Graves' disease and the risk of five autoimmune diseases: A Mendelian randomization and colocalization study.

BACKGROUND: Epidemiological studies have consistently demonstrated a high prevalence of concurrent autoimmune diseases in individuals with Graves' disease (GD). OBJECTIVE: The objective of this study is to establish a causal association between GD and autoimmune diseases. METHODS: We employed a two-sample Mendelian randomization (MR) to infer a causal association between GD and five autoimmune diseases, namely rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease (CD), ulcerative colitis (UC), and amyotrophic lateral sclerosis (ALS), in the East Asian and European population. Genetic correlations were explored through linkage disequilibrium score regression analysis (LDSC). Finally, colocalization analyses were performed to investigate possible genetic foundations. RESULTS: Bidirectional MR analysis indicated that genetically predicted GD increased the risk of RA (Odds Ratio (OR): 1.34, 95 % Confidence Interval (CI): 1.21 to 1.47, P < 0.001) and SLE (OR: 1.21, 95%CI: 1.08 to 1.35, P < 0.001) in the East Asian population. In contrast, we found that genetically predicted RA (OR: 1.14, 95%CI: 1.05 to 1.24, P = 0.002) and SLE (OR: 1.10, 95%CI: 1.03 to 1.17, P = 0.003) were associated with a higher risk of GD. The results have been partially validated in European cohorts. Colocalization analysis suggested the potential existence of shared causal variants between GD and other autoimmune diseases. In particular, gene ARID5B may play an important role in the incidence of autoimmune diseases. CONCLUSION: This study has confirmed that GD was associated with RA and SLE and found a possible key gene ARID5B. It may be necessary to strengthen detection to prevent the occurrence of comorbidities in clinical practice.

Efficacy and Safety of Vonoprazan-Amoxicillin Dual Regimen With Varying Dose and Duration for Helicobacter pylori Eradication: A Multicenter, Prospective, Randomized Study.

BACKGROUND & AIMS: Previous studies confirm vonoprazan-amoxicillin effectiveness for Helicobacter pylori. This study aims to investigate vonoprazan with varying amoxicillin dose and duration. METHODS: This multicenter, prospective, randomized controlled, noninferiority trial enrolled patients with treatment naive H pylori infection from 5 clinical centers. Eligible participants were randomly assigned to H-VA-10 (vonoprazan 20 mg twice a day (b.i.d.) + amoxicillin 750 mg 4 times a day, 10 days), L-VA-10 (vonoprazan 20 mg b.i.d. + amoxicillin 1000 mg b.i.d, 10 days), and H-VA-14 (vonoprazan 20 mg b.i.d + amoxicillin 750 mg 4 times a day, 14 days) in a 1:1:1 ratio. The eradication rate was assessed using the 13C-urea breath test at least 28 days after treatment. RESULTS: Of the 623 eligible patients, 516 patients were randomized. In both the intention-to-treat and per-protocol analyses, eradication rates were comparable between H-VA-10 and H-VA-14 groups (86.6% vs 89.5% and 90.9% vs 94.5%, P = .021 and .013 for noninferiority, respectively). However, eradication rates were significantly lower in the L-VA-10 group than the H-VA-14 group (79.7% vs 89.5% and 82.0% vs 94.5%, P = .488 and .759, respectively). Rates of study withdrawal, loss to follow-up, and adverse events were similar across study groups. CONCLUSIONS: H-VA-10 and H-VA-14 regimens provide satisfactory efficacy for H pylori infection, and the L-VA-10 regimen was inferior. CLINICALTRIALS: gov number: NCT05719831.

Extensive involvement of indolent T-cell lymphoma in a patient with ulcerative colitis.

Indolent T-cell lymphoma is a rare disease. Here we presented a 53-year-old male patient initially diagnosed as ulcerative colitis in 2000 that finally developed into extensive indolent T-cell lymphoma in 2022. We also described the differences between indolent T-cell lymphoma and inflammatory bowel disease, and the possible disease progression into lymphoma after biological therapy.

Extra intravenous Ustekinumab reinduction is an effective optimization strategy for patients with refractory Crohn's disease.

Objectives: Ustekinumab (UST) optimization strategies, including shortening intervals and intravenous reinduction, should be administered to patients with partial or loss of respond. Evidence comparing these types of optimization treatments is limited. We evaluated the efficacy and safety of weight-based UST intravenous reinduction in patients with refractory Crohn's disease (CD). Methods: This was a single-center retrospective observational study. Optimization strategies were designed for patients showing partial or loss of response to standardized UST therapy. Clinical, biochemical, and endoscopic response and remission rate were determined by Crohn's disease activity index (CDAI), C-reactive protein (CRP) levels, and SES-CD evaluation. UST trough concentrations were detected and adverse events were recorded. Results: A total of 128 patients receiving UST optimization therapies were included, with 105 patients administered shortening intervals of q8w or q4w, and 23 receiving intravenous reinduction followed by subcutaneous q8w or q4w. The follow-up duration for the shortening interval and reinduction cohorts were 15.0 (10.0, 31.0) and 23.0 (13.0, 70.0) weeks, respectively. A significant CDAI delta variation pre-and post-treatment could be found between groups [17.0 (-4.4, 65.9) vs. 69.0(10.7, 151.0), p = 0.013]. the trough concentration of UST increased [2.5 (1.3, 5.3) vs. 1.1 (0.5, 2.3), p = 0.001] after intravenous reinduction. Clinical and endoscopic remission were achieved in 69.6 and 31.8% of patients in the intravenous reinduction cohort, and 62.9 and 22.2% of patients in the shortening interval cohort, respectively. No significant difference was found between groups regarding safety. Conclusion: Intravenous reinduction brought about favorable recapture of clinical and endoscopic remission, and should have significant priority over the strategy of merely shortening drug intervals, which should be launched before switching to other biologics targeting different inflammatory pathways.Clinical Trial Registration: identifier NCT04923100. https://classic.clinicaltrials.gov/ct2/show/NCT04923100?id=04923100&draw=2&rank=1.

Computed tomography-based radiomics nomogram using machine learning for predicting 1-year surgical risk after diagnosis of Crohn's disease.

BACKGROUND: Identifying patients with aggressive Crohn's disease (CD) threatened by a high risk of early onset surgery is challenging. PURPOSE: We aimed to establish and validate a radiomics nomogram to predict 1-year surgical risk after the diagnosis of CD, thereby facilitating therapeutic strategies making. METHODS: Patients with CD who had undergone baseline computed tomography enterography (CTE) examination at diagnosis were recruited and randomly divided into training and test cohorts at a ratio of 7:3. Enteric phase CTE images were obtained. Inflamed segments and mesenteric fat were semiautomatically segmented, followed by feature selection and signature building. A nomogram of radiomics was constructed and validated using a multivariate logistic regression algorithm. RESULTS: A total of 268 eligible patients were retrospectively included, 69 of whom underwent surgery 1-year after diagnosis. A total of 1218 features from inflamed segments and 1218 features from peripheral mesenteric fat were extracted, and reduced to 10 and 15 potential predictors, respectively, to construct two radiomic signatures. By incorporating the radiomics signatures and clinical factors, the radiomics-clinical nomogram showed favorable calibration and discrimination in the training cohort, with an area under the curve (AUC) of 0.957, which was confirmed in the test set (AUC, 0.898). Decision curve analysis and net reclassification improvement index demonstrated the clinical usefulness of the nomogram. CONCLUSIONS: We successfully established and validated a CTE-based radiomic nomogram with both inflamed segment and mesenteric fat simultaneously evaluated to predict 1-year surgical risk in CD patients, which assisted in clinical decision-making and individualized management.

Combination of vonoprazan and amoxicillin as the first-line Helicobacter pylori eradication therapy: a multicenter, prospective, randomized, parallel-controlled study.

The eradication rate of Helicobacter pylori (H. pylori) decreased gradually. This study aimed to analyze the efficacy and safety of a 14-day combination of vonoprazan and amoxicillin as the first-line eradication therapy for H. pylori infection and compared them with those of the bismuth quadruple therapy. A prospective randomized clinical trial (RCT) was designed, involving patients with H. pylori infection in 6 institutions who did not receive any treatment yet. They were randomly assigned into the VA-dual group (vonoprazan 20 mg b.i.d + amoxicillin 750 mg q.i.d) or EACP-quadruple group (esomeprazole 20 mg + amoxicillin 1000 mg + clarithromycin 500 mg + colloidal bismuth subcitrate 220 mg b.i.d) for 14 days in a ratio of 1:1. At least 28 days later, the eradication rate was detected by the 13C-urea breath test (UBT). A total of 562 patients from February 2022 to September 2022 were enrolled and 316 were random. In the ITT analysis, the eradication rates of H. pylori in the VA-dual group and EACP-quadruple group were 89.9% and 81.0%, respectively, p = 0.037. In the PP analysis were 97.9% and 90.8%, p = 0.009. The different eradication rate was 8.9% (95% CI 1.2-16.5%) and 7.2% (95% CI 1.8-12.4%) in ITT and PP analyses, both lower limit of the 95%CI was still higher than the prespecified margin. In addition, the incidence of adverse events in the VA-dual group was significantly lower than that in the EACP-quadruple group (19.0% vs. 43.0%, P < 0.001). The efficacy and safety of a 14-day combination therapy of vonoprazan and amoxicillin in eradicating H. pylori are superior to bismuth quadruple therapy, and this combination significantly reduces the use of antibiotics.

Therapeutic effect of ustekinumab on patients with extra-intestinal manifestations of Crohn's disease.

INTRODUCTION: Ustekinumab serves as an important alternative option for patients with various extraintestinal manifestations (EIMs), which leads to poor quality of life and heavy burden of care. Therefore, a comprehensive review summarizing the efficacy and safety of ustekinumab in patients with CDassociated EIMs is needed to provide reference for clinical medication and help with the appliance of precision medicine. AREAS COVERED: In this review, we collected and summarized the efficacy and paradoxical side effects of ustekinumab in patients with CDassociated EIMs including musculoskeletal, cutaneous, ocular, and hepatobiliary manifestations. This literature review was performed using PubMed to identify and collect relevant studies published in English. EXPERT OPINION: The effectiveness of ustekinumab on patients with CDassociated EIMs is mainly reflected in musculoskeletal and cutaneous manifestations compared to ocular or hepatobiliary manifestations. Relevant data from large scale cohort studies and prospective randomized trials are needed to further demonstrate the efficacy and safety of ustekinumab in patients with multiple EIMs.

Ustekinumab Promotes Radiological Fistula Healing in Perianal Fistulizing Crohn's Disease: A Retrospective Real-World Analysis.

There is insufficient evidence to confirm the efficacy of ustekinumab (UST) in promoting fistula closure in perianal fistulizing Crohn's disease (CD) patients. We aimed to evaluate the efficacy of UST in a real-world setting. The data were retrospectively analyzed. Intestinal clinical and endoscopic changes were evaluated. Fistula radiological outcomes were determined using the Van Assche score. A total of 108 patients were included, 43.5% of whom had complex perianal fistulas. Intestinal clinical and endoscopic remission was achieved in 65.7% and 31.5% of patients, respectively. The fistula clinical remission and response rates were 40.7% and 63.0%, respectively, with a significant reduction in Perianal Crohn's disease Activity Index [5.0(3.0, 8.0) vs. 7.5(5.0, 10.0), p < 0.001] and Crohn's Anal Fistula Quality of Life [23.5(9.3, 38.8) vs. 49.0(32.3, 60.0), p < 0.001]. Radiological healing, partial response, no change, and deterioration were observed in 44.8%, 31.4%, 13.4%, and 10.4% of patients, respectively. The cut-off UST trough concentration for predicting fistula clinical remission was 2.11 µg/mL with an area under the curve of 0.795, a sensitivity of 93.3%, and a specificity of 67.6%. UST is efficacious in promoting radiological fistula closure in patients with perianal fistulizing CD. A UST trough concentration over 2.11 µg/mL was correlated with a higher likelihood of perianal fistula clinical remission.

Clinical characteristics and risk factors of ovarian reserve decreases in women with Crohn's disease: a case-control study.

BACKGROUND: Crohn's disease (CD), often occurring in women of child-bearing age, can decline the fertility rate. However, whether it reduces ovarian reserve has been rarely reported. This study aimed to evaluate the ovarian reserve in women with CD from the perspective of anti-Müllerian hormone (AMH), and explore the factors that can decrease ovarian reserve. METHODS: A case-control retrospective study was designed. We analyzed the AMH levels in a total of 135 CD women and 878 healthy controls. Through propensity score matching, the subjects were assigned in a ratio of 1:3 to CD group (n = 121) and control group (n = 324). Both groups shared similar basic characteristics, like age, body mass index and smoking status. Serum AMH levels were measured by chemiluminescence. RESULTS: The AMH level in the CD group was significantly lower than that in the control group (2.17 ± 2.23 µg/L vs 3.95 ± 2.01 µg/L, 95%CI [1.34-2.21], P < 0.001). In both groups, the AMH levels decreased as age increased, but without between-group difference in the decreasing rate (P = 0.639). Multivariate analysis showed that age > 30 years (OR, 2.905; 95%CI [1.053-8.531], P = 0.017), disease activity (OR,4.314; 95%CI [1.561-12.910], P = 0.002) and thalidomide use (OR,12.628; 95%CI [4.351 -42.820], P < 0.001) were independent risk factors associated with decreased ovarian reserve (AMH<1.1µg/L). CONCLUSION: Ovarian reserve is lower in CD women than in healthy women. Age, CD activity and medication of thalidomide are risk factors that can aggravate the decline of ovarian reserve.

MYBL2 regulates de novo purine synthesis by transcriptionally activating IMPDH1 in hepatocellular carcinoma cells.

BACKGROUND: Metabolic reprogramming is a hallmark of cancer, alteration of nucleotide metabolism of hepatocellular carcinoma (HCC) is not well-understood. MYBL2 regulates cell cycle progression and hepatocarcinogenesis, its role in metabolic regulation remains elusive. PATIENTS AND METHODS: Copy number, mRNA and protein level of MYBL2 and IMPDH1 were analyzed in HCC, and correlated with patient survival. Chromatin Immunoprecipitation sequencing (Chip-seq) and Chromatin Immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) were used to explore the relationship between MYBL2 and IMPDH1. Metabolomics were used to analyze how MYBL2 affected purine metabolism. The regulating effect of MYBL2 in HCC was further validated in vivo using xenograft models. RESULTS: The Results showed that copy-number alterations of MYBL2 occur in about 10% of human HCC. Expression of MYBL2, IMPDH1, or combination of both were significantly upregulated and associated with poor prognosis in HCC. Correlation, ChIP-seq and ChIP-qPCR analysis revealed that MYBL2 activates transcription of IMPDH1, while knock-out of MYBL2 retarded IMPDH1 expression and inhibited proliferation of HCC cells. Metabolomic analysis post knocking-out of MYBL2 demonstrated that it was essential in de novo purine synthesis, especially guanine nucleotides. In vivo analysis using xenograft tumors also revealed MYBL2 regulated purine synthesis by regulating IMPDH1, and thus, influencing tumor progression. CONCLUSION: MYBL2 is a key regulator of purine synthesis and promotes HCC progression by transcriptionally activating IMPDH1, it could be a potential candidate for targeted therapy for HCC.

The efficacy and safety of thalidomide in the treatment of refractory Crohn's disease in adults: a double-center, double-blind, randomized-controlled trial.

Background: Thalidomide is applied in therapy for refractory Crohn's disease (CD) in adults, but systematic and rigorous clinical evidence is scant. The aim was to provide theoretical references for the efficacy of thalidomide in the therapy for refractory CD in adults. Methods: A double-center, double-blind, placebo-controlled, randomized clinical trial of refractory CD in adults in two inflammatory bowel disease centers in China. In the double-blind trial, patients were randomly assigned to 100 mg of thalidomide or placebo daily for 8 weeks. The primary outcome was considered as the clinical remission rate calculated based on the Crohn's disease activity index at the eighth week following thalidomide or placebo treatment. In open label, non-response to placebo was additionally treated with 8 weeks of thalidomide; all responders were continuously treated with thalidomide until the 48th week. Results: Twenty-five patients were randomly assigned to each group. At the eighth week, the clinical remission rate in the thalidomide group was significantly higher than that in the placebo group (68.0% [17/25] vs 16.0% [4/25]; relative risk, 4.2; 95% confidence interval, 1.8-10.9, P < 0.001). After a 48-week follow-up, the continuous treatment rate of thalidomide was 46.3% (19/41). Adverse events during the whole process were reported in 58.5% of patients, mainly involving drowsiness, rash, and peripheral neuropathy that were mild and tolerable. Conclusion: Thalidomide can be used in the induction and maintenance therapy of refractory CD in adults. And it could be one of the treatment options for refractory CD.

Correlation between altered gut microbiota and elevated inflammation markers in patients with Crohn's disease.

Prior studies reported inconsistent results on the altered gut microbial composition in patients with Crohn's disease (CD), likely under the influences of many confounding factors including genetic, life style and environmental variations among different study cohorts. This study aims to examine the gut microbiota of CD patients with particular efforts to minimize the impact of the confounding factors. For this purpose, the healthy relatives of the patients were enrolled as control subjects so that the paired study subjects may have similar genetic background, dietary habits, and household environment. The fecal microbiota of the study subjects were examined by 16S rRNA sequencing. After the identification of the differential bacterial genera, multivariate regression analysis was performed to adjust the results for the impact of confounding factors. We found that the microbiota of the CD patients were featured with reduced short chain fatty acid (SCFA) producing bacteria and elevated opportunistic pathogen Escherichia-Shigella. Correlation analysis indicated that the elevation in Escherichia-Shigella and the reduction in SCFA-producing bacteria usually occur simultaneously. These differential genera exhibited a high capacity in distinguishing between CD and healthy controls achieving an area under curve of 0.89, and were correlated with the changes in inflammation related blood biochemical markers. Consistent with the reduction in SCFA-producing bacteria in CD, metabolomics analysis revealed decreased blood level of SCFAs in the patients. The differential genera identified in this study demonstrated outstanding capability to serve as diagnosis markers for CD and are potential targets for intervention.

Predictors of Chronic Postsurgical Pain in Elderly Patients Undergoing Hip Arthroplasty: A Multi-Center Retrospective Cohort Study.

BACKGROUND: Identifying patients at high risk of developing chronic postsurgical pain (CPSP) is of extreme importance in order to help launch appropriate therapeutic strategies and intensive initiation of pain management. AIM: In this study, we aimed to conduct a multi-center retrospective cohort study to establish a prognostic model and a nomogram to predict the risks of CPSP in elderly patients who underwent hip arthroplasty at 6 months postoperatively. METHODS: We collected data from 736 patients aged >65 years who had undergone hip arthroplasty from October 1, 2016 to September, 30, 2018 at multiple tertiary referral centers in Guangzhou, China. All data were randomly stratified into a training set and a testing set at a ratio of 8:2. Data were analyzed via multiple logistic regression analysis with receiver operating characteristic (ROC) curves and areas under the curve. This model was further validated by estimating calibration and discrimination. A nomogram was ultimately developed. RESULTS: A total of 736 eligible patients were enrolled, 27.20% of whom developed CPSP within 6 months postoperatively. Preoperative pain in the surgical area (OR=2.456, 95% CI:1.814-3.327, P<0.001), preoperative depression state (OR=1.256, 95% CI:1.146-1.378, P<0.001), surgical type (OR=7.138, 95% CI:3.548-14.364, P<0.001), acute postoperative numerical rating scale score (OR=5.537, 95% CI:3.607-8.499, P<0.001) and analgesic type (patient-controlled epidural analgesia: OR=0.129, 95% CI:0.055-0.299, P<0.001; patient-controlled intravenous analgesia: OR=0.033, 95% CI:0.011-0.097, P<0.001) were identified as independent significant factors associated with CPSP. A prognostic model was established and further validated. An ROC curve confirmed the predictive ability of this model with a high sensitivity value of 92.12% (95% CI:86.90-95.74) and specificity value of 91.72% (95% CI:88.77-94.11). A nomogram was developed to simplify the use of the predictive model in clinical practice. CONCLUSION: This prognostic model could be of great value in clinical practice, serving as the basis for early personalized analgesic management of elderly patients undergoing hip arthroplasty.

Ustekinumab trough concentration affects clinical and endoscopic outcomes in patients with refractory Crohn's disease: a Chinese real-world study.

BACKGROUND: Ustekinumab (UST), a newly-used biologic targeting p40 subunit of IL12 and IL23 in China, exerts a confirmed therapeutic effect on the induction and maintenance therapies for refractory Crohn's disease (CD). Therapeutic drug monitoring based on trough and antibody concentration is of core importance when treating patients who lose response to UST. We aimed to analyze the UST exposure-response relationship in CD treatment in the real-world setting. METHODS: We retrospectively enrolled patients with CD who received UST between March 1, 2020 and May 31, 2021, at the inflammatory bowel disease (IBD) center of the Sun Yat-Sun Affiliated Sixth Hospital. Baseline characteristic information, biomarker examination, clinical outcomes determined by the Crohn's disease activity index (CDAI), and endoscopic outcomes evaluated using a simple endoscopic score for Crohn's disease (SES-CD) at week 16/20 were collected. The optimal UST cut-off trough concentration was identified using receiver operating characteristic curve (ROC) analysis. RESULTS: Nineteen eligible patients were included in the study, the mean age was 29.1 ± 9.1 years and the mean disease duration was 5.5 ± 4.7 years. At the initiation of the study, 89.5% of the patients had been exposed to prior biologics, 42.1% had previous CD-related surgeries, and 52.6% had perianal diseases. At week 16/20 after the UST initiation, clinical response, clinical remission, endoscopic response, and endoscopic remission were 89.5%, 84.2%, 42.2%, and 73.7%, respectively. The cut-off optimal trough concentration for UST was 1.12 µg/mL, as determined by the ROC with an area under the curve (AUC) of 0.78, sensitivity of 87.5%, and specificity of 72.7%. Patients with a UST trough concentration > 1.12 µg/mL had a significantly higher rate of endoscopic remission than those without (70.0% vs. 11.1%, P = 0.02). CONCLUSIONS: UST is an effective therapeutic option for refractory CD treatment. A UST trough concentration above 1.12 µg/mL was associated with endoscopic remission at week 16/20 after UST initiation. Trial registration This study was approved and retrospectively registered by the Ethics Committee of Sun Yat-Sen University (2021ZSLYEC-066, March 29, 2021) and the Clinical Trial Registry (NCT04923100, June 10, 2021).

Development and validation of a new algorithm model for differential diagnosis between Crohn's disease and intestinal tuberculosis: a combination of laboratory, imaging and endoscopic characteristics.

BACKGROUND: Sometimes in clinical practice, it is a great challenge to distinguish Crohn's disease (CD) and intestinal tuberculosis (ITB), we conducted this study to identify simple and useful algorithm for distinguishing them. METHODS: We retrospectively reviewed the medical history of the patients who were diagnosed as ITB or CD. We firstly identified ITB patients, and then the patients diagnosed with CD were matched by age, sex, and admission time in a 1:1 ratio. Patients who admitted between May 1, 2013 and April 30, 2019 were regarded as training cohort, and patients admitted between May 1, 2019 and May 1, 2020 were regarded as validation cohort. We used multivariate analysis to identify the potential variables, and then we used R package rpart to build the classification and regression tree (CART), and validated the newly developed model. RESULTS: In total, the training cohort included 84 ITB and 84 CD patients, the validation cohort included 22 ITB and 22 CD patients. Multivariate analysis showed that, positive interferon-gamma release assays (IGRAs), ≥ 4 segments involved, longitudinal ulcer, circular ulcer, and aphthous ulcer were confirmed as independent discriminating factors. Using these parameters to build the CART model made an overall accuracy rate was 88.64%, with sensitivity, specificity, NPV, and PPV being 90.91%, 86.36%, 90.48% and 86.96%, respectively. CONCLUSION: We developed a simple and novel algorithm model covering laboratory, imaging, and endoscopy parameters with CART to differentiate ITB and CD with good accuracy. Positive IGRAs and circular ulcer were suggestive of ITB, while ≥ 4 segments involved, longitudinal ulcer, and aphthous ulcer were suggestive of CD.

A Validated Prognostic Model and Nomogram to Predict Early-Onset Complications Leading to Surgery in Patients With Crohn's Disease.

BACKGROUND: Predicting aggressive Crohn's disease is crucial for determining therapeutic strategies. OBJECTIVE: We aimed to develop a prognostic model to predict complications leading to surgery within 1 year after diagnosis of Crohn's disease and to create a nomogram to facilitate clinical decision making. DESIGN: This is a retrospective study. SETTING: This study was conducted from January 2012 to December 2016 in a single tertiary IBD center. PATIENTS: Patients diagnosed with Crohn's disease showing B1 behavior according to the Montreal classification were included. MAIN OUTCOME MEASURES: We measured the occurrence of complications that would ultimately lead to surgery, including severe GI bleeding (Glasgow-Blatchford score ≥6), stenosis, and perforations, confirmed by endoscopy, CT scan, and/or interventional radiology. RESULTS: The mean follow-up period was 54 months (SD 13 months). Of the 614 eligible patients, 13.5% developed complications leading to surgery. Multivariable logistic regression revealed the independent predictors of early-onset complications to be age (adjusted odds ratio per 10-year increase in age = 0.4; 95% CI, 0.2-0.8; p = 0.004), disease duration (adjusted odds ratio = 2.7, 95% CI, 1.9-3.8; p < 0.001), perianal disease (adjusted odds ratio = 16.0; 95% CI, 4.3-59.9; p < 0.001), previous surgery (adjusted odds ratio = 3.7; 95% CI, 1.6-8.6; p = 0.003), and extraintestinal manifestations (adjusted odds ratio = 7.6; 95% CI, 2.3-24.9; p = 0.001). The specificity and sensitivity of the prognostic model were 88.3% (95% CI, 84.8%-91.2%) and 96.6% (95% CI, 88.1%-99.6%), and the area under the curve was 0.97 (95% CI, 0.95-0.98). This model was validated with good discrimination and excellent calibration using the Hosmer-Lemeshow goodness-of-fit test. A nomogram was created to facilitate clinical bedside practice. LIMITATIONS: This was a retrospective design and included a small sample size from 1 center. CONCLUSIONS: Our validated prognostic model effectively predicted early-onset complications leading to surgery and screened aggressive Crohn's disease, which will enable physicians to customize therapeutic strategies and monitor disease. See Video Abstract at http://links.lww.com/DCR/B442.Registered at Chinese Clinical Trial Registry (ChiCTR1900025751). UN MODELO DE PRONSTICO VALIDADO Y UN NOMOGRAMA PARA PREDECIR COMPLICACIONES PRECOCES QUE REQUIRAN CIRUGA EN PACIENTES CON ENFERMEDAD DE CROHN: ANTECEDENTES:Predecir una enfermedad de Crohn muy agresiva es fundamental para determinar la estrategia terapéutica.OBJETIVO:Desarrollar un modelo de pronóstico para predecir las complicaciones que requieran cirugía dentro el primer año al diagnóstico de enfermedad de Crohn y crear un nomograma para facilitar la toma de decisiones clínicas.DISEÑO:El presente etudio es retrospectivo.AJUSTE:Estudio realizado entre Enero 2012 y Diciembre 2016, en un único centro terciario de tratamiento de enfermedad inflamatoria intestinal.PACIENTES:Se incluyeron todos aquellos pacientes diagnosticados de enfermedad de Crohn que mostraban manifestaciones tipo B1 según la clasificación de Montreal.PRINCIPALES MEDIDAS DE RESULTADO:Medimos la aparición de complicaciones que finalmente conducirían a una cirugía, incluida la hemorragia digestiva grave (puntuación de Glasgow-Blatchford ≥ 6), estenosis y perforaciones, confirmadas por endoscopía, tomografía computarizada y / o radiología intervencionista.RESULTADOS:El período medio de seguimiento fue de 54 meses (desviación estándar 13 meses). De los 614 pacientes elegibles, el 13,5% desarrolló complicaciones que llevaron a cirugía. La regresión logística multivariable reveló que los predictores independientes de complicaciones de inicio temprano eran la edad (razón de probabilidades ajustada [ORa] por aumento de 10 años en la edad = 0,4; intervalos de confianza del 95% [IC del 95%]: 0,2-0,8, p = 0,004), duración de la enfermedad (ORa = 2,7, IC del 95%: 1,9-3,8, p <0,001), enfermedad perianal (ORa = 16,0, IC del 95%: 4,3-59,9, p <0,001), cirugía previa (ORa = 3,7, 95% IC: 1,6-8,6, p = 0,003) y manifestaciones extraintestinales (ORa = 7,6, IC del 95%: 2,3-24,9, p = 0,001). La especificidad y sensibilidad del modelo pronóstico fueron 88,3% (IC 95%: 84,8% -91,2%) y 96,6% (IC 95%: 88,1% -99,6%), respectivamente, y el área bajo la curva fue 0,97 (95% % CI: 0,95-0,98). Este modelo fue validado con buena discriminación y excelente calibración utilizando la prueba de bondad de ajuste de Hosmer-Lemeshow. Se creó un nomograma para facilitar la práctica clínica al pié de la cama.LIMITACIONES:Diseño retrospectivo que incluyó un tamaño de muestra pequeña en un solo centro.CONCLUSIONES:Nuestro modelo de pronóstico validado predijo eficazmente las complicaciones precoces que conllevaron a cirugía y la detección de enfermedad de Crohn agresiva, lo que permitió a los médicos personalizar las estrategias terapéuticas y controlar la enfermedad. Consulte Video Resumen en http://links.lww.com/DCR/B442.Registrado en el Registro de Ensayos Clínicos de China (ChiCTR1900025751).

CircFAT1 Suppresses Colorectal Cancer Development Through Regulating miR-520b/UHRF1 Axis or miR-302c-3p/UHRF1 Axis.

Background: It was reported that circular RNAs (circRNAs) exerted important functions in various human cancers. However, the function of circFAT1 was less known. The purpose of this study was to reveal the functional mechanism of circFAT1 in colorectal cancer (CRC). Materials and Methods: Quantitative real-time polymerase chain reaction and Western blot assay were used to detect the levels of genes. Cell proliferation ability was assessed by 3-(4, 5-dimethyl-2-thiazoyl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry was used to investigate cell apoptosis rate. The glucose consumption and lactate production were determined using related kits. Furthermore, the interaction between circFAT1 or ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) and miR-520b or miR-302c-3p was predicted by starbase3.0, and then confirmed by the dual-luciferase reporter assay. Besides, xenograft experiment was performed to analyze the effect of circFAT1 on tumor growth in vivo. Results: The levels of circFAT1 and UHRF1 were increased, as well as the levels of miR-520b and miR-302c-3p were decreased in CRC tissues and cells. CircFAT1 knockdown suppressed cell proliferation, cycle, and glycolysis as well as induced apoptosis. Interestingly, circFAT1 was a sponge of miR-520b and miR-302c-3p, and miR-520b and miR-302c-3p could target UHRF1. Both miR-520b overexpression and miR-302c-3p overexpression inhibited CRC cell growth. Furthermore, both miR-520b knockdown and miR-302c-3p depletion weakened the effect of circFAT1 knockdown on the growth of CRC cells. Besides, circFAT1 depletion repressed tumor growth in vivo. Conclusion: The authors' findings suggested that circFAT1 upregulated UHRF1 to affect CRC cell proliferation, apoptosis, and glycolysis through targeting miR-520b and miR-302c-3p, providing theoretical basis for the treatment of CRC.

Development of a prognostic model for one-year surgery risk in Crohn's disease patients: A retrospective study.

BACKGROUND: Accelerated therapeutic treatment should be considered in patients with progressive Crohn's disease (CD) to prevent complications as well as surgery. Therefore, screening for risk factors and predicting the need for early surgery are of great importance in clinical practice. AIM: To establish a model to predict CD-related early surgery. METHODS: This was a retrospective study collecting data from CD patients diagnosed at our inflammatory bowel disease center from January 1, 2012 to December 31, 2016. All data were randomly stratified into a training set and a testing set at a ratio of 8:2. Multivariable logistic regression analysis was conducted with receiver operating characteristic curves constructed and areas under the curve calculated. This model was further validated with calibration and discrimination estimated. A nomogram was finally developed. RESULTS: A total of 1002 eligible patients were enrolled with a mean follow-up period of 53.54 ± 13.10 mo. In total, 24.25% of patients received intestinal surgery within 1 year after diagnosis due to complications or disease relapse. Disease behavior (B2: OR [odds ratio] = 6.693, P < 0.001; B3: OR = 14.405, P < 0.001), smoking (OR = 4.135, P < 0.001), body mass index (OR = 0.873, P < 0.001) and C-reactive protein (OR = 1.022, P = 0.001) at diagnosis, previous perianal (OR = 9.483, P < 0.001) or intestinal surgery (OR = 8.887, P < 0.001), maximum bowel wall thickness (OR = 1.965, P < 0.001), use of biologics (OR = 0.264, P < 0.001), and exclusive enteral nutrition (OR = 0.089, P < 0.001) were identified as independent significant factors associated with early intestinal surgery. A prognostic model was established and further validated. The receiver operating characteristic curves and calculated areas under the curves (94.7%) confirmed an ideal predictive ability of this model with a sensitivity of 75.92% and specificity of 95.81%. A nomogram was developed to simplify the use of the predictive model in clinical practice. CONCLUSION: This prognostic model can effectively predict 1-year risk of CD-related intestinal surgery, which will assist in screening progressive CD patients and tailoring therapeutic management.

Gentiopicroside Ameliorates Diabetic Peripheral Neuropathy by Modulating PPAR- Γ/AMPK/ACC Signaling Pathway.

BACKGROUND/AIMS: Gentiopicroside is promising as an important secoiridoid compound against pain. The present study aimed to investigate the analgesic effect and the probable mechanism of Gentiopicroside on Diabetic Peripheral Neuropathy (DPN), and to figure out the association among Gentiopicroside, dyslipidemia and PPAR- γ/AMPK/ACC signaling pathway. METHODS: DPN rat models were established by streptozotocin and RSC96 cells were cultured. Hot, cold and mechanical tactile allodynia were conducted. Blood lipids, nerve blood flow, Motor Nerve Conduction Velocity (MNCV) and Sensory Nerve Conduction Velocity (SNCV) were detected. Gene and protein expression of PPAR- γ/AMPK/ACC pathway was analyzed by reverse transcription-quan titative polymerase chain reaction (RT-qPCR) and Westernblot. Besides, PPAR-γ antagonist GW9662 and agonist rosiglitazone, AMPK antagonist compound C and activator AICAR as well as ACC inhibitor TOFA were used to further confirm the relationship between PPAR-γ and AMPK. RESULTS: The results demonstrated that Gentiopicroside markedly ameliorated hyperalgesia with prolonged paw withdrawal latency to heat and cold stimuli and fewer responses to mechanical allodynia compared with DPN model group. Gentiopicroside regulated dyslipidemia, enhanced nerve blood flow and improved MNCV as well as SNCV. Gentiopicroside suppressed ACC expression through the activation of AMPK and PPAR-γ mediated the activation of AMPK and subsequent inhibition of ACC expression. CONCLUSION: In conclusion, the present study demon strated that Gentiopicroside exerted nerve-protective effect and attenuated experimental DPN by restoring dyslipidmia and improved nerve blood flow through regulating PPAR-γ/AMPK/ACC signal pathway. These results provided a promising potential treatment of DPN.