Objective:To investigate the impact of pre-treatment TPMT and NUDT15 genotyping on medication selection, tolerability and discontinuation rates of azathioprine or 6-mercaptopurine therapy in children with inflammatory bowel disease (IBD).Methods:A retrospective cohort study was conducted on 181 children with IBD who were scheduled for azathioprine or 6-mercaptopurine therapy at the Department of Gastroenterology, Children′s Hospital, Zhejiang University School of Medicine between January 2010 and January 2023. Among them, 168 children who received treatment were divided into a genotyped group and non-genotyped group based on pre-treatment TPMT and NUDT15 genotyping. The incidence of drug-related adverse reactions was compared between the two groups. The impact of genotyping on medication selection and discontinuation rates was analyzed. Chi-square test or Fisher exact test were used for intergroup comparisons. Logistic regression analysis was used to control the confounding factors. Firth Logistic regression analysis was applied for data with complete separation. The probability of discontinuation was assessed using survival analysis with Cox proportional hazards modeling.Results:Among the 181 children with IBD, 13 did not receive azathioprine or 6-mercaptopurine due to genetic variants, while the remaining 168 underwent the therapy (154 cases of Crohn′s disease and 14 cases ulcerative colitis; 108 males and 60 females). Excluding the 13 untreated cases, 77 children underwent TPMT and NUDT15 genotyping were assigned to the genotyped group, and the remaining 91 to the non-genotyped group. Adverse reactions included myelosupression (26 cases,15.5%), hepatotoxicity (18 cases,10.7%), gastrointestinal disturbance (25 cases,14.9%), alopecia (12 cases,7.1%), fever (3 cases,1.8%), rash (2 cases,1.2%), and pancreatitis (1 case,0.6%). The incidence of overall adverse reactions was significantly higher in the non-genotyped group compared to that of the genotyped group (40.7% (37/91) vs. 26.0% (20/77), P<0.05). Specifically, the non-genotyped group had a higher rate of gastrointestinal reactions compared to the genotyped group (24.2% (22/91) vs. 3.3% (3/77), P<0.01). Cox regression analysis revealed that non-genotyped group had a higher risk of treatment discontinuation due to the adverse reactions ( HR=1.47, 95% CI 0.65-3.30). Conclusion:Pre-treatment genotyping of TPMT and NUDT15 variants can help guide the selection of clinical drugs, reduce the incidence of drug-related adverse reactions and enhance tolerability of azathioprine or 6-mercaptopurine therapy in IBD children.

Objective:To analyze the clinical and genetic features of four children with pediatric acute liver failure (PALF) caused by neuroblastoma-amplified sequence ( NBAS) gene variant, as well as the correlation between clinical phenotype and genotype. Methods:The clinical data and genetic test results of four children with NBAS gene variants admitted to the Department of Gastroenterology, Children's Hospital Affiliated to Zhejiang University School of Medicine from August 2015 to June 2023 mainly presenting with pediatric acute liver failure (PALF) were retrospectively analyzed. The relevant literature from January 2015 to May 2024 was retrieved using the Chinese and English keywords " NBAS," "neuroblastoma amplified sequence," "SOPH," "short stature with optic nerve atrophy and Pelger Hu?t anomaly," "liver failure," and "neuroblastoma amplified sequence" indexed in the CNKI database, Wanfang Data Knowledge Service Platform, and PubMed database. The clinical features and gene mutation characteristics of domestic patients were summarized. Results:The age at which the initial PALF attack occurred in the four children varied from eight months to three years and seven months. All patients developed PALF within 1-2 days after the onset of fever, with symptoms such as vomiting, convulsions, and mental depression or confusion, accompanied by a sharp increase in transaminases, elevated bilirubin and blood ammonia, hyperlactatemia, and hepatomegaly. The PALF gradually improved, and three pediatric patients showed extrahepatic manifestations following antipyretic, fluid replacement, and other symptomatic supportive treatment. Long-term follow-up showed that active temperature control and symptomatic therapy reduced the recurrence of PALF. Genetic testing identified eight kinds of NBAS gene variants sites. Family testing validated compound heterozygous variants, which included four missense variants, one nonsense variants, and three frameshift mutations. A literature study revealed that out of 51 Chinese patients with NBAS gene variants, 98.0% (50/51) had liver involvement, and 37 cases showed PALF. A total of 61 mutation sites were identified, with c.3596G>A (45.1%, 23/51) as a hotspot variants. Conclusions:PALF caused by NBAS gene variant has obvious clinical and genetic characteristics, and there is a correlation between genotype and clinical phenotype. The c.3596G>A variant site is a hotspot mutation in China and is strongly correlated with the liver failure phenotype.

Objective:To investigate the impact of pre-treatment TPMT and NUDT15 genotyping on medication selection, tolerability and discontinuation rates of azathioprine or 6-mercaptopurine therapy in children with inflammatory bowel disease (IBD).Methods:A retrospective cohort study was conducted on 181 children with IBD who were scheduled for azathioprine or 6-mercaptopurine therapy at the Department of Gastroenterology, Children′s Hospital, Zhejiang University School of Medicine between January 2010 and January 2023. Among them, 168 children who received treatment were divided into a genotyped group and non-genotyped group based on pre-treatment TPMT and NUDT15 genotyping. The incidence of drug-related adverse reactions was compared between the two groups. The impact of genotyping on medication selection and discontinuation rates was analyzed. Chi-square test or Fisher exact test were used for intergroup comparisons. Logistic regression analysis was used to control the confounding factors. Firth Logistic regression analysis was applied for data with complete separation. The probability of discontinuation was assessed using survival analysis with Cox proportional hazards modeling.Results:Among the 181 children with IBD, 13 did not receive azathioprine or 6-mercaptopurine due to genetic variants, while the remaining 168 underwent the therapy (154 cases of Crohn′s disease and 14 cases ulcerative colitis; 108 males and 60 females). Excluding the 13 untreated cases, 77 children underwent TPMT and NUDT15 genotyping were assigned to the genotyped group, and the remaining 91 to the non-genotyped group. Adverse reactions included myelosupression (26 cases,15.5%), hepatotoxicity (18 cases,10.7%), gastrointestinal disturbance (25 cases,14.9%), alopecia (12 cases,7.1%), fever (3 cases,1.8%), rash (2 cases,1.2%), and pancreatitis (1 case,0.6%). The incidence of overall adverse reactions was significantly higher in the non-genotyped group compared to that of the genotyped group (40.7% (37/91) vs. 26.0% (20/77), P<0.05). Specifically, the non-genotyped group had a higher rate of gastrointestinal reactions compared to the genotyped group (24.2% (22/91) vs. 3.3% (3/77), P<0.01). Cox regression analysis revealed that non-genotyped group had a higher risk of treatment discontinuation due to the adverse reactions ( HR=1.47, 95% CI 0.65-3.30). Conclusion:Pre-treatment genotyping of TPMT and NUDT15 variants can help guide the selection of clinical drugs, reduce the incidence of drug-related adverse reactions and enhance tolerability of azathioprine or 6-mercaptopurine therapy in IBD children.

Objective:To analyze the clinical and genetic features of four children with pediatric acute liver failure (PALF) caused by neuroblastoma-amplified sequence ( NBAS) gene variant, as well as the correlation between clinical phenotype and genotype. Methods:The clinical data and genetic test results of four children with NBAS gene variants admitted to the Department of Gastroenterology, Children's Hospital Affiliated to Zhejiang University School of Medicine from August 2015 to June 2023 mainly presenting with pediatric acute liver failure (PALF) were retrospectively analyzed. The relevant literature from January 2015 to May 2024 was retrieved using the Chinese and English keywords " NBAS," "neuroblastoma amplified sequence," "SOPH," "short stature with optic nerve atrophy and Pelger Hu?t anomaly," "liver failure," and "neuroblastoma amplified sequence" indexed in the CNKI database, Wanfang Data Knowledge Service Platform, and PubMed database. The clinical features and gene mutation characteristics of domestic patients were summarized. Results:The age at which the initial PALF attack occurred in the four children varied from eight months to three years and seven months. All patients developed PALF within 1-2 days after the onset of fever, with symptoms such as vomiting, convulsions, and mental depression or confusion, accompanied by a sharp increase in transaminases, elevated bilirubin and blood ammonia, hyperlactatemia, and hepatomegaly. The PALF gradually improved, and three pediatric patients showed extrahepatic manifestations following antipyretic, fluid replacement, and other symptomatic supportive treatment. Long-term follow-up showed that active temperature control and symptomatic therapy reduced the recurrence of PALF. Genetic testing identified eight kinds of NBAS gene variants sites. Family testing validated compound heterozygous variants, which included four missense variants, one nonsense variants, and three frameshift mutations. A literature study revealed that out of 51 Chinese patients with NBAS gene variants, 98.0% (50/51) had liver involvement, and 37 cases showed PALF. A total of 61 mutation sites were identified, with c.3596G>A (45.1%, 23/51) as a hotspot variants. Conclusions:PALF caused by NBAS gene variant has obvious clinical and genetic characteristics, and there is a correlation between genotype and clinical phenotype. The c.3596G>A variant site is a hotspot mutation in China and is strongly correlated with the liver failure phenotype.

Objective:To investigate the correlation between red cell volume distribution width (RDW) variation coefficient and mortality in patients with liver cirrhosis complicated with sepsis.Methods:From 2008 to 2019, the real clinical data of patients admitted to the intensive care unit (ICU) of Beth Israel Deaconess Medical Center, Massachusetts Institute of Technology were selected from the American Medical Information Mart for Intensive Care-Ⅳ (MIMIC-Ⅳ) database. Structured Query Language was used to extract the demographic information, physiological indicators, laboratory test indicators, complications, in-hospital mortality, and sequential organ failure assessment (SOFA) score from the MIMIC-Ⅳ database. Analysis of variance and Kruskal-Wallis test were used to analyze the characteristics of patients in different quartiles of RDW variation coefficient and the correlation between RDW variation coefficient and different outcomes. The clinical and prognostic variables were included in the logistic regression model and its adjustment models for analysis. Model 1 was adjusted according to age and gender, and model 2 was adjusted according to age, gender, SOFA score, bilirubin, albumin, body weight, white blood cell count, serum creatinine, serum sodium, dialysis treatment, and with congestive heart failure or not. A cubic spline regression model was used to analyze the dose-response relationship between RDW variation coefficient and in-hospital mortality, ICU mortality, mild to moderate disorders of consciousness in patients with liver cirrhosis complicated with sepsis. Trend tests were performed to analyze the interaction between the RDW variation coefficient and the variables used for stratification.Results:A total of 1 443 patients with liver cirrhosis complicated with sepsis were included, with a median age of 59.0 (52.0, 67.0) years old. Among them, 954 (66.1%) were male and 489 (33.9%) were female. The RDW variation coefficient was 3.49±2.50. Totally 382 patients died during hospitalization, 246 patients died in ICU, and 259 patients with mild to moderate disorders of consciousness. When RDW variation coefficient was analyzed as a continuous variable, the OR values (95% confidence interval (95% CI)) of unadjusted model, model 1, and model 2 in in-hospital mortality, ICU mortality and mild to moderate disorders of consciousness were 1.12 (1.09 to 1.16), 1.14 (1.10 to 1.17), 1.08 (1.03 to 1.13); 1.11 (1.07 to 1.15), 1.12 (1.08 to 1.16), 1.07 (1.02 to 1.12); and 1.16 (1.12 to 1.20), 1.16 (1.12 to 1.20), 1.12 (1.07 to 1.17); respectively. The fourth quartile of RDW variation coefficient (>4.74, 29.08) was taken as the control group, the OR values (95% CI) of the unadjusted model, model 1, and model 2 were 3.00 (2.13 to 4.25), 3.32 (2.34 to 4.74), 1.76 (1.10 to 2.84); 3.42 (2.27 to 5.26), 3.81 (2.50 to 5.90), 1.77 (1.03 to 3.11); and 8.52 (5.23 to 14.63), 8.35 (5.10 to 14.38), 5.56 (2.87 to 11.69); respectively. There was a linear correlation between RDW variation coefficient and in-hospital mortality, ICU mortality, mild and moderate disorders of consciousness (all P<0.05). Among patients with higher SOFA scores, along with the increase of RDW variation coefficient, the increase of in-hospital mortality, ICU mortality and the incidence of mild and moderate disorders of consciousness, were more significant than those of patients with lower SOFA scores ( P=0.022, 0.024, and 0.001). Conclusion:Variation coefficient of RDW is associated with increased risk of disorders of consciousness and in-hospital mortality in patients with liver cirrhosis complicated with sepsis.

Objective:To analyze the efficacy of switching to adalimumab (ADA) treatment in pediatric with inflammatory bowel disease (IBD) after failure of infliximab (IFX) treatment.Methods:Clinical data of children with IBD who were treated at the Children's Hospital of Zhejiang University School of Medicine from January 2019 to May 2023 and switched to ADA treatment after IFX treatment failure were retrospectively included. The clinical symptoms, laboratory results, disease activity index of pediatrics, and endoscopic severity scores under colonoscopy were compared between baseline, treatment after 3 months and 12 months.Results:A total of 47 IBD patients were enrolled, including 36 cases of Crohn's disease, 4 cases of ulcerative colitis, and 7 cases of IBD unclassified. There were 28 male and 19 female patients. Among patients who were converted to ADA treatment, 31/47 (66.0%) had low trough concentration and high anti-IFX antibodies, 12/47 (25.5%) had allergic reactions to IFX, and 4/47 (8.5%) had low IFX trough concentration and no anti-IFX antibody. The overall 12 month retention rate of IBD patients who converted to ADA treatment after IFX treatment was 76.6% (36/47). After 3 months of ADA treatment, compared to the baseline, in body mass index for age, height for age, and serum albumin levels increased, while inflammatory markers such as high sensitivity C reactive protein, erythrocyte sedimentation rate, and pediatric Crohn's disease activity index scores decreased. Compared to 3 months of treatment, nutritional and inflammatory markers after 12 months of treatment were stable. No serious adverse reactions or severe infections were found. Six (13%) patients who had pain and swelling at the injection site. Two patients were detected to have high titers of antibodies.Conclusions:Pediatric IBD patients switched to ADA treatment after failure of IFX treatment with ADA for 3 months improves nutrition status and serum albumin levels, while reducing inflammatory markers and disease activity. No serious adverse reactions are found. Application of ADA after failure of IFX treatment provides a practical basis for converting biological agents for pediatric IBD.

Objective:To analyze the efficacy of switching to adalimumab (ADA) treatment in pediatric with inflammatory bowel disease (IBD) after failure of infliximab (IFX) treatment.Methods:Clinical data of children with IBD who were treated at the Children's Hospital of Zhejiang University School of Medicine from January 2019 to May 2023 and switched to ADA treatment after IFX treatment failure were retrospectively included. The clinical symptoms, laboratory results, disease activity index of pediatrics, and endoscopic severity scores under colonoscopy were compared between baseline, treatment after 3 months and 12 months.Results:A total of 47 IBD patients were enrolled, including 36 cases of Crohn's disease, 4 cases of ulcerative colitis, and 7 cases of IBD unclassified. There were 28 male and 19 female patients. Among patients who were converted to ADA treatment, 31/47 (66.0%) had low trough concentration and high anti-IFX antibodies, 12/47 (25.5%) had allergic reactions to IFX, and 4/47 (8.5%) had low IFX trough concentration and no anti-IFX antibody. The overall 12 month retention rate of IBD patients who converted to ADA treatment after IFX treatment was 76.6% (36/47). After 3 months of ADA treatment, compared to the baseline, in body mass index for age, height for age, and serum albumin levels increased, while inflammatory markers such as high sensitivity C reactive protein, erythrocyte sedimentation rate, and pediatric Crohn's disease activity index scores decreased. Compared to 3 months of treatment, nutritional and inflammatory markers after 12 months of treatment were stable. No serious adverse reactions or severe infections were found. Six (13%) patients who had pain and swelling at the injection site. Two patients were detected to have high titers of antibodies.Conclusions:Pediatric IBD patients switched to ADA treatment after failure of IFX treatment with ADA for 3 months improves nutrition status and serum albumin levels, while reducing inflammatory markers and disease activity. No serious adverse reactions are found. Application of ADA after failure of IFX treatment provides a practical basis for converting biological agents for pediatric IBD.

Abstract OBJECTIVE To investigate the effect of infliximab through concentration and antibody monitoring on the clinical outcome of children with Crohn's disease after 54 weeks of treatment. METHODS A retrospective analysis was conducted with clinical data of pediatric patients aged 6-17 years who were diagnosed with Crohn's disease at Children's Hospital, Zhejiang University School of Medicine from August 2017 to March 2023. They were divided into a reactive and a proactive monitoring group according to the monitoring method. The mucosal healing rate, disease activity, and laboratory indicators were compared after 54 weeks of treatment. RESULTS There were 77 pediatric patients with Crohn's disease included, with 34 patients from the reactive therapeutic drug monitoring group and 43 from the proactive therapeutic drug monitoring group, including 48 males and 29 females. At 54 weeks, the mucosal healing rate in the proactive therapeutic drug monitoring group was higher than that in the reactive therapeutic drug monitoring group, which was 80%(24/30) and 46.43%(13/28), respectively. The two groups had a statistical difference(P=0.01). The total clinical remission rate at 54 weeks was 84.42%(65/77), while the clinical remission rates at 54 weeks were 76.47%(26/34) in the reactive therapeutic drug monitoring group and 90.70%(39/43) in the proactive therapeutic drug monitoring group, respectively. The two groups had no statistical difference. The improvement of hypersensitive C-reactive protein, erythrocyte sedimentation rate, and serum albumin level in the proactive monitoring group was greater than in the reactive monitoring group. There was no statistical difference in the production rate of antibodies to infliximab between the two groups. CONCLUSION Proactive therapeutic drug monitoring in detecting through concentration of infliximab and antibodies may improve the mucosal healing rate compared with reactive therapeutic drug monitoring after 54 weeks of infliximab treatment.

Objective:To observe the efficacy of maintenance treatment of thiopurines after exclusive enteral nutrition (EEN) therapy for Crohn′s disease (CD) children, and explore the influencing factors of recurrence.Methods:A retrospective case-control study was conducted. CD children treated in the Children′s Hospital of Zhejiang University School of Medicine from March 2013 to March 2021 were included retrospectively. Data before EEN were collected including general demographics, Paris classification, the pediatric Crohn′s disease activity index (PCDAI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and serum albumin levels. According to the recurrence at 1 year of follow-up, patients were divided into remission group and recurrence group. The differences in clinical data before EEN between the 2 groups were analyzed. The factors influencing the recurrence were analyzed.Results:Thirty-five children were enrolled, including 25 (71.4%) males and 10 (28.6%) females. The age at diagnose was (11.2 ± 3.1) years old and the disease duration was 3.5 (2.2, 6.9) months. After 1 year of follow-up, 15 children had recurrence at least for one time and were divided into the recurrence group. Twenty (57.1%) children continued to maintain 6-mercaptopurine (6-MP) monotherapy and were divided into the remission group. There was no significant differences in gender, diagnostic age, and CRP, ESR, serum albumin and PCDAI before EEN between the two groups (all P>0.05). There was significant difference in the percentage of patients with disease duration of longer than 1 year before EEN between the two groups ( P = 0.026) . Conclusions:The children with the disease duration of longer than 1 year before EEN may be in high risk of recurrence on the regimen of maintenance treatment of thiopurines after EEN.

Objective:To explore the incidence and the risk factors of post-polypectomy bleeding and polyp recurrence after colonoscopic high-frequency electrocoagulation snare polypectomy.Methods:Clinical data of 1 826 children who underwent colonoscopic high-frequency electrocoagulation snare polypectomy in the Children′s Hospital, Zhejiang University School of Medicine from January 2009 to December 2020 was retrospectively analyzed. Demographic characteristics, endoscopic manifestations, pathological features, diagnosis, occurrence of post-polypectomy bleeding and polyp recurrence were collected. The associated risk factors were analyzed by Logistic regression.Results:A total of 1 826 children (1 191 males and 635 females) with 1 967 polypectomies were included. The age was 4.6 (3.2, 6.4) years at initial diagnosis. According to the initial colonoscopy, 1 611 children (88.2%) had solitary polyps, 1 707 children (93.5%) had pedicled polyps, 1 151 children (63.0%) had polyps involving the rectum, and 1 757 children (96.2%) had hamartomatous polyps. Polyposis syndromes were diagnosed in 73 children (4.0%). The post-polypectomy bleeding occurrence was 3.8% (75/1 967). Polyps recurred in 88 children (4.8%). Girls ( OR=2.01, 95% CI 1.26-3.23) and sessile polyps ( OR=2.28, 95% CI 1.15-4.49) were risk factors for post-polypectomy bleeding (both P<0.05). Multiple polyps ( OR=17.49, 95% CI 9.82-31.18), right-colon involvement ( OR=3.44, 95% CI 1.89-6.26) and non-hamartoma ( OR=2.51, 95% CI 1.04-6.07) were risk factors for polyp recurrence (all P<0.05). Conclusions:Colonoscopic high-frequency electrocoagulation snare polypectomy has low incidence of post-polypectomy bleeding and polyp recurrence. Female patients and sessile polyps have higher risk for post-polypectomy bleeding. Multiple polyps, right-colon involvement and non-hamartoma polyps increase the risk for polyp recurrence.