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Background Medicine is one of the most demanding academic fields with an extensive curriculum that entails plenty of potential stressors. There is sufficient evidence that medical students are more prone to psychological distress when compared to their peer group of other disciplines. Despite the established need to prioritize resilience skills building within the medical curriculum, very few medical programmes in the Middle East and North Africa region (MENA) proactively empower the students to help themselves in sustaining their mental health. The purpose of the current study is to explore the perception of medical students in Dubai, United Arab Emirates (UAE) regarding their understanding of, and personal experience with building resilience, and their engagement with the content of an innovative curriculum-based resilience skills building course, designed in alignment with the constructivism theory of education. Method The current study utilized a qualitative phenomenological research design. The curriculum-based resilience skills building course, that was investigated as part of this study, is offered at a medical school in Dubai, UAE. A total of 37 students submitted reflective essays about resilience building, in general, and the respective course, in specific. The collected data was inductively analysed following a six-step framework. Findings The qualitative analysis generated three interlinked themes, namely: Awareness, Application, and Appraisal. Conclusion This study showed that integrating a resilience skills building course into medical curricula is likely to be positively appraised by the students, where it raises their level of awareness and likelihood of proactively applying the learned concepts in their daily lives. This is especially true when the course is anchored in constructivism experiential learning theory and designed to foster self-directed learning.

Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis, is a debilitating condition with a rising incidence globally over recent years. Frondanol, a widely available nutraceutical extract of the edible sea cucumberOne hundred patients will be randomized (1:1) to receive Frondanol or placebo as an adjunct to their standard therapy for the period of six months. Blood and stool samples will be obtained during routine visits at baseline, and after three months and six months of treatment, and tissue samples from colon biopsies will be obtained during clinically indicated colonoscopies at baseline and after six months of treatment. The levels of inflammatory markers will be compared in serum and tissue samples between patients treated with Frondanol and those treated with placebo, and findings will be correlated with clinical and histological parameters.If proven beneficial, treatment with Frondanol may increase the likelihood of patients remaining in remission and potentially provide an effective, natural and safe addition/alternative for treatment-naive patients in the future.(Clinical trial registration number: NCT05194007).

Highlights • The mean age of 119,883 healthcare workers identified in this study was 38.37 years (95% CI, 36.72 – 40.03) and males comprised 21.4% (95% CI, 12.4 – 34.2) of the population. • The most prevalent symptoms were fever 27.5% (95% CI, 17.6-40.3) and cough 26.1% (95% CI, 18.1-36) • The prevalence of hospitalization of healthcare workers infected with COVID-19 was 15.1% (95% CI, 5.6-35) and mortality of (95% CI, 0.5-3.9). • Comparisons of healthcare workers with and without infection showed an increased relative risk for COVID-19 related to PPE, workplace setting, profession, exposure, contacts, and testing-related factors., Background The COVID-19 pandemic has focused attention on the challenges and risks faced by frontline healthcare workers (HCW). Our aim is to describe the clinical outcomes and risk factors for SARS- CoV-2 infection in HCW. Methods Three databases were surveyed identifying 328 articles. Of these, 225 articles did not meet inclusion criteria; 97 full-text article were reviewed. Finally, after further revision, 30 articles were included in the systematic review and 28 used for meta-analysis. Results A total of 28 studies were identified involving 119,883 patients. The mean age of the patients was 38.37 years (95% CI, 36.72 – 40.03) and males comprised 21.4% (95% CI, 12.4 – 34.2) of the population of health workers. The prevalence of HCW who tested positive for COVID-19 is 51.7% (95% CI, 34.7-68.2). The total prevalence of co-morbidities in 7 studies was 18.4% (95% CI, 15.5 – 21.7). The most prevalent symptoms were fever 27.5% (95% CI, 17.6-40.3), cough 26.1% (95% CI, 18.1-36).The prevalence of hospitalization of HCW was 15.1% (95% CI, 5.6-35) in 13 studies and the prevalence of death was 1.5% (95% CI, 0.5-3.9) in 12 studies. Comparisons of HCW with and without infection showed an increased relative risk for COVID-19 related to PPE, workplace setting, profession, exposure, contacts, and testing. Conclusion A significant number of HCW have been reported to be infected with COVID-19 during the first 6 months of the pandemic, with a prevalence of hospitalization of 15.1% and mortality of 1.5%. Further data is needed to track the continued risks in HCW as the pandemic evolves and health systems adapt.

Background The coronavirus disease 2019 (COVID‐19) pandemic continues to cause global havoc posing uncertainty to educational institutions worldwide. Understanding the clinical characteristics of COVID‐19 in children is important because of the potential impact on clinical management and public health decisions. Methods A meta‐analysis was conducted for pediatric COVID‐19 studies using PubMed and Scopus. It reviewed demographics, co‐morbidities, clinical manifestations, laboratory investigations, radiological investigations, treatment, and outcomes. The 95% confidence interval (CI) was utilized. Results Out of 3927 articles, 31 articles comprising of 1816 patients were selected from December 2019 to early October 2020 and were defined by 77 variables. Of these studies 58% originated from China and the remainder from North America, Europe and the Middle East. This meta‐analysis revealed that 19.2% (CI 13.6%–26.4%) of patients were asymptomatic. Fever (57%, CI 49.7%–64%) and cough (44.1%, CI 38.3%–50.2%) were the most common symptoms. The most frequently encountered white blood count abnormalities were lymphopenia 13.5% (CI 8.2%–21.4%) and leukopenia 12.6% (CI 8.5%–18.3%). Ground glass opacities were the most common radiological finding of children with COVID‐19 (35.5%, CI 28.9%–42.7%). Hospitalization rate was 96.3% (CI 92.4%–98.2%) of which 10.8% (CI 4.2%–25.3%) were ICU admissions, and 2.4% (CI 1.7%–3.4%) died. Conclusion The majority of pediatric patients with COVID‐19 were asymptomatic or had mild manifestations. Among hospitalized patients there remains a significant number that require intensive care unit care. Overall across the literature, a considerable level of understanding of COVID‐19 in children was reached, yet emerging data related to multisystemic inflammatory syndrome in children should be explored.

Background: Mucus protects the epithelium against invaders and toxic materials. Sticky and thick mucus is characteristic of CF. Objective: The aim of this systematic review is to characterize the specific mucins secreted in the lung and intestinal tract of CF patients. Methods: A systematic literature search was conducted up to December 31, 2019. The following terms were used: “cystic fibrosis” AND “mucin.” Case-control studies comparing mucin expression in CF patients to healthy controls were included. Results: We found 741 eligible studies, 694 studies were rejected because they were performed in animals and not in full text, and 32 studies were excluded being editorials, duplications, review articles, meta-analysis, or not in English. Fifteen studies were eligible for our study, including 150 CF patients compared to 82 healthy controls, all fulfilled the inclusion criteria. The main mucin types expressed in the sinus submucosal glands, sputum, tracheobronchial surface epithelium, and lung submucosal glands were MUC5AC and MUC5B. Increase in the number of sinusoidal submucosal glands and expression of MUC5B was found in CF patients, but no such difference from healthy controls was found for the number of goblet cells in the surface epithelium nor in the expression of ­MUC5AC. The opposite was found in the tracheobronchial surface epithelium and in the lungs. Conclusions: Increased expression of MUC5AC in the surface epithelium and of MUC5B in the subepithelial glands may be the result of higher secretion rate of mucin into the lumen of the respiratory tract, causing mucus plaque, infection, and inflammation.

Live bacterial therapeutics (LBT) could reverse disease by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally-raised (CR) hosts have been unsuccessful, because engineered microbial organisms (i.e., chassis) cannot colonize the hostile luminal environment. In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli isolated from stool cultures of CR mice were modified to express functional bacterial (bile salt hydrolase) and eukaryotic (Interleukin-10) genes. Reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E. coli can induce functional changes that affect host physiology and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to “knock-in” specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts, and enables LBT with curative intent.

BACKGROUND: Early hospital readmission for patients with cirrhosis continues to challenge the healthcare system. Risk stratification may help tailor resources, but existing models were designed using small, single-institution cohorts or had modest performance. AIMS: We leveraged a large clinical database from the Department of Veterans Affairs (VA) to design a readmission risk model for patients hospitalized with cirrhosis. Additionally, we analyzed potentially modifiable or unexplored readmission risk factors. METHODS: A national VA retrospective cohort of patients with a history of cirrhosis hospitalized for any reason from January 1, 2006 to November 30, 2013 was developed from 123 centers. Using 174 candidate variables within demographics, laboratory results, vital signs, medications, diagnoses and procedures, and healthcare utilization we built a 47 variable penalized logistic regression model with the outcome of all-cause 30-day readmission. We excluded patients who left against medical advice, transferred to a non-VA facility, or if the hospital length of stay was greater than thirty days. We evaluated calibration and discrimination across variable volume and compared the performance to recalibrated pre-existing risk models for readmission. RESULTS: We analyzed 67,749 patients and 179,298 index hospitalizations. The 30-day readmission rate was 23%. Ascites was the most common cirrhosis-related cause of index hospitalization and readmission. The AUC of the model was 0.670 compared to existing models (0.649, 0.566, 0.577). The Brier score of 0.165 showed good calibration. CONCLUSIONS: Our model achieved better discrimination and calibration compared to existing models, even after local recalibration. Assessment of calibration by variable parsimony revealed performance improvements for increasing variable inclusion well beyond those detectable for discrimination.

BACKGROUND: Alcohol-related liver disease is one of the most prevalent chronic liver diseases worldwide. Mechanisms involved in the pathogenesis of alcohol-related liver disease are not well understood. Oxylipins play a crucial role in numerous biological processes and pathological conditions. Nevertheless, oxylipins are not well studied in alcohol-related liver disease. AIMS: (1) To characterize the patterns of bioactive ω-3 and ω-6 polyunsaturated fatty acid metabolites in alcohol use disorder and alcoholic hepatitis patients, and (2) to identify associations of serum oxylipins with clinical parameters in patients with alcohol-related liver disease METHODS: We performed a comprehensive liquid chromatography with tandem mass spectrometry (LC-MS/MS)analysis of serum and fecal oxylipins derived from ω-6 arachidonic acid, ω-3 eicosapentaenoic acid and docosahexaenoic acid in a patient cohort with alcohol-related liver disease. RESULTS: Our results show profound alterations in the serum oxylipin profile of patients with alcohol use disorder and alcoholic hepatitis compared to non-alcoholic controls. Spearman correlation of the oxylipins with clinical parameters show a link between different serum oxylipins and intestinal permeability, aspartate aminotransferase, bilirubin, albumin, international normalized ratio, platelet count, steatosis, fibrosis and model for end-stage liver disease (MELD) score. Especially, higher level of serum 20- HETE was significantly associated with decreased albumin, increased hepatic steatosis, polymorphonuclear infiltration, and 90-day mortality. CONCLUSIONS: Patients with alcohol-related liver disease have different oxylipin profiles. Future studies are required to confirm oxylipins as disease biomarker or to connect oxylipins to disease pathogenesis.

OBJECTIVE This study aimed to evaluate a possible association between the use of obesogenic medications and inadequate weight loss in a behavioral weight-management program. METHODS This is a case-control, single-center study of 666 adult patients within a Veterans Health Administration health system who participated in the MOVE! behavioral weight-loss program. The cohort was divided into responders (n = 150), patients who achieved ≥ 5% total weight loss by the end of the MOVE! program, and nonresponders (n = 516), those who achieved

Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e., chassis) have difficulty in colonizing the hostile luminal environment. In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli bacteria isolated from the stool cultures of CR mice were modified to express functional genes. The reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E. coli can induce functional changes that affect physiology of and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to "knock in" specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts and enables LBT with curative intent.

BACKGROUND COVID-19 has infected over 123 million people globally. The first confirmed case in the United Arab Emirates (UAE) was reported on January 29, 2020. According to studies conducted in the early epicenters of the pandemic, COVID-19 has fared mildly in the pediatric population. To date, there is a lack of published data about COVID-19 infection among children in the Arabian region. OBJECTIVE This study aims to investigate the clinical characteristics, laboratory findings, treatment, and outcomes of children with COVID-19. METHODS This cross-sectional, multicenter study included children with confirmed COVID-19 infection admitted to 3 large hospitals in Dubai, UAE, between March 1 and June 15, 2020. Serial COVID-19 polymerase chain reaction (PCR) testing data were collected, and patients’ demographics, premorbid clinical characteristics, and inpatient hospital courses were examined. RESULTS In all, 111 children were included in our study and represented 22 nationalities. Of these, 59 (53.2%) were boys. The mean age of the participants was 7 (SD 5.3) years. About 15.3% of children were younger than 1 year. Only 4 (3.6%) of them had pre-existing asthma, all of whom had uneventful courses. At presentation, of the 111 children, 43 (38.7%) were asymptomatic, 68 (61.2%) had mild or moderate symptoms, and none (0%) had severe illness requiring intensive care. Fever (23/111, 20.7%), cough (22/111, 19.8%), and rhinorrhea (17/111, 15.3%) were the most common presenting symptoms, and most reported symptoms resolved by day 5 of hospitalization. Most patients had no abnormality on chest x-ray. The most common laboratory abnormalities on admission included variations in neutrophil count (22/111, 24.7%), aspartate transaminase (18/111, 22.5%), alkaline phosphatase (29/111, 36.7%), and lactate dehydrogenase (31/111, 42.5%). Children were infrequently prescribed targeted medications, with only 4 (3.6%) receiving antibiotics. None of the 52 patients tested for viral coinfections were positive. COVID-19 PCR testing turned negative at a median of 10 days (IQR: 6-14) after the first positive test. Overall, there was no significant difference of time to negative PCR results between symptomatic and asymptomatic children. CONCLUSIONS This study of COVID-19 presentations and characteristics presents a first look into the burden of COVID-19 infection in the pediatric population in the UAE. We conclude that a large percentage of children experienced no symptoms and that severe COVID-19 disease is uncommon in the UAE. Various laboratory abnormalities were observed despite clinical stability. Ongoing surveillance, contact tracing, and public health measures will be important to contain future outbreaks. CLINICALTRIAL

SARS-CoV-2 is a newly discovered virus which causes COVID-19 (coronavirus disease of 2019), initially documented as a human pathogen in 2019 in the city of Wuhan China, has now quickly spread across the globe with an urgency to develop effective treatments for the virus and emerging variants. Therefore, to identify potential therapeutics, an antiviral catalogue of compounds from the CAS registry, a division of the American Chemical Society was evaluated using a pharmacoinformatics approach. A total of 49,431 compounds were initially recovered. After a biological and chemical curation, only 23,575 remained. A machine learning approach was then used to identify potential compounds as inhibitors of SARS-CoV-2 based on a training dataset of molecular descriptors and fingerprints of known reported compounds to have favorable interactions with SARS-CoV-2. This approach identified 178 compounds, however, a molecular docking analysis revealed only 39 compounds with strong binding to active sites. Downstream molecular analysis of four of these compounds revealed various non-covalent interactions along with simultaneous modulation between ligand and protein active site pockets. The pharmacological profiles of these compounds showed potential drug-likeness properties. Our work provides a list of candidate anti-viral compounds that may be used as a guide for further investigation and therapeutic development against SARS-CoV-2.

Background To date, coronavirus disease-2019 (COVID-19) has infected over 82 million people globally. The first confirmed case in the United Arab Emirates (UAE)was reported on 29th January 2020. Current data suggests that children with COVID-19 have a mild disease course. There is a lack of extensive published data about COVID-19 infection among children in the Arabian Gulf region. Methods This cross-sectional multicenter study included children with confirmed COVID-19 infection admitted between March 1st and June 15th, 2020 to three large hospitals in Dubai, UAE. Serial nasal swabs for COVID-19 polymerase chain reaction (PCR) testing were collected during hospitalization. We investigated patients’ demographics,clinical characteristics, radiological and laboratory investigations during their inpatient hospital course. Results 111 children were included in our study and represented 22 nationalities. Fifty-nine (53.2%) were boys. The mean age was 7 years (±5.3), and 15.3% of children were younger than 1 year. Only 4 (3.6%) children had pre-existing asthma, all of whom had an uneventful clinical course. At presentation 43 (38.7%) were asymptomatic, 68 (61.2%) had mild or moderate symptoms and none had severe illness requiring intensive care. Fever (20.7%), cough (19.8%) and rhinorrhea (15.3%) were the most common presenting symptoms, most of which resolved by day 5 of hospitalization. Most of our patients had a normal chest x-ray. The most common laboratory abnormalities on admission included variations in neutrophil count (24.7%), aspartate transaminase (22.5%), alkaline phosphatase (36.7%) and lactate dehydrogenase (42.5%). Children were infrequently prescribed targeted medications, with only 4 (3.6%) receiving antibiotics. None of the 52 patients tested for viral co-infections were positive. COVID-19 PCR turned negative at a median of 10 days [6–14 days] after the first positive test. Overall, there was no significant difference in time to negative PCR between symptomatic and asymptomatic children. Conclusion This pediatric study of COVID-19 presents a first look into the burden of COVID-19 infection among children in the UAE. Patients had various laboratory abnormalities despite clinical stability. We conclude that a large percentage of children with COVID-19 infection experience no symptoms, and severe disease is uncommon in the UAE. Ongoing surveillance, contact tracing and public health measures will be essential in containing future outbreaks.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.

Background: The COVID-19 pandemic has caused a global havoc with our limited understanding of the SARS-CoV-2, disease manifestations and management. Inadequacy of available data in pediatric patients coupled with evolving disease course makes it imperative to conduct a meta-analysis assessing the results of pediatric COVID-19 studies over the course of the pandemic. Methods: A random-effect meta-analysis was conducted using PRISMA guidelines. Two databases were screened for pediatric COVID-19 studies and selected articles reviewed for demographic, co-morbidities, clinical manifestations, laboratory and radiological evaluation, treatment and outcomes. Prevalence with mean and 95% confidence interval was calculated. Results: Out of 1703 articles, 37 articles comprising of 993 patients for a period of over six months and 72 variables were selected. This meta-analysis revealed that one-fourth of patients were asymptomatic (23.8%, 95% CI 17.6-31.2%) Fever (52.5%, 95% CI 45.7–59.1%) and cough (47.6%, 95% CI 41.2–54.0%) were the most common symptoms. The most frequently encountered white blood count abnormalities were neutropenia (16.6%, 95% CI 10.2-25.8%), lymphocytosis (15.3%, 95% CI 9.9–23.0%) and leukopenia (13.9%, 95% CI 10.1–18.8%). Ground glass opacities were the most common radiological finding of children with COVID-19 (35.9%, 95% CI 29.4-43%). The hospitalization rate was 95.9% (95% CI 91.9-98.0%) of which 11.2% (95% CI 4.7-24.2) were ICU admissions, and 4.2% (95% CI 2.6-6.9%) died. Conclusion: Majority of pediatric patients are asymptomatic or have mild manifestations similar to other upper respiratory viruses. Serious disease and death occurred in 15.4%. More studies are needed from a wider geographic area as the pandemic continues.

Background Coronavirus disease-2019 (COVID-19) has infected over 20 million people globally. The first confirmed case in the United Arab Emirates (UAE) was reported on 29th January 2020. To date there is no published data about COVID-19 infection among children in the Arabian region. Objective To describe the epidemiologic, clinical and laboratory characteristics of children hospitalized with COVID-19 infection in Dubai, UAE Methods A cross-sectional multicentre study of children with confirmed COVID-19 infection admitted between March 1st and June 15th, 2020 to three large hospitals in Dubai, UAE. Their demographics, clinical characteristics and inpatient hospital course were investigated. Results 111 children were included in our study and represented 22 nationalities. Fifty-nine (53.2%) were boys. The mean age was 7 years, with 15.3% younger than 1 year. At presentation 43 (38.7%) were asymptomatic, 68 (61.2%) had mild or moderate symptoms and none had severe symptoms. Fever, cough and rhinorrhoea were common presenting symptoms and resolved by day 5 of hospitalization. Most of our patients had no abnormality on chest x-ray. The most common laboratory abnormalities on admission included variations in neutrophil count (24.7%), aspartate transaminase (22.5%), alkaline phosphatase (36.7%) and lactate dehydrogenase (42.5%). COVID-19 PCR turned negative at a median of 10 days after first positive. There was no significant difference to time of negative PCR between symptomatic and asymptomatic children. Conclusion A large percentage of children with COVID19 experience no symptoms, and severe disease is uncommon in the UAE. Ongoing surveillance and contact tracing will be important to contain future outbreaks.

Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol-related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal-specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti-Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90-day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11-8.82; P = 0.031). Conclusion: Patients with alcohol-associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.

Background and Aims: Tumor necrosis factor (TNF) is a major pathogenic effector and a therapeutic target in inflammatory bowel disease (IBD), yet the basis for TNF-induced intestinal epithelial cell (IEC) death is unknown, because TNF does not kill normal IECs. Here, we investigated how chronic nuclear factor (NF)- κB activation, which occurs in human IBD, promotes TNF-dependent IEC death in mice. Methods: Human IBD specimens were stained for p65 and cleaved caspase-3. C57BL/6 mice with constitutively active IKKβ in IEC (Ikkβ(EE)IEC), Ripk1D138N/D138N knockin mice, and Ripk3-/- mice were injected with TNF or lipopolysaccharide. Enteroids were also isolated from these mice and challenged with TNF with or without RIPK1 and RIPK3 inhibitors or butylated hydroxyanisole. Ripoptosome-mediated caspase-8 activation was assessed by immunoprecipitation. Results: NF-κB activation in human IBD correlated with appearance of cleaved caspase-3. Congruently, unlike normal mouse IECs that are TNF-resistant, IECs in Ikkβ(EE)IEC mice and enteroids were susceptible to TNF-dependent apoptosis, which depended on the protein kinase function of RIPK1. Constitutively active IKKβ facilitated ripoptosome formation, a RIPK1 signaling complex that mediates caspase-8 activation by TNF. Butylated hydroxyanisole treatment and RIPK1 inhibitors attenuated TNF-induced and ripoptosome-mediated caspase-8 activation and IEC death in vitro and in vivo. Conclusions: Contrary to common expectations, chronic NF-κB activation induced intestinal crypt apoptosis after TNF stimulation, resulting in severe mucosal erosion. RIPK1 kinase inhibitors selectively inhibited TNF destructive properties while preserving its survival and proliferative properties, which do not require RIPK1 kinase activity. RIPK1 kinase inhibition could be a potential treatment for IBD. Keywords: IBD, RIPK1, Intestinal Epithelial Cell, Ripoptosome, Cell Death

Alcoholic hepatitis is a severe manifestation of alcohol-associated liver disease with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with alcohol-associated liver disease. We extracted virus-like particles from 89 patients with alcoholic hepatitis who were enrolled in a multicenter observational study, 36 with alcohol use disorder, and 17 individuals without alcohol use disorder (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with alcohol-associated liver disease, with the most significant changes in samples from patients with alcoholic hepatitis. Escherichia-, Enterobacteria-, and Enterococcus phages were overrepresented in fecal samples from patients with alcoholic hepatitis, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median model for end-stage liver disease (MELD) score, and associated with increased 90-day mortality. In conclusion, intestinal viral taxa are altered in fecal samples from patients with alcoholic hepatitis and associated with disease severity and mortality. Our study, for the first time, described an intestinal virome signature associated with alcoholic hepatitis.

Background Hepatitis C virus (HCV) infection and alcohol use disorder (AUD) both adversely affect the immune system resulting in alterations in immune cell signaling and inflammatory processes. The aim of this study was to investigate how comorbid AUD contributes to abnormalities in inflammatory mediators and psychiatric impairments in adults with HCV. Methods Alcohol use, mood, and inflammatory factors were evaluated at 3 time points (baseline, week 4, and week 12) in Veterans with HCV, with (n = 42) and without (n = 13) comorbid AUD. Peripheral indices of immune activation, blood-brain barrier (BBB) damage (S100 calcium-binding protein B [S100B]), liver function, and viral load were measured using immunoassays and polymerase chain reaction assays. Results Comorbid AUD was associated with increased symptoms of depression and anxiety, elevated levels of liver enzymes, and altered expression of inflammatory factors. Alcohol consumption was positively correlated with the severity of psychiatric symptoms. Univariate analysis identified significant group differences in interleukin (IL)-8 (p = 0.006), IL-10 (p = 0.03), and S100B (p = 0.048), with increased levels in participants with AUD, which persisted over time despite reductions in alcohol use and no significant change in HCV viral load. Statistically significant effects of study group or time were not found for the other immune factors assessed. Exploratory receiver operating characteristic curve analysis evaluated the ability of IL-8, IL-10, and S100B to differentiate between levels of alcohol consumption and generated biomarker cutoff values used to identify low risk and unhealthy alcohol use groups. Conclusions These results demonstrate that HCV and comorbid AUD are associated with greater psychiatric impairments, potentially resulting from increased inflammation, dysregulated cytokine expression, and compromised BBB function. Alcohol-induced BBB damage may increase the risk of neuropathological consequences within the context of chronic HCV infection.

BACKGROUND Mucins are heavily glycosylated glycoproteins, synthesized by mucosal surfaces and have an important role in healthy state and malignant diseases. Change in mucins synthesis or secretion may be primary event or secondary to inflammation or carcinogenesis. AIM The aim of this study is to assess the current knowledge about mucin expression in esophageal lesions, and to establish a role for different mucin expressions as prognostic markers. METHOD English Medical literature searches were conducted for "mucin" and "esophagus." Observational studies were included. Meta-analysis was performed using comprehensive meta-analysis software. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated. RESULTS In the random-effect model, mucin expression was significantly higher in esophageal lesions than in normal esophageal mucosa with OR=5.456 (95% CI, 1.883-15.807, P=0.002). Measure of heterogeneity, demonstrated in the included studies, was high: Q=287.501, df (Q)=44.00, P

Background COVID-19 has infected over 123 million people globally. The first confirmed case in the United Arab Emirates (UAE) was reported on January 29, 2020. According to studies conducted in the early epicenters of the pandemic, COVID-19 has fared mildly in the pediatric population. To date, there is a lack of published data about COVID-19 infection among children in the Arabian region. Objective This study aims to investigate the clinical characteristics, laboratory findings, treatment, and outcomes of children with COVID-19. Methods This cross-sectional, multicenter study included children with confirmed COVID-19 infection admitted to 3 large hospitals in Dubai, UAE, between March 1 and June 15, 2020. Serial COVID-19 polymerase chain reaction (PCR) testing data were collected, and patients’ demographics, premorbid clinical characteristics, and inpatient hospital courses were examined. Results In all, 111 children were included in our study and represented 22 nationalities. Of these, 59 (53.2%) were boys. The mean age of the participants was 7 (SD 5.3) years. About 15.3% of children were younger than 1 year. Only 4 (3.6%) of them had pre-existing asthma, all of whom had uneventful courses. At presentation, of the 111 children, 43 (38.7%) were asymptomatic, 68 (61.2%) had mild or moderate symptoms, and none (0%) had severe illness requiring intensive care. Fever (23/111, 20.7%), cough (22/111, 19.8%), and rhinorrhea (17/111, 15.3%) were the most common presenting symptoms, and most reported symptoms resolved by day 5 of hospitalization. Most patients had no abnormality on chest x-ray. The most common laboratory abnormalities on admission included variations in neutrophil count (22/111, 24.7%), aspartate transaminase (18/111, 22.5%), alkaline phosphatase (29/111, 36.7%), and lactate dehydrogenase (31/111, 42.5%). Children were infrequently prescribed targeted medications, with only 4 (3.6%) receiving antibiotics. None of the 52 patients tested for viral coinfections were positive. COVID-19 PCR testing turned negative at a median of 10 days (IQR: 6-14) after the first positive test. Overall, there was no significant difference of time to negative PCR results between symptomatic and asymptomatic children. Conclusions This study of COVID-19 presentations and characteristics presents a first look into the burden of COVID-19 infection in the pediatric population in the UAE. We conclude that a large percentage of children experienced no symptoms and that severe COVID-19 disease is uncommon in the UAE. Various laboratory abnormalities were observed despite clinical stability. Ongoing surveillance, contact tracing, and public health measures will be important to contain future outbreaks.

Background and Aims Alcohol use disorders (AUDs) are common among people with chronic hepatitis C (HCV) and accelerate the development of fibrosis and cirrhosis caused by HCV. Baclofen, a gamma-aminobutyric acid (GABA) beta-receptor agonist, differs from medications for AUDs currently approved by the United States Food and Drug Administration (FDA), as it is metabolized primarily through the kidneys. The primary outcome of this study was to compare baclofen with a placebo in the percentage of days abstinent from alcohol. Design A double-blind, placebo-controlled randomized trial. Setting Hepatology clinics in four separate US Veteran Affairs Medical Centers in the United States. Participants One hundred and eighty Veteran men and women older than 18 years with chronic HCV, a comorbid AUD and current alcohol use. Intervention and Comparator Oral baclofen was given at dosages of 0 (placebo) or 30 mg/day over 12 weeks with concomitant manual-guided counseling. Measurements The primary measurement was percentage of days abstinent during the 12-week study period between the baclofen and placebo groups [measured by time-line follow-back (TLFB)]. Secondary measurements were the percentage of Veterans who achieved complete abstinence, the percentage of Veterans who achieved no heavy drinking between weeks 4 and 12 of the study, alcohol craving, anxiety, depression and post-traumatic stress disorder (PTSD). Findings Primary outcome: compared with placebo, baclofen did not improve the percentage of days abstinent. For all subjects there were significant reductions from baseline to 12 weeks in percentage of days abstinent from 37.0% [standard error (SE) = 2.7] to 68.6% (SE = 2.8, F(1151.1) = 66.1, P

The AspireAssist System (AspireAssist) is an endoscopic weight loss device that is comprised of an endoscopically placed percutaneous gastrostomy tube and an external device to facilitate drainage of about 30% of the calories consumed in a meal, in conjunction with lifestyle (diet and exercise) counseling.In this 52-week clinical trial, 207 participants with a body-mass index (BMI) of 35.0-55.0 kg/mAt 52 weeks, participants in the AspireAssist group, on a modified intent-to-treat basis, had lost a mean (±s.d.) of 31.5±26.7% of their excess body weight (12.1±9.6% total body weight), whereas those in the Lifestyle Counseling group had lost a mean of 9.8±15.5% of their excess body weight (3.5±6.0% total body weight) (P0.001). A total of 58.6% of participants in the AspireAssist group and 15.3% of participants in the Lifestyle Counseling group lost at least 25% of their excess body weight (P0.001). The most frequently reported adverse events were abdominal pain and discomfort in the perioperative period and peristomal granulation tissue and peristomal irritation in the postoperative period. Serious adverse events were reported in 3.6% of participants in the AspireAssist group.The AspireAssist System was associated with greater weight loss than Lifestyle Counseling alone.

Colonoscopy is an important diagnostic and screening tool for colorectal cancer detection and prevention, and adequate bowel preparation is critical for successful colonoscopy. Complications related to colonoscopy are increased in elderly patients, either directly or indirectly related to the procedure, and the risks and benefits of colonoscopy procedures need to be carefully considered in these patients. Recent studies have shown that the 4 liter polyethylene glycol with a split preparation is safe and effective for elderly patients, and is the preferred preparation for patients with medical comorbidites. Preparations containing sodium phosphate are generally not recommended for the elderly due to increased renal complications. In addition, a low residue diet may aid in tolerance and willingness to undergo the procedure compared with a clear liquid diet, with comparable bowel preparation adequacy. Risk factors for inadequate bowel preparations include poor adherence to split preparation instructions or volume of solution ingested, and certain patient related medications and comorbidities, such as diabetes, elevated body mass index, and antidepressant or narcotic use. Methods for achieving safe and adequate bowel preparations in the elderly include clear instructions, reminder calls, and case management for potential confounding patient related factors.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1–3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin—a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6—as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis. In patients with alcoholic hepatitis, cytolysin-positive Enterococcus faecalis strains are correlated with liver disease severity and increased mortality, and in mouse models these strains can be specifically targeted by bacteriophages.

ObjectiveCirrhotic patients are at high hospitalisation risk with subsequent high mortality. Current risk prediction models have varied performances with methodological room for improvement. We used current analytical techniques using automatically extractable variables from the electronic health record (EHR) to develop and validate a posthospitalisation mortality risk score for cirrhotic patients and compared performance with the model for end-stage liver disease (MELD), model for end-stage liver disease with sodium (MELD-Na), and the CLIF Consortium Acute Decompensation (CLIF-C AD) models.DesignWe analysed a retrospective cohort of 73 976 patients comprising 247 650 hospitalisations between 2006 and 2013 at any of 123 Department of Veterans Affairs hospitals. Using 45 predictor variables, we built a time-dependent Cox proportional hazards model with all-cause mortality as the outcome. We compared performance to the three extant models and reported discrimination and calibration using bootstrapping. Furthermore, we analysed differential utility using the net reclassification index (NRI).ResultsThe C-statistic for the final model was 0.863, representing a significant improvement over the MELD, MELD-Na, and the CLIF-C AD, which had C-statistics of 0.655, 0.675, and 0.679, respectively. Multiple risk factors were significant in our model, including variables reflecting disease severity and haemodynamic compromise. The NRI showed a 24% improvement in predicting survival of low-risk patients and a 30% improvement in predicting death of high-risk patients.ConclusionWe developed a more accurate mortality risk prediction score using variables automatically extractable from an EHR that may be used to risk stratify patients with cirrhosis for targeted postdischarge management.