Publications by authors named "Suzanne Lewis"

105 Publications

A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder.

NPJ Genom Med 2021 Nov 4;6(1):91. Epub 2021 Nov 4.

Service de Génétique clinique, CH de Chambéry, Chambéry, France.

Autism Spectrum Disorder (ASD) is genetically complex with ~100 copy number variants and genes involved. To try to establish more definitive genotype and phenotype correlations in ASD, we searched genome sequence data, and the literature, for recurrent predicted damaging sequence-level variants affecting single genes. We identified 18 individuals from 16 unrelated families carrying a heterozygous guanine duplication (c.3679dup; p.Ala1227Glyfs*69) occurring within a string of 8 guanines (genomic location [hg38]g.50,721,512dup) affecting SHANK3, a prototypical ASD gene (0.08% of ASD-affected individuals carried the predicted p.Ala1227Glyfs*69 frameshift variant). Most probands carried de novo mutations, but five individuals in three families inherited it through somatic mosaicism. We scrutinized the phenotype of p.Ala1227Glyfs*69 carriers, and while everyone (17/17) formally tested for ASD carried a diagnosis, there was the variable expression of core ASD features both within and between families. Defining such recurrent mutational mechanisms underlying an ASD outcome is important for genetic counseling and early intervention.
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http://dx.doi.org/10.1038/s41525-021-00254-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568906PMC
November 2021

Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings.

Genes (Basel) 2021 07 8;12(7). Epub 2021 Jul 8.

Department of Medical Genetics, University of British Columbia (UBC), Vancouver, BC V6H 3N1, Canada.

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (, , , , and ). All are shared among the three children, except , which is only present in the most severely affected child. The compound heterozygous variants in and the maternally inherited variant in are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. is also involved in synapse functions, and and are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.
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http://dx.doi.org/10.3390/genes12071053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303619PMC
July 2021

Sex differences in conditioned orienting and the role of estradiol in addiction-related behaviors.

Behav Neurosci 2021 Jul 22. Epub 2021 Jul 22.

Department of Psychology, The University of Texas at Austin.

Conditioned orienting response (OR) is a form of cue-directed behavior thought to indicate increased attentional and/or motivational processing of reward-associated stimuli. OR as a phenotype has been shown to predict both direct drug proclivity in female rats and behaviors indirectly related to drug proclivity in male rats, but no extant research has compared males and females in terms of their OR behavior or its notable substrates. As females are at increased risk for substance abuse, and the ovarian hormone estradiol is often cited as a driving factor for this predilection, it is important to characterize sex differences between males and females and explore what, if any, contribution estradiol has in behaviors which predict substance abuse. In these experiments, male and female rats [intact or ovariectomized (OVX) with/without estradiol replacement] were compared on a battery of behavioral tasks, including OR, novelty-seeking, attentional set-shifting, and ultrasonic vocalizations (USVs) to amphetamine treatment. Female rats, regardless of estradiol replacement, had higher OR scores than males. OR score was a predictor of attention impairments, and estradiol availability contributed to this relationship in females. Sex differences were not observed in novelty-seeking, attentional set-shifting, or USV response to amphetamine; however, estradiol replacement did alter the presentation of these behaviors. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/bne0000484DOI Listing
July 2021

Plume Dynamics Structure the Spatiotemporal Activity of Mitral/Tufted Cell Networks in the Mouse Olfactory Bulb.

Front Cell Neurosci 2021 30;15:633757. Epub 2021 Apr 30.

Department of Psychology, University of Washington, Seattle, WA, United States.

Although mice locate resources using turbulent airborne odor plumes, the stochasticity and intermittency of fluctuating plumes create challenges for interpreting odor cues in natural environments. Population activity within the olfactory bulb (OB) is thought to process this complex spatial and temporal information, but how plume dynamics impact odor representation in this early stage of the mouse olfactory system is unknown. Limitations in odor detection technology have made it difficult to measure plume fluctuations while simultaneously recording from the mouse's brain. Thus, previous studies have measured OB activity following controlled odor pulses of varying profiles or frequencies, but this approach only captures a subset of features found within olfactory plumes. Adequately sampling this feature space is difficult given a lack of knowledge regarding which features the brain extracts during exposure to natural olfactory scenes. Here we measured OB responses to naturally fluctuating odor plumes using a miniature, adapted odor sensor combined with wide-field GCaMP6f signaling from the dendrites of mitral and tufted (MT) cells imaged in olfactory glomeruli of head-fixed mice. We precisely tracked plume dynamics and imaged glomerular responses to this fluctuating input, while varying flow conditions across a range of ethologically-relevant values. We found that a consistent portion of MT activity in glomeruli follows odor concentration dynamics, and the strongest responding glomeruli are the best at following fluctuations within odor plumes. Further, the reliability and average response magnitude of glomerular populations of MT cells are affected by the flow condition in which the animal samples the plume, with the fidelity of plume following by MT cells increasing in conditions of higher flow velocity where odor dynamics result in intermittent whiffs of stronger concentration. Thus, the flow environment in which an animal encounters an odor has a large-scale impact on the temporal representation of an odor plume in the OB. Additionally, across flow conditions odor dynamics are a major driver of activity in many glomerular networks. Taken together, these data demonstrate that plume dynamics structure olfactory representations in the first stage of odor processing in the mouse olfactory system.
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http://dx.doi.org/10.3389/fncel.2021.633757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127944PMC
April 2021

Automated interpretation of biopsy images for the detection of celiac disease using a machine learning approach.

Comput Methods Programs Biomed 2021 May 27;203:106010. Epub 2021 Feb 27.

Department of Electronics and Computer Engineering, Ngee Ann Polytechnic, Singapore; School of Science and Technology, Singapore University of Social Sciences, Singapore; School of Business, University of Southern Queensland Springfield, Australia; Department of Bioinformatics and Medical Engineering, Asia University, Taiwan; International Research Organization for Advanced Science and Technology (IROAST) Kumamoto University, Kumamoto, Japan. Electronic address:

Background And Objectives: Celiac disease is an autoimmune disease occurring in about 1 in 100 people worldwide. Early diagnosis and efficient treatment are crucial in mitigating the complications that are associated with untreated celiac disease, such as intestinal lymphoma and malignancy, and the subsequent high morbidity. The current diagnostic methods using small intestinal biopsy histopathology, endoscopy, and video capsule endoscopy (VCE) involve manual interpretation of photomicrographs or images, which can be time-consuming and difficult, with inter-observer variability. In this paper, a machine learning technique was developed for the automation of biopsy image analysis to detect and classify villous atrophy based on modified Marsh scores. This is one of the first studies to employ conventional machine learning to automate the use of biopsy images for celiac disease detection and classification.

Methods: The Steerable Pyramid Transform (SPT) method was used to obtain sub bands from which various types of entropy and nonlinear features were computed. All extracted features were automatically classified into two-class and multi-class, using six classifiers.

Results: An accuracy of 88.89%, was achieved for the classification of two-class villous abnormalities based on analysis of Hematoxylin and Eosin (H&E) stained biopsy images. Similarly, an accuracy of 82.92% was achieved for the two-class classification of red-green-blue (RGB) biopsy images. Also, an accuracy of 72% was achieved in the classification of multi-class biopsy images.

Conclusion: The results obtained are promising, and demonstrate the possibility of automating biopsy image interpretation using machine learning. This can assist pathologists in accelerating the diagnostic process without bias, resulting in greater accuracy, and ultimately, earlier access to treatment.
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http://dx.doi.org/10.1016/j.cmpb.2021.106010DOI Listing
May 2021

Engaging Carers in Co-Design: Development of the Carer Readiness Tool.

Int J Integr Care 2021 Mar 15;21(1):13. Epub 2021 Mar 15.

Clinical Safety, Quality and Governance Directorate, Central Coast Local Health District, Gosford, NSW, Australia.

Introduction: The Carer Support Unit (CSU) of the Central Coast Local Health District (CCLHD), NSW, Australia, developed, trialled and implemented a Carer Readiness Tool (CRT) to help carers gauge their readiness to care at home, highlight to hospital staff areas for additional support for carers, and provide evidence of carer engagement in discharge planning.

Description: A rigorous co-design process was followed with carer consultation at key milestones in development of the CRT. The tool was piloted in two cancer/chronic renal disease inpatient units commencing November 2019.

Discussion: The CRT was well-received by carers who appreciated the opportunity to complete the tool in their own time, not in front of the patient. Positive feedback was received from clinicians, including the breadth of the CRT's content which contributed to better discharge planning. The need to manually incorporate a hard copy form into the electronic medical record is a limitation of the CRT.

Conclusion: The CRT is context-specific and fit for purpose. During the development of the CRT, the project team focused on the face validity and usefulness of the tool. The next stage of the project will be formal evaluation of the tool to measure its impact.
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http://dx.doi.org/10.5334/ijic.5527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977025PMC
March 2021

Immunophenotypic Spectrum and Genomic Landscape of Refractory Celiac Disease Type II.

Am J Surg Pathol 2021 07;45(7):905-916

Department of Pathology and Cell Biology, Columbia University Irving Medical Center.

Refractory celiac disease type II (RCD II), also referred to as "cryptic" enteropathy-associated T-cell lymphoma (EATL) or "intraepithelial T-cell lymphoma," is a rare clonal lymphoproliferative disorder that arises from innate intraepithelial lymphocytes. RCD II has a poor prognosis and frequently evolves to EATL. The pathogenesis of RCD II is not well understood and data regarding the immunophenotypic spectrum of this disease and underlying genetic alterations are limited. To gain further biological insights, we performed comprehensive immunophenotypic, targeted next-generation sequencing, and chromosome microarray analyses of 11 RCD II cases: CD4-/CD8- (n=6), CD8+ (n=4), and CD4+ (n=1), and 2 of 3 ensuing EATLs. Genetic alterations were identified in 9/11 (82%) of the RCD II cases. All 9 displayed mutations in members of the JAK-STAT signaling pathway, including frequent, recurrent STAT3 (7/9, 78%) and JAK1 (4/9, 44%) mutations, and 9/10 evaluable cases expressed phospho-STAT3. The mutated cases also harbored recurrent alterations in epigenetic regulators (TET2, n=5 and KMT2D, n=5), nuclear factor-κB (TNFAIP3, n=4), DNA damage repair (POT1, n=3), and immune evasion (CD58, n=2) pathway genes. The CD4-/CD8- and other immunophenotypic subtypes of RCD II exhibited similar molecular features. Longitudinal genetic analyses of 4 RCD II cases revealed stable mutation profiles, however, additional mutations were detected in the EATLs, which occurred at extraintestinal sites and were clonally related to antecedent RCD II. Chromosome microarray analysis demonstrated copy number changes in 3/6 RCD II cases, and 1 transformed EATL with sufficient neoplastic burden for informative analysis. Our findings provide novel information about the immunophenotypic and genomic characteristics of RCD II, elucidate early genetic events in EATL pathogenesis, and reveal potential therapeutic targets.
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http://dx.doi.org/10.1097/PAS.0000000000001658DOI Listing
July 2021

Using Head-Mounted Ethanol Sensors to Monitor Olfactory Information and Determine Behavioral Changes Associated with Ethanol-Plume Contact during Mouse Odor-Guided Navigation.

eNeuro 2021 Jan-Feb;8(1). Epub 2021 Jan 22.

Department of Psychology, University of Washington, Seattle, Washington 98195

Olfaction guides navigation and decision-making in organisms from multiple animal phyla. Understanding how animals use olfactory cues to guide navigation is a complicated problem for two main reasons. First, the sensory cues used to guide animals to the source of an odor consist of volatile molecules, which form plumes. These plumes are governed by turbulent air currents, resulting in an intermittent and spatiotemporally varying olfactory signal. A second problem is that the technologies for chemical quantification are cumbersome and cannot be used to detect what the freely moving animal senses in real time. Understanding how the olfactory system guides this behavior requires knowing the sensory cues and the accompanying brain signals during navigation. Here, we present a method for real-time monitoring of olfactory information using low-cost, lightweight sensors that robustly detect common solvent molecules, like alcohols, and can be easily mounted on the heads of freely behaving mice engaged in odor-guided navigation. To establish the accuracy and temporal response properties of these sensors we compared their responses with those of a photoionization detector (PID) to precisely controlled ethanol stimuli. Ethanol-sensor recordings, deconvolved using a difference-of-exponentials kernel, showed robust correlations with the PID signal at behaviorally relevant time, frequency, and spatial scales. Additionally, calcium imaging of odor responses from the olfactory bulbs (OBs) of awake, head-fixed mice showed strong correlations with ethanol plume contacts detected by these sensors. Finally, freely behaving mice engaged in odor-guided navigation showed robust behavioral changes such as speed reduction that corresponded to ethanol plume contacts.
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http://dx.doi.org/10.1523/ENEURO.0285-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877453PMC
June 2021

Beyond the black stump: rapid reviews of health research issues affecting regional, rural and remote Australia.

Med J Aust 2020 12;213 Suppl 11:S3-S32.e1

CHAPTER 1: RETAIL INITIATIVES TO IMPROVE THE HEALTHINESS OF FOOD ENVIRONMENTS IN RURAL, REGIONAL AND REMOTE COMMUNITIES: Objective: To synthesise the evidence for effectiveness of initiatives aimed at improving food retail environments and consumer dietary behaviour in rural, regional and remote populations in Australia and comparable countries, and to discuss the implications for future food environment initiatives for rural, regional and remote areas of Australia.

Study Design: Rapid review of articles published between January 2000 and May 2020.

Data Sources: We searched MEDLINE (EBSCOhost), Health and Society Database (Informit) and Rural and Remote Health Database (Informit), and included studies undertaken in rural food environment settings in Australia and other countries.

Data Synthesis: Twenty-one articles met the inclusion criteria, including five conducted in Australia. Four of the Australian studies were conducted in very remote populations and in grocery stores, and one was conducted in regional Australia. All of the overseas studies were conducted in rural North America. All of them revealed a positive influence on food environment or consumer behaviour, and all were conducted in disadvantaged, rural communities. Positive outcomes were consistently revealed by studies of initiatives that focused on promotion and awareness of healthy foods and included co-design to generate community ownership and branding.

Conclusion: Initiatives aimed at improving rural food retail environments were effective and, when implemented in different rural settings, may encourage improvements in population diets. The paucity of studies over the past 20 years in Australia shows a need for more research into effective food retail environment initiatives, modelled on examples from overseas, with studies needed across all levels of remoteness in Australia. Several retail initiatives that were undertaken in rural North America could be replicated in rural Australia and could underpin future research. CHAPTER 2: WHICH INTERVENTIONS BEST SUPPORT THE HEALTH AND WELLBEING NEEDS OF RURAL POPULATIONS EXPERIENCING NATURAL DISASTERS?: Objective: To explore and evaluate health and social care interventions delivered to rural and remote communities experiencing natural disasters in Australia and other high income countries.

Study Design: We used systematic rapid review methods. First we identified a test set of citations and generated a frequency table of Medical Subject Headings (MeSH) to index articles. Then we used combinations of MeSH terms and keywords to search the MEDLINE (Ovid) database, and screened the titles and abstracts of the retrieved references.

Data Sources: We identified 1438 articles via database searches, and a further 62 articles via hand searching of key journals and reference lists. We also found four relevant grey literature resources. After removing duplicates and undertaking two stages of screening, we included 28 studies in a synthesis of qualitative evidence.

Data Synthesis: Four of us read and assessed the full text articles. We then conducted a thematic analysis using the three phases of the natural disaster response cycle.

Conclusion: There is a lack of robust evaluation of programs and interventions supporting the health and wellbeing of people in rural communities affected by natural disasters. To address the cumulative and long term impacts, evidence suggests that continuous support of people's health and wellbeing is needed. By using a lens of rural adversity, the complexity of the lived experience of natural disasters by rural residents can be better understood and can inform development of new models of community-based and integrated care services. CHAPTER 3: THE IMPACT OF BUSHFIRE ON THE WELLBEING OF CHILDREN LIVING IN RURAL AND REMOTE AUSTRALIA: Objective: To investigate the impact of bushfire events on the wellbeing of children living in rural and remote Australia.

Study Design: Literature review completed using rapid realist review methods, and taking into consideration the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement for systematic reviews.

Data Sources: We sourced data from six databases: EBSCOhost (Education), EBSCOhost (Health), EBSCOhost (Psychology), Informit, MEDLINE and PsycINFO. We developed search terms to identify articles that could address the research question based on the inclusion criteria of peer reviewed full text journal articles published in English between 1983 and 2020. We initially identified 60 studies and, following closer review, extracted data from eight studies that met the inclusion criteria.

Data Synthesis: Children exposed to bushfires may be at increased risk of poorer wellbeing outcomes. Findings suggest that the impact of bushfire exposure may not be apparent in the short term but may become more pronounced later in life. Children particularly at risk are those from more vulnerable backgrounds who may have compounding factors that limit their ability to overcome bushfire trauma.

Conclusion: We identified the short, medium and long term impacts of bushfire exposure on the wellbeing of children in Australia. We did not identify any evidence-based interventions for supporting outcomes for this population. Given the likely increase in bushfire events in Australia, research into effective interventions should be a priority. CHAPTER 4: THE ROLE OF NATIONAL POLICIES TO ADDRESS RURAL ALLIED HEALTH, NURSING AND DENTISTRY WORKFORCE MALDISTRIBUTION: Objective: Maldistribution of the health workforce between rural, remote and metropolitan communities contributes to longstanding health inequalities. Many developed countries have implemented policies to encourage health care professionals to work in rural and remote communities. This scoping review is an international synthesis of those policies, examining their effectiveness at recruiting and retaining nursing, dental and allied health professionals in rural communities.

Study Design: Using scoping review methods, we included primary research - published between 1 September 2009 and 30 June 2020 - that reported an evaluation of existing policy initiatives to address workforce maldistribution in high income countries with a land mass greater than 100 000 km .

Data Sources: We searched MEDLINE, Ovid Embase, Ovid Emcare, Informit, Scopus, and Web of Science. We screened 5169 articles for inclusion by title and abstract, of which we included 297 for full text screening. We then extracted data on 51 studies that had been conducted in Australia, the United States, Canada, United Kingdom and Norway.

Data Synthesis: We grouped the studies based on World Health Organization recommendations on recruitment and retention of health care workers: education strategies (n = 27), regulatory change (n = 11), financial incentives (n = 6), personal and professional support (n = 4), and approaches with multiple components (n = 3).

Conclusion: Considerable work has occurred to address workforce maldistribution at a local level, underpinned by good practice guidelines, but rarely at scale or with explicit links to coherent overarching policy. To achieve policy aspirations, multiple synergistic evidence-based initiatives are needed, and implementation must be accompanied by well designed longitudinal evaluations that assess the effectiveness of policy objectives. CHAPTER 5: AVAILABILITY AND CHARACTERISTICS OF PUBLICLY AVAILABLE HEALTH WORKFORCE DATA SOURCES IN AUSTRALIA: Objective: Many data sources are used in Australia to inform health workforce planning, but their characteristics in terms of relevance, accessibility and accuracy are uncertain. We aimed to identify and appraise publicly available data sources used to describe the Australian health workforce.

Study Design: We conducted a scoping review in which we searched bibliographic databases, websites and grey literature. Two reviewers independently undertook title and abstract screening and full text screening using Covidence software. We then assessed the relevance, accessibility and accuracy of data sources using a customised appraisal tool.

Data Sources: We searched for potential workforce data sources in nine databases (MEDLINE, Embase, Ovid Emcare, Scopus, Web of Science, Informit, the JBI Evidence-based Practice Database, PsycINFO and the Cochrane Library) and the grey literature, and examined several pre-defined websites.

Data Synthesis: During the screening process we identified 6955 abstracts and examined 48 websites, from which we identified 12 publicly available data sources - eight primary and four secondary data sources. The primary data sources were generally of modest quality, with low scores in terms of reference period, accessibility and missing data. No single primary data source scored well across all domains of the appraisal tool.

Conclusion: We identified several limitations of data sources used to describe the Australian health workforce. Establishment of a high quality, longitudinal, linked database that can inform all aspects of health workforce development is urgently needed, particularly for rural health workforce and services planning. CHAPTER 6: RAPID REALIST REVIEW OF OPIOID TAPERING IN THE CONTEXT OF LONG TERM OPIOID USE FOR NON-CANCER PAIN IN RURAL AREAS: Objective: To describe interventions, barriers and enablers associated with opioid tapering for patients with chronic non-cancer pain in rural primary care settings.

Study Design: Rapid realist review registered on the international register of systematic reviews (PROSPERO) and conducted in accordance with RAMESES standards.

Data Sources: English language, peer-reviewed articles reporting qualitative, quantitative and mixed method studies, published between January 2016 and July 2020, and accessed via MEDLINE, Embase, CINAHL Complete, PsycINFO, Informit or the Cochrane Library during June and July 2020. Grey literature relating to prescribing, deprescribing or tapering of opioids in chronic non-cancer pain, published between January 2016 and July 2020, was identified by searching national and international government, health service and peek organisation websites using Google Scholar.

Data Synthesis: Our analysis of reported approaches to tapering conducted across rural and non-rural contexts showed that tapering opioids is complex and challenging, and identified several barriers and enablers. Successful outcomes in rural areas appear likely through therapeutic relationships, coordination and support, by using modalities and models of care that are appropriate in rural settings and by paying attention to harm minimisation.

Conclusion: Rural primary care providers do not have access to resources available in metropolitan centres for dealing with patients who have chronic non-cancer pain and are taking opioid medications. They often operate alone or in small group practices, without peer support and access to multidisciplinary and specialist teams. Opioid tapering approaches described in the literature include regulation, multimodal and multidisciplinary approaches, primary care provider support, guidelines, and patient-centred strategies. There is little research to inform tapering in rural contexts. Our review provides a synthesis of the current evidence in the form of a conceptual model. This preliminary model could inform the development of a model of care for use in implementation research, which could test a variety of mechanisms for supporting decision making, reducing primary care providers' concerns about potential harms arising from opioid tapering, and improving patient outcomes.
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http://dx.doi.org/10.5694/mja2.50881DOI Listing
December 2020

Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial.

Gastroenterology 2021 02 29;160(3):720-733.e8. Epub 2020 Oct 29.

Takeda Pharmaceuticals Inc Co, Cambridge, Massachusetts. Electronic address:

Background & Aims: Gluten challenge is used to diagnose celiac disease (CeD) and for clinical research. Sustained gluten exposure reliably induces histologic changes but is burdensome. We investigated the relative abilities of multiple biomarkers to assess disease activity induced by 2 gluten doses, and aimed to identify biomarkers to supplement or replace histology.

Methods: In this randomized, double-blind, 2-dose gluten-challenge trial conducted in 2 US centers (Boston, MA), 14 adults with biopsy-proven CeD were randomized to 3 g or 10 g gluten/d for 14 days. The study was powered to detect changes in villous height to crypt depth, and stopped at planned interim analysis on reaching this end point. Additional end points included gluten-specific cluster of differentiation (CD)4 T-cell analysis with HLA-DQ2-gluten tetramers and enzyme-linked immune absorbent spot, gut-homing CD8 T cells, interleukin-2, symptoms, video capsule endoscopy, intraepithelial leukocytes, and tissue multiplex immunofluorescence.

Results: All assessments showed changes with gluten challenge. However, time to maximal change, change magnitude, and gluten dose-response relationship varied. Villous height to crypt depth, video capsule endoscopy enteropathy score, enzyme-linked immune absorbent spot, gut-homing CD8 T cells, intraepithelial leukocyte counts, and HLA-DQ2-restricted gluten-specific CD4 T cells showed significant changes from baseline at 10 g gluten only; symptoms were significant at 3 g. Symptoms and plasma interleukin-2 levels increased significantly or near significantly at both doses. Interleukin-2 appeared to be the earliest, most sensitive marker of acute gluten exposure.

Conclusions: Modern biomarkers are sensitive and responsive to gluten exposure, potentially allowing less invasive, lower-dose, shorter-duration gluten ingestion. This work provides a preliminary framework for rational design of gluten challenge for CeD research. ClinicalTrials.gov number, NCT03409796.
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http://dx.doi.org/10.1053/j.gastro.2020.10.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878429PMC
February 2021

Integrated Care Search: development and validation of a PubMed search filter for retrieving the integrated care research evidence.

BMC Med Res Methodol 2020 01 21;20(1):12. Epub 2020 Jan 21.

Flinders Filters, Flinders University, GPO Box 2100, Adelaide, South Australia, Australia.

Background: Integrated care is an increasingly important principle for organising healthcare. Integrated care models show promise in reducing resource wastage and service fragmentation whilst improving the accessibility, patient-centredness and quality of care for patients. Those needing reliable access to the growing research evidence base for integrated care can be frustrated by search challenges reflective of the topic's complexity. The aim of this study is to report the empirical development and validation of two search filters for rapid and effective retrieval of integrated care evidence in PubMed. One filter is optimised for recall and the other for precision.

Methods: An Expert Advisory Group comprising international integrated care experts guided the study. A gold standard test set of citations was formed from screening Handbook Integrated Care chapter references for relevance. This set was divided into a Term Identification Set (20%) for determining candidate terms using frequency analysis; a Filter Development Set (40%) for testing performance of term combinations; and a Filter Validation Set (40%) reserved for confirming final filter performance. In developing the high recall filter, recall was steadily increased while maintaining precision at ≥50%. Similarly, the high precision filter sought to maximise precision while keeping recall ≥50%. For each term combination tested, an approximation of precision was obtained by reviewing the first 100 citations retrieved in Medline for relevance.

Results: The gold standard set comprised 534 citations. The search filter optimised for recall ('Broad Integrated Care Search') achieved 86.0-88.3% recall with corresponding low precision (47-53%). The search filter optimised for precise searching ('Narrow Integrated Care Search') demonstrated precision of 73-95% with recall reduced to between 55.9 and 59.8%. These filters are now available as one-click URL hyperlinks in the website of International Foundation for Integrated Care.

Conclusions: The Broad and Narrow Integrated Care Search filters provide potential users, such as policy makers and researchers, seamless, reliable and ongoing access to integrated care evidence for decision making. These filters were developed according to a rigorous and transparent methodology designed to circumvent the challenges of information retrieval posed by this complex, multifaceted topic.
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http://dx.doi.org/10.1186/s12874-020-0901-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971984PMC
January 2020

Celiac disease diagnosis from videocapsule endoscopy images with residual learning and deep feature extraction.

Comput Methods Programs Biomed 2020 Apr 20;187:105236. Epub 2019 Nov 20.

School of Instrument Science and Opto-electronic Engineering, Hefei University of Technology, Hefei 230009, China. Electronic address:

Background And Objective: Videocapsule endoscopy (VCE) is a relatively new technique for evaluating the presence of villous atrophy in celiac disease patients. The diagnostic analysis of video frames is currently time-consuming and tedious. Recently, computer-aided diagnosis (CAD) systems have become an attractive research area for diagnosing celiac disease. However, the images captured from VCE are susceptible to alterations in light illumination, rotation direction, and intestinal secretions. Moreover, textural features of the mucosal villi obtained by VCE are difficult to characterize and extract. This work aims to find a novel deep learning feature learning module to assist in the diagnosis of celiac disease.

Methods: In this manuscript, we propose a novel deep learning recalibration module which shows significant gain in diagnosing celiac disease. In this recalibration module, the block-wise recalibration component is newly employed to capture the most salient feature in the local channel feature map. This learning module was embedded into ResNet50, Inception-v3 to diagnose celiac disease using a 10-time 10-fold cross-validation based upon analysis of VCE images. In addition, we employed model weights to extract feature points from training and test samples before the last fully connected layer, and then input to a support vector machine (SVM), k-nearest neighbor (KNN), and linear discriminant analysis (LDA) for differentiating celiac disease images from heathy controls.

Results: Overall, the accuracy, sensitivity and specificity of the 10-time 10-fold cross-validation were 95.94%, 97.20% and 95.63%, respectively.

Conclusions: A novel deep learning recalibration module, with global response and local salient factors is proposed, and it has a high potential for utilizing deep learning networks to diagnose celiac disease using VCE images.
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http://dx.doi.org/10.1016/j.cmpb.2019.105236DOI Listing
April 2020

Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract.

Haematologica 2020 07 26;105(7):1895-1906. Epub 2019 Sep 26.

Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, USA

Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract are rare clonal T-cell diseases that more commonly occur in the intestines and have a protracted clinical course. Different immunophenotypic subsets have been described, but the molecular pathogenesis and cell of origin of these lymphocytic proliferations is poorly understood. Hence, we performed targeted next-generation sequencing and comprehensive immunophenotypic analysis of ten indolent T-cell lymphoproliferative disorders of the gastrointestinal tract, which comprised CD4 (n=4), CD8 (n=4), CD4/CD8 (n=1) and CD4/CD8 (n=1) cases. Genetic alterations, including recurrent mutations and novel rearrangements, were identified in 8/10 (80%) of these lymphoproliferative disorders. The CD4, CD4/CD8, and CD4/CD8 cases harbored frequent alterations of JAK-STAT pathway genes (5/6, 82%); mutations (n=3), deletion (n=1) and rearrangement (n=1), and 4/6 (67%) had concomitant mutations in epigenetic modifier genes (, , ). Conversely, 2/4 (50%) of the CD8 cases exhibited structural alterations involving the 3' untranslated region of the gene. Longitudinal genetic analysis revealed stable mutational profiles in 4/5 (80%) cases and acquisition of mutations in one case was a harbinger of disease transformation. The CD4 and CD4/CD8 lymphoproliferative disorders displayed heterogeneous Th1 (T-bet), Th2 (GATA3) or hybrid Th1/Th2 (T-bet/GATA3) profiles, while the majority of CD8 disorders and the CD4/CD8 disease showed a type-2 polarized (GATA3) effector T-cell (Tc2) phenotype. Additionally, CD103 expression was noted in 2/4 CD8 cases. Our findings provide insights into the pathogenetic bases of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and confirm the heterogeneous nature of these diseases. Detection of shared and distinct genetic alterations of the JAK-STAT pathway in certain immunophenotypic subsets warrants further mechanistic studies to determine whether therapeutic targeting of this signaling cascade is efficacious for a proportion of patients with these recalcitrant diseases.
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http://dx.doi.org/10.3324/haematol.2019.230961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327650PMC
July 2020

RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit-successes and challenges.

Eur J Pediatr 2019 Aug 7;178(8):1207-1218. Epub 2019 Jun 7.

Division of Neonatology, Department of Paediatrics, University of British Columbia, Vancouver, Canada.

Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women's Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant's phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%.Conclusion: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis. Health service implementation challenges and successes are discussed. What is Known: • Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation. What is New: • This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES). • In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management.
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http://dx.doi.org/10.1007/s00431-019-03399-4DOI Listing
August 2019

Automated diagnosis of celiac disease by video capsule endoscopy using DAISY Descriptors.

J Med Syst 2019 Apr 26;43(6):157. Epub 2019 Apr 26.

Department of Electronics and Computer Engineering, Ngee Ann Polytechnic, Singapore, 599489, Singapore.

Celiac disease is a genetically determined disorder of the small intestine, occurring due to an immune response to ingested gluten-containing food. The resulting damage to the small intestinal mucosa hampers nutrient absorption, and is characterized by diarrhea, abdominal pain, and a variety of extra-intestinal manifestations. Invasive and costly methods such as endoscopic biopsy are currently used to diagnose celiac disease. Detection of the disease by histopathologic analysis of biopsies can be challenging due to suboptimal sampling. Video capsule images were obtained from celiac patients and controls for comparison and classification. This study exploits the use of DAISY descriptors to project two-dimensional images onto one-dimensional vectors. Shannon entropy is then used to extract features, after which a particle swarm optimization algorithm coupled with normalization is employed to select the 30 best features for classification. Statistical measures of this paradigm were tabulated. The accuracy, positive predictive value, sensitivity and specificity obtained in distinguishing celiac versus control video capsule images were 89.82%, 89.17%, 94.35% and 83.20% respectively, using the 10-fold cross-validation technique. When employing manual methods rather than the automated means described in this study, technical limitations and inconclusive results may hamper diagnosis. Our findings suggest that the computer-aided detection system presented herein can render diagnostic information, and thus may provide clinicians with an important tool to validate a diagnosis of celiac disease.
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http://dx.doi.org/10.1007/s10916-019-1285-6DOI Listing
April 2019

Measurement of Forearm Bone Density by Dual Energy X-Ray Absorptiometry Increases the Prevalence of Osteoporosis in Men With Celiac Disease.

Clin Gastroenterol Hepatol 2020 01 10;18(1):99-106. Epub 2019 Apr 10.

Division of Gastroenterology, Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, New York.

Background & Aims: Guidelines advise measurement of bone mineral density (BMD) in patients with a diagnosis of celiac disease. The lumbar spine (LS) and hip sites are usually measured. Although skeletal sites rich in trabecular bone are believed to be vulnerable to osteoporosis in patients with celiac disease, most studies have not measured the cortical distal 1/3-radius.

Methods: We collected data from 721 patients (mean age, 43.6 years; 68.4% female) with celiac disease who underwent 3-site dual energy x-ray absorptiometry (DXA, at a median 1.22 years after diagnosis). We assessed skeletal site- and sex-specific osteoporosis prevalence and the incremental utility of 1/3-radius measurement by DXA.

Results: Mean T- and Z-scores were normal in patients, but 43.3% had osteopenia and 19.6% had osteoporosis. Osteoporosis was found in 12.1% of patients at the LS, 5.3% of patients at the total hip, 7.6% of patients at the femoral neck, and 11.5% of patients at the 1/3-radius. A greater degree of villous atrophy at diagnosis was associated with male sex and lower T-scores at the 1/3-radius (P = .03), but not other skeletal sites. Isolated forearm osteoporosis was detected in 4.9% of patients. A higher proportion of patients with isolated forearm osteoporosis were male and had a greater weight and body mass index (all P < .01, compared to patients with osteoporosis only at other sites). Z-scores were lower at the LS and 1/3-radius and osteoporosis was more common in men than women. In men, the 1/3-radius was the most frequent site for osteoporosis. Among patients 50 years or older, isolated forearm osteoporosis was present in 10.7%.

Conclusions: Based on DXA analysis of patients with celiac disease, the prevalence of osteoporosis appears to be underestimated-particularly in men when BMD at the 1/3-radius is not measured. Degree of villous atrophy is associated with BMD at the 1/3-radius and nearly 5% of patients have osteoporosis limited to that site. Recommendations for osteoporosis screening in patients with celiac disease should include measurement of the distal 1/3-radius in addition to the hip and LS.
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http://dx.doi.org/10.1016/j.cgh.2019.03.049DOI Listing
January 2020

Capsule Endoscopy and Enteroscopy in Celiac Disease.

Gastroenterol Clin North Am 2019 03 14;48(1):73-84. Epub 2018 Dec 14.

The University of Chicago, 5841 South Maryland Avenue, MC 4080 S401, Chicago, IL 60637, USA.

Celiac disease predominantly involves the proximal small bowel, but villus atrophy can be patchy, spare the duodenum, and be present more distally. Video capsule endoscopy is more sensitive than standard endoscopy to detect villus atrophy, and can define extent of disease, though it cannot obtain biopsies. Duodenal biopsy is the gold standard for diagnosis. Video capsule endoscopy assists in special circumstances when biopsy is not possible, and in equivocal diagnosis. Video capsule endoscopy and enteroscopy are recommended for evaluating complicated celiac disease, especially refractory celiac disease type II. Future developments include computer-assisted capsule programs and advanced capsule and enteroscope design.
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http://dx.doi.org/10.1016/j.gtc.2018.09.005DOI Listing
March 2019

Color masking improves classification of celiac disease in videocapsule endoscopy images.

Comput Biol Med 2019 03 24;106:150-156. Epub 2018 Dec 24.

Department of Medicine - Celiac Disease Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.

Background: Videocapsule endoscopy images are useful to detect pathologic alterations, including villous atrophy, in the small intestinal mucosa, which is helpful for diagnosing celiac disease. In prior work, quantitative videocapsule analysis was found useful to classify celiac versus control images. However, the effect of dark/extraneous substances on classification efficacy requires remediation.

Method: For quantitative analysis, data from the Medtronic SB2 and SB3 systems were pooled. Videocapsule images of the distal duodenum/proximal jejunum were acquired from 13 celiac and 13 control patients. Dark regions, extraneous fluids, and air bubbles were mostly removed by utilizing color masking. Two different red-green-blue (RGB) color masks were constructed from 20 to 30 reference pixels obtained from mucosal and from extraneous regions. Each image pixel was accepted or rejected for subsequent analysis based on whether its distance was closest to a mucosal or to an extraneous reference in RGB space. Four images were then randomly selected from each videoclip for processing (52 images from each group). After masking, celiac versus control images were plotted in a three-space consisting of mean and standard deviation in pixel brightness, and surface area remaining after masking. A linear discriminant function was used for classification. The paradigm was repeated with a second random data set for validation.

Results: Masking improved classification of celiac versus control images to nearly 80% accuracy as compared to 70-77% without masking. Celiac disease patients tended to have lesser mean pixel brightness and greater variability in brightness, in accord with prior work, and more masking was needed to remove extraneous features.

Conclusions: Color masking is useful to remove dim/extraneous features from videocapsule images and it results in improved classification/assessment to distinguish celiac with villous atrophy from control videocapsule image. This can be helpful to detect and map regions of pathology, to screen for celiac disease, and to determine the efficacy of a gluten free diet.
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http://dx.doi.org/10.1016/j.compbiomed.2018.12.011DOI Listing
March 2019

Finding the Integrated Care Evidence Base in PubMed and Beyond: A Bibliometric Study of the Challenges.

Int J Integr Care 2018 Aug 17;18(3):11. Epub 2018 Aug 17.

Flinders University, South Australia, AU.

Introduction: Integrated care research evidence should be optimally visible and accessible to stakeholders. This study examines the contribution of specific databases to the discovery of integrated care evidence, and tests the usefulness of Medical Subject Heading (MeSH) indexing of this literature within PubMed.

Methods: We used bibliometric methods to analyse the integrated care literature indexed within six databases between 2007 and 2016. An international expert advisory group assessed the relevance of citations randomly retrieved from PubMed using MeSH term 'Delivery of Health Care, Integrated'.

Results: Integrated care evidence is diffuse, spread across many journals. Between 2007 and 2016, integrated care citations grew substantially, with the rate of increase highest in Embase. PubMed contributes the largest proportion of unique citations (citations not included in any of the other databases analysed), followed by Embase, PsycINFO and CINAHL. On average, expert reviewers rated 42.5% of citations retrieved by MeSH term 'Delivery of Health Care, Integrated' as relevant to integrated care. When these citations were dual reviewed, inter-rater agreement was low.

Conclusion: MeSH terms alone are insufficient to retrieve integrated care content from PubMed. Embase and CINAHL contain unique content not found in PubMed that should not be overlooked. A validated search filter is proposed to simplify the process of finding integrated care research for clinicians, managers and decision-makers.
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http://dx.doi.org/10.5334/ijic.3975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137672PMC
August 2018

Exome sequencing identified a de novo mutation of PURA gene in a patient with familial Xp22.31 microduplication.

Eur J Med Genet 2019 Feb 13;62(2):103-108. Epub 2018 Jun 13.

Department of Pathology and Laboratory Medicine, UBC, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada. Electronic address:

The clinical significance of Xp22.31 microduplication is controversial as it is reported in subjects with developmental delay (DD), their unaffected relatives and unrelated controls. We performed multifaceted studies in a family of a boy with hypotonia, dysmorphic features and DD who carried a 600 Kb Xp22.31 microduplication (7515787-8123310bp, hg19) containing two genes, VCX and PNPLA4. The duplication was transmitted from his cognitively normal maternal grandfather. We found no evidence of the duplication causing the proband's DD and congenital anomalies based on unaltered expression of PNPLA4 in the proband and his mother in comparison to controls and preferential activation of the paternal chromosome X with Xp22.31 duplication in proband's mother. However, a de novo, previously reported deleterious, missense mutation in Pur-alpha gene (PURA) (5q31.2), with a role in neuronal differentiation was detected in the proband by exome sequencing. We propose that the variability in the phenotype in carriers of Xp22.31 microduplication can be due to a second and more deleterious genetic mutation in more severely affected carriers. Widespread use of whole genome next generation sequencing in families with Xp22.31 CNV could help identify such cases.
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http://dx.doi.org/10.1016/j.ejmg.2018.06.010DOI Listing
February 2019

Clonal T cell receptor gene rearrangements in coeliac disease: implications for diagnosing refractory coeliac disease.

J Clin Pathol 2018 Sep 27;71(9):825-831. Epub 2018 Apr 27.

Department of Pathology and Cell Biology, New York Presbyterian Hospital/Columbia University Medical Center, New York, USA.

Aims: Refractory coeliac disease type II (RCDII), a rare complication of coeliac disease (CD) associated with high morbidity, requires identification of a clonal population of phenotypically aberrant intraepithelial lymphocytes (IELs) for diagnosis. However, data regarding the frequency and significance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII are limited.

Methods: We analysed results of TCR-GR analyses performed on SB biopsies at our institution over a 3-year period, which were obtained from eight active CD, 172 CD on gluten-free diet (GFD), 33 RCDI, and three RCDII patients and 14 patients without CD. TCR-GR patterns were divided into clonal, polyclonal and prominent clonal peaks (PCPs) and these patterns were correlated with clinical and pathological features.

Results: Clonal TCR-GR products were detected in biopsies from 67% of patients with RCDII, 17% of patients with RCDI and 6% of patients with GFD. PCPs were observed in all disease phases (range 12%-33%). There was no significant difference in the TCR-GR patterns between the non-RCDII disease categories (p=0.39). A higher frequency of surface CD3(-) IELs was noted in cases with clonal TCR-GR, but the PCP pattern did not show associations with any clinical or pathological feature. Persistence of clonal or PCP pattern on repeat biopsy was seen for up to 2 years without evidence of RCDII.

Conclusions: Clonal TCR-GRs are not infrequent in cases lacking features of RCDII, while PCPs are frequent in all disease phases. TCR-GR results should be assessed in conjunction with immunophenotypic, histological and clinical findings for appropriate diagnosis and classification of RCD.
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http://dx.doi.org/10.1136/jclinpath-2018-205023DOI Listing
September 2018

Stool PCR for Gastrointestinal Pathogens in Patients With and Without Immune-Mediated Intestinal Diseases.

Dig Dis Sci 2018 Apr 6;63(4):996-1002. Epub 2018 Feb 6.

Division of Digestive and Liver Diseases, Columbia University College of Physicians and Surgeons, New York, NY, USA.

Background: Patients with celiac disease and inflammatory bowel disease, two immune-mediated luminal conditions, have higher rates of certain infections than healthy counterparts. The prevalence of many gastrointestinal infections in these patients, however, is unknown.

Aims: Using a novel clinical stool pathogen PCR test, we investigated the hypothesis that patients with celiac disease/inflammatory bowel disease had different distributions of diarrheal pathogens than other patients.

Methods: We performed a retrospective cohort study of outpatients who underwent stool pathogen testing with the FilmArray Gastrointestinal PCR Panel (BioFire Diagnostics, Salt Lake City, UT) at our institution from January 1 to December 31, 2015. Rates of pathogens were measured in patients with or without celiac disease/inflammatory bowel disease.

Results: Of 955 patients, 337 had positive test for any pathogen, with 465 bacterial, parasitic, or viral pathogens identified. One hundred and twenty-seven patients (13.3%) had celiac disease or inflammatory bowel disease, of which 29/127 (22.8%) had a positive test, compared to 308/828 other patients (37.2%) (p = 0.002). Patients with celiac disease/inflammatory bowel disease had significantly fewer viruses (1.6 vs. 8.1% of patients; p = 0.008) and parasites (0 vs. 3.3%; p = 0.039), with nonsignificant trend toward fewer bacteria (21.3 vs. 29.2%; p = 0.063). Escherichia coli species were most common in both populations.

Conclusions: Stool PCR identified numerous pathogens in patients with or without celiac disease/inflammatory bowel disease. Patients with celiac disease/inflammatory bowel disease were significantly less likely to have any pathogen identified, and had significantly fewer viruses and parasites. In this population, knowledge of common pathogens can guide diagnostic evaluation and offer opportunities for treatment.
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http://dx.doi.org/10.1007/s10620-018-4959-xDOI Listing
April 2018

Outcome of breath tests in adult patients with suspected small intestinal bacterial overgrowth.

Gastroenterol Hepatol Bed Bench 2017 ;10(3):168-172

Department of Medicine, Celiac Disease Center, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, USA.

Aim: The aim was to investigate breath test outcomes in patients with suspected SIBO and indicative symptoms of SIBO, diagnosed by breath testing.

Background: Breath testing is used to detect small intestinal bacterial overgrowth (SIBO) by measuring hydrogen and methane produced by intestinal bacteria.

Methods: This retrospective cross sectional study included 311 patients with gastrointestinal symptoms who underwent the breath test for evaluation of SIBO at Celiac Disease Center at Columbia University, New York, in 2014-2015. The patients were divided into two groups based on the physician's choice: lactulose breath test group (72%) and glucose breath test group (28%). Among them, 38% had a history of celiac disease or non-celiac gluten sensitivity.

Results: In total, 46% had a positive breath test: 18% were positive for methane, 24 % positive for hydrogen and 4% positive for both gases (p=0.014). Also, 50% had a positive lactulose breath result and 37% had a positive glucose breath result (p=0.036). The most common symptom for performing the breath test was bloating and the only clinical symptom that significantly showed a positive glucose breath test was increased gas (p=0.028).

Conclusion: Lactulose breath test was more often positive than glucose breath test. Positivity for hydrogen was more common than methane. Bloating was the most frequently perceived symptom of the patients undergoing the breath test but the only statistically significant clinical symptom for a positive glucose breath test was increased gas. Furthermore, the results showed that there was no significant association between positive breath test result and gender, age, non-celiac gluten sensitivity or celiac disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660265PMC
January 2017

Cardiovascular involvement in celiac disease.

World J Cardiol 2017 Aug;9(8):652-666

Department of Medicine, Celiac Disease Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, United States.

Celiac disease (CD) is an autoimmune response to ingestion of gluten protein, which is found in wheat, rye, and barley grains, and results in both small intestinal manifestations, including villous atrophy, as well as systemic manifestations. The main treatment for the disease is a gluten-free diet (GFD), which typically results in the restoration of the small intestinal villi, and restoration of other affected organ systems, to their normal functioning. In an increasing number of recently published studies, there has been great interest in the occurrence of alterations in the cardiovascular system in untreated CD. Herein, published studies in which CD and cardiovascular terms appear in the title of the study were reviewed. The publications were categorized into one of several types: (1) articles (including cohort and case-control studies); (2) reviews and meta-analyses; (3) case studies (one to three patient reports); (4) letters; (5) editorials; and (6) abstracts (used when no full-length work had been published). The studies were subdivided as either heart or vascular studies, and were further characterized by the particular condition that was evident in conjunction with CD. Publication information was determined using the Google Scholar search tool. For each publication, its type and year of publication were tabulated. Salient information from each article was then compiled. It was determined that there has been a sharp increase in the number of CD - cardiovascular studies since 2000. Most of the publications are either of the type "article" or "case study". The largest number of documents published concerned CD in conjunction with cardiomyopathy (33 studies), and there have also been substantial numbers of studies published on CD and thrombosis (27), cardiovascular risk (17), atherosclerosis (13), stroke (12), arterial function (11), and ischemic heart disease (11). Based on the published research, it can be concluded that many types of cardiovascular issues can occur in untreated CD patients, but that most tend to resolve on a GFD, often in conjunction with the healing of small intestinal villous atrophy. However, in some cases the alterations are irreversible, underscoring the need for CD screening and treatment when cardiovascular issues arise of unknown etiology.
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http://dx.doi.org/10.4330/wjc.v9.i8.652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5583538PMC
August 2017

Use of shape-from-shading to characterize mucosal topography in celiac disease videocapsule images.

World J Gastrointest Endosc 2017 Jul;9(7):310-318

Edward J Ciaccio, Govind Bhagat, Suzanne K Lewis, Peter H Green, Department of Medicine, Celiac Disease Center, Columbia University, New York, NY 10032, United States.

Aim: To use a computerized shape-from-shading technique to characterize the topography of the small intestinal mucosa.

Methods: Videoclips comprised of 100-200 images each were obtained from the distal duodenum in 8 celiac and 8 control patients. Images with high texture were selected from each videoclip and projected from two to three dimensions by using grayscale pixel brightness as the Z-axis spatial variable. The resulting images for celiac patients were then ordered using the Marsh score to estimate the degree of villous atrophy, and compared with control data.

Results: Topographic changes in celiac patient three-dimensional constructs were often more variable as compared to controls. The mean absolute derivative in elevation was 2.34 ± 0.35 brightness units for celiacs 1.95 ± 0.28 for controls ( = 0.014). The standard deviation of the derivative in elevation was 4.87 ± 0.35 brightness units for celiacs 4.47 ± 0.36 for controls ( = 0.023). Celiac patients with Marsh IIIC villous atrophy tended to have the largest topographic changes. Plotted in two dimensions, celiac data could be separated from controls with 80% sensitivity and specificity.

Conclusion: Use of shape-from-shading to construct three-dimensional projections approximating the actual spatial geometry of the small intestinal substrate is useful to observe features not readily apparent in two-dimensional videocapsule images. This method represents a potentially helpful adjunct to detect areas of pathology during videocapsule analysis.
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http://dx.doi.org/10.4253/wjge.v9.i7.310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507822PMC
July 2017

Determinants of Follow-up Care for Patients With Celiac Disease.

J Clin Gastroenterol 2018 10;52(9):784-788

Department of Medicine, Celiac Disease Center, Columbia University Medical Center, New York, NY.

Goals: This study aimed to investigate follow-up patterns among celiac disease (CD) patients.

Background: Gender factors are important in CD with women diagnosed more frequently than men despite equal seropositivity in screening studies. To determine if gender influences postdiagnosis care, we performed a retrospective cohort study investigating the impact of gender and mode of presentation on follow-up patterns after diagnosis.

Study: The study included adults with biopsy-proven CD presenting to a single tertiary care center between 2005 and 2014. The primary exposure was at least 1 visit with a CD specialist. The primary outcome was ≥2 follow-up visits, including office visits and endoscopic procedures. Data extracted included whether patients had tissue transglutaminase antibodies performed by our laboratory.

Results: We analyzed 708 patients of which 70.5% were female. Follow-up was good with a majority of patients (69%) having at least 1 follow-up visit. On bivariate analysis, patients least likely to follow-up were ages 18 to 29 (P=0.03) and women with atypical presentations (P=0.003). After adjusting for potential confounders, individuals over age 65 were significantly more likely to attend at least 2 follow-up visits (odds ratio, 2.07; 95% confidence interval, 1.21-3.55; P=0.0079). Individuals with an abnormal baseline tissue transglutaminase antibody value in our laboratory were significantly more likely to follow-up (odds ratio, 1.99; 95% confidence interval, 1.39-2.85; P=0.0002).

Conclusions: Gender had no impact on follow-up patterns despite prior studies demonstrating an impact on diagnosis rates. Future attention should focus on retaining young patients and those with atypical modes of presentation.
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http://dx.doi.org/10.1097/MCG.0000000000000851DOI Listing
October 2018

Coeliac disease and the videocapsule: what have we learned till now.

Ann Transl Med 2017 May;5(9):197

Department of Medicine, Celiac Disease Center, Columbia University Medical Center, New York, NY, USA.

Celiac disease is diagnosed in part by finding areas of pathology in the small bowel (SB) mucosa. This can often be difficult because the pathologic alterations, including atrophy of the small intestinal villi, can often be sparse and subtle. Some of the quantitative methods for detecting and measuring the presence of villous atrophy from videocapsule endoscopy (VCE) images are presented and discussed. These methods consist of static features of measurement including texture, gray level, and presence and abundance of fissures contained within each acquired image. The methods also consist of dynamic measurements including spectral analysis, and determining motion from a sequence of endoscopic images as obtained from a VCE clip. Thus far, several methods have been found useful to characterize the SB mucosa of untreated celiac disease patients versus control patients lacking villous atrophy, which have revealed significant differences in texture, frequency, and motion on analysis of VCE. In untreated celiac patients undergoing endoscopy, there tends to be greater magnitude of changes and spatial differences in textural descriptors, longer periodic components, indicating slower periodic activity, and differences in feature location, suggesting alterations in motility at areas of pathology as compared to patients without villous atrophy. Improvements in the quantitative analysis of VCE imaging in celiac patients is important to detect pathology in suspected patients, so that biopsies can be obtained from pertinent regions of the small intestinal mucosa. Improvements are also necessary so that patients with celiac disease can be monitored to evaluate the progress of mucosal healing after onset of treatment.
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http://dx.doi.org/10.21037/atm.2017.05.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438789PMC
May 2017

Whole exome sequencing of families with 1q21.1 microdeletion or microduplication.

Am J Med Genet A 2017 Jul 5;173(7):1782-1791. Epub 2017 May 5.

Department of Pathology, University of British Columbia (UBC), Vancouver, British Columbia, Canada.

Recurrent microduplications/microdeletions of 1q21.1 are characterized by variable phenotypes ranging from normal development to developmental delay (DD) and congenital anomalies. Their interpretation is challenging especially in families with affected and unaffected carriers. We used whole exome sequencing (WES) to look for sequence variants in two male probands with inherited 1q21.1 CNVs that could explain their more severe phenotypes. One proband had a 1q21.1 deletion transmitted from maternal grandmother, while the other had a paternal duplication. We found mutations in five genes (SMPD1, WNK3, NOS1, ATF6, and EFHC1) that could contribute to the more severe phenotype in the probands in comparison to their mildly affected or unaffected 1q21.1 CNV carrying relatives. Interestingly, all genes have roles in stress responses (oxidative/Endoplasmic Reticulum (ER)/osmotic). One of the variants was in an X-linked gene WNK3 and segregated with the developmental features and X inactivation pattern in the family with 1q21.1 deletion transmitted from maternal grandmother. In silico analysis of all rare deleterious variants in both probands identified enrichment in nervous system diseases, metabolic pathways, protein processing in the ER and protein export. Our studies suggest that rare deleterious variants outside of the 1q21.1 CNV, individually or as a pool, could contribute to phenotypic variability in carriers of this CNV. Rare deleterious variants in stress response genes are of interest and raise the possibility of susceptibility of carriers to variable environmental influences. Next generation sequencing of additional familial cases with 1q21.1 CNV could further help determine the possible causes of phenotypic variability in carriers of this CNV.
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http://dx.doi.org/10.1002/ajmg.a.38247DOI Listing
July 2017

The impact of acid suppression medications and non-steroidal anti-inflammatory drugs on clinical and histologic features in celiac disease.

Dig Liver Dis 2017 Aug 2;49(8):883-886. Epub 2017 Apr 2.

Celiac Disease Center, Department of Medicine, Columbia University Medical Center, United States; Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, United States. Electronic address:

Introduction: The prevalence of celiac disease (CD) in the US has increased in past decades, as has use of proton pump inhibitors (PPIs), histamine-2-receptor antagonists (H2RAs), aspirin (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs). We aimed to measure the association between medication use and distribution of villous flattening (VF) among newly diagnosed CD patients.

Methods: We performed a cross-sectional study of adult patients with newly-diagnosed CD at two institutions. We collected data on regular use of these medications, clinical presentation, CD serologic status, and distribution of VF. We compared current ASA/NSAID users to non-users, and current PPI/H2RA users to non-users, with regard to these clinical characteristics.

Results: Of 148 patients with newly-diagnosed CD, current users of ASA/NSAIDs were older than non-users (47 vs 39 years, p=0.003) and users of PPI/H2RAs were older than non-users (48 vs 39 years, p=0.004). PPI/H2RA users comprised 12% of seropositive patients, compared to 55% of seronegative patients (p<0.01). Patient gender and distribution of villous flattening in the bulb and distal duodenum did not differ by PPI/H2RA or ASA/NSAID use.

Conclusions: PPI/H2RA use was associated with seronegative CD. Given the effect of these medications on gastric milieu, the impact of these drugs on presentation and course of CD deserves further investigation.
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http://dx.doi.org/10.1016/j.dld.2017.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511753PMC
August 2017
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