Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis.

BACKGROUND: Namodenoson, an A3 adenosine receptor (A3AR) agonist, improved liver function/pathology in non-alcoholic steatohepatitis (NASH) preclinical models. AIM: To evaluate the efficacy and safety of namodenoson for the treatment of non-alcoholic fatty liver disease (NAFLD) with or without NASH METHODS: This phase 2 study included 60 patients with NAFLD (ALT ≥60 IU/L) who were randomised (1:1:1) to oral namodenoson 12.5 mg b.d. (n = 21), 25 mg b.d. (n = 19), or placebo (n = 20) for 12 weeks (total follow-up: 16 weeks). The main efficacy endpoint involved serum ALT after 12 weeks of treatment. RESULTS: Serum ALT decreased over time with namodenoson in a dose-dependent manner. The difference between change from baseline (CFB) for ALT in the namodenoson 25 mg b.d. arm vs placebo trended towards significance at 12 weeks (P = 0.066). Serum AST levels also decreased with namodenoson in a dose-dependent manner; at 12 weeks, the CFB for 25 mg b.d. vs placebo was significant (P = 0.03). At Week 12, 31.6% in the namodenoson 25 mg b.d. arm and 20.0% in the placebo arm achieved ALT normalisation (P = 0.405). At week 16, the respective rates were 36.8% and 10.0% (P = 0.038). A3AR expression levels were stable over time across study arms. Both doses of namodenoson were well tolerated with no drug-emergent severe adverse events, drug-drug interactions, hepatotoxicity, or deaths. Three adverse events were considered possibly related to study treatment: myalgia (12.5 mg b.d. arm), muscular weakness (25 mg b.d. arm), and headache (25 mg b.d. arm). CONCLUSION: A3AR is a valid target; namodenoson 25 mg b.d. was safe and demonstrated efficacy signals (ClinicalTrials.gov #NCT02927314).

Nonattendance to gastroenterologist follow-up after discharge is associated with a thirty-days re-admission in patients with inflammatory bowel disease: a multicenter study.

BACKGROUND: Inflammatory bowel disease (IBD) is a set of chronic inflammatory diseases associated with significant morbidity and high hospitalization rate. IBD patients are particularly prone to rehospitalization resulting in high medical cost and morbidity. The aim of this study was to assess laboratory and clinical predictors of readmission in patients who were hospitalized with IBD flare. METHODS: A multicenter, retrospective, cross-sectional analysis included IBD patients who were admitted with disease exacerbation from January 1, 2019 to January 1, 2020 in three Israeli university hospitals (Nazareth Hospital, Galilee Medical Center and Hadassah Medical Organization). RESULTS: Overall, a total of 176 hospitalizations for IBD flares were included. Seventeen patients were readmitted within 30 days after discharge (group A), as compared to 159 patients who were not (group B). The average age was 35.3±19.2 years in group A vs. 38.6±16 years in group B. Eight (47.1%) and 9 (52.9%) patients had Crohn's disease (CD) and ulcerative colitis (UC) in group A as compared to 102 (64.2%) and 57 (35.9%) in group B, respectively. On univariate analysis, only the attendance to gastroenterology clinic follow-up after discharge from hospitalization due to IBD flare was significantly protective factor to with 30-days readmission (OR=0.37, 95% CI: 0.13-1, P=0.05). There were no associations with the other assessed clinical and laboratory parameters and importantly IBD type (OR=1.99, 95% CI: 0.74-5.34, P=0.17). Notably, there was no effect of the day of discharge white blood counts, albumin and C reactive protein (CRP) values on readmission rates (odds ratio [OR]=1.07, 95% CI: 0.96-1.20, P=0.19, OR=0.86, 95% CI: 0.39-1.91, P=0.71 and OR=0.99, 95% CI: 0.97-1.01, P=0.59), respectively. CONCLUSIONS: Attendance to out-patient gastroenterologist follow-up is the only significant protective parameter to 30-days readmission in patients with IBD. This finding highlights the vital need of adequate gastroenterological follow-up of these patients after hospital discharge. Further studies are warranted to precisely define timing and role of outpatient follow-up in reducing IBD readmissions.

Unawareness of thromboprophylaxis is associated with low venous thromboembolism occurrence in hospitalized patients with acute inflammatory bowel disease flare.

BACKGROUND: Inflammatory bowel disease (IBD) is a set of chronic inflammatory diseases associated with significant morbidity. Generally, IBD patients have twice the risk of venous thromboembolism (VTE) compared to healthy controls. VTE can occur both, during hospital stay or after discharge. We aimed to assess the incidence among IBD patients who were hospitalized for disease exacerbation. METHODS: In a retrospective cross-sectional analysis all IBD patients who were admitted with disease exacerbation at Galilee Medical Center and Hadassah Medical Organization were included in the study. Excluding criteria was IBD with already known hypercoagulable state. RESULTS: One-hundred and sixteen patients with 176 admissions due to IBD flare were included in the study. The average age was 38.3±16.3 years. Sixty-six admissions (37.5%) occurred in patients with ulcerative colitis exacerbation and 110 in patients with Crohn's disease exacerbation (62.5%). Thirty-nine patients (22.1%) were smokers. Fifty-four patients (30.7%) and 68 patients (38.6%) were on previous (within 3 months) biological and steroid treatment, respectively. Twelve patients (6.8%) were on prophylactic subcutaneous anticoagulation (enoxaparin) throughout their hospital stay and only 3 patient (1.7%) developed in-hospital clinical VTE episode. The mean hospitalization length was 6.8±7.9 days and among patients who developed VTE episode, the length of stay was significantly higher as compared to patients without VTE episodes (36.7 vs. 6.3 days, P<0.0001). Notably, in-hospital IBD related-surgical procedure was the only risk factor for the development of VTE (Odds Ratio: 36.2; P=0.01). CONCLUSIONS: In-hospital VTE is rare among IBD patients admitted with exacerbation. Further studies are warranted to assess risk factors for in-hospital VTE development and to assess further the role of prophylactic anticoagulation among IBD patients with bloody diarrhea.

A Validated Score Assessing the Risk of an Intra-Abdominal Abscess in Patients with Crohn's Disease Presenting at the Emergency Department.

BACKGROUND AND AIMS: A majority of acutely ill Crohn's disease [CD] patients who present to Emergency Department [ED] will undergo an abdominal CT to rule out disease complications. We aimed to generate a simple non-invasive scoring model to predict the presence of an intra-abdominal abscess in CD patients in the ED. METHODS: We performed a retrospective case-control study at four Israeli hospitals from January 1, 2010 to May 30, 2018. Inclusion criteria included patients with an established diagnosis of CD that had cross-sectional abdominal imaging performed. A total of 322 patients were included, and 81 [25%] were diagnosed with an intra-abdominal abscess. RESULTS: In univariate analysis, ileo-colonic location (odds ratio [OR] 1.88, p = 0.0148), perianal CD [OR 7.01, p = 0.0004], fever [OR 1.88, p = 0.0247], neutrophil-to-lymphocyte ratio [OR 1.12, p < 0.0001], and C-reactive protein [OR 1.10, p < 0.0001] were significantly associated with abscess formation, whereas current use of corticosteroids was negatively associated with abscess formation [OR 0.46, 95% CI, 0.2-0.88, p = 0.0192]. We developed a diagnostic score that included five parameters that were significant on multivariate regression analysis, with assignment of weights for each variable according to the coefficient estimate. A low cut-off score of ≤7 was associated with a negative predictive value [NPV] of 93% for abscess formation, whereas a high cut-off score of >9 was associated with a positive predictive value of 65%. We validated this score with an independent cohort [area under the curve of 0.881 and NPV of 98.5%]. CONCLUSION: We recommend incorporating this score as an aid for stratifying acutely ill CD patients in the ED with low or high probability of the presence of an intra-abdominal abscess.

Acute Portal Vein Thrombosis Predicts Concomitant Diagnosis of Hepatocellular Carcinoma in Cirrhotic Patients.

PURPOSE: Portal vein thrombosis (PVT) is a common condition in cirrhotic patients and mostly attributed to portal hypertension. The objective of our study was to examine the association of PVT with hepatocellular carcinoma (HCC) in cirrhotic patients. METHODS: A retrospective study was performed to identify cirrhotic patients with thrombosis of the portal system. Clinical and laboratory characteristics were collected and analyzed. RESULTS: Thirty-nine patients were identified. Twenty-four out of 39 patients with PVT did not develop HCC (group A) after follow-up time of 38.5 months from the diagnosis of PVT. Eight patients (20.5%) were diagnosed with HCC within two weeks following diagnosis of PVT (group B). Seven patients (17.9%) were diagnosed with tumor thrombus (group C) at time of PVT diagnosis. The average age was 53.5, 66.5, and 69 years for groups A, B, and C respectively. Most patients (75 and 87.5% for groups B and C respectively) diagnosed with PVT and HCC were males. The most common cause of cirrhosis in groups B and C was chronic hepatitis B virus infection (HBV) in 62.5% and 50% respectively. The most common clinical presentation of PVT in group A was abdominal pain in 55.5% compared to new/worsening ascites in 43% and 37.5% for groups B and C respectively. The platelet count in groups B and C was higher as compared to that in group A (126 and 125 vs. 107 thousand, P = NS). CONCLUSION: In 38.4% of cases, new diagnosis of PVT was associated with concomitant diagnosis of HCC. Identifiable risk factors were chronic HBV infection and higher platelet count.

Portal lymphadenopathy predicts non-alcoholic steatohepatitis and advanced fibrosis in non-alcoholic fatty liver disease.

BACKGROUND AND AIM: The progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) is believed to be the driver for future development of fibrosis and cirrhosis. Nevertheless, there remains a clear deficit in non-invasive methods for the diagnosis of NASH. The aim of the present study was to evaluate the prevalence of portal lymphadenopathy (PL) in biopsy- proven NAFLD patients and to determine whether PL correlates with NAFLD stage and severity. METHODS: A retrospective study included biopsy-proven NAFLD patients with up to date (within one year) abdominal imaging by computed tomography (CT) and/or magnetic resonance imaging (MRI). Patients were clustered into three groups based on their NAFLD Activity Score (NAS): NAS1-2 (mild), NAS3-4 (moderate) and NAS≥5 (advanced). We Assessed for association between PL and other clinical and laboratory findings with NAS, NAS components and fibrosis. RESULTS: Seventy-five patients with NAFLD and no other competing etiologies for liver diseases or PL were included. The mean age was 50.7±14.84 years with male predominance (N = 47, 62.7%). Twenty-five (33.3%), 37 (49.3%) and 13 (17.3%) patients had mild, moderate and advanced NAS, respectively. PL significantly correlated with advanced NAS ≥ 5 (Fisher's (F) 9.5, P = 0.009). Correlation was driven mainly by a link to hepatocytes ballooning (F of 5.9, P = 0.043). In addition, PL significantly correlated with portal inflammation (F 4.29, P = 0.038). As for hepatic fibrosis, the F test wasn't significant, though spearman's coefficient (SC) was significant (0.277, P = 0.012). On multivariate analysis, PL was identified as a sole predictor of advanced NAS score (Odds ratio of 2.68, P = 0.002). Incorporation of PL into noninvasive fibrosis scores improved their diagnostic yield. CONCLUSION: PL predicts severity of NAFLD. Its presence may serve as a novel radiological marker for NAFLD/NASH differentiation and disease progression.

State of the art review with literature summary on gastric peroral endoscopic pyloromyotomy for gastroparesis.

Gastroparesis is a debilitating progressive disease that significantly impacts a patient's life with limited and challenging treatments available. Although the pathogenesis is multifactorial, pylorospasm is believed to have a major underlying role. Several therapeutic interventions directed to the pylorus have been developed over the last decade, including intra-pyloric injections of botulinum toxin, transpyloric stenting, and surgical pyloroplasty. All of these treatment options had limited and disappointing results. More recently, gastric peroral endoscopic myotomy (G-POEM) has been reported as a treatment for refractory gastroparesis. In this review article, we provide an overview on gastroparesis with a focus on the therapeutic interventions. In addition, we provide a literature summary and pool analysis of the clinical efficacy, scintigraphic efficacy, and safety profile of all studies that evaluated G-POEM in gastroparesis. Overall, seven studies have reported on the use of G-POEM in gastroparesis, and the pooled analysis of these studies showed a technical success of 100%, with clinical efficacy as assessed by the Gastroparesis Cardinal Symptoms Index of 81.5%, gastric emptying scintigraphy normalization in approximately 55.5% of the cases, perioperative complications in 7.6%, and intraoperative complications in 6.6%. This suggests that G-POEM is a new promising therapeutic intervention for the treatment of gastroparesis with durable effect and limited potential adverse events.

Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects.

The analysis of individuals with telomere defects may shed light on the delicate interplay of factors controlling genome stability, premature aging, and cancer. We herein describe two Coats plus patients with telomere and genomic defects; both harbor distinct, novel mutations in STN1, a member of the human CTC1-STN1-TEN1 (CST) complex, thus linking this gene for the first time to a human telomeropathy. We characterized the patients' phenotype, recapitulated it in a zebrafish model and rescued cellular and clinical aspects by the ectopic expression of wild-type STN1 or by thalidomide treatment. Interestingly, a significant lengthy control of the gastrointestinal bleeding in one of our patients was achieved by thalidomide treatment, exemplifying a successful bed-to-bench-and-back approach.