Objective To explore the pharmacokinetic characteristics of sufentanil in individuals with normal body mass index(BMI),overweight BMI,and different CYP3A4/5 enzyme genotypes.Methods The patients receiving laparoscopic surgery under general anesthesia in the First Affiliated Hospital of Army Medical University from November 2020 to September 2021 were prospectively recruited in this study.Before the operation,the oral swabs were collected from all the patients for genotyping using the human CYP3A4/5 gene kit.Based on the potential impact of combination of their polymorphisms on sufentanil metabolism and the proportion of different genotype combinations of CYP3A4/5 enzymes,the patients were divided into groups I(3A4 homozygous mutation or 3A4 heterozygous mutation+3A5 homozygous mutation),II(3A4 heterozygous mutation+3A5 heterozygous mutation),and III(3A4 wild type or 3A4 heterozygous mutation+3A5 wild type).According to their BMI,they were also assigned into a normal body weight group(18.5～24.0 kg/m2)and an overweight group(24～<28 kg/m2),and the differences in drug metabolism parameters were statistically analyze between the 2 groups.After routine general anesthesia induction(sufentanil 0.5 μg/kg),venous blood samples were collected to detect the changes in its concentration using high performance liquid chromatography-mass spectrometry(HPLC-MS).The pharmacokinetic data of sufentanil were calculated between the normal BMI group and overweight group in all participants and between the 2 body weight groups among those with different genotype combinations.Results Among the 90 participants completing the blood drug concentration test,8 patients had their blood samples contaminated(including 1 case with an anesthesia duration of<2 h),and 3 were excluded due to low weight or overweight.Eventually,79 participants were included in the pharmacokinetic analysis on the normal body weight group and the overweight group.Compared with the normal body weight group,the central compartment volume of distribution in the overweight group was significantly reduced(P<0.05),while no obvious differences were observed between the 2 groups in terms of peripheral compartment volume of distribution,total clearance rate,peripheral compartment clearance rate,distribution half-life,clearance half-life,and area under the blood concentration-time curve.In group Ⅰ(n=26),the overweight patients(n=13)had significantly reduced central compartment volume of distribution,peripheral compartment volume of distribution,and peripheral compartment clearance rate when compared with the normal body weight patients(n=13)(P<0.05),while no differences were observed in other pharmacokinetic parameters.In groups Ⅱ(n=25)and Ⅲ(n=28),the overweight patients and normal body weight patients had no statistical differences in all pharmacokinetic parameters.Conclusion Among the patients with the same genotype combination of CYP3A4/5 mutations,there was no difference in the metabolism of sufentanil between the overweight and normal weight patients.Additionally,in the population of 3A4 homozygous mutation or 3A4 heterozygous mutation+3A5 homozygous mutation,the overweight patients have smaller peripheral distribution range of sufentanil,and weakened metabolic process.

Objective To explore the epidemiological characteristics of mycoplasma pneumoniae (MP) infection in hospitalized children between 2019 and 2022, and to provide a basis for the prevention and treatment of the disease in the clinic. Methods Blood samples of 12 830 children hospitalized for respiratory tract infection in our hospital between January 2019 and December 2022 were collected, and tested for MP infection, then the prevalence of MP infection in different years, seasons, genders and ages was analyzed. Results The total positive rate of MP was 16.55% (2 123 / 12 830). The annual prevalence rate of MP infection decreased from 17.97% in 2019 to 16.48% in 2022, with statistical difference (P<0.05). In terms of gender, the prevalence of MP infection was higher in females at a rate of 19.38% (1 198 / 6 182) compared with a rate of 13.91% (925 / 6 648) in males, with statistical difference (χ²=69.277, P<0.05).The positive rates in summer (19.84%) and autumn (19.57%) were higher than those in spring (12.97%) and winter (12.38%) (P<0.05) In terms of age, the positive rate of MP infection was 9.68% in < 1 age group, 12.95% in 1-3 age group, 18.23% in 4-6 age group and 23.23% in > 6 age group (P<0.05), with the highest positive rate in > 6 age group. The positive rate of MP infection was 15.49% in acute upper respiratory tract infection , 17.28% in acute lower respiratory tract infection , 16.43% in severe pneumonia, and 16.71% in other diseases, with no statistical difference (P>0.05). Conclusion MP is one of the main pathogens of respiratory infections in hospitalized children. Despite the decreasing trend in MP infection rate in hospitalized children between 2019 and 2022, it remains above the norm. MP infection is characterized by a high prevalence in summer and autumn, children >6 years of age, and girls, so effective measures should be taken to guide clinical anti-infection strategies to improve the physical and mental health of children in this region.

Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore, overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment. Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicin-induced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice. These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.

Objective:To investigate the prognostic value of colony forming unit-granulocyte and macrophage (CFU-GM) in allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:Seventy-three patients who received allo-HSCT in Hebei Yanda Lu Daopei Hospital from February 2015 to January 2017 were selected. According to the level of CFU-GM from bone marrow (BM) culture at the time of allo-HSCT, the patients were fit into high CFU-GM group and low CFU-GM group. The overall survival rate (OS) and relapse-free mortality rate (NRM) of patients after transplantation were tested by χ2 test after a follow-up of 37.0 (12.5, 50.5) months. Kaplan-Meier method was used to compare OS and event-free survival (EFS) of patients with different CFU-GM levels. Logistic regression model was used to analyze the prognostic factors. Cox regression model was used to further analyze the prognostic risk of patients.Results:Compared with the low CFU-GM group, the high CFU-GM group had a higher OS (81.40% vs 60.00%, χ2=4.067, P=0.044) and a lower NRM (11.63% vs 36.67%, χ2=6.474, P=0.011). Compared with the low CFU-GM group, the mean OS time (57.6 and 37.1 months, respectively, P=0.039) and the mean EFS time (61.7 and 38.5 months, respectively, P=0.011) were significantly higher in the high CFU-GM group. Logistic regression analysis showed that both the level of CFU-GM and BM MNC were significant influencing factors of OS ( OR=2.917, 95% CI 1.011-8.418, P=0.048 and OR=1.510, 95% CI 1.058-2.154, P=0.023, respectively) and EFS ( OR=4.400, 95% CI 1.336-14.492, P=0.015 and OR=1.447, 95% CI 1.002-2.090, P=0.049, respectively)after transplantation. The level of CFU-GM was an independent risk factor for evaluating EFS ( HR=0.279, 95% CI 0.097-0.805, P=0.018). BM MNC was an independent risk factor for OS ( HR=1.345, 95% CI 1.052-1.720, P=0.018). Conclusion:The level of CFU-GM and BM MNC were related to the prognosis of allo-HSCT. The patients in the high CFU-GM group had higher EFS.

Objective:To investigate the relationship between the levels of serum cytokines and chemokines and the prognosis of patients with acute B-ALL after receiving chimeric antigen receptor (CAR)-T cell immunotherapy and acute graft-versus-host disease (aGVHD) in patients after bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT).Methods:According to the case-control principle, Forty-two patients with B-ALL who received CD19-CAR-T cell immunotherapy bridged to allo-HSCT at Heibei Yanda Ludaopei Hospital from September 18, 2019 to May 9, 2022 were enrolled. Mann-Whitney U test was used to compare the changes of aGVHD-related cytokines and chemokine levels between CAR-T cell immunotherapy and bridging transplantation in different patients at the same time. Their plasma levels of cytokines and chemokines related to aGVHD were monitored at the day before CAR-T therapy and after CAR-T treatment at day 4, 7,14,21,28. The receiver operating characteristic curve was drawn to evaluate the predictive value of cytokines and chemokines in predicting the occurrence and the death of aGVHD patients. Kaplan-Meier method and Log-rank tests were used for Overall survival (OS) analysis. Results:Twenty-four of total 42 patients had aGVHD, of which 11 patients died and 31 patients survived. There was no significant difference in cytokines and chemokines between the aGVHD group and the non-aGVHD group on the day before CAR-T cell treatment. According to statistical analysis, the serum Elafin levels of aGVHD group was higher than that of non-aGVHD group at the 21st day [4 482 (2 811, 6 061) ng/L vs 2 466 (1 948, 3 375) ng/L, Z=3.145, P=0.001] and the 28st day [4 391 (2 808, 5594) ng/L vs 2 463 (1 658, 2 830) ng/L, Z=2.038, P=0.048] separately. At the 14th day, serum cytokines and chemokines levels between the two group were as follows,MIP-1 α [21.02 (12.36, 30.35) ng/L vs 5.56 (3.64, 10.79) ng/L], sCD25 [422.47 (257.99, 1 233.78) IU/ml vs 216.11 (133.75,457.39) IU/ml], Elafin [4 101 (2 393, 5 006) ng/L vs 2 155 (1 781, 3 033) ng/L], IL-6 [119.08 (23.97, 183.43) ng/L vs 8.39 (2.91, 17.42) ng/L] and IL-8 [13.56 (12.50, 24.52) ng/L vs 2.83 (1.73,6.87) ng/L] were at higher levels ( Z=2.653, P=0.007; Z=2.176, P=0. 030; Z=2.058, P=0.041; Z=3.329, P<0.001; Z=3.162, P=0.001). The KM survival curve showed that the cumulative survival rates of patients with higher serum levels of MIP-1α, sCD25, Elafin, IL-6 and IL-8 were lower than those with low levels at day 14, and the difference was statistically significant (χ 2=12.353, 4.890, 6.551, 10.563, 20.755, P<0.05). Conclusion:The outcomes of patients treated with CAR-T cell therapy bridged to allo-HSCT was correlated with serum MIP-1α, sCD25, Elafin, IL-6 and IL-8 levels after receiving CAR-T therapy. High concentrations of MIP-1α, sCD25, Elafin, IL-6 and IL-8 suggest poor prognosis and can be used as biomarkers to suggest appropriate clinical selection of therapy.

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

Objective:To investigate the application effects of MOTOmed in stepped individualized rehabilitation intervention of older adult patients with post-stroke hemiplegia.Methods:A total of 130 older adult patients with post-stroke hemiplegia who received treatment in the Affiliated People's Hospital of Ningbo University from June 2019 to June 2021 were included in this study. They were randomly assigned to undergo either stepped individualized rehabilitation intervention with MOTOmed training system (observation group, n = 65) or routine rehabilitation intervention (control group, n = 65) for 1 month. Before and after intervention, the Fugl- Meyer Assessment score, Berg Balance Scale score, Functional Ambulation Category scale score, modified Ashworth scale score, and modified Barthel Index, Self-Perceived Burden Scale score, nerve growth factor, brain-derived neurotrophic factor and neurotrophin 3 levels were compared between the two groups. Results:After intervention, Fugl-Meyer Assessment and Berg Balance Scale scores in the observation groups were (75.48 ± 6.54) points and (48.55 ± 5.18) points, which were significantly greater than (72.55 ± 6.33) points and (46.50 ± 4.79) points in the control group ( t = 2.59, 2.34, both P < 0.05). Functional Ambulation Category scale score in the observation group was significantly higher than that in the control group [(3.22 ± 0.43) points vs. (3.05 ± 0.39) points, t = 2.36, P < 0.05). Modified Ashworth scale score in the observation group was significantly lower than that in the control group [(1.23 ± 0.24) points vs. (1.33 ± 0.26) points, t = 2.27, P < 0.05). Modified Barthel Index score in the observation group was significantly higher than that in the control group [(59.32 ± 5.18) points vs. (57.33 ± 4.92) points, t = 2.24, P < 0.05]. There was no significant difference in Self-Perceived Burden Scale score between the two groups ( t = 1.64, P > 0.05). Nerve growth factor level in the observation group was significantly higher than that in the control group [(12.93 ± 2.31) ng/L vs. (12.06 ± 2.29) ng/L, t = 2.15, P < 0.05]. There were no significant differences in brain-derived neurotrophic factor and neurotrophin 3 levels between the two groups ( t = 0.91, 1.25, both P > 0.05). Conclusion:The stepped individualized rehabilitation intervention with MOTOmed training system can greatly improve the limb function, balance ability, walking ability and self-care ability, reduce muscle tension, and increase nerve growth factor level in older adult patients with post-stroke hemiplegia, which are conducive to the rehabilitation and prognosis of post-stroke hemiplegia.

Although primary vesical calculi is an ancient disease, the mechanism of calculi formation remains unclear. In this study, we established a novel primary vesical calculi model with d,l-choline tartrate in mice. Compared with commonly used melamine and ethylene glycol models, our model was the only approach that induced vesical calculi without causing kidney injury. Previous studies suggest that proteins in the daily diet are the main contributors to the prevention of vesical calculi, yet the effect of fat is overlooked. To assay the relationship of dietary fat with the formation of primary vesical calculi, d,l-choline tartrate-treated mice were fed a high-fat, low-fat, or normal-fat diet. Genetic changes in the mouse bladder were detected with transcriptome analysis. A high-fat diet remarkably reduced the morbidity of primary vesical calculi. Higher fatty acid levels in serum and urine were observed in the high-fat diet group, and more intact epithelia in bladder were observed in the same group compared with the normal- and low-fat diet groups, suggesting the protective effect of fatty acids on bladder epithelia to maintain its normal histological structure. Transcriptome analysis revealed that the macrophage differentiation-related gene C-X-C motif chemokine ligand 14 (Cxcl14) was upregulated in the bladders of high-fat diet-fed mice compared with those of normal- or low-fat diet-fed mice, which was consistent with histological observations. The expression of CXCL14 significantly increased in the bladder in the high-fat diet group. CXCL14 enhanced the recruitment of macrophages to the crystal nucleus and induced the transformation of M2 macrophages, which led to phagocytosis of budding crystals and prevented accumulation of calculi. In human bladder epithelia (HCV-29) cells, high fatty acid supplementation significantly increased the expression of CXCL14. Dietary fat is essential for the maintenance of physiological functions of the bladder and for the prevention of primary vesical calculi, which provides new ideas for the reduction of morbidity of primary vesical calculi.

Objective:To investigate the significance of multicolor flow cytometry (MFC) monitoring of minimal residual disease (MRD) in the course of allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CD19-chimeric antigen receptor(CAR)-T cell immunotherapy for patients with refractory, relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL).Methods:37 patients with r/r B-ALL admitted to Hebei Yanda Lu Daopei Hospital from January to July 2019, aged 15 (6, 19) years old, including 24 males and 13 females, were treated with CD19-CAR-T cell immunotherapy bridging allo-HSCT. MFC with cytoplasmic CD79a antibody to set up B-cell gates was used to monitor patients′ bone marrow (BM), cerebrospinal fluid (CSF), and tissue samples on day 0 (prior to the CAR-T cell immunotherapy), day 15, day 28 post CAR-T cell immunotherapy, and post transplantation.The MRD values of these samples were analyzed to evaluate the residual tumor cells and metastasis. The killing effect of the CAR-T cells was evaluated by the recovery of CD19+B cells before transplantation and the period between the timepoint when CD19+B cells was recovered and the timepoint when CAR-T cells were infused. Peripheral blood CAR-T cells were counted at different time points. Statistic analysis was performed by Kaplan-Meie assay and Log-rank test to analyze the difference of univariate cumulative survival.Results:(1)Among the 37 patients, 8 died and 29 survived. 5 patients relapsed after transplantation, of which 4 relapsed patients died and 1 survived. (2)MFC MRD negative remission rate of the death group was lower than that of the survival group at the following time points: post-CAR-T therapy and prior to transplantation (5/8 vs. 28/29, χ 2=7.540, P=0.006); day 15 of the CAR-T cell reinfusion (3/8 vs. 24/29, χ 2=6.512, P=0.011); day 28 of the reinfusion (3/8 vs. 276/29, χ 2=10.065, P=0.002). The probability of extramedullary MFC MRD positive tumor infiltration in the death group was higher than that in the survival group(7/8 vs. 14/29, χ 2=3.931, P=0.047). After CAR-T cell immunotherapy, the recovery period of CD19-positive cells in the death group, or the time for CAR-T cells to kill CD19-positive cells, was shorter than that in the survival group [42.00 days(30.00,49.00) vs. 55.00 days(41.50,73.50), Z=0.022, P=0.020]. Conclusion:The positive results of MRD by MFC at the following timepoints may predict unfavorable outcomes, such as post-CAR-T therapy and prior to transplantation, day 15 and 28 of the CAR-T cell immunotherapy, which may provide some guidance for clinical management.

In 2013, Shanghai Medical College of Fudan University restarted the enrollment of the undergraduate students in directional pediatrics. To cultivate medical talents in pediatrics, a serious of educational innovations and practices have been carried out guided by competency training, including training a team of teachers with simulated teaching skills and establishing a teaching platform for simulation teaching. Medical students can practice medicine and gain experience through the risk-free simulated scenarios, that is helpful to enhance their confidence in clinical skills and communications and decrease medical errors in their future careers.