Background::With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation (UCBT), the correlation between immune reconstitution (IR) after UCBT and graft-versus-host disease (GVHD) has been reported successively, but reports on double-negative T (DNT) cell reconstitution and its association with acute GVHD (aGVHD) after UCBT are lacking.Methods::A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology, the First Affiliated Hospital of USTC, between August 2018 and June 2021. IR differences were compared between the patients with and without aGVHD.Results::The absolute number of DNT cells in the healthy Chinese population was 109 (70-157)/μL, accounting for 5.82 (3.98-8.19)% of lymphocytes. DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation. Importantly, the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year ( F = 4.684, P = 0.039 and F = 5.583, P = 0.026, respectively). In addition, the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased, and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD (HR = 0.46, 95% confidence interval [CI]: 0.23-0.93; P = 0.031). Conclusions::Compared to the number of DNT cells in Chinese healthy people, the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow. In addition, the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.

Three novel sesquiterpenoid heterodimers,designated as auckcostusolides A-C(1-3),were isolated from Aucklandia costus leaves.The structures of compounds 1-3 were elucidated through comprehensive spectroscopic analysis,with their absolute configurations established using a combination of X-ray single-crystal diffraction and electronic circular dichroism(ECD)calculations.Notably,compounds 1 and 2,despite sharing identical planar structures derived from two identical sesquiterpenoids,exhibited oppos-ite configurations at C-11 and C-8'.This configurational difference can be attributed to distinct Diels-Alder cycloaddition processes between the sesquiterpenoid monomers.Additionally,the cytotoxic effects of compounds 1-3 were evaluated against colorectal can-cer HCT116 cells,fibrosarcoma HT1080 cells,and hepatocellular carcinoma HepG2 cells.Compounds 1-3 induced cell death was characterized by endoplasmic reticulum(ER)swelling and cytoplasmic vacuolization,typical morphological changes associated with paraptosis.Mechanistic studies revealed that compounds 1 and 3 triggered paraptosis-like cell death through the accumulation of react-ive oxygen species(ROS),activation of ER stress,and stimulation of the MAPK signaling pathway.

Objective:To investigate the effect of inflammatory factors(IL-2,INF-γ,IL-10,TNF-α)and CD4+and CD8+T cells in vaginal lavage in high-grade cervical squamous intraepithelial lesions(HSIL)and early cervical cancer(CC).Methods:To collect clinical data of HSIL(n=120)and early CC patients(n=44)after high-risk human papilloma virus(HR-HPV)infection.And healthy middle-aged women not infected with HR-HPV were randomly selected as control.The clinical data of the subjects in three groups were compared,inflammatory factors distribution and ratio of CD4+and CD8+T cells in serum and vaginal lavage fluid were compared.Multivariate Logistic regression performed to analyze the influencing factors of HSIL progression to early CC,ROC and calibration plot were drawn to evaluate the model.Results:The difference was not statistically significant in serum IL-2,INF-γ,IL-10,TNF-α levels,CD4+T cell distribution,CD8+T cell distribution and CD4+/CD8+ratio in sub-jects of control group,HSIL group and early CC group(P>0.05).The difference was statistically significant in the vaginal lavage levels of IL-2,INF-γ,IL-10,TNF-α levels,CD4+T cell distribution,CD8+T cell distribution and CD4+/CD8+ratio(P<0.05),plus the level of HSIL patients was higher than that of control subjects(P<0.05).Logistic regression analysis showed that parity>2(OR=3.119,95%CI:4.353～6.737)and the percentage of CD4+T cells in vaginal lavage fluid(OR=0.327,95%CI:0.188-0.478)in model 2(P<0.001,AUC=0.908),CD4+/CD8+(OR=0.809,95%CI:0.356-1.868)(P<0.001,AUC=0.873)in model 3 has an independent influence on the development of HSIL to early CC;the difference is not significant(Z=1.550 4,P=0.121)in ROC curves of the two models.CD4+/CD8+ratio as only one indictor in Model 3 can be good predic-tion,and the calibration curve of this model is close to the standard curve.Conclusions:After HR-HPV infection,the systemic immune status does not participate in HSIL and HSIL progression to early CC,but the cervical local immune status is involved,in which CD4+/CD8+T cell ratio is an independent protective factor.

Objective To observe the clinical effect of hypomethylating agents (HMAs) in the treatment of patients with intermediate- and high-risk myelodysplastic syndrome (MDS). Methods A retrospective study was conducted in 58 patients with intermediate-and high-risk MDS. The study group(25 patients) received azacitidine or decitabine for hypomethylating treatment, while the control group(33 patients) received routine symptomatic supportive treatment. The clinical efficacy, hematologic parameters, quality of life, and adverse events were observed and compared between the two groups. Results After treatment, the complete remission rate, objective response rate, and disease control rate were higher in the study group than in the control group, while the disease progression rate was lower (P < 0.05). The 1-year survival rate was 92.00% in the study group, which was higher than 75.76% in the control group, but the difference showed no statistically significant (P>0.05). After treatment, hemoglobin, white blood cell, and platelet levels were higher in both groups than before treatment, and were higher in the study group than in the control group (P < 0.05). The total incidence of adverse events was lower in the study group than that in the control group (P < 0.05). After treatment, the quality of life scores (physical function, cognitive function, emotional function, role function, and social function) were higher in the study group than those in the control group (P < 0.05). Conclusion HMAs treatment is superior to routine symptomatic supportive treatment in patients with intermediate-and high-risk MDS, and not only improves the quality of life but also has good safety.

Objective To construct and validate a risk prediction model for enteral nutrition feeding intolerance (FI) in patients with severe cerebral hemorrhage based on machine learning algorithms. Methods The clinical data of 485 patients with cerebral hemorrhage admitted to the neurological intensive care unit of Northern Jiangsu People's Hospital Affiliated to Yangzhou University from January 2020 to December 2022 were retrospectively analyzed. The patients were randomly divided into training set (n=339) and validation set (n=146) in a 7 to 3 ratio. Five machine learning algorithms were used to construct FI risk prediction models. The receiver operating characteristic (ROC) curve was plotted, and the model with the best predictive performance was selected based on the area under the curve (AUC). A nomogram model was constructed based on the optimal model. The calibration curve and decision curve analysis (DCA) were used to evaluate the calibration and clinical net benefit of the nomogram model. Results The incidence of enteral nutrition FI in patients with severe cerebral hemorrhage was 38.4%(186/485). Among the five machine learning algorithm models, the Logistic regression model had the best predictive performance(AUC=0.88). The analysis results of the Logistic regression model showed that the use of diuretics, mechanical ventilation, Glasgow Coma Scale score ≤5, vasoactive drugs, and albumin level<35 g/L were risk factors for enteral nutrition FI in patients with severe cerebral hemorrhage. A nomogram model was further constructed based on these five risk factors. The calibration curve analysis showed that the calibration curve fitted well with the ideal curve, indicating a high calibration degree of the nomogram model. The DCA results showed that when the threshold probability was 5% to 73%, the application of the nomogram model for screening could clinically benefit patients. Conclusion The construction of a nomogram model for predicting the risk of enteral nutrition FI in patients with severe cerebral hemorrhage based on machine learning methods can help to early screen high-risk patients for enteral nutrition FI and timely formulate preventive measures, thereby reducing the incidence of enteral nutrition FI in patients with severe cerebral hemorrhage.

Tuberculosis (TB) is an ancient infectious disease. Before the availability of effective drug therapy, it had high morbidity and mortality. In the past 100 years, the discovery of revolutionary anti-TB drugs such as streptomycin, isoniazid, pyrazinamide, ethambutol and rifampicin, along with drug combination treatment, has greatly improved TB control globally. As anti-TB drugs were widely used, multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis emerged due to acquired genetic mutations, and this now presents a major problem for effective treatment. Genes associated with drug resistance have been identified, including katG mutations in isoniazid resistance, rpoB mutations in rifampin resistance, pncA mutations in pyrazinamide resistance, and gyrA mutations in quinolone resistance. The major mechanisms of drug resistance include loss of enzyme activity in prodrug activation, drug target alteration, overexpression of drug target, and overexpression of the efflux pump. During the disease process, Mycobacterium tuberculosis may reside in different microenvironments where it is expose to acidic pH, low oxygen, reactive oxygen species and anti-TB drugs, which can facilitate the development of non-replicating persisters and promote bacterial survival. The mechanisms of persister formation may include toxin-antitoxin (TA) modules, DNA protection and repair, protein degradation such as trans-translation, efflux, and altered metabolism. In recent years, the use of new anti-TB drugs, repurposed drugs, and their drug combinations has greatly improved treatment outcomes in patients with both drug-susceptible TB and MDR/XDR-TB. The importance of developing more effective drugs targeting persisters of Mycobacterium tuberculosis is emphasized. In addition, host-directed therapeutics using both conventional drugs and herbal medicines for more effective TB treatment should also be explored. In this article, we review historical aspects of the research on anti-TB drugs and discuss the current understanding and treatments of drug resistant and persistent tuberculosis to inform future therapeutic development.
Humans ; Pyrazinamide/therapeutic use* ; Isoniazid/therapeutic use* ; Antitubercular Agents/therapeutic use* ; Tuberculosis, Multidrug-Resistant/microbiology* ; Mycobacterium tuberculosis/genetics* ; Tuberculosis/drug therapy* ; Rifampin/therapeutic use* ; Mutation ; Drug Resistance, Multiple, Bacterial/genetics*

Objective:To investigate the effect of intravenous anesthesia on the detection rate of lesions in diagnostic gastroscopy.Methods:A total of 9 071 subjects who underwent diagnostic gastroscopy at the Digestive Endoscopy Center of Yangzhou University Affiliated Hospital from March 2021 to February 2022 were selected. Data were collected from the gastroscopy quality control system, including age, gender, examination physician, Helicobacter pylori infection, examination method, withdrawal time, number of images left, number of biopsies, biopsy site, gastroscopy diagnosis, pathological diagnosis, etc. They were divided into anesthesia group and general group based on the examination method, and propensity score matching (PSM) was performed on the two groups of subjects. Excluding confounding factors, the detection of lesion location and lesion type in two groups of subjects was analyzed; Simultaneously, univariate and multivariate logistic regression analysis was used to analyze the influencing factors of the detection rate of precancerous lesions and malignant tumors in the upper gastrointestinal tract.Results:After PSM, 1 655 subjects were included in both groups. In terms of lesion location, the detection rate of gastric body lesions in the anesthesia group was higher than that in the general group ( P<0.05), and the detection rate of esophageal lesions in the anesthesia group was lower than that in the general group ( P<0.05); In terms of lesion types, the detection rate of precancerous lesions such as gastric polyps, mucosal protrusions, mucosal atrophy, and intestinal metaplasia in the anesthesia group was higher than that in the general group (all P<0.05). The results of logistic regression analysis showed that intravenous anesthesia was an independent influencing factor for the detection rate of precancerous lesions and malignant tumors in diagnostic gastroscopy ( OR=1.338, 95% CI: 1.070-1.674, P<0.05). Conclusions:Intravenous anesthesia is an independent influencing factor for the detection rate of precancerous lesions and malignant tumors in diagnostic gastroscopy, and can improve the detection rate of upper gastrointestinal lesions.

Objective:To study the risk factors of very early recurrence (VER, within 3 months) after R 0 resection of hepatocellular carcinoma (HCC), and to establish a predictive model. Methods:Of 427 HCC patients [with 368 males, 59 females, aged (52.7±12.1) years] who developed early recurrence (within 2 years) after R 0 resection from January to December 2008 at Zhongshan Hospital, Fudan University were enrolled in the test cohort. Another 590 patients [with 525 males, 65 females, aged (54.7±11.0) years] who underwent R 0 resection from January to June 2009 were enrolled in the validation cohort. Risk factors were investigated and a predictive model was established. Results:In the test cohort, 126 patients (29.5%) developed VER and their survival outcomes were extremely poor. Serum α-fetoprotein (AFP) level >827 μg/L, multiple tumors, microvascular invasion (MVI) and tumor number were independent risk factors for VER. A new predictive model (0.809·AFP+ 1.262·tumor number+ 0.983·MVI) was established by logistic regression in predicting VER after surgery. The receiver operating characteristic curve showed that the area under the curve (AUC) in predicting VER was 0.722 (95% CI: 0.669-0.774, P<0.001). In the validation cohort, the AUC of this model was 0.785 (95% CI: 0.715-0.855, P<0.001). Conclusions:A high AFP level, multiple tumors, and MVI were independent risk factors for VER of HCC after R 0 resection. The prediction model consisting of these three factors demonstrated robustness and it has the potential in clinical application.

Objective To investigate the feasibility and safty of indocyanine green (ICG) fluorescence staining by laparoscopic ultrasound and three-dimensional (3D) visualization guided portal branch puncture approach in anatomical segmentectomy.Methods The retrospective cross-sectional study was conducted.The clinical data of 26 patients who underwent anatomical segmentectomy using ICG fluorescence staining by laparoscopic ultrasound and 3D visualization guided portal branch puncture approach in the Zhongshan Hospital of Fudan University between December 2016 and April 2018 were collected.The preoperative 3D visualization reconstruction and areas of portal branch perfusion were analyzed,laparoscopic ultrasound localization was intraoperatively applied to tumor and portal vein of targeted hepatic segment,and then portal branch puncture and staining were done under laparoscopic ultrasound and 3D visualization,finally laparoscopic anatomical segmentectomy was performed.Observation indicators:(1) intraoperative situations:success rate of portal vein puncture,targeted hepatic segment,effect of ICG fluorescence staining,intraoperative complications,operation time,volume of intraoperative blood loss,blood transfusion,conversion to open surgery,tumor diameter,the minimum resection margin to tumor;(2) postoperative situations:postoperative complications (Clavien-Dindo classification as a criteria) and duration of hospital stay;(3) follow-up situations:cases with follow-up,follow-up time and postoperative tumor recurrence.Follow-up using outpatient examination and telephone interview was performed to detect postoperative tumor recurrence up to April 2018.Measurement data with normal distribution and count data were respectively described as average (range) and percentage.Results (1) Intraoperative situations:a success rate of laparoscopic ultrasound and 3D visualization guided portal branch puncture in 26 patients was 100.0％ (26/26),and punctures in S8,S7,S2,S3,S6,S5 and S4 of the liver were respectively performed to 7,6,4,3,3,2 and 1 patients.Of 26 patients,22 achieved expected effect of ICG fluorescence staining,with a statisfaction of 84.6％ (22/26) and 4 failed to get expected effect,including 2 with uneven dying,1 with staining-uncovered partial areas of targeted liver segment and 1 with adjacent hepatic segmental staining induced to unclear boundary.All the 26 patients were not complicated with ICG injection induced to allergy.Average operation time and volume of intraoperative blood loss were 184 minutes (range,60-315 minutes) and 97 mL (range,10-400 mL),without intraoperative blood transfusion and conversion to open surgery.Average tumor diameter and average minimum resection margin to tumor in 26 patients were respectively 3.2 cm (range,1.2-10.0 cm) and 1.5 cm (range,0.4-3.0 cm).(2) Postoperative situations:of 26 patients,2 with grade Ⅰ-Ⅱ of Clavien-Dindo classification were improved by drug treatments (1 with deep venous thrombosis of the lower extremities and 1 with pleural effusion),no patient had grade Ⅲ and above complications,and there was no bile leakage,infection and hepatic dysfunction.Average duration of hospital stay in 26 patients was 6.9 days (range,5.0-14.0 days).(3) Follow-up situations:26 patients were followed up for 0.3-17.0 months,with a median time of 6.0 months.During the follow-up,1 patient with hepatocellular carcinoma had adrenal metastasis and 25 had tumor-free survival.Conclusion Laparoscopic anatomical segmentectomy with ICG fluorescence staining by laparoscopic ultrasound and 3D visualization guided portal branch puncture approaeh is safe and feasible,especially suitable in posterosuperior liver segments.

Objective To study the clinical impact of microvascular invasion (MVI) on patients with intrahepatic cholangiocarcinoma (ICC) after R0 resections.Methods The clinicopathological data of 359 patients with ICC who underwent R0 resection in the Zhongshan Hospital,Fudan University between January 2000 and December 2008 were retrospectively studied.Univariate analysis and multivariate analysis were carried out to study factors related to postoperative survival outcomes and recurrence.The impact of MVI on patients with ICC after R0 resection was studied.Results The incidence of MVI was 13.6％ in the study cohort.MVI was correlated with HBV infection (P ＜ 0.05),liver cirrhosis (P ＜ 0.05) and tumor differentiation (P ＜ 0.05).The 1-,3-,5-year overall survival (OS) between the MVI positive and negative groups were 50.0％,20.9％,12.2％ and 63.9％,33.1％,22.0％ respectively (P ＜ 0.05),and the median survival time was 13 months and 18.5 months (P ＜0.05).The 1-,3-,5-year recurrence free survival (RFS) rates between the MVI positive and negative groups were 29.7％,12.7％,8.5％ and 50.6％,26.9％,18.4％,respectively (P ＜0.05),and the median recurrence free survival time was 8 months and 12.5 months (P ＜ 0.05).Multivariate analysis showed that MVI was an independent risk factor affecting recurrence after R0 resection (HR 1.852,95％ CI:1.075 ～ 3.195,P ＜ 0.05).Conclusions The occurrence of MVI in ICC patients was associated with hepatitis B infection.MVI was an independent risk factor affecting recurrence in ICC patients after R0 resection.However,it was not an independent risk factor of overall survival in patients after R0 resection.The clinical impact of MVI on patients with ICC was not as strong as for hepatocellular carcinoma.