Publications by authors named "Samuel B Ho"

118 Publications

Response to "RE: COVID-19 and healthcare workers: A systematic review and meta-analysis."

Int J Infect Dis 2021 Mar 16;106:140-141. Epub 2021 Mar 16.

College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, United Arab Emirates. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2021.03.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962501PMC
March 2021

COVID-19 under 19: A meta-analysis.

Pediatr Pulmonol 2021 Feb 25. Epub 2021 Feb 25.

College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ppul.25312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013606PMC
February 2021

COVID-19 and healthcare workers: A systematic review and meta-analysis.

Int J Infect Dis 2021 Mar 11;104:335-346. Epub 2021 Jan 11.

College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, Dubai, United Arab Emirates; Department of Medicine, Mediclinic City Hospital, Dubai Healthcare City, Dubai, United Arab Emirates. Electronic address:

Background: The COVID-19 pandemic has focused attention on the challenges and risks faced by frontline healthcare workers (HCW). This study aimed to describe the clinical outcomes and risk factors for SARS-CoV-2 infection in HCW.

Methods: Three databases were surveyed and 328 articles were identified. Of these, 225 articles did not meet inclusion criteria; therefore, 97 full-text article were reviewed. Finally, after further revision, 30 articles were included in the systematic review and 28 were used for meta-analysis.

Results: Twenty-eight 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 HCW. The percentage of HCW who tested positive for COVID-19 was 51.7% (95% CI 34.7-68.2). The total prevalence of comorbidities in seven studies was 18.4% (95% CI 15.5-21.7). 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 hospitalisation was 15.1% (95% CI 5.6-35) in 13 studies and 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 personal protective equipment, workplace setting, profession, exposure, contacts, and testing.

Conclusion: A significant number of HCW were reported to be infected with COVID-19 during the first 6 months of the COVID-19 pandemic, with a prevalence of hospitalisation of 15.1% and mortality of 1.5%. Further data are needed to track the continued risks in HCW as the pandemic evolves and health systems adapt.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2021.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798435PMC
March 2021

Mucin secretion in cystic fibrosis - a systematic review.

Dig Dis 2020 Oct 13. Epub 2020 Oct 13.

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 31.12.2019. 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 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 sub-mucosal glands, sputum, trachea-bronchial surface epithelium and lung sub -mucosal glands were MUC5AC and MUC5B. Increase in the number of sinusoidal sub-mucosal 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 trachea-bronchial surface epithelium and in the lungs. Conclusions Increased expression of MUC5AC in the surface epithelium and of MUC5B in the sub-epithelial glands may be the result of higher secretion rate of mucin into the lumen of the respiratory tract, causing mucus plaque, infection and inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000512268DOI Listing
October 2020

Intestinal Virome in Patients With Alcoholic Hepatitis.

Hepatology 2020 12 10;72(6):2182-2196. Epub 2020 Oct 10.

Department of Medicine, University of California San Diego, La Jolla, CA.

Background And Aims: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) 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 ALD.

Approach And Results: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (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 ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, 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 score, and associated with increased 90-day mortality.

Conclusions: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31459DOI Listing
December 2020

Inverted Yield Curve: The Alarming Rising Incidence of CRC in Young People.

Dig Dis Sci 2020 06;65(6):1590-1592

College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-020-06083-yDOI Listing
June 2020

Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.

Nature 2019 11 13;575(7783):505-511. Epub 2019 Nov 13.

Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice, 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 faecalis-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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-019-1742-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872939PMC
November 2019

RIPK1 Mediates TNF-Induced Intestinal Crypt Apoptosis During Chronic NF-κB Activation.

Cell Mol Gastroenterol Hepatol 2020 10;9(2):295-312. Epub 2019 Oct 10.

Department Rheumatology, San Diego, California; Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, Bellaterra, Barcelona, Spain. Electronic address:

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)), Ripk1 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) 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmgh.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957844PMC
May 2021

A clinical risk prediction model to identify patients with hepatorenal syndrome at hospital admission.

Int J Clin Pract 2019 Nov 7;73(11):e13393. Epub 2019 Aug 7.

Tennessee Valley Healthcare System (TVHS) Veterans Administration Medical Center, Veteran's Health Administration, Nashville, Tennessee.

Background: Hepatorenal syndrome (HRS) is a life-threatening complication of cirrhosis and early detection of evolving HRS may provide opportunities for early intervention. We developed a HRS risk model to assist early recognition of inpatient HRS.

Methods: We analysed a retrospective cohort of patients hospitalised from among 122 medical centres in the US Department of Veterans Affairs between 1 January 2005 and 31 December 2013. We included cirrhotic patients who had Kidney Disease Improving Global Outcomes criteria based acute kidney injury on admission. We developed a logistic regression risk prediction model to detect HRS on admission using 10 variables. We calculated 95% confidence intervals on the model building dataset and, subsequently, calculated performance on a 1000 sample holdout test set. We report model performance with area under the curve (AUC) for discrimination and several calibration measures.

Results: The cohort included 19 368 patients comprising 32 047 inpatient admissions. The event rate for hospitalised HRS was 2810/31 047 (9.1%) and 79/1000 (7.9%) in the model building and validation datasets, respectively. The variable selection procedure designed a parsimonious model involving ten predictor variables. Final model performance in the validation dataset had an AUC of 0.87, Brier score of 0.05, slope of 1.10 and intercept of 0.04.

Conclusions: We developed a probabilistic risk model to diagnose HRS within 24 hours of hospital admission using routine clinical variables in the largest ever published HRS cohort. The performance was excellent and this model may help identify high-risk patients for HRS and promote early intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ijcp.13393DOI Listing
November 2019

Descriptive Usability Study of CirrODS: Clinical Decision and Workflow Support Tool for Management of Patients With Cirrhosis.

JMIR Med Inform 2019 Jul 3;7(3):e13627. Epub 2019 Jul 3.

Department of Veterans Affairs San Diego Healthcare System, San Diego, CA, United States.

Background: There are gaps in delivering evidence-based care for patients with chronic liver disease and cirrhosis.

Objective: Our objective was to use interactive user-centered design methods to develop the Cirrhosis Order Set and Clinical Decision Support (CirrODS) tool in order to improve clinical decision-making and workflow.

Methods: Two work groups were convened with clinicians, user experience designers, human factors and health services researchers, and information technologists to create user interface designs. CirrODS prototypes underwent several rounds of formative design. Physicians (n=20) at three hospitals were provided with clinical scenarios of patients with cirrhosis, and the admission orders made with and without the CirrODS tool were compared. The physicians rated their experience using CirrODS and provided comments, which we coded into categories and themes. We assessed the safety, usability, and quality of CirrODS using qualitative and quantitative methods.

Results: We created an interactive CirrODS prototype that displays an alert when existing electronic data indicate a patient is at risk for cirrhosis. The tool consists of two primary frames, presenting relevant patient data and allowing recommended evidence-based tests and treatments to be ordered and categorized. Physicians viewed the tool positively and suggested that it would be most useful at the time of admission. When using the tool, the clinicians placed fewer orders than they placed when not using the tool, but more of the orders placed were considered to be high priority when the tool was used than when it was not used. The physicians' ratings of CirrODS indicated above average usability.

Conclusions: We developed a novel Web-based combined clinical decision-making and workflow support tool to alert and assist clinicians caring for patients with cirrhosis. Further studies are underway to assess the impact on quality of care for patients with cirrhosis in actual practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/13627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636234PMC
July 2019

Intestinal Fungal Dysbiosis and Systemic Immune Response to Fungi in Patients With Alcoholic Hepatitis.

Hepatology 2020 02 20;71(2):522-538. Epub 2019 Aug 20.

Department of Medicine, University of California San Diego, La Jolla, CA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.30832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925657PMC
February 2020

Serum and Fecal Oxylipins in Patients with Alcohol-Related Liver Disease.

Dig Dis Sci 2019 07 10;64(7):1878-1892. Epub 2019 May 10.

Department of Medicine, University of California San Diego, La Jolla, CA, USA.

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 nonalcoholic controls. Spearman correlation of the oxylipins with clinical parameters shows 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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-019-05638-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588282PMC
July 2019

Effect of Obesogenic Medications on Weight-Loss Outcomes in a Behavioral Weight-Management Program.

Obesity (Silver Spring) 2019 05;27(5):716-723

Veterans Affairs San Diego Healthcare System, San Diego, California, USA.

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 < 5% total weight loss. We reviewed each patient's medical records for exposure to obesogenic medication during the time of treatment.

Results: Approximately 62% (n = 411) of patients entering MOVE! had a prescription for obesogenic medications. Obesogenic medication use was associated with worse weight-loss outcomes, and participants were 37% less likely to achieve a clinically meaningful (≥ 5% total weight loss) outcome at the end of the MOVE! program (odds ratio, 0.633; 95% CI: 0.427-0.937; adjusted P = 0.022). Patients who received three or more medications (n = 72) had the greatest difficulty achieving 5% weight loss compared with the control group (odds ratio, 0.265; 95% CI: 0.108-0.646; adjusted P = 0.003).

Conclusions: The use of provider-prescribed obesogenic medications was associated with worse weight-loss outcomes in a behavioral weight-loss program. Closer scrutiny of patient medications is necessary to help improve outcomes of weight-loss treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/oby.22444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544176PMC
May 2019

Reply.

Gastroenterology 2019 03 19;156(4):1218-1220. Epub 2019 Feb 19.

Division of Gastroenterology and Research and Development, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, Washington.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2019.02.024DOI Listing
March 2019

Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice.

Gut 2019 08 17;68(8):1504-1515. Epub 2018 Nov 17.

Department of Medicine, University of California San Diego, La Jolla, California, USA.

Objective: Antimicrobial C-type lectin regenerating islet-derived 3 gamma (REG3G) is suppressed in the small intestine during chronic ethanol feeding. Our aim was to determine the mechanism that underlies REG3G suppression during experimental alcoholic liver disease.

Design: Interleukin 22 (IL-22) regulates expression of REG3G. Therefore, we investigated the role of IL-22 in mice subjected to chronic-binge ethanol feeding (NIAAA model).

Results: In a mouse model of alcoholic liver disease, we found that type 3 innate lymphoid cells produce lower levels of IL-22. Reduced IL-22 production was the result of ethanol-induced dysbiosis and lower intestinal levels of indole-3-acetic acid (IAA), a microbiota-derived ligand of the aryl hydrocarbon receptor (AHR), which regulates expression of IL-22. Importantly, faecal levels of IAA were also found to be lower in patients with alcoholic hepatitis compared with healthy controls. Supplementation to restore intestinal levels of IAA protected mice from ethanol-induced steatohepatitis by inducing intestinal expression of IL-22 and REG3G, which prevented translocation of bacteria to liver. We engineered to produce IL-22 (/IL-22) and fed them to mice along with the ethanol diet; these mice had reduced liver damage, inflammation and bacterial translocation to the liver compared with mice fed an isogenic control strain and upregulated expression of REG3G in intestine. However, /IL-22 did not reduce ethanol-induced liver disease in mice.

Conclusion: Ethanol-associated dysbiosis reduces levels of IAA and activation of the AHR to decrease expression of IL-22 in the intestine, leading to reduced expression of REG3G; this results in bacterial translocation to the liver and steatohepatitis. Bacteria engineered to produce IL-22 induce expression of REG3G to reduce ethanol-induced steatohepatitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2018-317232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387784PMC
August 2019

The effects of provider-prescribed obesogenic drugs on post-laparoscopic sleeve gastrectomy outcomes: a retrospective cohort study.

Int J Obes (Lond) 2019 06 21;43(6):1154-1163. Epub 2018 Sep 21.

School of Medicine, University of California, San Diego, CA, USA.

Background: Laparoscopic sleeve gastrectomy (LSG) is one of the most commonly performed bariatric procedures and has proven effective in providing weight loss. However, considerable variance has been noted in the degree of weight loss. Physician prescription practices may be negatively affecting weight loss post-LSG and, thus, contributing to the broad range of weight loss outcomes. The aim of our study was to determine whether commonly prescribed obesogenic medications negatively affect weight loss outcomes post-LSG.

Subjects/methods: This single center retrospective cohort study performed at a University hospital included 323 patients (≥18 years) within the University California, San Diego Healthcare System who underwent LSG between 2007 and 2016. We identified a list of 32 commonly prescribed medications that have weight gain as a side effect. We compared the percent excess weight loss (%EWL) of patients divided into two groups based on post-LSG exposure to obesogenic medications. A linear regression model was used to analyze %EWL at 12 months post-LSG while controlling for age, initial body mass index (BMI), and use of leptogenic medications.

Results: A total of 150 patients (Meds group) were prescribed obesogenic medications within the one-year post-LSG follow up period, whereas 173 patients (Control group) were not prescribed obesogenic medications. The Meds group lost significantly less weight compared to the Control group (%EWL ± SEM at 12 months 53.8 ± 2.4 n = 78, 65.0 ± 2.6, n = 84 respectively, P = 0.002). This difference could not be attributed to differences in age, gender, initial BMI, co-morbidities, or prescription of leptogenic medications between the two groups.

Conclusions: The use of provider-prescribed obesogenic medications was associated with worse weight loss outcomes post-LSG. Closer scrutiny of patient medications may be necessary to help improve outcomes of weight loss treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41366-018-0207-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428627PMC
June 2019

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death.

Proc Natl Acad Sci U S A 2018 09 12;115(39):E9192-E9200. Epub 2018 Sep 12.

Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, CA 92093;

Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1810584115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166836PMC
September 2018

Application of contextual design methods to inform targeted clinical decision support interventions in sub-specialty care environments.

Int J Med Inform 2018 09 30;117:55-65. Epub 2018 May 30.

Health Service Research and Development, VA San Diego Healthcare System, San Diego, CA, USA; Department of Medicine, University of California, San Diego, CA, USA. Electronic address:

Background & Objectives: In healthcare, the routine use of evidence-based specialty care management plans is mixed. Targeted computerized clinical decision support (CCDS) interventions can improve physician adherence, but adoption depends on CCDS' 'fit' within clinical work. We analyzed clinical work in outpatient and inpatient settings as a basis for developing guidelines for optimizing CCDS design.

Methods: The contextual design approach guided data collection, collation and analysis. Forty (40) consenting physicians were observed and interviewed in general internal medicine inpatient units and gastroenterology (GI) outpatient clinics at two academic medical centers. Data were collated using interpretive debriefing, and consolidated using thematic analysis and three work modeling approaches (communication flow, sequence and artifact models).

Results: Twenty-six consenting physicians were observed at Site A and 14 at Site B. Observations included attending (33%) and resident physicians. During research team debriefings, 220 of 341 unique topics were categorized into 5 CCDS-relevant themes. Resident physicians relied on patient assessment & planning processes to support their roles as communication and coordination hubs within the medical team. Artifact analysis further elucidated the evolution of assessment and planning over work shifts.

Conclusions: The usefulness of CCDS tools may be enhanced in clinical care if the design: 1) accounts for clinical work that is distributed across people, space, and time; 2) targets communication and coordination hubs (specific roles) that can amplify the usefulness of CCDS interventions; 3) integrates CCDS with early clinical assessment & planning processes; and 4) provides CCDS in both electronic & hardcopy formats. These requirements provide a research agenda for future research in clinician-CCDS integration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijmedinf.2018.05.005DOI Listing
September 2018

No Association Between Screening for Hepatocellular Carcinoma and Reduced Cancer-Related Mortality in Patients With Cirrhosis.

Gastroenterology 2018 10 5;155(4):1128-1139.e6. Epub 2018 Jul 5.

Division of Gastroenterology, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, Washington; Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle, Washington. Electronic address:

Background & Aims: Screening patients with cirrhosis for hepatocellular carcinoma (HCC) has been recommended. We conducted a matched case-control study within the US Veterans Affairs (VA) health care system to determine whether screening by abdominal ultrasonography (USS) and/or by measuring serum level of α-fetoprotein (AFP) was associated with decreased cancer-related mortality in patients with cirrhosis.

Methods: We defined cases (n = 238) as patients with cirrhosis who died of HCC from January 1, 2013 through August 31, 2015 and had been in VA care with a diagnosis of cirrhosis for at least 4 years before the diagnosis of HCC. We matched each case to 1 control (n = 238), defined as a patient with cirrhosis who did not die of HCC and had been in VA care for at least 4 years before the date of the matched case's HCC diagnosis. Controls were matched to cases by year of cirrhosis diagnosis, race and ethnicity, age, sex, etiology of cirrhosis, Model for End-Stage Liver Disease score, and VA medical center. We identified all USS and serum AFP tests performed within 4 years before the date of HCC diagnosis in cases or the equivalent index date in controls and determined by chart extraction (blinded to case or control status) whether these tests were performed for screening.

Results: There were no significant differences between cases and controls in the proportions of patients who underwent screening USS (52.9% vs 54.2%), screening measurement of serum AFP (74.8% vs 73.5%), screening USS or measurement of serum AFP (81.1% vs 79.4%), or screening USS and measurement of serum AFP (46.6% vs 48.3%) within 4 years before the index date, with or without adjusting for potential confounders. There also was no difference in receipt of these screening tests within 1, 2, or 3 years before the index date.

Conclusions: In a matched case-control study of the VA health care system, we found that screening patients with cirrhosis for HCC by USS, measurement of serum AFP, either test, or both tests was not associated with decreased HCC-related mortality. We encourage additional case-control studies to evaluate the efficacy of screening for HCC in other health care systems, in which available records are sufficiently detailed to enable identification of the indication for USS and AFP tests.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2018.06.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180323PMC
October 2018

S100B and Inflammatory Cytokine Levels in Blood as Potential Markers of Blood-Brain Barrier Damage and Psychiatric Impairment in Comorbid Hepatitis C Viral Infection and Alcohol Use Disorder.

Alcohol Clin Exp Res 2018 Jun 28. Epub 2018 Jun 28.

VA Long Beach Health Care System , Long Beach, California.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acer.13796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310679PMC
June 2018

Implementation of Mass Cytometry as a Tool for Mechanism of Action Studies in Inflammatory Bowel Disease.

Inflamm Bowel Dis 2018 10;24(11):2366-2376

Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, La Jolla, California.

Background: Novel therapeutics for inflammatory bowel disease (IBD) are under development, yet mechanistic readouts at the tissue level are lacking. Techniques to assess intestinal immune composition could represent a valuable tool for mechanism of action (MOA) studies of novel drugs. Mass cytometry enables analysis of intestinal inflammatory cell infiltrate and corresponding molecular fingerprints with unprecedented resolution. Here, we aimed to optimize the methodology for isolation and cryopreservation of cells from intestinal tissue to allow for the potential implementation of mass cytometry in MOA studies.

Methods: We investigated key technical issues, including minimal tissue requirements, cell isolation protocols, and cell storage, using intestinal biopsies and peripheral blood from healthy individuals. High-dimensional mass cytometry was employed for the analyses of biopsy-derived intestinal cellular subsets.

Results: Dithiothreitol and mechanical dissociation decreased epithelial cell contamination and allowed for isolation of adequate cell numbers from 2 to 4 colonic or ileal biopsies (6 × 104±2 × 104) after a 20-minute collagenase digestion, allowing for reliable detection of most major immune cell subsets. Biopsies and antibody-labeled mononuclear cells could be cryopreserved for later processing and acquisition (viability > 70%; P < 0.05).

Conclusions: Mass cytometry represents a unique tool for deep immunophenotyping intestinal cell composition. This technique has the potential to facilitate analysis of drug actions at the target tissue by identifying specific cellular subsets and their molecular signatures. Its widespread implementation may impact not only IBD research but also other gastrointestinal conditions where inflammatory cells play a role in pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ibd/izy214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185553PMC
October 2018

Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis.

J Hepatol 2018 08 12;69(2):396-405. Epub 2018 Apr 12.

Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA. Electronic address:

Background & Aims: The degree of cholestasis is an important disease driver in alcoholic hepatitis, a severe clinical condition that needs new biomarkers and targeted therapies. We aimed to identify the largely unknown mechanisms and biomarkers linked to cholestasis in alcoholic hepatitis.

Methods: Herein, we analyzed a well characterized cohort of patients with alcoholic hepatitis and correlated clinical and histological parameters and outcomes with serum bile acids and fibroblast growth factor 19 (FGF19), a major regulator of bile acid synthesis.

Results: We found that total and conjugated bile acids were significantly increased in patients with alcoholic hepatitis compared with controls. Serum FGF19 levels were strongly increased and gene expression of FGF19 was induced in biliary epithelial cells and ductular cells of patients with alcoholic hepatitis. De novo bile acid synthesis (CYP7A1 gene expression and C4 serum levels) was significantly decreased in patients with alcoholic hepatitis. Importantly, total and conjugated bile acids correlated positively with FGF19 and with disease severity (model for end-stage liver disease score). FGF19 correlated best with conjugated cholic acid, and model for end-stage liver disease score best with taurine-conjugated chenodeoxycholic acid. Univariate analysis demonstrated significant associations between FGF19 and bilirubin as well as gamma glutamyl transferase, and negative correlations between FGF19 and fibrosis stage as well as polymorphonuclear leukocyte infiltration, in all patients with alcoholic hepatitis.

Conclusion: Serum FGF19 and bile acids are significantly increased in patients with alcoholic hepatitis, while de novo bile acid synthesis is suppressed. Modulation of bile acid metabolism or signaling could represent a promising target for treatment of alcoholic hepatitis in humans.

Lay Summary: Understanding the underlying mechanisms that drive alcoholic hepatitis is important for the development of new biomarkers and targeted therapies. Herein, we describe a molecule that is increased in patients with alcoholic hepatitis. Modulating the molecular pathway of this molecule might lead to promising targets for the treatment of alcoholic hepatitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhep.2018.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054564PMC
August 2018

Development of an automated phenotyping algorithm for hepatorenal syndrome.

J Biomed Inform 2018 04 9;80:87-95. Epub 2018 Mar 9.

Geriatric Research Education and Clinical Center (GRECC), Tennessee Valley Healthcare System Veterans Administration Medical Center, Nashville, TN, USA; Division of General Internal Medicine and Public Health, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.

Objective: Hepatorenal Syndrome (HRS) is a devastating form of acute kidney injury (AKI) in advanced liver disease patients with high morbidity and mortality, but phenotyping algorithms have not yet been developed using large electronic health record (EHR) databases. We evaluated and compared multiple phenotyping methods to achieve an accurate algorithm for HRS identification.

Materials And Methods: A national retrospective cohort of patients with cirrhosis and AKI admitted to 124 Veterans Affairs hospitals was assembled from electronic health record data collected from 2005 to 2013. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. Five hundred and four hospitalizations were selected for manual chart review and served as the gold standard. Electronic Health Record based predictors were identified using structured and free text clinical data, subjected through NLP from the clinical Text Analysis Knowledge Extraction System. We explored several dimension reduction techniques for the NLP data, including newer high-throughput phenotyping and word embedding methods, and ascertained their effectiveness in identifying the phenotype without structured predictor variables. With the combined structured and NLP variables, we analyzed five phenotyping algorithms: penalized logistic regression, naïve Bayes, support vector machines, random forest, and gradient boosting. Calibration and discrimination metrics were calculated using 100 bootstrap iterations. In the final model, we report odds ratios and 95% confidence intervals.

Results: The area under the receiver operating characteristic curve (AUC) for the different models ranged from 0.73 to 0.93; with penalized logistic regression having the best discriminatory performance. Calibration for logistic regression was modest, but gradient boosting and support vector machines were superior. NLP identified 6985 variables; a priori variable selection performed similarly to dimensionality reduction using high-throughput phenotyping and semantic similarity informed clustering (AUC of 0.81 - 0.82).

Conclusion: This study demonstrated improved phenotyping of a challenging AKI etiology, HRS, over ICD-9 coding. We also compared performance among multiple approaches to EHR-derived phenotyping, and found similar results between methods. Lastly, we showed that automated NLP dimension reduction is viable for acute illness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbi.2018.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920557PMC
April 2018

Publisher Correction: Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus.

Nat Commun 2017 12 12;8(1):2137. Epub 2017 Dec 12.

Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.

In the original PDF version of this Article, which was published on 16 October 2017, the publication date was incorrectly given as 10 October 2017. This has now been corrected in the PDF; the HTML version of the paper was correct from the time of publication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-01779-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727102PMC
December 2017

Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus.

Nat Commun 2017 10 16;8(1):837. Epub 2017 Oct 16.

Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.

Chronic liver disease is rising in western countries and liver cirrhosis is the 12th leading cause of death worldwide. Simultaneously, use of gastric acid suppressive medications is increasing. Here, we show that proton pump inhibitors promote progression of alcoholic liver disease, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis in mice by increasing numbers of intestinal Enterococcus spp. Translocating enterococci lead to hepatic inflammation and hepatocyte death. Expansion of intestinal Enterococcus faecalis is sufficient to exacerbate ethanol-induced liver disease in mice. Proton pump inhibitor use increases the risk of developing alcoholic liver disease among alcohol-dependent patients. Reduction of gastric acid secretion therefore appears to promote overgrowth of intestinal Enterococcus, which promotes liver disease, based on data from mouse models and humans. Recent increases in the use of gastric acid-suppressive medications might contribute to the increasing incidence of chronic liver disease.Proton pump inhibitors (PPIs) reduce gastric acid secretion and modulate gut microbiota composition. Here Llorente et al. show that PPIs induce bacterial overgrowth of enterococci, which, in turn, exacerbate ethanol-induced liver disease both in mice and humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-00796-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643518PMC
October 2017

HCV Integrated Care: A Randomized Trial to Increase Treatment Initiation and SVR with Direct Acting Antivirals.

Int J Hepatol 2017 27;2017:5834182. Epub 2017 Jul 27.

VA San Diego Healthcare System, San Diego, CA, USA.

Background And Aims: Psychiatric or substance use disorders are barriers to successful HCV antiviral treatment. In a randomized, controlled trial (RCT), the effects of HCV Integrated Care (IC) for increasing treatment rates and sustained viral response (SVR) were studied with direct acting antivirals (DAA).

Methods: In 2012-13, VA patients, whose screening was positive for depression, PTSD, or substance use ( = 79), were randomized to IC or Usual Care (UC). IC consisted of brief psychological interventions and case management. The primary endpoint was SVR among patients followed for an average of 16.6 months.

Results: 42% of the study participants were previously homeless and 79% had HCV genotype 1. Twice as many IC participants (45%) initiated treatment compared with UC participants (23%) ( = 4.59, = 0.032). Among those treated, SVR rates did not significantly differ (IC: 12/18 = 67%; UC: 5/9 = 55%; = 0.23). Among all randomized participants, IC participants trended toward better SVR rates (30.0% versus 12.8% in UC; = 0.07).

Conclusions: Although first-generation DAAs are no longer used, this smaller RCT helps confirm the results of a larger multisite RCT showing that Integrated Care results in higher treatment initiation and SVR rates among HCV-infected persons with comorbid psychological disorders. Integrated mental health services can facilitate treatment among the most challenging HCV patients, many of whom have not been successfully treated. This trial is registered with ClinicalTrials.gov number NCT00722423.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2017/5834182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551521PMC
July 2017

Mucin Expression in the Esophageal Malignant and Pre-malignant States: A Systematic Review and Meta-analysis.

J Clin Gastroenterol 2018 02;52(2):91-96

Gastroenterology Clinic, Henry Dunant Hospital, Athens, Greece.

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<0.0001, I=84.696%. There is a gradient of mucin expression and complexity in esophageal premalignant to malignant lesions, lower in Barrett's mucosa with low grade dysplasia (LGD), increased in high grade dysplasia (HGD), and highest in esophageal adenocarcinoma (EAC). MUC2, MUC3, MUC5AC, and MUC6 expression was higher in EAC than HGD, and higher in HGD than in LGD mucosa. The opposite was found for MUC1 and MUC4.

Conclusion: Increased expression of certain mucin genes in esophageal mucosa may be further studied as a potential diagnostic tool, and this may add important information in the surveillance of Barrett's esophagus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCG.0000000000000863DOI Listing
February 2018

Intestinal fungi contribute to development of alcoholic liver disease.

J Clin Invest 2017 Jun 22;127(7):2829-2841. Epub 2017 May 22.

Department of Medicine, UCSD, La Jolla, California, USA.

Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin-like receptor CLEC7A on Kupffer cells and possibly other bone marrow-derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non-alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI90562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490775PMC
June 2017

Engagement in Care of High-Risk Hepatitis C Patients with Interferon-Free Direct-Acting Antiviral Therapies.

Dig Dis Sci 2017 06 4;62(6):1472-1479. Epub 2017 Apr 4.

Medicine, Pharmacy, Nursing, and Research Services, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA, 92161, USA.

Background And Aims: The extent to which hepatitis C (HCV) treatment uptake is improved following introduction of interferon-free direct-acting antiviral (DAA) treatments is unknown. The purpose of this study was to determine HCV patient engagement and barriers to care for accessing DAA treatments in a real-world setting.

Methods: Patients with HCV viremia at high risk for fibrosis were identified using the Veterans Affairs (VA) registry within San Diego's VA in October 2014. Patients not enrolled in HCV clinic were systematically contacted by letter and phone. Logistic regression was used to examine patient factors associated with subsequent engagement in care over 12-20 months.

Results: In the local registry of 2089 patients, 481 were identified with high-risk fibrosis scores. Of those, 380 (79%) were eligible for antiviral treatment, and 178/380 (47%) patients were actively followed in clinic. The remaining 202/380 (53%) patients were never seen by a HCV clinic provider or lost to follow-up. Of these, 114/380 (30%) of the treatment-eligible cohort remained non-engaged in care following outreach. Compared with patients engaged in care, non-engaged patients were significantly more likely to have homelessness, COPD comorbidity, or active alcohol or/and drug use. Overall 74.4% of patients engaged in HCV clinic received antiviral treatment.

Conclusions: A significant portion of eligible HCV patients could not be engaged in treatment after a programmatic outreach effort. These data indicate that more sustained or innovative outreach efforts are needed in order to maximize treatment access, with specific interventions targeting those with unstable housing and active alcohol/substance use disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-017-4548-4DOI Listing
June 2017

Optimal Bowel Cleansing for Colonoscopy in the Elderly Patient.

Drugs Aging 2017 03;34(3):163-172

VA San Diego Healthcare System and University of California, 3350 La Jolla Village Drive, San Diego, CA, 92161, USA.

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, either directly or indirectly related to the procedure, are increased in elderly patients, and the risks and benefits of colonoscopy procedures need to be carefully considered in these patients. Recent studies have shown that 4 L polyethylene glycol with a split preparation is safe and effective for elderly patients, and is the preferred preparation for patients with medical comorbidities. Preparations containing sodium phosphate are generally not recommended for the elderly because of 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40266-017-0436-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374979PMC
March 2017