1.Multi-component Quality Consistency Evaluation of Leonuri Herba Granules Based on HPLC-DAD-CAD Multi-detector Technique and Chemometrics
Shuangyan LI ; Jun ZHANG ; Cong GUO ; Siyuan LI ; Jipeng DI ; Jiangmin SU ; An LIU ; Xiaodi KOU ; Yan LIU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(8):174-181
ObjectiveTo systematically evaluate the content differences of 4 components in Leonuri Herba granules, reveal the quality fluctuation patterns of products from the same and different manufacturers, providing scientific basis for the optimization of production process and quality control. MethodsHigh performance liquid chromatography-diode array detector-charged aerosol detector(HPLC-DAD-CAD) was employed to determine the contents of 4 components(syringic acid, leonurine hydrochloride, ferulic acid, and stachydrine hydrochloride) in samples from 19 manufacturers(53 batches, 159 boxes). Additionally, fingerprint profiles were constructed, and the fingerprint dissimilarity(PS) and relative standard deviation(RSD) of different samples from the same manufacturer were calculated. A principal component analysis(PCA) model was established with PS and the RSD values of the 4 components as variables to classify the manufacturers. Finally, samples from 5 manufacturers(M1-M5) covering three consistency groups were selected to calculate three quality consistency parameters, namely intra-batch consistency(PA), inter-batch consistency(PB), and PS. Then, PCA was performed with PA, PB, and PS of these 5 manufacturers as variables. ResultsThe average total content of the 4 index components per bag across the 19 manufacturers ranged from 41.10 mg to 97.54 mg. Among them, the content of stachydrine hydrochloride(a pharmacopoeial quality control component) was 32.46-72.70 mg per bag, all meeting the requirements of the 2025 edition of the Pharmacopoeia of the People's Republic of China, with RSD of 1.7%-17.1%. The content ranges of the other 3 components were as follows:syringic acid of 1.43-41.92 mg per bag, leonurine hydrochloride of 0.67-11.85 mg per bag, and ferulic acid of 0.11-3.81 mg per bag. Notably, leonurine hydrochloride exhibited the most significant content fluctuation among samples from the same manufacturer(RSD of 4.8%-59.2%). PCA results showed that the 19 manufacturers could be classified into 3 categories. Samples from 8 manufacturers(M2, M6, M7, M8, M10, M15, M17, M18) demonstrated relatively high consistency, five manufacturers(M3, M9, M12, M13, M14) showed moderate consistency, six manufacturers(M1, M4, M5, M11, M16, M19) exhibited low consistency. The two methods yielded consistent classification results for the 5 representative manufacturers, verifying the reliability of the proposed method. Among these, manufacturer M2 showed the best quality consistency and the highest total content of indicator components among M1-M5. ConclusionThe HPLC-DAD-CAD multi-detector hyphenation technology established in this study enables the accurate detection of 4 components in Leonuri Herba granules. Significant differences in the total content of these four components are observed among products from 19 manufacturers. The application of 2 consistency evaluation methods combined with PCA can effectively classify their consistency into 3 categories, and the classification results of the 2 methods are highly consistent. This study provides scientific basis for the process optimization and quality standard improvement of Leonuri Herba granules.
2.Multi-component Quality Consistency Evaluation of Leonuri Herba Granules Based on HPLC-DAD-CAD Multi-detector Technique and Chemometrics
Shuangyan LI ; Jun ZHANG ; Cong GUO ; Siyuan LI ; Jipeng DI ; Jiangmin SU ; An LIU ; Xiaodi KOU ; Yan LIU
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(8):174-181
ObjectiveTo systematically evaluate the content differences of 4 components in Leonuri Herba granules, reveal the quality fluctuation patterns of products from the same and different manufacturers, providing scientific basis for the optimization of production process and quality control. MethodsHigh performance liquid chromatography-diode array detector-charged aerosol detector(HPLC-DAD-CAD) was employed to determine the contents of 4 components(syringic acid, leonurine hydrochloride, ferulic acid, and stachydrine hydrochloride) in samples from 19 manufacturers(53 batches, 159 boxes). Additionally, fingerprint profiles were constructed, and the fingerprint dissimilarity(PS) and relative standard deviation(RSD) of different samples from the same manufacturer were calculated. A principal component analysis(PCA) model was established with PS and the RSD values of the 4 components as variables to classify the manufacturers. Finally, samples from 5 manufacturers(M1-M5) covering three consistency groups were selected to calculate three quality consistency parameters, namely intra-batch consistency(PA), inter-batch consistency(PB), and PS. Then, PCA was performed with PA, PB, and PS of these 5 manufacturers as variables. ResultsThe average total content of the 4 index components per bag across the 19 manufacturers ranged from 41.10 mg to 97.54 mg. Among them, the content of stachydrine hydrochloride(a pharmacopoeial quality control component) was 32.46-72.70 mg per bag, all meeting the requirements of the 2025 edition of the Pharmacopoeia of the People's Republic of China, with RSD of 1.7%-17.1%. The content ranges of the other 3 components were as follows:syringic acid of 1.43-41.92 mg per bag, leonurine hydrochloride of 0.67-11.85 mg per bag, and ferulic acid of 0.11-3.81 mg per bag. Notably, leonurine hydrochloride exhibited the most significant content fluctuation among samples from the same manufacturer(RSD of 4.8%-59.2%). PCA results showed that the 19 manufacturers could be classified into 3 categories. Samples from 8 manufacturers(M2, M6, M7, M8, M10, M15, M17, M18) demonstrated relatively high consistency, five manufacturers(M3, M9, M12, M13, M14) showed moderate consistency, six manufacturers(M1, M4, M5, M11, M16, M19) exhibited low consistency. The two methods yielded consistent classification results for the 5 representative manufacturers, verifying the reliability of the proposed method. Among these, manufacturer M2 showed the best quality consistency and the highest total content of indicator components among M1-M5. ConclusionThe HPLC-DAD-CAD multi-detector hyphenation technology established in this study enables the accurate detection of 4 components in Leonuri Herba granules. Significant differences in the total content of these four components are observed among products from 19 manufacturers. The application of 2 consistency evaluation methods combined with PCA can effectively classify their consistency into 3 categories, and the classification results of the 2 methods are highly consistent. This study provides scientific basis for the process optimization and quality standard improvement of Leonuri Herba granules.
3.Adiponectin alleviates high glucose-induced retinal angiogenesis by inhibiting NLRP3 inflammasome
Yong ZHANG ; Xiaodi WANG ; Yixin ZHANG ; Guomin YAO
International Eye Science 2026;26(5):732-737
AIM: To explore the effect of adiponectin(ADPN)on angiogenesis of human retinal microvascular endothelial cells(hRMECs)in high glucose(HG)environment and role of NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome.METHODS: The hRMECs were divided into six groups, including control group(without treatment), HG group: incubated with D-glucose, ADPN group: pretreatment with ADPN and then incubated with D-glucose, CY-09 group: pretreatment with CY-09(an NLRP3 inhibitor)and then incubated with D-glucose, Nigericin group: pretreatment with nigericin(an NLRP3 activator)and then incubated with D-glucose, Nigericin+ADPN group: pretreatment with nigericin and ADPN and then incubated with D-glucose. NLRP3 level was detected using Western blot analysis. hRMECs migration was measured using scratch wound healing assay. The tube formation of hRMECs was detected using Matrigel.RESULTS: The NLRP3 expression in hRMECs cultured in an HG environment was significantly increased(P<0.01), while ADPN and CY-09 reduced the elevated NLRP3(both P<0.05 vs HG group). Nigericin significantly increased NLRP3 levels(P<0.01 vs control group)which was reversed by ADPN(P=0.032 vs Nigericin group). hRMECs migration ability(P<0.001), and total master segments length and number of meshes increased in HG group(P<0.001)while decreased in ADPN and CY-09 groups(all P<0.01 vs HG group). The hRMECs migration ability and tube formation(total master segments length and number of meshes)in HG environment were significantly increased by nigericin(P=0.003), while ADPN inversed the change. CONCLUSION: ADPN alleviates the migration and angiogenesis of hRMECs under HG conditions.
4.Literature analysis of euglycemic diabetic ketoacidosis induced by empagliflozin
Zhenzhen LEI ; Wei RUI ; Yanling SHI ; Jiayue ZHU ; Ying GANG ; Xiaodi SUN ; Hao ZHAN ; Junnan WANG ; Yukun NIU ; Wenxiang ZHANG
China Pharmacy 2026;37(14):1874-1879
OBJECTIVE To investigate the clinical characteristics of euglycemic diabetic ketoacidosis (euDKA) induced by empagliflozin, and provide references for safe medication. METHODS Case reports of euDKA induced by empagliflozin were retrieved and analyzed from PubMed, Web of Science, CNKI, and Wanfang Data. The Naranjo’s scale was adopted to assess the causal relationship between empagliflozin and euDKA. RESULTS A total of 29 patients were enrolled, including 16 males and 13 females,with a median age of 58 years. All patients were diagnosed with type 2 diabetes mellitus; 22 patients had at least one comorbidity. The median time to euDKA onset was 60 days after administration, and 7 cases occurred within 2 weeks of treatment. Perioperative periods,fasting,and low-carbohydrate or ketogenic diets were the main predisposing factors. Common presentations included nausea,vomiting, fatigue, tachypnea,and tachycardia. The causal relationship between empagliflozin and euDKA was assessed as “probable” in all cases. According to adverse reaction severity grading, 13 cases were grade 3 (severe) and 16 cases were grade 4 (life-threatening). All patients discontinued empagliflozin and recovered after corresponding treatment. CONCLUSIONS euDKA is a serious adverse reaction to empagliflozin, which mostly occurs early in treatment. Perioperative periods, fasting, and ketogenic diets are prone to induce euDKA. Elderly patients and those with comorbidities are at higher risk. Risk assessment should be conducted before clinical administration; blood ketones and acid-base monitoring should be strengthened in the early medication period; withhold the drug before elective surgery, avoid prolonged fasting;upon diagnosis, discontinue empagliflozin and initiate intravenous insulin, provide fluid resuscitation promptly, and use other treatments to improve patient prognosis.
5.Changing trend of non-alcoholic fatty liver disease among young people aged 20—44 years in East Asian countries in 1990—2023
Fei SU ; Chunzhi SU ; Xianxin MENG ; Jingyao LI ; Xiaodi ZHU ; Jinli ZHANG
Journal of Clinical Hepatology 2026;42(5):1048-1055
ObjectiveTo investigate the disease burden of non-alcoholic fatty liver disease (NAFLD) among young people in East Asian countries (including China, North Korea, Japan, Mongolia, and South Korea) in 1990—2023, and to provide a basis for formulating and adjusting the prevention and treatment strategies for NAFLD. MethodsRelated disease burden data of NAFLD among the young people in these five East Asian countries were collected from the Global Burden of Disease 2023 (GBD 2023) database, including incidence rate, prevalence rate, and disability-adjusted life years (DALY), and the young people were divided into groups based on country, sex, and age. Estimated annual percentage change (EAPC) was used to comprehensively evaluate the changing trend of the disease burden of NAFLD among young people from 1990 to 2023, and the Autoregressive Integrated Moving Average model was used to predict the disease burden of NAFLD among the young people in China. ResultsIn 2023, the standardized incidence rates of NAFLD among the young people in China, North Korea, Japan, Mongolia, and South Korea were 926.57/100 000, 805.83/100 000, 412.66/100 000, 747.66/100 000, and 534.08/100 000, respectively; the standardized prevalence rates of NAFLD among the young people in China, North Korea, Japan, Mongolia, and South Korea were 16 817.94/100 000, 14 500.98/100 000, 8 534.40/100 000, 13 705.28/100 000, and 11 587.93/100 000, respectively; the standardized DALY rates of NAFLD among the young people in China, North Korea, Japan, Mongolia, and South Korea were 6.34/100 000, 10.18/100 000, 5.23/100 000, 47.93/100 000, and 6.76/100 000, respectively. From 1990 to 2023, there was a tendency of increase in the standardized incidence rate of NAFLD among the young people in China, North Korea, Japan, Mongolia, and South Korea, with an EAPC of 0.87%, 0.52%, 0.26%, 0.48%, and 0.87%, respectively; there was also a tendency of increase in the standardized prevalence rate of NAFLD among the young people in China, North Korea, Japan, Mongolia, and South Korea, with an EAPC of 0.99%, 0.49%, 0.24%, 0.59%, and 0.93%, respectively; conversely, there was a tendency of reduction in the standardized DALY rate of NAFLD among the young people in China, Japan, Mongolia, and South Korea, with an EAPC of -2.21%, -2.01%, -0.37%, and -4.62%, respectively, while the standardized DALY rate of NAFLD among the young people in North Korea remained relatively stable, with an EAPC of -0.01%. The subgroup analysis based on sex showed that there was a significant difference in the disease burden of NAFLD between the young people with different sexes in the five East Asian countries, and the subgroup analysis based on age showed that the incidence rate of NAFLD in young people decreased with the increase in age, while the prevalence rate and DALY rate of NAFLD increased with age. In addition, the standardized incidence rate and standardized prevalence rate of NAFLD among Chinese young people would further increase in the future, while there would be a reduction in standardized DALY rate in the future. ConclusionThere is a significant difference in the disease burden of NAFLD in young people across different countries, sexes, and age groups. In the future, targeted prevention and treatment measures should be developed based on the distribution characteristics of the disease burden of NAFLD, in order to effectively reduce the disease burden of NAFLD among young people.
6.Effect of influenza vaccination on influenza cluster epidemic in primary and secondary schools in Beijing in surveillance during 2023-2024
Yingying WANG ; Ying SUN ; Jia LI ; Wei DUAN ; Chunna MA ; Jiaojiao ZHANG ; Jiaxin MA ; Lu ZHANG ; Xiaodi HU ; Daitao ZHANG ; Li ZHANG
Chinese Journal of Epidemiology 2025;46(9):1580-1585
Objective:To analyze the effect of influenza vaccination on influenza cluster epidemic in primary and secondary schools in Beijing during the 2023-2024 surveillance season and provide evidence for the improvement of influenza vaccination strategies.Methods:The incidence data of influenza cluster epidemic and influenza vaccination coverage in the schools in Beijing during 2023-2024 were collected. Descriptive epidemiological methods were used to analyze cluster epidemic characteristics, and χ2 test was used to compare incidence differences between groups, and OR value and vaccine effectiveness [VE=(1- OR)×100%] were calculated. A negative binomial regression model was used to evaluate the association between school vaccination rates and cluster epidemic risk. Joinpoint regression was used to analyze trends in relative risk ( RR) with increasing vaccination coverage and to determine the optimal vaccination threshold. Results:A total of 126 influenza cluster epidemic were reported in 115 primary and secondary schools in Beijing during 2023-2024 with the median size of 15 case, the average attack rate was 36.26% (2 033/5 607). The epidemics mainly occurred in urban area (70, 55.56%). Primary schools were the main setting (78, 61.90%), and influenza A(H3N2) was the predominant subtype (108, 85.71%). The overall influenza vaccination coverage in the primary and secondary students was 54.26%, while the average vaccination in classes affected by the epidemics was 58.57%. The overall protection rate was 47.62%, the protection rate was higher in primary schools (49.65%) than in secondary schools (46.60%). The protection rates against influenza A(H1N1)pdm09 (80.93%) and influenza B (Victoria lineage) (81.65%) were significantly higher than that against influenza A(H3N2) (44.19%). When school vaccination coverage reached ≥76.00%, the epidemic risk decreased by 52.82%.Conclusions:Even the match between influenza vaccine strains and circulating strains is suboptimal, increasing influenza vaccination coverage in schools can effectively reduce the risk for influenza cluster epidemic. In the future, measures such as policy guidance and public health education should be taken to further improve vaccination coverage, thereby establishing herd immunity and reducing the transmission risk of influenza in schools.
7.Values of multiple indexes in early diagnosis of nosocomial infections in ICU patients undergoing surgical procedures
Liqin GU ; Xiaodi ZHOU ; Haifeng ZHANG ; Hong CHEN ; Shuai LIU ; Yanju ZHANG
Chinese Journal of Nosocomiology 2025;35(17):2636-2640
OBJECTIVE T o explore the values of body temperature,white blood cells(WBC),neutrophils(NEUT),platelets(PLT),red blood cell distribution width(RDW),procalcitonin(PCT)and C-reactive procal-citonin(PCT)in early diagnosis of postoperative nosocomial infections in the intensive care unit(ICU)patients undergoing surgical procedures.METHODS The clinical data that were collected from the surgery patients who were hospitalized in ICU of Affiliated Hospital of Nantong University from Mar.2021 to May 2022 were retro-spectively analyzed,and the enrolled patients were divided into the infection group with 45 cases and the non-infection group with 130 case according to the status of nosocomial infections.The highest body temperature and the levels of WBC,NEUT,PLT,RDW,PCT and CRP were observed and compared between the infection group within 48 hours before diagnosis with nosocomial infections and the non-infection group after ICU stay for 48 hours.The values of the single and joint detection of the indexes in prediction of postoperative nosocomial infec-tions in the ICU patients were analyzed.RESULTS The body temperature,WBC,NEUT,RDW,PCT and CRP of the infection group were 38.30(37.80,38.80)℃,14.10(10.90,17.30)× 109/L,12.22(9.32,15.12)×109/L,14.10(12.70,15.50)%,1.20(0.10,2.30)ng/ml and 55.00(40.00,70.00)mg/L,respectively,high er than those of the non-infection group(P<0.05).CRP,body temperature,PCT,NEUT and WBC showed remarkable diag-nostic effects;the area under the curves(AUCs)of the above indexes were 0.968,0.952,0.939,0.896 and 0.886,respectively.The sensitivity of the joint detection of PCT and CRP was 0.978,with the specificity 0.985 and AUC 0.980;the sensitivity of the joint detection of body temperature,PCT and CRP was 0.978,with the specificity 0.992,AUC 0.991.CONCLUSIONS The ICU patients with postoperative nosocomial infections show high levels of body temperature,WBC,NEUT,PCT and CRP.The body temperature,PCT and CRP have high sensitivity and specificity,showing certain values in prediction of postoperative nosocomial infection in the ICU pa-tients;the joint detection of the indexes has higher diagnostic efficiency.
8.The value of orthopedic metal artifact reduction technology in dual-layer detector CT for improving postoperative CT image quality in patients with lumbar internal fixation implants
Yuting WEN ; Yu YANG ; Xinyue LI ; Yan ZHENG ; Xuelin PAN ; Xiaodi ZHANG ; Huafeng CUI ; Zhenlin LI
Chinese Journal of Radiology 2025;59(5):591-598
Objective:To evaluate the clinical utility of dual-layer detector CT integrated with virtual monoenergetic imaging (VMI) and an orthopedic metal artifact reduction (O-MAR) algorithm in improving the image quality of patients after lumbar pedicle screw fixation surgery, and to analyze its impact on different types of artifacts and image quality of different tissues.Methods:The study was a prospective study, The study enrolled patients who underwent lumbar pedicle screw fixation at West China Hospital of Sichuan University between March and September 2024. All patients underwent lumbar CT scans using a dual-layer detector system, and four image sets were reconstructed. CLumbar routine scans were performed using dual-layer detector CT, and four image sets were reconstructed:onventional images (CI non-O-MAR), conventional images with O-MAR (CI O-MAR), virtual monoenergetic images (VMI non-O-MAR), and VMI with O-MAR (VMI O-MAR). Objective metrics including artifact index (AI), signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were quantified, alongside subjective image quality assessment. One-way ANOVA or Friedman test were used to compare the objective evaluation indicators of image quality between VMI non-O-MAR and VMI O-MAR at different energy levels. Paired t-test or Wilcoxon signed-rank test was used for CI non-O-MAR/VMI non-O-MAR versus CI O-MAR/VMI O-MAR comparisons. Results:A total of 30 patients were included, and all underwent internal fixation with titanium alloy pedicle screws. Objective analysis revealed that in both high-and low-density artifact regions, the AI values of the VMI O-MAR group decreased with the increase of energy levels, and were significantly lower than those of the corresponding VMI non-O-MAR group, with a statistically significant difference (all P<0.001). When the energy level≥140 keV, the AI value of the VMI O-MAR group was simultaneously lower than that of the CI non-O-MAR group and the CI O-MAR group, with statistically significant differences (all P<0.05). The SNR and CNR on the vertebral bodies in the VMI non-O-MAR group and the VMI O-MAR group showed a decreasing trend with increasing energy levels, and were always lower than those in the CI group at high energy levels (100-180 keV) (all P<0.05). At high energy levels (100-180 keV), the SNR of VMI O-MAR in the intervertebral disc and intraspinal tissues was higher than that of the VMI non-O-MAR group, with statistically significant differences (all P<0.05). Compared to other groups, subjective analysis indicated that the 140 keV VMI combined with O-MAR group received the highest image quality scores ( P<0.05). Conclusions:The combined application of VMI and O-MAR technology effectively reduces metal artifacts in post-lumbar fixation CT images. The 140 keV VMI with O-MAR reconstruction provides superior image quality and enhances diagnostic confidence.
9.Influence of continuous improvement projects based on FOCUS-PDCA on pathogen sample submission rate
Yanju ZHANG ; Xiaodi ZHOU ; Haifeng ZHANG ; Hong CHEN ; Biyang JIAO ; Liqin GU
Academic Journal of Naval Medical University 2025;46(6):824-830
Objective To investigate the effectiveness of continuous improvement projects based on FOCUS-PDCA on the pathogen sample submission rate before antimicrobial therapy for inpatients.Methods FOCUS-PDCA was used to improve the pathogen sample submission rate in Affiliated Hospital of Nantong University from Jun.to Jul.2023.The inpatients from Jan.to May 2023(before improvement)were enrolled as control group,and the inpatients from Aug.to Dec.2023(after improvement)were enrolled as improvement group.The utilization rate of antibiotics,the submission rate of pathogen samples,the submission rate of clinical microbial samples and the detection rate of multidrug-resistant organisms were compared between the 2 groups.Results The utilization rate of therapeutic antimicrobial agents(32.18%vs 32.93%,P=0.003)and antimicrobial consumption intensity(39.99 defined daily dose[DDD]/100 patient-days vs 44.19 DDD/100 patient-days)in the improvement group were significantly lower than those in the control group.The pathogen sample submission rates before antimicrobial therapy and key antimicrobial combination therapy in the improvement group were significantly higher than those in the control group(52.01%vs 23.64%,87.74%vs 77.71%;both P<0.001).The qualified rate of microbial specimens in the improvement group was significantly higher than that in the control group(88.77%vs 80.11%,P<0.001).The detection rates of multidrug-resistant organisms and carbapenem-resistant Klebella pneumoniae in the improvement group were significantly lower than those in the control group(40.45%vs 48.42%,29.65%vs 43.17%;both P<0.001).Conclusion The continuous improvement projects based on FOCUS-PDCA can improve the pathogen sample submission rate,reduce the detection rate of multidrug-resistant organisms,and promote standardized hospital infection quality management.
10.Multimodal MRI-based neurophenotype correlated to structural bowel damage in Crohn's disease
Zhuangnian FANG ; Ruonan ZHANG ; Lili HUANG ; Xiaodi SHEN ; Qingzhu ZHENG ; Yangdi WANG ; Xuehua LI ; Zhoulei LI ; Shaochun LIN
The Journal of Practical Medicine 2025;41(15):2398-2405
Objective To characterize neurological alterations associated with structural bowel damage in patients with Crohn's disease(CD)through radiomics-assisted neurophenotyping,utilizing multiparametric brain MRI.Methods This prospective study enrolled patients with CD who underwent brain MRI,MR enterography,and ileocolonoscopy within one week.The Lémann Index was used to quantitatively assess cumulative structural bowel damage.CD patients were stratified into two groups based on a cutoff value of 4.8:those with bowel damage(LI>4.8)and those without bowel damage(LI≤4.8).A neurophenotype model was developed to characterize the neural changes associated with bowel damage in CD.Key features were selected from first-order features extracted from multiparametric brain MRI in the training cohort and validated in an independent test cohort.Results The final study population comprised 109 patients,including 51 individuals with bowel damage and 58 without bowel damage.The neurophenotype model scores were 0.785(95%CI:0.506~0.945)in the bowel damage group and 0.155(95%CI:0.093~0.394)in the non-bowel damage group,showing a statistically significant difference between the two groups(P<0.001).The developed model exhibited strong discriminative performance,with area under the receiver operating characteristic curve(AUC)values ranging from 0.824 to 0.918 across the training,vali-dation,and test cohorts(all P<0.05).Conclusion Our radiomics-assisted neurophenotype analysis reveals neural alterations in CD patients with bowel damage,which may indicate extraintestinal manifestations associated with cumulative intestinal injury.

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