Objective To explore the effect and potential mechanisms of melatonin combined with gemcitabine on the chemosensitivity of human pancreatic cancer cell line PANC-1.Methods Human pancreatic cancer cell line PANC-1 was trea-ted with gemcitabine alone or in combination with melatonin.Cell viability was assessed using CCK-8.Effect of melatonin and gem-citabine alone or in combination on the clonogenic capacity of PANC-1 cells were observed through colony formation experiments.Scratch assays and transwell experiments were conducted to evaluate cell migration ability.Reactive oxygen species(ROS)and mitochondrial membrane point JC-1 assay kit were used to determine reactive oxygen species synthesis and membrane potential levels.Intracellular Fe2+level was measured using ferrous ion fluorescent probe.The protein expression levels of LC3,P62,GPX4 and SLC7A11 in different treatment groups were detected by immunofluorescence and Western blotting.Results CCK-8 results showed that the viability of PANC-1 cells was inhibited by gemcitabine alone after 48 h and 72 h of treatment in a time-and dose-dependent manner.The cell viability of gemcitabine combined with melatonin group was significantly lower than that of gemcitabine group,and the cell viability decreased with the increase of melatonin concentration.Scratch assays,transwell experiments,and plate colony formation assay results demonstrated that the proliferation and migration of cells in the gemcitabine combined with the me-latonin group were significantly inhibited compared with the gemcitabine group.The levels of reactive oxygen species and Fe2+in PANC-1 in gemcitabine combined with the melatonin group were higher than those in the gemcitabine group,and the mitochondri-al membrane potential was significantly decreased(P＜0.01).Western blotting and immunofluorescence results showed that the ra-tio of autophagy-related protein LC3-Ⅱ/LC3-Ⅰ in gemcitabine combined with the melatonin group was lower than that in the gem-citabine group,and the expression of P62 was up-regulated,and the expression of anti-iron death-related protein GPX4 and SLC7A11 was significantly inhibited(P＜0.05),suggesting that melatonin combined with gemcitabine can inhibit autophagy and promote ferroptosis in PANC-1 cells.Conclusion Melatonin enhances the chemosensitivity of pancreatic cancer cell PANC-1 to gemcitabine by inhibiting autophagy and promoting ferroptosis of tumor cells.

Objective To investigate the expression of Midkine(MDK)in cholangiocarcinoma(CCA)and its value in predicting the prognosis of CCA,as well as the potential mechanism of the effect of MDK on the progression of CCA.Methods The data of CCA samples were obtained from TCGA database to analyze the difference in the expression of MDK between cancer tissue and paracancerous tissue and its association with clinical features,and the data collected from GEO database and 11 CCA patients who underwent surgical resection in The Fifth Medical Center of Chinese PLA General Hospital from June 2018 to September 2021 were used for validation.STRING and Cytoscape were used to construct a protein-protein interaction network,and gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were used to investigate the biological functions and tumor-related pathways involving MDK-related genes.In addition,TIMER and TISIDB databases were used to analyze the correlation between MDK expression and immune cell infiltration in CCA tissue.The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups,and the Fisher's exact test was used for comparison of categorical data between two groups.The Kaplan-Meier method was used to plot survival curves,and the Log-rank test was used for comparison between groups.The Spearman correlation analysis was used to investigate the correlation between two variables.Results The expression level of MDK in cancer tissue and paracancerous tissue of CCA patients was compared based on TCGA database,and the results of the non-paired and paired analyses showed that the expression level of MDK in CCA tumor tissue was significantly higher than that in paracancerous tissue(P<0.001).Transcriptome sequencing was performed for the tumor tissue and its corresponding paracancerous tissue from 11 CCA patients,and the results showed that the expression level of MDK in CCA tumor tissue was significantly higher than that in corresponding paracancerous tissue(P<0.01).High expression of MDK was associated with lymph node metastasis(P=0.045)and vascular invasion(P=0.044).Survival analysis showed that compared with the CCA patients with low MDK expression,the CCA patients with high MDK expression had significantly shorter overall survival time(χ2=5.30,P=0.028)and disease-specific survival time(χ2=6.25,P=0.019).The GO and KEGG enrichment analyses showed that the 30 MDK-related genes were closely associated with ubiquitin-mediated proteolysis and affected the prognosis of CCA patients.The TIMER analysis showed that the expression level of MDK was positively correlated with the infiltration of B cells(r=0.356,P=0.035 6)and dendritic cells(r=0.409,P=0.014 7)in tumor microenvironment of CCA;the TISIDB analysis showed that the expression level of MDK was positively correlated with CXCL16(r=0.465,P=0.004 67)and was negatively correlated with CXCL12(r=-0.389,P=0.019 7)and CXCR5(r=-0.393,P=0.018 5),and it was also negatively correlated with the immune checkpoint regulators VTCN1(r=-0.393,P=0.018 3),LTA(r=-0.380,P=0.022 7),and PVR(r=-0.350,P=0.037 3).Conclusion High expression of MDK is associated with poor prognosis in CCA patients,and MDK has the potential of being used as a molecular marker for predicting the prognosis of CCA.MDK may promote the development and progression of CCA by regulating ubiquitin-mediated proteolysis and the infiltration of B cells and dendritic cells.

Objective To investigate the short-term efficacy of celiac plexus block combined with the interstitial permanent implantation of 125I seeds in the treatment of advanced pancreatic cancer(inoperable locally advanced and metastatic pancreatic cancers).Methods A total of 100 patients with advanced pancreatic cancer were selected and treated with celiac plexus block combined with the interstitial permanent implantation of 125I seeds under CT guidance.Pain relief and changes in the tumor marker CA19-9 were assessed on the seventh day,the first and third months after surgery.In the third month after surgery,tumor size was assessed by CT.Results Among the 100 patients with advanced pancreatic cancer,complete response(CR)was found in 12 cases,partial response(PR)in 78 cases,stable disease in five cases,and progression of disease in five cases three months after surgery.The CA19-9 level and the sum of short and long tumor diameters were significantly decreased(both P<0.01).A total of 100 patients had severe pain before treatment(visual analogue scale(VAS)):7-10 points),59 patients reported pain disappearance(VAS:0 points),35 patients had mild pain(VAS:1-3 points),and six patients experienced moderate pain(VAS:4-6 points)in the third month after treatment.The pain relief rate was 100%.Conclusion Celiac plexus block combined with the interstitial permanent implantation of 125I seeds has good short-term efficacy and can effectively improve short-term pain in patients with advanced pancreatic cancer.

Objective To analyze the long-term outcome of modified Morrow surgery (interventricular septal cardiomyectomy) in the treatment of hypertrophic obstructive cardiomyopathy (HOCM) in children. Methods The clinical data of the children with HOCM (aged≤14 years) who underwent modified Morrow surgery from January 2010 to August 2022 in Guangdong Provincial People's Hospital were retrospectively analyzed, including changes in hospitalization status, perioperative period, and long-term 15-lead electrocardiogram and echocardiography. Results A total of 29 patients were collected, including 22 males and 7 females, aged 10.00 (5.00, 12.00) years. Five (17.9%) patients had New York Heart Association (NYHA) heart function grade Ⅲ or Ⅳ. Ventricular septal cardiomyectomy was performed in all patients. All 29 patients survived and their cardiac function recovered after operation. Before discharge, right bundle branch block was observed in 2 patients and left bundle branch block in 6 patients. After surgery, in the left ventricular septal cardiomyectomy, the left atrial diameter decreased (P＜0.001), left ventricular end-systolic diameter increased (P=0.009), the peak pressure gradient of left ventricular outflow tract decreased (P＜0.001), and the thickness of ventricular septum decreased (P＜0.001). The systolic anterior motion of mitral valve disappeared and mitral regurgitent jet area decreased (P＜0.001). The flow velocity and peak pressure gradient of right ventricular outflow tract also decreased in the patients who underwent right ventricular septal cardiomyectomy. The average follow-up of the patients was 69.03±10.60 months. All the patients survived with their NYHA cardiac function grading Ⅰ or Ⅱ. No new-onset arrythmia event was found. Echocardiography indicated that the peak pressure gradient of the left ventricular outflow tract remained low (P<0.001). Moderate mitral regurgitation occurred in 2 patients, and left ventricular outflow tract obstruction with moderate mitral regurgitation occurred in 1 patient after simple right ventricular septal cardiomyectomy. Conclusion Right ventricular or biventricular obstruction is frequent in the children with HOCM and they usually have more symptoms before surgery. Modified Morrow surgery can effectively relieve outflow tract obstruction and improve their cardiac function. The long-term outcome is satisfactory. However, the posterior wall of the left ventricle remains hypertrophic. Also, there is an increased risk of a conduction block.

Objective To analyze the current patient satisfaction levels and their influencing factors from the perspective of medical experience in private rehabilitation hospitals in Chongqing.This analysis aimed to provide references for these hospitals to improve the quality of medical services.Methods A questionnaire survey of 467 inpatients from three private rehabilitation hospitals in Chongqing was conducted,using convenience sampling.The x2 test and logistic regression analysis were used to i-dentify factors influencing patient satisfaction.Results The overall satisfaction rate of inpatient care was 78.6％,with an aver-age satisfaction score of 3.84±0.52.The complaint and advice service scored the higher,while logistics and environmental serv-ice and rehabilitation treatment service were assessed with lower scores.Regression analysis showed that the per capita monthly household income ranged between 2 001 and 4 000 yuan(OR=0.221,95％CI:0.077-0.635),and between 4 001 and 6 000 yuan(OR=0.296,95％CI:0.125-0.700).Additionally,out-of-pocket payment(OR=4.198,95％CI:1.035-17.027),and others payment methods,including commercial insurance(OR=9.591,95％CI:1.767-52.049)were identified as influential factors.Conclusion Inpatients'overall satisfaction with their medical experience is acceptable,but still has considerable room for improvement.It is recommended that a multidimensional approach be adopted to improve patient satisfaction.

Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Objective Analyzing risk factors for prolonged ICU stay after cardiac surgery of Infective Endocarditis(IE)provides a basis for preventing extended ICU durations in postoperative IE cases.Methods From January 1,2019,to March 31,2021,a total of 223 patients with infective endocarditis who underwent cardiac surgery in the cardiac surgery department of Guangdong Provincial People's Hospital were included.Patients were divided into non-prolonged group(<3 days)and prolonged group(≥3 days)based on postoperative ICU stay duration.There were 156 cases in the non-prolonged group and 67 cases in the prolonged group.Single-factor analysis of risk factors for prolonged ICU stay was conducted using t-tests or rank-sum tests.Variables with P<0.05 in the single-factor analysis were further subjected to binary logistic regression for multivariate analysis.The accuracy of the model was evaluated using the ROC curve.Results Among the 223 patients,67 experienced prolonged ICU stay,with an incidence rate of 30%.Single-factor analysis results included gender,age,history of coronary heart disease,history of stroke,preoperative heart failure,aortic valve regurgitation area,left ventricular end-diastolic diameter,left ventricular ejection fraction(LVEF)<60%,extracorporeal circulation time,aortic cross-clamp time,use of Intra-Aortic Balloon Pump(IABP),endotracheal tube reintubation,pulmonary infection,use of Continuous Renal Replacement Therapy(CRRT),and prolonged mechanical ventilation time(>24 hours),among others.Multivariate analysis results revealed that preoperative LVEF<60%(OR=3.004,P=0.041),postopera-tive use of IABP(OR=31.686,P=0.008),and mechanical ventilation time>24 hours(OR=8.135,P<0.001)were independent risk factors for prolonged ICU stay after cardiac surgery.The model's AUC value for predicting risk factors for prolonged ICU stay was 0.858(95%CI:0.806～0.901,P<0.001).Conclusion Preoperative left ventricular ejection fraction(LVEF)<60%,the use of IABP,and mechanical ventilation time>24 hours were identified as independent risk factors for prolonged ICU stay after infective endocarditis(IE)surgery.In clinical practice,it is important to comprehensively address and manage various risk factors with the aim of reducing ICU stay duration and improving the overall success rate of the surgery.

Background/Aims: Previous studies have shown that diet and physical activity can influence constipation. However, the combined effect of diet and physical activity on constipation remains unclear. Methods: Constipation was defined based on stool consistency and frequency, while overall diet quality was assessed using Healthy Eating Index (HEI)-2015 scores. Participants were categorized into low (metabolic equivalent [MET]-min/wk < 500) and high physical activitygroups (MET-min/wk ≥ 500). The association between diet and constipation across physical activity groups was analyzed using surveylogistic regression and restricted cubic splines. Results: Higher HEI-2015 scores were associated with reduced constipation risk in the high physical activity group when constipation was defined by stool consistency (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97-0.99). However, in the low physical activity group, increased HEI-2015 scores did not significantly affect constipation risk (OR, 1.01; 95% CI, 0.97-1.05). Similar results were found when constipation was defined based on stool frequency. In the high physical activity group, increased HEI-2015 scores were significantly associated with a reduced constipation risk (OR, 0.96; 95% CI, 0.94-0.98). Conversely, in the low physical activity group, increased HEI-2015 scores did not affect the risk of constipation (OR, 0.96; 95% CI, 0.90-1.03). Conclusions Our findings suggest that a higher HEI-2015 score is negatively associated with constipation among individuals with high physical activity levels but not among those with low physical activity levels. This association was consistent when different definitions of constipation were used. These results highlight the importance of combining healthy diet with regular physical activity to alleviate constipation.

Children with certain comorbidities and immunocompromising conditions are highly vulnerable to SARS-CoV-2 infection. Vaccination against SARS-CoV-2 is an important strategy to reduce death， critical illness and overall disease burden. With the evolving and increasing transmission of SARS-CoV-2， universal vaccination is essential to achieve this goal. Children with special medical conditions are considered as the priorities for SARS-CoV-2 vaccination. However， vaccine hesitancy towards the implementation of SARS-CoV-2 vaccination currently remains an urgent challenge. In order to promote the sustainable vaccination for those children in Shanghai as well as China， Shanghai municipal center for disease control and prevention， together with the national children’s medical center， children’s hospital of Fudan university and the expert group on immunization planning of the Shanghai preventive medicine association， organized a consensus expert working group to formulate the evidence-based recommendations and implementation suggestions for children with common chronic diseases， allergy history， diseases involving adverse events related to vaccination， and immunocompromising conditions， based on the published evidence of SARS-CoV-2 vaccination for populations and children with special medical conditions.

Emerging SARS-CoV-2 variants have made COVID-19 convalescents susceptible to re-infection and have raised concern about the efficacy of inactivated vaccination in neutralization against emerging variants and antigen-specific B cell response. To this end, a study on a long-term cohort of 208 participants who have recovered from COVID-19 was conducted, and the participants were followed up at 3.3 (Visit 1), 9.2 (Visit 2), and 18.5 (Visit 3) months after SARS-CoV-2 infection. They were classified into three groups (no-vaccination (n = 54), one-dose (n = 62), and two-dose (n = 92) groups) on the basis of the administration of inactivated vaccination. The neutralizing antibody (NAb) titers against the wild-type virus continued to decrease in the no-vaccination group, but they rose significantly in the one-dose and two-dose groups, with the highest NAb titers being observed in the two-dose group at Visit 3. The NAb titers against the Delta variant for the no-vaccination, one-dose, and two-dose groups decreased by 3.3, 1.9, and 2.3 folds relative to the wild-type virus, respectively, and those against the Omicron variant decreased by 7.0, 4.0, and 3.8 folds, respectively. Similarly, the responses of SARS-CoV-2 RBD-specific B cells and memory B cells were boosted by the second vaccine dose. Results showed that the convalescents benefited from the administration of the inactivated vaccine (one or two doses), which enhanced neutralization against highly mutated SARS-CoV-2 variants and memory B cell responses. Two doses of inactivated vaccine among COVID-19 convalescents are therefore recommended for the prevention of the COVID-19 pandemic, and vaccination guidelines and policies need to be updated.