Single-Day Low-Residue Diet Prior to Colonoscopy Demonstrates Improved Bowel Preparation Quality and Patient Tolerance over Clear Liquid Diet: A Randomized, Single-Blinded, Dual-Center Trial.

BACKGROUND AND AIMS: Patients often refer to bowel preparation and associated dietary restrictions as the greatest deterrents to having a colonoscopy completed or performed. Large studies comparing a low-residue diet (LRD) and a clear liquid diet (CLD) are still limited. The aim of this study is to compare LRD and CLD with regard to bowel preparation quality, tolerance, and satisfaction among a diverse patient population. METHODS: This study is a dual-center, randomized, single-blinded, prospective trial involving adult patients undergoing outpatient colonoscopy at the University of California Irvine Medical Center and an affiliated Veterans Administration hospital. Patients were randomized to consume either a CLD or a planned LRD for the full day prior to colonoscopy. Both groups consumed 4L split-dosed PEG-ELS. The adequacy of bowel preparation was evaluated using the Boston Bowel Preparation Score (BBPS). Adequate preparation was defined as a BBPS ≥ 6 with no individual segment less than a score of 2. Hunger and fatigue pre - and post-procedure were graded on a ten-point scale. Nausea, vomiting, bloating, abdominal cramping, overall discomfort, satisfaction with the diet, willingness to repeat the same preparation and overall experience were assessed. RESULTS: A total of 195 subjects who underwent colonoscopy from October 2014 to October 2017 were included. The mean BBPS for the LRD and CLD groups was 8.38 and 7.93, respectively (p = 0.1). There was a significantly higher number of adequate preparations in the LRD group compared to CLD (p = 0.05). Evening hunger scores just before starting the bowel preparation were significantly lower in the LRD than the CLD group, 2.81 versus 5.97, respectively (p = 0.006). Subjects in the LRD group showed significantly less nausea (p = 0.047) and bloating (p = 0.04). Symptom scores for vomiting, abdominal cramping, and overall discomfort were similar between the groups. Satisfaction with diet was significantly higher in the LRD group than CLD, 72% versus 37.66%, respectively (p < 0.001). The overall colonoscopy experience and the satisfaction with the preparation itself were also better reported in the LRD group (p < 0.001 and p = 0.002, respectively). CONCLUSIONS: This study, which included a diverse group of patients, demonstrated that patients using a LRD before colonoscopy achieve a bowel preparation quality that is superior to patients on a CLD restriction. This study shows that a low-residue diet improves patient satisfaction and results in significantly better tolerability of bowel preparation. As a less restrictive dietary regimen, the low-residue diet may help improve patient participation in colorectal cancer screening programs.

Artificial intelligence using convolutional neural networks for real-time detection of early esophageal neoplasia in Barrett's esophagus (with video).

BACKGROUND AND AIMS: The visual detection of early esophageal neoplasia (high-grade dysplasia and T1 cancer) in Barrett's esophagus (BE) with white-light and virtual chromoendoscopy still remains challenging. The aim of this study was to assess whether a convolutional neural artificial intelligence network can aid in the recognition of early esophageal neoplasia in BE. METHODS: Nine hundred sixteen images from 65 patients of histology-proven early esophageal neoplasia in BE containing high-grade dysplasia or T1 cancer were collected. The area of neoplasia was masked using image annotation software. Nine hundred nineteen control images were collected of BE without high-grade dysplasia. A convolutional neural network (CNN) algorithm was pretrained on ImageNet and then fine-tuned with the goal of providing the correct binary classification of "dysplastic" or "nondysplastic." We developed an object detection algorithm that drew localization boxes around regions classified as dysplasia. RESULTS: The CNN analyzed 458 test images (225 dysplasia and 233 nondysplasia) and correctly detected early neoplasia with sensitivity of 96.4%, specificity of 94.2%, and accuracy of 95.4%. With regard to the object detection algorithm for all images in the validation set, the system was able to achieve a mean average precision of .7533 at an intersection over union of .3 CONCLUSIONS: In this pilot study, our artificial intelligence model was able to detect early esophageal neoplasia in BE images with high accuracy. In addition, the object detection algorithm was able to draw a localization box around the areas of dysplasia with high precision and at a speed that allows for real-time implementation.

Successful Curative Cryoablation of an Esophageal Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The most common location of GIST is the stomach; however, occurrences of GIST in the esophagus are also possible albeit rare. Although the current standard of care for gastric and intestinal GIST involves surgery and tyrosine kinase inhibitors, this case report focuses on the potential of treating esophageal GIST through a novel means of cryoablation therapy.

The Implementation of Integrated Behavioral Health Protocols In Primary Care Settings in Project Care.

PURPOSE: The majority of adults with mental health (MH) and substance use (SU) disorders in the United States do not receive treatment. The Affordable Care Act will create incentives for primary care centers to begin providing behavioral health (MH and SU) services, thus promising to address the MH and SU treatment gaps. This paper examines the implementation of integrated care protocols by three primary care organizations. METHODS: The Behavioral Health Integration in Medical Care (BHIMC) tool was used to evaluate the integrated care capacity of primary care organizations that chose to participate in the Kern County (California) Mental Health Department's Project Care annually for 3years. For a subsample of clinics, change over time was measured. Informed by the Conceptual Model of Evidence-Based Practice Implementation in Public Service Sectors, inner and outer contextual factors impacting implementation were identified and analyzed using multiple data sources and qualitative analytic methods. RESULTS: The primary care organizations all offered partially integrated (PI) services throughout the study period. At baseline, organizations offered minimally integrated/partially integrated (MI/PI) services in the Program Milieu, Clinical Process - Treatment, and Staffing domains of the BHIMC, and scores on all domains were at the partially integrated (PI) level or higher in the first and second follow-ups. Integrated care services emphasized the identification and management of MH more than SU in 52.2% of evaluated domains, but did not emphasize SU more than MH in any of them. Many of the gaps between MH and SU emphases were associated with limited capacities related to SU medications. Several outer (socio-political context, funding, leadership) and inner (organizational characteristics, individual adopter characteristics, leadership, innovation-values fit) contextual factors impacted the development of integrated care capacity. CONCLUSIONS: This study of a small sample of primary care organizations showed that it is possible to improve their integrated care capacity as measured by the BHIMC, though it may be difficult or unfeasible for them to provide fully integrated behavioral health services. Integrated services emphasized MH more than SU, and enhancing primary care clinic capacities related to SU medications may help close this gap. Both inner and outer contextual factors may impact integrated service capacity development in primary care clinics. Study findings may be used to inform future research on integrated care and inform the implementation of efforts to enhance integrated care capacity in primary care clinics.

Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells.

Interleukin 22 (IL-22) is a member of the IL-10 cytokine family that is involved in inflammatory and wound healing processes. Originally considered a T helper type 1 (T(H)1)-associated cytokine, IL-22 has since been shown to be produced mainly by IL-17-producing helper T cells (T(H)-17 cells). Here we describe a previously uncharacterized IL-22-producing human helper T cell population that coexpressed the chemokine receptor CCR6 and the skin-homing receptors CCR4 and CCR10. These cells were distinct from both T(H)-17 cells and T(H)1 cells. Downregulation of either the aryl hydrocarbon receptor (AHR) or the transcription factor RORC by RNA-mediated interference affected IL-22 production, whereas IL-17 production was affected only by downregulation of RORC by RNA-mediated interference. AHR agonists substantially altered the balance of IL-22- versus IL-17-producing cells. This subset of IL-22-producing cells may be important in skin homeostasis and pathology.

TGF-beta signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis.

One unresolved issue in immune tolerance is what prevents self-reactive T cells from activation. In this study, we used a transgenic mouse model of targeted functional inactivation of TGF-betaR signaling in CD11c(+) cells (CD11c(dnR) mice) and showed a direct impact on the development of experimental autoimmune encephalomyelitis (EAE). We found that MOG(35-55) immunization of CD11c(dnR) mice results in strong inflammation of CNS, high frequency of T cells in CNS, increased levels of T helper 1 (T(H)1) and T(H)17 cytokines in the periphery, and lack of remission from EAE. Once crossed with mice prone to autoimmunity, double-transgenic CD11c(dnR)Mog(TCR) mice revealed a spontaneous EAE-like disease characterized by early infiltration of activated myelin-specific T cells into CNS, activation of microglial cells, inflammation of CNS, dysfunction of locomotion, and premature death. We constructed chimeric mice and demonstrated that inactivation of TGF-betaR signaling in dendritic cells (DCs) results in augmented EAE-associated T cell responses. Our data provide direct evidence that TGF-beta can control autoimmunity via actions on DCs.

ICOS mediates the development of insulin-dependent diabetes mellitus in nonobese diabetic mice.

Initiation of diabetes in NOD mice can be mediated by the costimulatory signals received by T cells. The ICOS is found on Ag-experienced T cells where it acts as a potent regulator of T cell responses. To determine the function of ICOS in diabetes, we followed the course of autoimmune disease and examined T cells in ICOS-deficient NOD mice. The presence of ICOS was indispensable for the development of insulitis and hyperglycemia in NOD mice. In T cells, the deletion of ICOS resulted in a decreased production of the Th1 cytokine IFN-gamma, whereas the numbers of regulatory T cells remained unchanged. We conclude that ICOS is critically important for the induction of the autoimmune process that leads to diabetes.

Inactivation of JNK1 enhances innate IL-10 production and dampens autoimmune inflammation in the brain.

Environmental insults such as microbial pathogens can contribute to the activation of autoreactive T cells, leading to inflammation of target organs and, ultimately, autoimmune disease. Various infections have been linked to multiple sclerosis and its animal counterpart, autoimmune encephalomyelitis. The molecular process by which innate immunity triggers autoreactivity is not currently understood. By using a mouse model of multiple sclerosis, we found that the genetic loss of the MAPK, c-Jun N-terminal kinase 1 (JNK1), enhances IL-10 production, rendering innate myeloid cells unresponsive to certain microbes and less capable of generating IL-17-producing, encephalitogenic T cells. Moreover, JNK1-deficient central nervous system myeloid cells are unable to respond to effector T cell inflammatory cytokines, preventing further progression to neuroinflammation. Thus, we have identified the JNK1 signal transduction pathway in myeloid cells to be a critical component of a regulatory circuit mediating inflammatory responses in autoimmune disease. Our findings provide further insights into the pivotal MAPK-regulated network of innate and adaptive cytokines in the progression to autoimmunity.

Gadd45 beta and Gadd45 gamma are critical for regulating autoimmunity.

The number of effector T cells is controlled by proliferation and programmed cell death. Loss of these controls on self-destructive effector T cells may precipitate autoimmunity. Here, we show that two members of the growth arrest and DNA damage-inducible (Gadd45) family, beta and gamma, are critical in the development of pathogenic effector T cells. CD4(+) T cells lacking Gadd45beta can rapidly expand and invade the central nervous system in response to myelin immunization, provoking an exacerbated and prolonged autoimmune encephalomyelitis in mice. Importantly, mice with compound deficiency in Gadd45beta and Gadd45gamma spontaneously developed signs of autoimmune lymphoproliferative syndrome and systemic lupus erythematosus. Our findings therefore identify the Gadd45beta/Gadd45gamma-mediated control of effector autoimmune lymphocytes as an attractive novel target for autoimmune disease therapy.

Bone marrow-derived versus parenchymal sources of inducible nitric oxide synthase in experimental autoimmune encephalomyelitis.

The role of nitric oxide (NO) in central nervous system (CNS) inflammation is uncertain. Whereas experimental autoimmune encephalomyelitis (EAE) is exacerbated in mice deficient in inducible nitric oxide synthase (iNOS), inhibitor studies have suggested a pro-inflammatory role for NO. These discrepancies may reflect balance between immunoregulatory and neurocytopathologic roles for NO. We investigated selective effects of bone marrow-derived versus CNS parenchymal sources of iNOS in EAE in chimeric mice. Chimeras that selectively expressed or ablated iNOS in leukocytes both showed significant delay in disease onset, with no difference in disease severity. We conclude that bone marrow-derived and CNS parenchymal sources of iNOS-derived NO both play a regulatory role in EAE.

CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes.

Pancreatic lymph node-derived CD4+CD25+ T regulatory (Treg) cells inhibit in situ differentiation of islet-reactive CD8+ T cells into cytotoxic T lymphocytes, thereby preventing diabetes progression. The mechanism by which these Treg cells suppress anti-islet CD8+ T cells is unknown. Here, we show by using a CD8+ T cell-mediated model of type 1 diabetes that transforming growth factor (TGF)-beta-TGF-beta receptor signals are critical for CD4+CD25+ Treg cell regulation of autoreactive islet-specific cytotoxic T lymphocytes. Transgenic expression of tumor necrosis factor alpha from birth to 25 days of age in the islets of B6 mice that constitutively express CD80 on their beta cells results in accumulation of CD4+CD25+TGF-beta+ cells exclusively in the islets and pancreatic lymph nodes, which delays diabetes progression. In contrast, expression of tumor necrosis factor alpha until 28 days of age prevents islet accumulation of CD4+CD25+TGF-beta+ Treg cells, resulting in acceleration to diabetes. Furthermore, adoptive transfer experiments demonstrated that CD4+CD25+ Treg cells could not control naïve or activated islet-reactive CD8+ T cells bearing a dominant negative TGF-beta receptor type II. Our data demonstrate that, in vivo, TGF-beta signaling in CD8+ T cells is critical for CD4+CD25+ Treg cell suppression of islet-reactive CD8+ T cells in type 1 diabetes.

Constitutive expression of a costimulatory ligand on antigen-presenting cells in the nervous system drives demyelinating disease.

It has been proposed that the activation status of antigen-presenting cells (APCs) plays a significant role in the development of autoimmune disease. Whether expression of costimulatory ligands on tissue-resident APCs controls organ-specific autoimmune responses has not been tested. We here report that transgenic mice constitutively expressing the costimulatory ligand B7.2/CD86 on microglia in the central nervous system (CNS) and on related cells in the proximal peripheral nervous tissue spontaneously develop autoimmune demyelinating disease. Disease-affected nervous tissue in transgenic mice showed infiltration characterized by a predominance of CD8+ memory-effector T cells, as well as CD4+ T cells. Transgenic animals lacking alphabeta TCR+ T cells were completely resistant to disease development. Transgenic T cells induced disease when adoptively transferred into T cell-deficient B7.2 transgenic recipients but not into non-transgenic recipients. These data provide evidence that B7/CD28 interactions within the nervous tissue are critical determinants of disease development. Our findings have important implications for understanding the etiology of nervous system autoimmune diseases such as multiple sclerosis (MS) and Guillain-Barré syndrome (GBS).