Integrating the Patient Perspective to Validate a Measure of Disease Severity in Inflammatory Bowel Disease: Online Survey of Patients and Their Physicians.

BACKGROUND: The patient perspective is essential for assessing disease severity, but it is not always adequately considered. We describe how a comprehensive clinical disease severity index (DSI) for inflammatory bowel disease (IBD) correlates with patient global self-assessment (PGSA). METHODS: In an individually linked parallel online survey, physicians provided the DSI, and patients provided self-assessed severity using a global question and visual analog scale (0-100) (PGSA). Mean DSI values by PGSA were calculated with 95% confidence intervals. Pearson correlation (r) and the intraclass correlation coefficient were calculated for PGSA vs DSI. Positive predictive values for identifying severe disease with PGSA categories as a reference were based on a threshold >22 points. RESULTS: The primary analysis included 89 pairs (46 Crohn's disease [CD], 43 ulcerative colitis [UC]) with strict criteria and 147 pairs when less stringent. Common reasons for exclusion were missing values for albumin or colonoscopy. Mean DSI values showed no clear trend with increasing PGSA in CD but good discrimination between moderate, severe, and very severe PGSA in UC. For PGSA on the visual analog scale, r was 0.54 for CD and 0.59 for UC (difference in means: CD 27.7, UC 13.8; intraclass correlation coefficient: CD 0.48, UC 0.58). A high DSI predicted severe disease in 76.2% of CD and 65.2% of UC. CONCLUSIONS: The DSI showed good discrimination for patient-reported disease severity in UC but performed unsatisfactorily in CD. Correlations were moderate. Further refinement of the DSI is suggested to better reflect the patient perspective.

The performance of an inflammatory bowel disease severity score was compared with self-perceived severity based on an individually linked online survey of patients and their physicians. Agreement and prediction of severe disease were moderate and should be improved by integrating the patients' perspective.

Gut microbiota predicts severity and reveals novel metabolic signatures in acute pancreatitis.

OBJECTIVE: Early disease prediction is challenging in acute pancreatitis (AP). Here, we prospectively investigate whether the microbiome predicts severity of AP (Pancreatitis-Microbiome As Predictor of Severity; P-MAPS) early at hospital admission. DESIGN: Buccal and rectal microbial swabs were collected from 424 patients with AP within 72 hours of hospital admission in 15 European centres. All samples were sequenced by full-length 16S rRNA and metagenomic sequencing using Oxford Nanopore Technologies. Primary endpoint was the association of the orointestinal microbiome with the revised Atlanta classification (RAC). Secondary endpoints were mortality, length of hospital stay and severity (organ failure >48 hours and/or occurrence of pancreatic collections requiring intervention) as post hoc analysis. Multivariate analysis was conducted from normalised microbial and corresponding clinical data to build classifiers for predicting severity. For functional profiling, gene set enrichment analysis (GSEA) was performed and normalised enrichment scores calculated. RESULTS: After data processing, 411 buccal and 391 rectal samples were analysed. The intestinal microbiome significantly differed for the RAC (Bray-Curtis, p value=0.009), mortality (Bray-Curtis, p value 0.006), length of hospital stay (Bray-Curtis, p=0.009) and severity (Bray-Curtis, p value=0.008). A classifier for severity with 16 different species and systemic inflammatory response syndrome achieved an area under the receiving operating characteristic (AUROC) of 85%, a positive predictive value of 67% and a negative predictive value of 94% outperforming established severity scores. GSEA revealed functional pathway units suggesting elevated short-chain fatty acid (SCFA) production in severe AP. CONCLUSIONS: The orointestinal microbiome predicts clinical hallmark features of AP, and SCFAs may be used for future diagnostic and therapeutic concepts. TRIAL REGISTRATION NUMBER: NCT04777812.

High prevalence of incidental endoscopic findings at routine endoscopy after atrial fibrillation ablation: Do we need a screening endoscopy for the upper gastrointestinal tract in the general population?

INTRODUCTION: High-power short-duration ablation (HPSD) is an effective therapy for atrial fibrillation with thermal esophageal injury as a rare but relevant side effect. AIM AND METHODS: In this retrospective single-center analysis we evaluated the incidence and relevance of ablation-induced findings and the prevalence of ablation-independent incidental gastrointestinal findings. For 15 months all patients undergoing ablation were screened by postablation esophagogastroduodenoscopy. Pathological findings were followed up and treated if necessary. RESULTS: 286 consecutive patients (66±10 years; 54.9% male) were included. 19.6% of patients showed ablation-associated alterations (10.8% esophageal lesions, 10.8% gastroparesis, 1.7% both findings). Logistic multivariable regression analysis confirmed an influence of lower BMI on the occurrence of RFA-associated endoscopic findings (OR 0.936, 95% CI 0.878-0.997, p<0.05). 48.3% of patients demonstrated incidental gastrointestinal findings. In 1.0% neoplastic lesions were present, 9.4% showed precancerous lesions and in 4.2% neoplastic lesions of unknown dignity were found requiring further diagnostics or therapy. 18.1% of patients demonstrated findings associated with a potentially increased risk of bleeding under anticoagulation. Patients with clinically relevant incidental findings were significantly more often male, 68.8% vs. 49.5% (p<0.01). CONCLUSION: HPSD ablation is safe, no devasting complication occurred in any patient. It resulted in 19.6% ablation-induced thermal injury whereas incidental findings of the upper GI tract were found in 48.3% of patients. Due to the high prevalence of 14.7% of findings requiring further diagnostics, therapy, or surveillance in a cohort that is mimicking the general population, screening endoscopy of the upper GI tract seems to be reasonable in the general population.

NF-κB/RelA controlled A20 limits TRAIL-induced apoptosis in pancreatic cancer.

The emergence of resistance to systemic therapies in pancreatic ductal adenocarcinoma (PDAC) is still a major obstacle in clinical practice. Both, constitutive and inducible NF-κB activity are known as key players in this context. To identify differentially expressed and TRAIL resistance mediating NF-κB target genes, TRAIL sensitive and resistant PDAC cell lines were analyzed by transcriptome assays. In this context, A20 was identified as an NF-κB/RelA inducible target gene. Translational PDAC tissue analysis confirmed the correlation of elevated A20 protein expression with activated RelA expression in PDAC patients. In in vitro experiments, an elevated A20 expression is accompanied by a specific resistance toward TRAIL-mediated apoptosis but not to chemotherapeutic-induced cell death. This TRAIL resistance was attributed to A20´s E3-ligase activity-mediating Zink finger domain. Furthermore, the ubiquitin-binding scaffold protein p62 was identified as indispensable for the TRAIL-mediated apoptosis-inducing pathway affected by A20. The results of this study identify A20 as a possible therapeutic target to affect resistance to TRAIL-induced apoptosis in PDAC cells.

Incidence of ablation-induced esophageal lesions and gastroparesis in patients undergoing ablation index guided high power short duration atrial fibrillation ablation.

INTRODUCTION: Aim of this study was to evaluate the incidence of ablation-induced endoscopically detected esophageal lesions (EDEL) and gastroparesis in patients undergoing high-power short-duration (HPSD) atrial fibrillation (AF) ablation using different target ablation index (AI) values. METHODS AND RESULTS: Consecutive patients undergoing AF ablation were included. Radiofrequency (RF) ablation was performed using HPSD ablation (50 W, target AI of 320 and 350 (group 1) and 380 (group 2) at posterior wall). Postablation endoscopy was performed in all patients. In total, 233 patients (66.8 ± 10 years; 52% male) were included consecutively (n = 137 patients in group 1 and n = 96 patients in group 2). Mean AI values und RF time at posterior wall was significantly higher and longer in group 2 compared to group 1 patients (413 ± 9 vs. 392 ± 19 AI, p < 0.01; 9.0 ± 0.8 s vs. 7.8 ± 0.7 s, p < 0.01). Esophageal endoscopy revealed esophageal lesions or gastroparesis in 43 of 233 patients (18.5%) in the total cohort (13.1% in group 1 and 26.0% in group 2; p = 0.02). Incidence of EDEL was 8.0% and 13.5% in group 1 and group 2, respectively. According to logistic analysis incidence of EDEL and/or gastroparesis was significantly lower in patients with a higher body mass index and higher in group 2 patients compared to group 1 patients. CONCLUSION: The incidence of EDEL or gastroparesis in patients undergoing HPSD AF ablation was 18.5% in the total cohort. The risk of EDEL and gastroparesis was associated with a higher AI target value of 380 compared to 320 and 350 at posterior wall and was reversely associated with body mass index.

The HSF1-CPT1a Pathway Is Differentially Regulated in NAFLD Progression.

Obesity and obesity-associated diseases represent one of the key health challenges of our time. In this context, aberrant hepatic lipid accumulation is a central pathological aspect of non-alcoholic fatty liver disease (NAFLD). By comparing methylation signatures of liver biopsies before and after bariatric surgery, we recently demonstrated the strong enrichment of differentially methylated heat shock factor 1 (HSF1) binding sites (>400-fold) in the process of liver remodeling, indicating a crucial role of HSF1 in modulating central aspects of NAFLD pathogenesis. Using cellular models of NAFLD, we were able to show that HSF1 is activated during fat accumulation in hepatocytes, mimicking conditions in patients before bariatric surgery. This induction was abolished by starving the cells, mimicking the situation after bariatric surgery. Regarding this connection, carnitine palmitoyltransferase 1 isoform A (CTP1a), a central regulator of lipid beta-oxidation, was identified as a HSF1 target gene by promoter analysis and HSF1 knockdown experiments. Finally, pharmacological activation of HSF1 through celastrol reduced fat accumulation in the cells in a HSF1-dependent manner. In conclusion, we were able to confirm the relevance of HSF1 activity and described a functional HSF1-CPT1a pathway in NAFLD pathogenesis.

Endoscopic Management of Anastomotic Leakage after Esophageal Surgery: Ten Year Analysis in a Tertiary University Center.

BACKGROUND/AIMS: Anastomotic leakage after esophageal surgery remains a feared complication. During the last decade, management of this complication changed from surgical revision to a more conservative and endoscopic approach. However, the treatment remains controversial as the indications for conservative, endoscopic, and surgical approaches remain non-standardized. METHODS: Between 2010 and 2020, all patients who underwent Ivor Lewis esophagectomy for underlying malignancy were included in this study. The data of 28 patients diagnosed with anastomotic leak were further analyzed. RESULTS: Among 141 patients who underwent resection, 28 (19.9%) developed an anastomotic leak, eight (28.6%) of whom died. Thirteen patients were treated with endoluminal vacuum therapy (EVT), seven patients with self-expanding metal stents (SEMS) four patients with primary surgery, one patient with a hemoclip, and three patients were treated conservatively. EVT achieved closure in 92.3% of the patients with a large defect and no EVT-related complications. SEMS therapy was successful in clinically stable patients with small defect sizes. CONCLUSION: EVT can be successfully applied in the treatment of anastomotic leakage in critically ill patients, while SEMS should be limited to clinically stable patients with a small defect size. Surgery is only warranted in patients with sepsis with graft necrosis.

Cyclophosphamide therapy in Sweet's syndrome complicating refractory Crohn's disease − Efficacy and mechanism of action.

BACKGROUND: Sweet's syndrome is a rare extraintestinal manifestation of Crohn's disease that is usually treated by corticosteroids. Cyclophosphamide therapy has been shown to be effective in steroid-refractory Crohn's disease with extraintestinal manifestations. The mechanism of action remains obscure. Here, we report about a case of steroid-refractory Sweet's syndrome accompanying Crohn's colitis treated by cyclophosphamide. METHODS: At baseline and two weeks after initiating cyclophosphamide pulse therapy, clinical symptoms were evaluated and apoptosis in mononuclear cells of the colon mucosa was quantified via immunofluorescence TUNEL-labeling. Ongoing clinical follow-up lasts for more than three years. RESULTS: Cyclophosphamide pulse therapy resulted in complete resolution of luminal activity and extraintestinal manifestations. TUNEL-marked CD4(+), CD8(+) and CD68(+) cells in intestinal biopsies showed a 338% increase as compared to baseline. CONCLUSIONS: Cyclophosphamide therapy was highly effective in steroid-refractory Crohn's colitis accompanied by Sweet's syndrome for induction of remission. Furthermore, apoptosis of mononuclear cells in the colon mucosa, including CD68(+) macrophages as well as CD4(+) and CD8(+) cells, appears to be a component of the anti-inflammatory effect of cyclophosphamide in Crohn's disease.

Identification of a novel isoform predominantly expressed in gastric tissue and a triple-base pair polymorphism of the cathepsin W gene.

In order to investigate the prevalence of potential polymorphisms of the cathepsin W gene, the complete cDNA of 50 dyspeptic patients was analyzed. From those 37 (74%) revealed the wildtype sequence, 6 samples (12%) contained independent single base pair changes including 4 silent and 2 with amino acid changes. Furthermore, a triple-base pair polymorphism was found in 7 samples (14%, 4x heterozygous, 3x homozygous) leading to the following changes: F(217)S, H(248)Y, and I(250)T. Furthermore, a novel alternative splice variant concerning intron 10 was identified in 6 samples (12%). Notably, this novel isoform was only found in samples of gastric mucosa lymphocytes, whereas peripheral NK cells expressed cathepsin W wildtype only. Taken together, this study demonstrated for the fist time that a genetic variant and a novel isoform of cathepsin W are present in about 14% and 12%, respectively, within the Caucasian population.