Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

Objective:To explore the impact of the stimulator of interferon genes(STING)-interferon regulatory factor 3(IRF3)pathway on the senescence of rapid pacing HL-1 myocytes.Methods:HL-1 cells were divided into five groups: the control group(HL-1 cells without any treatment), pacing group(HL-1 cells paced for 48 hours), STING siRNA group(HL-1 cells paced for 48 hours and transfected with STING siRNA), NC siRNA group(HL-1 cells paced for 48 hours and transfected with NC siRNA), and H151 inhibitor group(HL-1 cells paced for 48 hours with the addition of 1 μmol/L STING inhibitor H151). Mitochondrial membrane potential was assessed in control and pacing group cells, and mitochondrial MitoTracker and TFAM co-localization staining was performed on these cells.Cellular senescence was evaluated using β-galactosidase staining in each group, and the positive rate of cellular senescence was observed and calculated.Western blotting was employed to detect the expression levels of STING, IRF3, P-IRF3, P16, P21, and P53 proteins in all groups.Immunofluorescence was utilized to examine the expression distribution of STING and P21 across the various groups.ELISA was performed to measure the concentrations of interleukin(IL)-1β, IL-6, and IL-8 in the cell supernatants from each group as part of the senescence-associated secretory phenotype(SASP).Results:Compared with the control group, the ratio of mitochondrial JC-1 multimer to monomer was significantly decreased in the pacing group( t=16.42, P<0.05), the co-localization of mitochondrial MitoTracker and TFAM in the cells was significantly weakened, the proportion of cells with positive cellular senescence-associated β-galactosidase staining significantly increased in the pacing group, the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 proteins were significantly elevated in the pacing group, and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants were markedly increased.Compared with the pacing group, the proportion of cells with positive cellular senescence-associated β-galactosidase staining decreased in the STING siRNA group and H151 inhibitor group ( F= 18.13, P<0.05), the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 were reduced in the STING siRNA group and H151 inhibitor group ( F=16.84, 26.56, 74.70, 31.80, 31.23, all P<0.05), and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants decreased( F=197.80、1 339.00、1 308.00, all P<0.001). Conclusions:Rapid pacing of HL-1 cells can promote mtDNA release into the cytoplasm, activate the STING-IRF3 pathway, accelerate cellular senescence, and enhance the secretion of SASP.Inhibiting the expression of STING can delay the senescence induced by the rapid pacing of HL-1 cells and reduce SASP secretion.

Objective:To explore the impact of the stimulator of interferon genes(STING)-interferon regulatory factor 3(IRF3)pathway on the senescence of rapid pacing HL-1 myocytes.Methods:HL-1 cells were divided into five groups: the control group(HL-1 cells without any treatment), pacing group(HL-1 cells paced for 48 hours), STING siRNA group(HL-1 cells paced for 48 hours and transfected with STING siRNA), NC siRNA group(HL-1 cells paced for 48 hours and transfected with NC siRNA), and H151 inhibitor group(HL-1 cells paced for 48 hours with the addition of 1 μmol/L STING inhibitor H151). Mitochondrial membrane potential was assessed in control and pacing group cells, and mitochondrial MitoTracker and TFAM co-localization staining was performed on these cells.Cellular senescence was evaluated using β-galactosidase staining in each group, and the positive rate of cellular senescence was observed and calculated.Western blotting was employed to detect the expression levels of STING, IRF3, P-IRF3, P16, P21, and P53 proteins in all groups.Immunofluorescence was utilized to examine the expression distribution of STING and P21 across the various groups.ELISA was performed to measure the concentrations of interleukin(IL)-1β, IL-6, and IL-8 in the cell supernatants from each group as part of the senescence-associated secretory phenotype(SASP).Results:Compared with the control group, the ratio of mitochondrial JC-1 multimer to monomer was significantly decreased in the pacing group( t=16.42, P<0.05), the co-localization of mitochondrial MitoTracker and TFAM in the cells was significantly weakened, the proportion of cells with positive cellular senescence-associated β-galactosidase staining significantly increased in the pacing group, the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 proteins were significantly elevated in the pacing group, and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants were markedly increased.Compared with the pacing group, the proportion of cells with positive cellular senescence-associated β-galactosidase staining decreased in the STING siRNA group and H151 inhibitor group ( F= 18.13, P<0.05), the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 were reduced in the STING siRNA group and H151 inhibitor group ( F=16.84, 26.56, 74.70, 31.80, 31.23, all P<0.05), and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants decreased( F=197.80、1 339.00、1 308.00, all P<0.001). Conclusions:Rapid pacing of HL-1 cells can promote mtDNA release into the cytoplasm, activate the STING-IRF3 pathway, accelerate cellular senescence, and enhance the secretion of SASP.Inhibiting the expression of STING can delay the senescence induced by the rapid pacing of HL-1 cells and reduce SASP secretion.

Objective:To understand the pathogen distributions of community-acquired pneumonia (CAP) in children, and to provide evidence for clinical diagnosis and treatment.Methods:The hospitalized children with CAP in Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine from January to December 2022 were selected as the research subjects. They were divided into infant group (28 d to less than one year), toddler group (one year to less than three years), preschool age group (three years to less than six years), and school age group (not less than six years) by age. According to the onset season, they were divided into spring group (February to April), summer group (May to July), autumn group (August to October), and winter group (January, November to December). Deep airway sputum samples were collected from all patients for bacterial culture identification. Respiratory viruses (influenza A virus (IVA), influenza B virus (IVB), respiratory syncytial virus (RSV), adenovirus, parainfluenza virus type 1 (PIV1), parainfluenza virus type 2 (PIV2), parainfluenza virus type 3 (PIV3)) were detected using direct immunofluorescence assay. Mycoplasma pneumoniae (MP) DNA was detected using fluorescent quantitative polymerase chain reaction, and particle agglutination was used to detect serum MP antibodies. Statistical analysis was performed using the chi-square test. Results:Among the 397 cases of CAP in children, pathogens were detected in 269 cases, with a positivity rate of 67.8%. A total of 309 pathogens were identified, including 204 strains of MP (66.0%), 60 strains of bacteria (19.4%), 42 strains of viruses (13.6%), and three strains of fungi (1.0%). Staphylococcus aureus (19 strains), Haemophilus influenzae (15 strains) and Streptococcus pneumoniae (five strains) were the predominant bacteria, while RSV (19 strains) and PIV3 (nine strains) were the main viruses. The distribution rates of MP, bacteria, and viruses showed statistically significant differences among different age groups ( χ2=99.82, 24.71 and 17.40, respectively, all P<0.05). MP infection was mainly observed in the preschool age group and school age group, and bacterial infection predominantly occurred in the infant group, and viral infection was most common in the toddler group. Among virus infected patients, RSV was detected in the toddler group and the preschool age group, while three cases of PIV3 cases were found in children over five years old. The distribution differences of MP, bacterial and viral infections between different seasons were statistically significant ( χ2=141.65, 20.44 and 31.87, respectively, all P<0.001), with a higher prevalence in winter. RSV infections demonstrated a clear seasonal trend, with 16 cases of RSV infections occurring in winter and spring. Conclusions:MP is the most frequently detected pathogen in children with CAP. Bacterial infection is the most common pathogen in infants with CAP. RSV is the most common viral pathogen, with infections concentrated in the toddler group and the preschool age group, and prevalence in winter and spring. Attention should be paid to PIV3 pneumonia in children over five years old. Rational drug use should be based on the pathogen spectrum characteristics of different seasons and age groups before selecting empirical treatment combinations.

Background/Aims: Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is widely accepted as a radical surgery for refractory ulcerative colitis (UC). Definite results on the appropriate pouch length for an evaluation of the risk-to-benefit ratio regarding technical complications and long-term quality of life (QOL) are still scarce. Methods: Data on UC patients who underwent IPAA from 2008 to 2022 in four well-established pouch centers affiliated to China UC Pouch Center Union were collected. Results: A total of 208 patients with a median follow-up time of 6.0 years (interquartile range, 2.3 to 9.0 years) were enrolled. The median lengths of the patients’ short and long pouches were 14.0 cm (interquartile range, 14.0 to 15.0 cm) and 22.0 cm (interquartile range, 20.0 to 24.0 cm), respectively. Patients with a short J pouch configuration were less likely to achieve significantly improved long-term QOL (p=0.015) and were prone to develop late postoperative complications (p=0.042), such as increased defecation frequency (p=0.003) and pouchitis (p=0.035). A short ileal pouch was an independent risk factor for the development of late postoperative complications (odds ratio, 3.100; 95% confidence interval, 1.519 to 6.329; p=0.002) and impaired longterm QOL improvement (odds ratio, 2.221; 95% confidence interval, 1.218 to 4.050, p=0.009). Conclusions The length of the J pouch was associated with the improvement in long-term QOL and the development of late post-IPAA complications. A long J pouch configuration could be a considerable surgical option for pouch construction.

This study was performed to explore the impact of glutamine(Gln)on the anti-tumor immune response of CD8+ T cells and its mechanism.TCGA database was used to analysis the relationship between tumor Gln metabolism and the quantity and functionality of infiltrating CD8+ T cells.CRISPR/Cas9 was employed to knock down GLS expression in mouse MC38 cells,and a mouse tumor model was established.Flow cytometry was conducted to assess tumor proliferation,apoptosis,and the quantity and functionality of tumor-infiltrating immune cells.Lymphocytes isolated from health individuals were treated with Gln-deficient media,complete media or media supplemented with GSH,RSL3 in vitro.Then the apoptosis,the expression levels of GPX4,Lipid-ROS,and effector function protein of CD8+ T cells were detected by flow cytometry.Furthermore,RNA-seq was performed to analyze the differential gene expression on the Gln-depleted CD8+ T cells.Data showed that tumor Gln metabolism was inversely associated with the quantity and functionality of tumor-infiltrating CD8+ T cells.Low expression of GLS in MC38 cells could inhibit C57BL/6 tumor growth,decrease Ki-67 expression,promote casepase-3 expression,increase the amount of tumor-infiltrating immune cells,suppress PD-1,TIM-3,and LAG-3 expression,and enhance CD137,CD107a,IFN-γ and TNF-α expression in tumor-infiltrating CD8+ T cells.RNA-seq results indicated an upregulation of ferroptosis genes TFRC,HMOX1,CYBB and SLC7A11 in CD8+ T cells following glutamine deficiency.Gln deficiency led to lower CD137,CD107a,IFN-γ,GSH,GPX4 expression,increased Lipid-ROS level,and caused cell death in CD8+ T cells.Supplementation of GSH upregulated GPX4 expression,downregulated Lipid-ROS level,and increased IFN-γ secretion in CD8+ T cells.In conclusion,Gln deficiency inhibits the effector function of CD8+ T cells by inducing ferroptosis,and promotes tumor growth.

Objective To investigate the relationship between parotid image texture and acute radiation xerostomia (grade) during radiotherapy in patients with head and neck cancer.The mathematical model was established to predict the severity of radiation dry mouth in the early stage.Methods 23 patients with head and neck cancer treated with radiotherapy were observed.The degree of xerostomia was evaluated according to RTOG criteria.The weekly validated CT images of these patients during radiotherapy were collected and transmitted to the MIM system to outline the parotid gland,and an internal analysis program was developed in MATLAB (R2013a).The changes of texture features of weekly parotid CT images during radiotherapy were analyzed,including mean CT value (MCTN),standard deviation (STD),skewness,kurtosis,entropy and volume.The mathematical model was established,and the KNN method was used to optimize the model and predict the level of xerostomia.Results There was no significant correlation among the changes of MCTN,volume and the degree of xerostomia (P ＞ 0.05).However,according to the weekly changes of MCTN and volume,the model was established to predict the grade of xerostomia with an accuracy of 99％.Conclusions The changes of parotid gland MCTN and volume were significantly correlated with acute radiation xerostomia during radiotherapy for head and neck cancer,and the MCTN changes can be used to predict the severity of xerostomia in the early stage.

The malignant phenotype of classical Hodgkin lymphoma ( cHL) is partly maintained by epige-netic aberrant ,of which consisted mainly abnormal histone methylation and deacetylation .Progress has been made in clinical trials related to the histone deacetylases inhibitors ( HDACis) in cHL.There is a close association noted between the epigenetic aberrants and the immune escape in cHL .DNA methyltransferase ( DNMT) inhibitors, HDACis and immune checkpoint blockade have shown synergistic effects .Further study to improve the cure rate in cHL by combination strategy is of significant importance .

Objective To investigate the clinical features and disease-causing mutations of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis.Methods In February 2016,a 24 year old female patient with left kidney stone and nephrocalcinosis in bilateral kidneys was admitted to our hospital.One month prior to this admission,she had been treated by PCNL to remove the most part of left kidney stone in otherhospital.Mter admission,She was found hypomagnesaemia (serum magnesium 0.65 mmol/ L) and hypercalciuria (24h urine calcium 364.0 mg) but with normal renal function (serum creatinine 101.5μmol/L).And the remained part of left kidney stone was removed by flexible ureteroscope.As she was considered probably with an autosomal recessive FHHNC,an analysis of CLDN16 and CLDN19 gene mutations was performed using her and her parents'peripheral white blood cells.Results Mutation analysis revealed this patient had two heterozygous mutations in the CLDN16.One is an one-base deletion mutation in the 123th codon in exon 2:368delA.The other is a missense mutation in the 139th codon in exon 2:416C →T which resulted in an amino acid change Ala139Val.Her parents respectively had one of each heterozygous mutation.In the six months follow-up,an oral administration with hvdrochlorothiazide,potassium citrate,and calcium magesium supplements significantly reduced her hypomagnesaemia (serum magnesiun 1.0 mmol/L) and hypercalciuria (24-h urine calcium 156.0 mg),and no stone recurrence and aggravation of nephrocalcinosis and renal dysfunction occurred.Conclusions We diagnosed a patient with FHHNC who had a novel compound heterozygous mutation of CLDN16.This rare disease should be suspected if there are three constant clinical features of hypomagnesaemia,hypercalciuria and nephrocalcinosis,and verified with CLDN16 and CLDN19 gene test.Currently the option for treatment of FHHNC is symptomatic treatment until severe deterioration of renal function.The hydrochlorothiazide,potassium citrate,and calcium magesium supplements may have considerable effects on hypomagnesaemia and hypercalciuria.

Objective To evaluate the safety and efficacy of robot﹣assisted laparoscopic living donor nephrectomy. Methods Clinical data of 31 donors and recipients undergoing robot﹣assisted laparoscopic living donor nephrectomy in Xijing Hospital of the Fourth Military Medical University from November 2013 to August 2015 were retrospectively analyzed. Results Donor nephrectomy was successfully performed in 31 cases.The operation time ranged from 110 to 190 min.Intraoperative hemorrhage volume was measured as 20﹣100 ml.The warm ischemia time of the donor kidney was 100 to 160 s.The retained length of renal vein was between 1.8 and 3.0 cm and the length of renal artery was 1.4 to 2.3 cm.In 2 cases,spleen injury occurred during the kidney extraction and was treated with splenorrhaphy.One donor had postoperative hemorrhage,which was treated with hemostasis and anemia correction.Thirty one donors received postoperative follow﹣up for over 6 months.No long﹣term complications were observed.Among 31 recipients,one patient had delayed recovery of renal graft function and the serum creatinine level returned to normal range after treatment at postoperative 1 month.The survival rate of kidney grafts was up to 100%. Conclusions Robot﹣assisted laparoscopic living donor nephrectomy is a safe and efficacious surgical procedure for kidney resection,which possesses the advantages of small trauma,rapid recovery and no influence upon renal function.