatine kinase isoenzyme MB(CK-MB),lactate dehydrogenase(LDH)]and related indexes of cardiomyocyte apoptosis[soluble factor-related apoptosis(sFas),soluble factor-related apoptosis ligand(sFasL)]before and after treatment,and inci-dence of adverse reactions were compared between two groups.Results:The total effective rate(91.30％vs.73.91％)of combined treatment group was significantly higher than that of dexamethasone group(P=0.028).Compared with dexamethasone group,there were significant reductions in serum levels of cTnⅠ[(4.38±1.02)ng/ml vs.(1.76±0.24)ng/ml],CK-MB[(29.85±5.30)U/L vs.(20.26±4.18)U/L],LDH[(202.84±16.70)U/L vs.(184.21±12.63)U/L],sFas[(2.82±0.37)ng/L vs.(2.39±0.24)ng/L]and sFasL[(0.16±0.04)ng/L vs.(0.08±0.02)ng/L]in combined treatment group after 4-week treatment(P＜0.001 all).There was no sig-nificant difference in incidence rate of adverse reactions during treatment between two groups(P=0.711).Conclusion:Ulinastatin combined with dexamethasone can further inhibit myocardial cell apoptosis,and promote the improvement of myocardial function with significant therapeutic effect in patients with acute severe viral myocarditis and it's safe.

BACKGROUND:Acupotomy is effective in the treatment of knee osteoarthritis,but its mechanism is not very clear. OBJECTIVE:To observe the effect of acupotomy on the apoptosis of knee chondrocytes in knee osteoarthritis rats based on osteoclast associated receptor(OSCAR)-tumor necrosis factor-associated apoptosis-inducing ligand(TRAIL)-osteoprotetin(OPG)pathway. METHODS:Twenty-seven Sprague-Dawley rats were randomly divided into normal group(n=9),model group(n=9)and acupotomy group(n=9).Rats in the normal group were routinely housed without any treatment.Animal models of knee osteoarthritis were established by knee injection of papain.Acupotomy intervention was performed 1 week after modeling,once a week for a total of three times.Relevant tests were performed at the end of the intervention. RESULTS AND CONCLUSION:The Lequesne MG behavioral scores of rats in the model group were elevated compared with the normal group(P<0.01),while the Lequesne MG behavioral scores of rats in the acupotomy group were decreased comparedwith the model group(P<0.01).Hematoxylin-eosin staining results showed that compared with the normal group,the cartilage surface of the rat's knee joints in the model group was worn and uneven and the chondrocytes were swollen,ruptured,reduced in number,and arranged disorderly;while the cartilage surface of the rat's knee joints in the acupotomy group was relatively smooth,and the chondrocytes were high in number and arranged in an orderly manner,with the structure basically clear.Immunohistochemical staining results showed that compared with the normal group,the positive expressions of OSCAR and TRAIL were increased in the model group(P<0.01),while the positive expression of OPG was decreased(P<0.01).Compared with the model group,the positive expressions of OSCAR and TRAIL in the acupotomy group were decreased(P<0.01),while the positive expression of OPG was increased(P<0.01).TUNEL staining results showed that compared with the normal group,the number of apoptotic cells in the model group were increased(P<0.01);compared with the model group,the number of apoptotic cells in the acupotomy group decreased(P<0.01).RT-qRCR and western blot results showed that compared with the normal group,the protein expressions of OSCAR,TRAIL and Bax in the model group were increased(P<0.01),and the protein expressions of OPG and Bcl-2 were decreased(P<0.01);compared with the model group,the protein expressions of OSCAR,TRAIL,and Bax in the acupotomy group were decreased(P<0.01),and the protein expressions of OPG and Bcl-2 were increased(P<0.01).To conclude,acupotomy can reduce cartilage injury of the knee joint in rats with knee osteoarthritis,which may be related to the blockage of mitochondrial pathway apoptotic signaling release by the OSCAR-TRAIL-OPG pathway.

OBJECTIVE: To observe the effect of needle-knife on the chondrocyte apoptosis of knee joint in rabbits with knee osteoarthritis (KOA) based on the CircSERPINE2-miR-1271-5P-E26 specific transformation-related gene (ERG) axis, and to explore the mechanism of needle-knife for KOA. METHODS: Thirty-six New Zealand white rabbits were randomly divided into a normal group, a model group, a needle-knife group and a sham needle-knife group, 9 rabbits in each group. The rabbits in the model group, the needle-knife group and the sham needle-knife group were treated with modified Videman method to prepare KOA model. After successful modeling, the rabbits in the needle-knife group were treated with needle-knife at cord adhesion and nodules near quadriceps femoris tendon and internal and external collateral ligament on the affected knee joint; the rabbits in the sham needle-knife group were treated with sham needle-knife baside the needle insertion point of the needle-knife group (needle-knife was only inserted, without any operation). The treatment was given once a week, 3 times in total. The Lequesne MG behavioral score was used to evaluate the knee joint damage in each group before and after intervention. After intervention, HE staining and transmission electron microscopy were used to observe the cartilage tissue morphology and ultrastructure of chondrocytes in the knee joint in each group; TUNEL method was used to detect the level of chondrocyte apoptosis in the knee joint; real-time fluorescence quantitative PCR was used to detect the expression of CircSERPINE2, miR-1271-5P and ERG mRNA in knee cartilage tissue in each group. RESULTS: After intervention, compared with the normal group, the Lequesne MG behavioral score in the model group was increased (P<0.01). Compared with the model group and the sham needle-knife group, the Lequesne MG behavioral score in the needle-knife group was decreased (P<0.01). In the model group and the sham needle-knife group, the number of chondrocytes and organelles was decreased, the cell nucleus was shrunk, mitochondria was swelling or disappeared; in the needle-knife group, the number of chondrocytes and organelles was increased, the cell nucleus was not obviously shrunk and the mitochondria was not obviously swelling. Compared with the normal group, the level of chondrocyte apoptosis in the model group was increased (P<0.01); compared with the model group and the sham needle-knife group, the level of chondrocyte apoptosis in the needle-knife group was decreased (P<0.01, P<0.05). Compared with the normal group, the expression of CircSERPINE2 and ERG mRNA in the model group was decreased (P<0.01), and the expression of miR-1271-5P mRNA was increased (P<0.01); compared with the model group and the sham needle-knife group, the expression of CircSERPINE2 and ERG mRNA in the needle-knife group was increased (P<0.01), and the expression of miR-1271-5P mRNA was decreased (P<0.01). CONCLUSION Needle-knife could reduce the knee joint damage and chondrocyte apoptosis in KOA rabbits, which may be related to up-regulating the expression of CircSERPINE2 and ERG mRNA, and inhibiting the expression of miR-1271-5P mRNA.
Rabbits ; Animals ; Osteoarthritis, Knee/metabolism* ; Chondrocytes/metabolism* ; Knee Joint/surgery* ; Apoptosis ; MicroRNAs/genetics*

Objective: To investigate the morbidity of chronic obstructive pulmonary diseases (COPD) in residents aged 30 years and above in Sichuan Province, and analyze the effect of smoking on the risk of morbidity on COPD. Methods: From 2004 to 2008, people were randomly selected from Pengzhou, Sichuan Province. All the local people aged 30-79 years were asked to receive questionnaire survey, physical examination and pulmonary function testing, and long-term follow-up to determine the morbidity of COPD. Cox proportional hazard regression model was used to analyze the relationship between smoking and COPD. Results: In 46 540 participants, the current smoking rates were 67.31% in males and 8.67% in females, there were 3 101 new cases of COPD, with a cumulative incidence of 6.66%. Adjusted for age, gender, occupation, marriage, income level, educational level, BMI, daily total physical activity, current cooking frequency, whether there was smoke exhaust device at present and frequency of passive smoking exposure, multivariate Cox proportional hazard regression analysis showed that compared with the non-smoking population, current smoking and quitting smoking increased the risk of COPD, with HR of 1.42 (95%CI:1.29-1.57) and 1.34 (95%CI:1.16-1.53). Compared with people who never or occasionally smoke, the risk of morbidity on COPD increased with the increase of average daily smoking volume, mixed smoking at present, mixed smoking at the beginning increased the risk of COPD, with HR of 1.79 (95%CI: 1.42-2.25) and 2.12 (95%CI: 1.53-2.92), started smoking at the age of <18 years old and ≥18 years old increased the risk of COPD, with HR of 1.61 (95%CI:1.43-1.82) and 1.34 (95%CI: 1.22-1.48), inhaling into the mouth, throat and lung during smoking increased the risk of COPD, with HR of 1.30 (95%CI: 1.16-1.45), 1.63 (95%CI: 1.45-1.83) and 1.37 (95%CI: 1.21-1.55). Adjusted for multiple confounding factors and adjusted for regression dilution bias, the average daily smoking volume, the age of starting smoking and the depth of smoking inhalation had an impact on the incidence of COPD, and the gender difference was particularly prominent. Conclusions: Smoking increased the risk of morbidity on COPD, which was related to the average daily smoking volume, the type of smoking, the age of starting smoking and the depth of smoking inhalation. Tobacco control should comprehensively consider the specific characteristics of smoking, so as to prevent COPD.
Female ; Male ; Humans ; Adolescent ; Prospective Studies ; Smoking ; Morbidity ; Pulmonary Disease, Chronic Obstructive ; China

Objective: To investigate the factors influencing total bilirubin elevation and its correlation with UGT1A1 gene polymorphism in the early postoperative period of transjugular intrahepatic portosystemic shunt (TIPS). Methods: 104 cases with portal hypertension and esophageal variceal hemorrhage (EVB) treated with elective TIPS treatment were selected as the study subjects and were divided into a bilirubin-elevated group and a normal bilirubin group according to the total bilirubin elevation level during the early postoperative period. Univariate analysis and logistic regression were used to analyze the factors influencing total bilirubin elevation in the early postoperative period. PCR amplification and first-generation sequencing technology were used to detect the polymorphic loci of the UGT1A1 gene promoter TATA box, enhancer c.-3279 T > G, c.211G > A, and c.686C > A. Logistic regression was used to analyze the correlation of four locus alleles and genotypes with elevated total bilirubin in the early postoperative period. Results: Among the 104 cases, 47 patients were in the bilirubin elevated group, including 35 males (74.5%) and 12 females (25.5%), aged (50.72 ± 12.56) years. There were 57 cases in the normal bilirubin group, including 42 males (73.7%) and 15 females (26.3%), aged (51.63 ± 11.10) years. There was no statistically significant difference in age (t = -0.391, P = 0.697) and gender (χ(2) = 0.008, P = 0.928) between the two groups of patients. Univariate analysis revealed that preoperative alanine transaminase (ALT) level (χ(2) = 5.954, P = 0.015), total bilirubin level (χ(2) = 16.638, P < 0.001), MELD score (χ(2) = 10.054, P = 0.018), Child-Pugh score (χ(2) = 6.844, P = 0.022), and postoperative portal vein branch development (χ(2) = 6.738, P = 0.034) were statistically significantly different between the two groups. Logistic regression analysis showed that preoperative ALT level, total bilirubin level, and portal vein branch development after TIPS were correlated with the elevated total bilirubin in the early postoperative period. The polymorphism of the c.211G > A locus of the UGT1A1 gene correlation had elevated total bilirubin in the early postoperative period of TIPS. The risk of elevated total bilirubin was increased in the population carrying allele A (P = 0.001, OR = 4.049) in the early postoperative period. Allelic polymorphisms in the TATA box promoter region and enhancer c.-3279 T > G and c.686C > A had no statistically significant difference between the bilirubin-elevated group and the normal bilirubin group. Conclusion: The preoperative ALT level, total bilirubin level, and portal vein branch development are correlated with the elevated total bilirubin in early postoperative patients. The polymorphisms of the UGT1A1 gene and enhancer c.211G > A are correlated with the occurrence of elevated total bilirubin in the early postoperative period of TIPS. Allele A carrier may have a higher risk of elevated total bilirubin in the early postoperative period.
Female ; Humans ; Male ; Bilirubin ; Esophageal and Gastric Varices ; Gastrointestinal Hemorrhage/surgery* ; Portasystemic Shunt, Transjugular Intrahepatic ; Postoperative Period ; Retrospective Studies ; Treatment Outcome ; Adult ; Middle Aged ; Glucuronosyltransferase/genetics*

Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.
Humans ; Middle Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Chemoradiotherapy ; Immune Checkpoint Inhibitors/therapeutic use* ; Neoadjuvant Therapy ; Prospective Studies ; Rectal Neoplasms/pathology* ; Thrombocytopenia/drug therapy* ; Treatment Outcome ; Adult ; Aged