Progressive dysbiosis of human orodigestive microbiota along the sequence of gastroesophageal reflux, Barrett's esophagus and esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma (EA) has drastically increased in the United States since 1970s for unclear reasons. We hypothesized that the widespread usage of antibiotics has increased the procarcinogenic potential of the orodigestive microbiota along the sequence of gastroesophageal reflux (GR), Barrett's esophagus (BE) and EA phenotypes. This case control study included normal controls (NC) and three disease phenotypes GR, BE and EA. Microbiota in the mouth, esophagus, and stomach, and rectum were analyzed using 16S rRNA gene sequencing. Overall, we discovered 44 significant pairwise differences in abundance of microbial taxa between the four phenotypes, with 12 differences in the mouth, 21 in the esophagus, two in the stomach, and nine in the rectum. Along the GR→BE→EA sequence, oral and esophageal microbiota were more diversified, the dominant genus Streptococcus was progressively depleted while six other genera Atopobium, Actinomyces, Veillonella, Ralstonia, Burkholderia and Lautropia progressively enriched. In NC, Streptococcus appeared to control populations of other genera in the foregut via numerous negative and positive connections, while in disease states, the rich network was markedly simplified. Inferred gene functional content showed a progressive enrichment through the stages of EA development in genes encoding antibiotic resistance, ligands of Toll-like and NOD-like receptors, nitrate-nitrite-nitric oxide pathway and acetaldehyde metabolism. The orodigestive microbiota is in a progressive dysbiotic state along the GR-BE-EA sequence. The increasing dysbiosis and antibiotic and procarcinogenic genes in the disease states warrants further study to define their roles in EA pathogenesis.

Endoscopic part-task training box scores correlate with endoscopic outcomes.

BACKGROUND: Competency in endoscopy has traditionally been based on number of procedures performed. With movement towards milestone-based accreditation, new standards of establishing competency are required. The Thompson Endoscopic Skills Trainer (TEST) is a training device previously shown to differentiate between novice and expert endoscopists. This study aims to correlate TEST scores to other markers of performance in endoscopy. METHODS: Trainees of a gastroenterology fellowship program were guided through the TEST. Their scores and sub-scores were correlated to their endoscopic metrics of performance, including adenoma detection rate, cecal intubation rate, cecal intubation time, withdrawal time, fentanyl usage, midazolam usage, pain score, overall procedure time, and performance on the ASGE Assessment of Competency in Endoscopy Tool (ACE Tool). RESULTS: The Overall Score positively correlated with the ACE Tool Total Score (r = 0.707, p = 0.010) and sub-scores (Cognitive Skills Score: r = 0.624, p = 0.030; Motor Skills Score: r = 0.756, p = 0.004), and negatively correlated with cecal intubation time (r = - 0.591, p = 0.043). The Gross Motor Score positively correlated with cecal intubation rate (r = 0.593, p = 0.042), ACE Tool Total Score (r = 0.594, p = 0.042) and Motor Skills Score (r = 0.623, p = 0.031), and negatively correlated with cecal intubation time (r = - 0.695, p = 0.012). The Fine Motor Score positively correlated with the ACE Tool Polypectomy Score (r = 0.601, p = 0.039), and negatively correlated with procedure time (r = - 0.640, p = 0.025), cecal intubation time (r = - 0.645, p = 0.024), and withdrawal time (r = - 0.629, p = 0.028). CONCLUSION: This study demonstrates that performance on the TEST correlate to endoscopic measures. Given these results, the TEST may be used in conjunction with existing assessment tools for demonstrating competency in endoscopy.

A Theory-based Educational Pamphlet With Low-residue Diet Improves Colonoscopy Attendance and Bowel Preparation Quality.

GOALS/BACKGROUND: Patients who "no-show" for colonoscopy or present with poor bowel preparation waste endoscopic resources and do not receive adequate examinations for colorectal cancer (CRC) screening. Using the Health Belief Model, we modified an existing patient education pamphlet and evaluated its effect on nonattendance rates and bowel preparation quality. STUDY: We implemented a color patient education pamphlet to target individual perceptions about CRC and changed bowel preparation instructions to include a low-residue diet instead of the previous clear liquid diet. We compared the nonattendance rate over a 2-month period before and after the introduction of the pamphlet, allowing for a washout period during which pamphlet use was inconsistent. We compared the Boston Bowel Preparation Scale (BBPS) in 100 consecutive patients who underwent colonoscopy during each of the 2 periods. RESULTS: Baseline characteristics between the 2 groups were similar, although patients who received the pamphlet were younger (P=0.03). The nonattendance rate was significantly lower in patients who received the pamphlet (13% vs. 21%, P=0.01). The percentage of patients with adequate bowel preparation increased from 82% to 86% after introduction of the pamphlet, although this was not statistically significant (P=0.44). The proportion of patients with a BBPS score of 9 was significantly higher in the pamphlet group (41% vs. 27%, P=0.03). There was no difference in adenoma and sessile serrated adenoma detection rates before and after pamphlet implementation. CONCLUSIONS: After implementing a theory-based patient education intervention with a low-residue diet, our absolute rate for colonoscopy nonattendance decreased by 8% and the proportion of patients with a BBPS score of 9 increased by 14%. The Health Belief Model appears to be a useful construct for CRC screening interventions.

Assessment of Abilities of Gastroenterology Fellows to Provide Information to Patients With Liver Disease.

BACKGROUND & AIMS: Patient education is critical in ensuring patient compliance and good health outcomes. Fellows must be able to effectively communicate with their patients, delivering enough information for the patient to understand their medical problem and maximize patient compliance. We created an objective structured clinical examination (OSCE) with 4 liver disease cases to assess fellows' knowledge and ability to inform standardized patients (SPs) about their clinical condition. METHODS: We developed 4 cases highlighting different aspects of liver disease and created a 4-station OSCE: hepatitis B, acute hepatitis C, new diagnosis of cirrhosis, and an end-stage cirrhotic nontransplant candidate. The SP with hepatitis B was minimizing the fact that she could not read English. The acute hepatitis C SP was a nursing student who is afraid that having hepatitis C might jeopardize her career. The SP with the new diagnosis of alcoholic cirrhosis needed to stop drinking, and the end-stage liver disease patient had to grapple with his advanced directives. Twelve fellows from 4 GI training programs participated. Our focus was to assess the fellows' knowledge about liver diseases and the Accreditation Council for Graduate Medical Education competencies of health literacy, shared decision making, advanced directives, and goals of care. The goal for the fellows was to communicate effectively with the SPs, and acknowledge that each patient had an emotionally charged issue to overcome. The SPs used a checklist to rate fellows' performance. Faculty and the SPs observed the cases and provided feedback. The fellows were surveyed on their performance regarding the case. RESULTS: The majority of fellows were able to successfully summarize findings and discuss a plan with the patient in the new diagnosis of cirrhosis (76.92%) and hepatitis C case (100%), but were less successful in the hepatitis B case (30.77%) and the end-of-life case (41.67%). Overall, a small percentage of fellows reflected that they did a good job (22%-33%), except at the end-of-life case (67%). The fellows' greatest challenge was trying to cover a lot of information in a single outpatient visit. CONCLUSIONS: Caring for patients with liver diseases can be complex and time consuming. The patients and fellows' observations were discordant in several areas: for example, the fellows believed they excelled in the end-of-life case, but the SP thought only a small percentage of fellows were able to successfully summarize and discuss the plan. This discrepancy and others highlight important areas of focus in training programs. OSCEs are important to help the fellows facilitate striking the right balance of information delivery and empathy, and this will lead to better patient education, compliance, rapport, and satisfaction.

Human Immunodeficiency Virus-Associated Diarrhea: Still an Issue in the Era of Antiretroviral Therapy.

Over half of patients with human immunodeficiency virus (HIV) experience diarrhea that contributes negatively to quality of life and adherence to antiretroviral therapy (ART). Opportunistic infectious agents that cause diarrhea in patients with HIV span the array of protozoa, fungi, viruses, and bacteria. With global use of ART, the incidence of diarrhea because of opportunistic infections has decreased; however, the incidence of noninfectious diarrhea has increased. The etiology of noninfectious diarrhea in patients with HIV is multifactorial and includes ART-associated diarrhea and gastrointestinal damage related to HIV infection (i.e., HIV enteropathy). A basic algorithm for the diagnosis of diarrhea in patients with HIV includes physical examination, a review of medical history, assessment of HIV viral load and CD4+ T cell count, stool microbiologic assessment, and endoscopic evaluation, if needed. For patients with negative diagnostic results, the diagnosis of noninfectious diarrhea may be considered. Pharmacologic options for the treatment of noninfectious diarrhea are primarily supportive; however, the use of many unapproved agents is based on unstudied and anecdotal information. In addition, these agents can be associated with treatment-limiting adverse events (AEs), such as drug-drug interactions with ART regimens, abuse liability, and additional gastrointestinal AEs. Currently, crofelemer, an antisecretory agent, is the only therapy approved in the USA for the symptomatic relief of noninfectious diarrhea in patients with HIV on ART.

Preferential HIV infection of CCR6+ Th17 cells is associated with higher levels of virus receptor expression and lack of CCR5 ligands.

Th17 cells are enriched in the gut mucosa and play a critical role in maintenance of the mucosal barrier and host defense against extracellular bacteria and fungal infections. During chronic human immunodeficiency virus (HIV) infection, Th17 cells were more depleted compared to Th1 cells, even when the patients had low or undetectable viremia. To investigate the differential effects of HIV infection on Th17 and Th1 cells, a culture system was used in which CCR6(+) CD4(+) T cells were sorted from healthy human peripheral blood and activated in the presence of interleukin 1ß (IL-1ß) and IL-23 to drive expansion of Th17 cells while maintaining Th1 cells. HIV infection of these cultures had minimal effects on Th1 cells but caused depletion of Th17 cells. Th17 loss correlated with greater levels of virus-infected cells and cell death. In identifying cellular factors contributing to higher susceptibility of Th17 cells to HIV, we compared Th17-enriched CCR6(+) and Th17-depleted CCR6(-) CD4 T cell cultures and noted that Th17-enriched CCR6(+) cells expressed higher levels of α4ß7 and bound HIV envelope in an α4ß7-dependent manner. The cells also had greater expression of CD4 and CXCR4, but not CCR5, than CCR6(-) cells. Moreover, unlike Th1 cells, Th17 cells produced little CCR5 ligand, and transfection with one of the CCR5 ligands, MIP-1ß (CCL4), increased their resistance against HIV. These results indicate that features unique to Th17 cells, including higher expression of HIV receptors and lack of autocrine CCR5 ligands, are associated with enhanced permissiveness of these cells to HIV.

Absence of HIV-1 evolution in the gut-associated lymphoid tissue from patients on combination antiviral therapy initiated during primary infection.

Mucosal mononuclear (MMC) CCR5+CD4+ T cells of the gastrointestinal (GI) tract are selectively infected and depleted during acute HIV-1 infection. Despite early initiation of combination antiretroviral therapy (cART), gut-associated lymphoid tissue (GALT) CD4+ T cell depletion and activation persist in the majority of HIV-1 positive individuals studied. This may result from ongoing HIV-1 replication and T-cell activation despite effective cART. We hypothesized that ongoing viral replication in the GI tract during cART would result in measurable viral evolution, with divergent populations emerging over time. Subjects treated during early HIV-1 infection underwent phlebotomy and flexible sigmoidoscopy with biopsies prior to and 15-24 months post initiation of cART. At the 2(nd) biopsy, three GALT phenotypes were noted, characterized by high, intermediate and low levels of immune activation. A representative case from each phenotype was analyzed. Each subject had plasma HIV-1 RNA levels <50 copies/ml at 2(nd) GI biopsy and CD4+ T cell reconstitution in the peripheral blood. Single genome amplification of full-length HIV-1 envelope was performed for each subject pre- and post-initiation of cART in GALT and PBMC. A total of 280 confirmed single genome sequences (SGS) were analyzed for experimental cases. For each subject, maximum likelihood phylogenetic trees derived from molecular sequence data showed no evidence of evolved forms in the GALT over the study period. During treatment, HIV-1 envelope diversity in GALT-derived SGS did not increase and post-treatment GALT-derived SGS showed no substantial genetic divergence from pre-treatment sequences within transmitted groups. Similar results were obtained from PBMC-derived SGS. Our results reveal that initiation of cART during acute/early HIV-1 infection can result in the interruption of measurable viral evolution in the GALT, suggesting the absence of de-novo rounds of HIV-1 replication in this compartment during suppressive cART.

Human microbiome and HIV/AIDS.

Understanding of the human microbiome continues to grow rapidly; however, reports on changes in the microbiome after HIV infection are still limited. This review surveys the progress made in methodology associated with microbiome studies and highlights the remaining challenges to this field. Studies have shown that commensal oral, gut, vaginal, and penile bacteria are vital to the health of the human immune system. Our studies on crosstalk among oral and gastrointestinal soluble innate factors, HIV, and microbes indicated that the oral and gut microbiome was altered in the HIV-positive samples compared to the negative controls. The importance of understanding the bacterial component of HIV/AIDS, and likelihood of "crosstalk" between viral and bacterial pathogens, will help in understanding the role of the microbiome in HIV-infected individuals and facilitate identification of novel antiretroviral factors for use as novel diagnostics, microbicides, or therapeutics against HIV infection.

Acute Liver Failure Secondary to Remdesivir in the Treatment of COVID-19.

Remdesivir has been the mainstay of coronavirus disease 2019 treatment since the start of the severe acute respiratory syndrome coronavirus 2 pandemic. Despite its growing use, safety data are limited. We present the case of an elderly man with obesity and coronavirus disease 2019 who developed acute liver failure after initiation of remdesivir. This report broadens our knowledge of the side effect profile of remdesivir and discusses potential risk factors and an approach to remdesivir-induced liver failure. Our case also highlights the importance of monitoring hepatic function after initiation of therapy with remdesivir.

Informed consent in the older adult: OSCEs for assessing fellows' ACGME and geriatric gastroenterology competencies.

OBJECTIVES: The American Gastroenterological Association fellowship curriculum identifies geriatric components for gastroenterology (GI) training; however, few tools are available for this purpose. Using an objective structured clinical examination (OSCE), we aimed to assess ACGME competencies of communication, professionalism, and geriatric-specific patient care among GI fellows. METHODS: We developed an informed-consent case involving a geriatric patient who needs surveillance colonoscopy. We used a validated faculty skills checklist to rate fellows across three competency domains. Fifteen fellows from four GI training programs participated. RESULTS: Although the fellows excelled at communication and professionalism, only 51% excelled at geriatric-specific patient-care skills. Fellows were least likely to demonstrate collaboration with the patient, to assess patient understanding, and to explain the limits of the test. Communication and geriatric-specific skills were correlated. CONCLUSIONS: OSCEs are a feasible method for assessing geriatric-related ACGME competencies for fellows. The results highlight the need for curriculum development.

Observing handoffs and telephone management in GI fellowship training.

OBJECTIVES: Gastroenterology (GI) training programs are mandated to teach fellows interpersonal communication and professionalism as basic competencies. We sought to assess important skill sets used by our fellows but not formally observed or measured: handoffs, telephone management, and note writing. We designed an Observed Standardized Clinical Examination (OSCE) form and provided the faculty with checklists to rate fellows' performance on specific criteria. METHODS: We created two new scenarios: a handoff between a tired overnight senior fellow on call and a more junior fellow, and a telephone management case of an ulcerative colitis flare. Fellows wrote a progress notes documenting the encounters. To add educational value, we gave the participants references about handoff communication. Four OSCE stations-handoff communication, telephone management, informed consent, and delivering bad news-were completed by fellows and observed by faculty. RESULTS: Eight faculty members and eight fellows from four GI training programs participated. All the fellows agreed that handoffs can be important learning opportunities and can be improved if they are structured, and that handoff skills can improve with practice. CONCLUSIONS: OSCEs can serve as practicums for assessing complex skill sets such as handoff communication and telephone management.

Recognition of bacterial glycosphingolipids by natural killer T cells.

Natural killer T (NKT) cells constitute a highly conserved T lymphocyte subpopulation that has the potential to regulate many types of immune responses through the rapid secretion of cytokines. NKT cells recognize glycolipids presented by CD1d, a class I-like antigen-presenting molecule. They have an invariant T-cell antigen receptor (TCR) alpha-chain, but whether this invariant TCR recognizes microbial antigens is still controversial. Here we show that most mouse and human NKT cells recognize glycosphingolipids from Sphingomonas, Gram-negative bacteria that do not contain lipopolysaccharide. NKT cells are activated in vivo after exposure to these bacterial antigens or bacteria, and mice that lack NKT cells have a marked defect in the clearance of Sphingomonas from the liver. These data suggest that NKT cells are T lymphocytes that provide an innate-type immune response to certain microorganisms through recognition by their antigen receptor, and that they might be useful in providing protection from bacteria that cannot be detected by pattern recognition receptors such as Toll-like receptor 4.

Acute Kidney Injury Presenting as Hepatorenal Syndrome in the Setting of Glecaprevir/Pibrentasvir Treatment for Hepatitis C.

A 65-year-old man with chronic hepatitis C virus and hepatocellular carcinoma, after surgical resection and chemotherapy, was started on a regimen of glecaprevir and pibrentasavir for treatment of his hepatitis C virus. Ten days later, he developed hepatotoxicity with subsequent progression to hepatorenal syndrome (HRS). On discontinuation of glecaprevir/pibrentasavir and initiation of HRS treatment, he had improvement in his renal and hepatic function. Although there have been recent safety concerns surrounding hepatocellular injury secondary to glecaprevir/pibrentasavir, this is the first case report of HRS secondary to severe hepatotoxicity induced by glecaprevir/pibrentasavir.

Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract.

Given its population of CCR5-expressing, immunologically activated CD4(+) T cells, the gastrointestinal (GI) mucosa is uniquely susceptible to human immunodeficiency virus (HIV)-1 infection. We undertook this study to assess whether a preferential depletion of mucosal CD4(+) T cells would be observed in HIV-1-infected subjects during the primary infection period, to examine the anatomic subcompartment from which these cells are depleted, and to examine whether suppressive highly active antiretroviral therapy could result in complete immune reconstitution in the mucosal compartment. Our results demonstrate that a significant and preferential depletion of mucosal CD4(+) T cells compared with peripheral blood CD4(+) T cells is seen during primary HIV-1 infection. CD4(+) T cell loss predominated in the effector subcompartment of the GI mucosa, in distinction to the inductive compartment, where HIV-1 RNA was present. Cross-sectional analysis of a cohort of primary HIV-1 infection subjects showed that although chronic suppression of HIV-1 permits near-complete immune recovery of the peripheral blood CD4(+) T cell population, a significantly greater CD4(+) T cell loss remains in the GI mucosa, despite up to 5 yr of fully suppressive therapy. Given the importance of the mucosal compartment in HIV-1 pathogenesis, further study to elucidate the significance of the changes observed here is critical.

Teaching the competencies: using observed structured clinical examinations for faculty development.

OBJECTIVES: Gastroenterology (GI) training programs must develop the teaching skills of their faculty and provide feedback to their fellows. Many faculty feel uncomfortable offering feedback or identifying specific areas for improvement to the fellows. We developed an Observed Structured Clinical Exam (OSCE) to assess fellows' skills and provided faculty with specific criteria to rate the fellows' performance. We propose that OSCEs can serve as tools for faculty development in delivering effective feedback. METHODS: Faculty completed a Web-based training module and received written guidelines on giving feedback. Four OSCE stations were completed by each fellow with faculty using standardized checklists to assess the fellows' skills. Afterwards, faculty rated each program component and assessed their comfort level with feedback. RESULTS: Eight faculty members and 10 fellows from 5 GI training programs in NYC participated. 100% of the faculty agreed that feedback is an important learning tool, should include the learner's self-assessment, and that feedback skills could improve with practice. Compared to faculty skills prior to the program, 87.5% of the faculty agreed that they focused more on specific behaviors and 75% agreed that giving negative feedback was now easier. CONCLUSIONS: OSCEs can serve as practicums for faculty development in giving constructive feedback.

Diversity of 16S rRNA genes within individual prokaryotic genomes.

Analysis of intragenomic variation of 16S rRNA genes is a unique approach to examining the concept of ribosomal constraints on rRNA genes; the degree of variation is an important parameter to consider for estimation of the diversity of a complex microbiome in the recently initiated Human Microbiome Project (http://nihroadmap.nih.gov/hmp). The current GenBank database has a collection of 883 prokaryotic genomes representing 568 unique species, of which 425 species contained 2 to 15 copies of 16S rRNA genes per genome (2.22 +/- 0.81). Sequence diversity among the 16S rRNA genes in a genome was found in 235 species (from 0.06% to 20.38%; 0.55% +/- 1.46%). Compared with the 16S rRNA-based threshold for operational definition of species (1 to 1.3% diversity), the diversity was borderline (between 1% and 1.3%) in 10 species and >1.3% in 14 species. The diversified 16S rRNA genes in Haloarcula marismortui (diversity, 5.63%) and Thermoanaerobacter tengcongensis (6.70%) were highly conserved at the 2 degrees structure level, while the diversified gene in B. afzelii (20.38%) appears to be a pseudogene. The diversified genes in the remaining 21 species were also conserved, except for a truncated 16S rRNA gene in "Candidatus Protochlamydia amoebophila." Thus, this survey of intragenomic diversity of 16S rRNA genes provides strong evidence supporting the theory of ribosomal constraint. Taxonomic classification using the 16S rRNA-based operational threshold could misclassify a number of species into more than one species, leading to an overestimation of the diversity of a complex microbiome. This phenomenon is especially seen in 7 bacterial species associated with the human microbiome or diseases.

Teaching the competencies: using objective structured clinical encounters for gastroenterology fellows.

BACKGROUND AIMS: Objective structured clinical encounters (OSCEs) are used widely to educate and assess the competence of medical students and residents; they generally are absent from fellowship training. The Accreditation Council for Graduate Education has cited OSCEs as a best practice for assessing the 6 core competencies. This article reports on the use of an OSCE to assess the competence of second-year gastroenterology fellows in the difficult-to-assess core competencies: interpersonal and communication skills and professionalism. METHODS: We developed a 4-station, faculty-observed OSCE with 4 standardized patients. Information gathering, relationship development, patient education, and counseling skills were assessed. Professionalism skills assessed included obtaining informed consent, delivering bad news, managing difficult situations, and showing interdisciplinary respect. In each station, faculty and standardized patients completed an 18- to 24-item checklist evaluating fellows' performance and provided feedback to the fellows. Nine fellows and 5 faculty from 4 gastroenterology training programs in NYC participated. RESULTS: Fellows and faculty generally highly rated the realism of the OSCE and favorably rated the OSCE for its difficulty and their overall experience. Across all cases, fellows were rated as receiving "well dones" for 56.4% of the communication items (SD, 18.3%) and for 79.1% of the professionalism items (SD, 16.4%). CONCLUSIONS: Integrating OSCEs into gastroenterology fellowship training may help enhance communication skills and prepare fellows for dealing with difficult clinical situations and provides mechanisms for constructive feedback. OSCEs developed collaboratively can assist in program self-evaluation and reduce costs by sharing resources, in addition to fulfilling Accreditation Council for Graduate Education mandates.

Split- versus single-dose preparation tolerability in a multiethnic population: decreased side effects but greater social barriers.

BACKGROUND: This study was performed to compare patient-reported tolerability and its barriers in single- vs. split-dose 4-L polyethylene glycol (PEG) bowel preparation for colonoscopy in a large multiethnic, safety-net patient population. METHODS: A cross-sectional, dual-center study using a multi-language survey was used to collect patient-reported demographic, medical, socioeconomic, and tolerability data from patients undergoing outpatient colonoscopy. Univariate and multivariate analyses were used to identify demographic and clinical factors significantly associated with patient-reported bowel preparation tolerability. RESULTS: A total of 1023 complete surveys were included, of which 342 (33.4%) completed single-dose and 681 (66.6%) split-dose bowel preparation. Thirty-nine percent of the patients were Hispanic, 50% had Medicaid or no insurance, and 34% had limited English proficiency. Patients who underwent split-dose preparation were significantly more likely to report a tolerable preparation, with less severe symptoms, than were patients who underwent single-dose preparation. Multiple logistic regression revealed that male sex and instructions in the preferred language were associated with tolerability of the single-dose preparation, while male sex and concerns about medications were associated with tolerability of the split-dose preparation. CONCLUSIONS: In a large multiethnic safety-net population, split-dose bowel preparation was significantly more tolerable and associated with less severe gastrointestinal symptoms than single-dose preparation. The tolerability of split-dose bowel preparation was associated with social barriers, including concerns about interfering with other medications.