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Benjamin Lebwohl,1,2 Emma Larsson,3 Jonas Söderling,4 Bjorn Roelstraete,4 Joseph A Murray,5 Peter HR Green,1 Jonas F Ludvigsson1,4,6 1Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, NY, USA; 2Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA; 3Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden; 4Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; 5Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; 6Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, SwedenCorrespondence: Jonas F LudvigssonDepartment of Medical Epidemiology and Biostatistics, Karolinska Institute, PO Box 281, Stockholm, SE-17177, SwedenTel +46-19-6021000Email jonasludvigsson@yahoo.comBackground: Patients with celiac disease (CeD) are at increased risk of certain viral infections and of pneumococcal pneumonia, raising concerns that they may be susceptible to severe coronavirus disease 2019 (Covid-19). We aimed to quantify the association between CeD and severe outcomes related to Covid-19.Methods: We performed a population-based cohort study, identifying individuals with CeD in Sweden, as defined by small intestinal villus atrophy diagnosed at all (n=28) Swedish pathology departments during the years spanning 1969– 2017, and alive on February 1, 2020. We compared these patients to controls matched by sex, age, county, and calendar period. We performed Cox proportional hazards with follow-up through July 31, 2020, assessing risk of 1) hospital admission with a primary diagnosis of laboratory-confirmed Covid-19 (co-primary outcome); and 2) severe disease as defined by admission to intensive care unit and/or death attributed to Covid-19 (co-primary outcome).Results: Among patients with CeD (n=40,963) and controls (n=183,892), the risk of hospital admission for Covid-19 was 2.9 and 2.2 per 1000 person-years respectively. After adjusting for comorbidities, the risk of hospitalization for Covid-19 was not significantly increased in patients with CeD (HR 1.10; 95% CI 0.80– 1.50), nor was the risk of severe Covid-19 increased (HR 0.97; 95% CI 0.59– 1.59). Results were similarly null when we compared CeD patients to their non-CeD siblings with regard to these outcomes. Among all patients with CeD and controls hospitalized with a diagnosis of Covid-19 (n=58 and n=202, respectively), there was no significant difference in mortality (HR for CeD compared to controls 0.96; 95% CI 0.46– 2.02).Conclusion: In this population-based study, CeD was not associated with an increased risk of hospitalization for Covid-19 or intensive care unit and/or death attributed to Covid-19.Keywords: Covid-19, celiac disease, epidemiology, infection, SARS-CoV-2

Stine Dydensborg Sander,1,2 Anne Vinkel Hansen,3,4 Ketil Størdal,5,6 Anne-Marie Nybo Andersen,3 Joseph A Murray,7 Steffen Husby1,2 1Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark; 2Institute of Clinical Research, Faculty of Health Science, University of Southern Denmark, Odense, Denmark; 3Department of Public Health, University of Copenhagen, Copenhagen, Denmark; 4Statistics Denmark, Copenhagen, Denmark; 5Department of Child Health, Norwegian Institute of Public Health, Oslo, Norway; 6Department of Pediatrics, Ostfold Hospital Trust, Grålum, Norway; 7Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA Purpose: The purpose of this study was to investigate the association between mode of delivery and the risk of celiac disease in two large population-based birth cohorts with different prevalence of diagnosed celiac disease. Patients and methods: This is an observational register-based cohort study using two independent population cohorts. We used data from administrative registers and health administrative registers from Denmark and Norway and linked the data at the individual level. We included all children who were born in Denmark from January 1, 1995 to December 31, 2010 and all children who were born in Norway from January 1, 2004 to December 31, 2012. Results: We included 1,051,028 children from Denmark. Cesarean sections were registered for 196,512 children (18.9%). Diagnosed celiac disease was registered for 1,395 children (0.13%). We included 537,457 children from Norway. Cesarean sections were registered for 90,128 children (16.8%). Diagnosed celiac disease was registered for 1,919 children (0.35%). We found no association between the mode of delivery and the risk of diagnosed celiac disease. The adjusted odds ratio for celiac disease for children delivered by any type of cesarean section compared to vaginal delivery was 1.11 (95% CI: 0.96–1.29) in the Danish cohort and 0.96 (95% CI: 0.84–1.09) in the Norwegian cohort. The adjusted odds ratio for celiac disease for children delivered by elective cesarean section compared to vaginal delivery was 1.20 (95% CI: 1.00–1.43) in the Danish cohort and 0.96 (95% CI: 0.79–1.17) in the Norwegian cohort. Conclusion: In this large registry-based study, mode of delivery was not associated with an increased risk of diagnosed celiac disease. Keywords: cesarean section, autoimmunity, epidemiology, administrative health register

Stine Dydensborg Sander,1-3 Ketil Størdal,4,5 Tine Plato Hansen,6 Anne-Marie Nybo Andersen,7 Joseph A Murray,8 Søren Thue Lillevang,9 Steffen Husby1,2 1Hans Christian Andersen Children’s Hospital, Odense University Hospital, 2Institute of Clinical Research, University of Southern Denmark, 3Odense Patient Data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark; 4Mental and Physical Health, Norwegian Institute of Public Health, Oslo, 5Department of Pediatrics, Ostfold Hospital Trust, Fredrikstad, Norway; 6Department of Pathology, Hvidovre Hospital, 7Department of Public Health, University of Copenhagen, Copenhagen, Denmark; 8Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; 9Department of Clinical Immunology, Odense University Hospital, Odense, Denmark Purpose: The purpose of this study was to validate the celiac disease diagnoses recorded in the Danish National Patient Register. To validate the diagnoses, we used information on duodenal biopsies from a national register of pathology reports (the Patobank) and information on celiac disease-specific antibodies and human leukocyte antigen (HLA) genotypes obtained from patient medical records.Patients and methods: We included all the children who were born from 1995 to 2012 and who were registered as having celiac disease in the Danish National Patient Register. We reviewed all the pathology reports on duodenal biopsies in the Patobank and the information in the medical records on celiac disease-specific antibodies (ie, anti-tissue transglutaminase 2 IgA and IgG, endomysial antibodies IgA, and anti-deamidated gliadin peptide IgG) and HLA genotypes.Results: We identified 2,247 children who were registered in the Danish National Patient Register with celiac disease. Duodenal biopsies for 1,555 of the children (69%) were registered in the Patobank; 1,127 (50%) had a biopsy that was compatible with celiac disease (ie, Marsh 2–3). We accessed the medical records of 95% of the children who were registered in the ­Danish National Patient Register with celiac disease. We found that 1,510 (67%) had one or more positive antibody-test results; 1,120 (50%) had anti-tissue transglutaminase 2, IgA at tenfold or greater the upper limit of the normal range and/or positive endomysial antibody results. The positive predictive value depended on the criteria used for validation and the types and numbers of registrations that were included in the analysis and ranged from 62% (95% confidence interval: 60%–64%) to 86% (95% confidence interval: 84%–87%).Conclusion: Our findings indicate that the Danish National Patient Register is a valuable source to identify patients who have been diagnosed with celiac disease. However, validation of the diagnoses is warranted before data on the patients are used for research purposes. Keywords: administrative health register, national patient register, pathology register, medical record, histology, serology

Samantha A Scanlon1, Joseph A Murray1,21Department of Internal Medicine, 2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USAAbstract: Celiac disease (CD) is an immune-mediated enteropathy triggered by exposure to wheat gluten and similar proteins found in rye and barley that affects genetically susceptible persons. This immune-mediated enteropathy is characterized by villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia. Once thought a disease that largely presented with malnourished children, the wide spectrum of disease activity is now better recognized and this has resulted in a shift in the presenting symptoms of most patients with CD. New advances in testing, both serologic and endoscopic, have dramatically increased the detection and diagnosis of CD. While the gluten-free diet is still the only treatment for CD, recent investigations have explored alternative approaches, including the use of altered nonimmunogenic wheat variants, enzymatic degradation of gluten, tissue transglutaminase inhibitors, induction of tolerance, and peptides to restore integrity to intestinal tight junctions.Keywords: immune-mediated enteropathy, gliadin, gluten, epidemiology, CD diagnosis, therapy

The Australian Defence Force (ADF) has recently completed a significant two-decade long series of major international deployments. With this has come a much greater awareness of the post deployment impact on veterans of operational service. This period of intense activity has also brought into focus, the emerging impact of Spiritual Injuries on personnel. Whilst this is sometimes addressed under the broader heading of Moral Injuries, there are range of distinct issues that require further attention. Not all veterans have a religious affiliation, faith and spiritual beliefs. For those that do, unresolved challenges to this schema can lead to mental health issues and broader affects to their overall well-being. This area is not currently being addressed by the ADF, the Department of Veterans Affairs, or indeed any of the major church or faith organisations within Australia. As such veterans are leaving the ADF and entering what is effectively a spiritual “grey zone” where there is little to no guidance and help available in spiritual or faith issues.

Objectives: To estimate the prevalence of cellac disease (CD) in pediatric and adult type 1 diabetes melitus in a defined population and to describe clinical features and HLA class II genotypes predictive of CD in screened patients with type 1 diabetes.Patients and Methods: All residents of Olmsted County, Minnesota, with type 1 diabetes mellitus on the prevalence date January 1, 2001, were identified with the use of an established medical records linkage system (Rochester Epidemiology Project) and defined clinical criteria. Consenting patients underwent serologic screening with endomyslal antibody and tissue transglutaminase antibody testing and Intestinal biopsies to confirm the diagnosis of CD. A subset of screened patients also underwent HLA class II genotyping. Quality-of-life screening (Medical Outcomes Study 36-Item Short-Form Health Survey) was completed in a subset of patients at the time of serologic screening.Results: Overall, 392 Olmsted County residents with type 1 diabetes on January 1, 2001, were Identified. A total of 158 patients with type 1 diabetes were tested, representing 40% (158/392) of the enumerated diabetic population, and 11 had biopsy-proven CD for an estimated point prevalence of 7.0% (95% confidence Interval, 3.5%-12.1%). Most CD-positive diabetic patients were asymptomatic and expressed an at-risk CD haplotype with at least one of but not both HLA DQ2 or DQ8.Conclusions: Celiac disease Is not rare In North American patients with type 1 diabetes, and most CD-positive diabetic patients are asymptomatic Irrespective of age at screening. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether undiagnosed celiac disease is associated with irritable bowel syndrome (IBS) or dyspepsia in the community. SUBJECTS AND METHODS: A self-report bowel disease questionnaire was mailed to a random sample of Olmsted County, Minnesota, residents aged 20 to 50 years. All respondents who reported symptoms of dyspepsia or IBS (cases) and all respondents without notable gastrointestinal symptoms (controls) were invited to participate (260 eligible subjects; 150 [58%] were studied). Each respondent was examined by a physician, and the medical records of each were reviewed (3 subjects did not meet the criteria for dyspepsia or IBS at the time of the physician interview). Serum was obtained to measure antiendomysial antibodies and tissue transglutaminase (TTg) IgA antibodies using validated assays. RESULTS: A total of 34 subjects had dyspepsia (20 had ulcerlike dyspepsia), 50 had IBS (19 had diarrhea-predominant IBS), and 15 met criteria for both dyspepsia and IBS; 78 were asymptomatic healthy controls. The overall prevalence of positive TTg serology was 4% (95% confidence interval [CI], 1.5%-8.5%). The number of subjects who were seropositive for TTg was 2 of 34 (5.9%) with dyspepsia (95% CI, 0.7%-19.7%), 2 of 50 (4.0%) with IBS (95% CI, 0.5%-13.7%), and 2 of 78 (2.6%) of asymptomatic controls (95% CI, 03%-9.0%) (P = .64 IBS vs controls; P = .58 dyspepsia vs controls). No subjects had positive antiendomysial antibodies. CONCLUSION: In this community, celiac disease did not explain the presence of either IBS or dyspepsia. [ABSTRACT FROM AUTHOR]

Celiac disease is a permanent intolerance to ingested gluten that results in immunologically mediated inflammatory damage to the small-intestinal mucosa. Celiac disease is associated with both human leukocyte antigen (HLA) and non-HLA genes and with other immune disorders, notably juvenile diabetes and thyroid disease. The classic sprue syndrome of steatorrhea and malnutrition coupled with multiple deficiency states may be less common than more subtle and often monosymptomatic presentations of the disease. Diverse problems such as dental anomalies, short stature, osteopenic bone disease, lactose intolerance, infertility, and nonspecific abdominal pain among many others may be the only manifestations of celiac disease. The rate at which celiac disease is diagnosed depends on the level of suspicion for the disease. Although diagnosis relies on intestinal biopsy findings, serologic tests are useful as screening tools and as an adjunct to diagnosis. The treatment of celiac disease is lifelong avoidance of dietary gluten. Gluten-free diets are now readily achievable with appropriate professional instruction and community support. Both benign and malignant complications of celiac disease occur but these can often be avoided by early diagnosis and compliance with a gluten-free diet. Copyright (c) 1999 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Abstract Background A large number of different plant lines are produced and maintained in a typical plant research laboratory, both as seed stocks and in active growth. These collections need careful and consistent management to track and maintain them properly, and this is a particularly pressing issue in laboratories undertaking research involving genetic manipulation due to regulatory requirements. Researchers and PIs need to access these data and collections, and therefore an easy-to-use plant-oriented laboratory information management system that implements, maintains and displays the information in a simple and visual format would be of great help in both the daily work in the lab and in ensuring regulatory compliance. Results Here, we introduce ‘Phytotracker’, a laboratory management system designed specifically to organise and track plasmids, seeds and growing plants that can be used in mixed platform environments. Phytotracker is designed with simplicity of user operation and ease of installation and management as the major factor, whilst providing tracking tools that cover the full range of activities in molecular genetics labs. It utilises the cross-platform Filemaker relational database, which allows it to be run as a stand-alone or as a server-based networked solution available across all workstations in a lab that can be internet accessible if desired. It can also be readily modified or customised further. Phytotracker provides cataloguing and search functions for plasmids, seed batches, seed stocks and plants growing in pots or trays, and allows tracking of each plant from seed sowing, through harvest to the new seed batch and can print appropriate labels at each stage. The system enters seed information as it is transferred from the previous harvest data, and allows both selfing and hybridization (crossing) to be defined and tracked. Transgenic lines can be linked to their plasmid DNA source. This ease of use and flexibility helps users to reduce their time needed to organise their plants, seeds and plasmids and to maintain laboratory continuity involving multiple workers. Conclusion We have developed and used Phytotracker for over five years and have found it has been an intuitive, powerful and flexible research tool in organising our plasmid, seed and plant collections requiring minimal maintenance and training for users. It has been developed in an Arabidopsis molecular genetics environment, but can be readily adapted for almost any plant laboratory research.

Abstract Background Papaya is a major fruit crop in tropical and subtropical regions worldwide. It is trioecious with three sex forms: male, female, and hermaphrodite. Sex determination is controlled by a pair of nascent sex chromosomes with two slightly different Y chromosomes, Y for male and Yh for hermaphrodite. The sex chromosome genotypes are XY (male), XYh (hermaphrodite), and XX (female). The papaya hermaphrodite-specific Yh chromosome region (HSY) is pericentromeric and heterochromatic. Physical mapping of HSY and its X counterpart is essential for sequencing these regions and uncovering the early events of sex chromosome evolution and to identify the sex determination genes for crop improvement. Results A reiterate chromosome walking strategy was applied to construct the two physical maps with three bacterial artificial chromosome (BAC) libraries. The HSY physical map consists of 68 overlapped BACs on the minimum tiling path, and covers all four HSY-specific Knobs. One gap remained in the region of Knob 1, the only knob structure shared between HSY and X, due to the lack of HSY-specific sequences. This gap was filled on the physical map of the HSY corresponding region in the X chromosome. The X physical map consists of 44 BACs on the minimum tiling path with one gap remaining in the middle, due to the nature of highly repetitive sequences. This gap was filled on the HSY physical map. The borders of the non-recombining HSY were defined genetically by fine mapping using 1460 F2 individuals. The genetically defined HSY spanned approximately 8.5 Mb, whereas its X counterpart extended about 5.4 Mb including a 900 Kb region containing the Knob 1 shared by the HSY and X. The 8.5 Mb HSY corresponds to 4.5 Mb of its X counterpart, showing 4 Mb (89%) DNA sequence expansion. Conclusion The 89% increase of DNA sequence in HSY indicates rapid expansion of the Yh chromosome after genetic recombination was suppressed 2–3 million years ago. The genetically defined borders coincide with the common BACs on the minimum tiling paths of HSY and X. The minimum tiling paths of HSY and its X counterpart are being used for sequencing these X and Yh-specific regions.

Abstract Background There is an increasing need for quantitative technologies suitable for molecular detection in a variety of settings for applications including food traceability and monitoring of genetically modified (GM) crops and their products through the food processing chain. Conventional molecular diagnostics utilising real-time polymerase chain reaction (RT-PCR) and fluorescence-based determination of amplification require temperature cycling and relatively complex optics. In contrast, isothermal amplification coupled to a bioluminescent output produced in real-time (BART) occurs at a constant temperature and only requires a simple light detection and integration device. Results Loop mediated isothermal amplification (LAMP) shows robustness to sample-derived inhibitors. Here we show the applicability of coupled LAMP and BART reactions (LAMP-BART) for determination of genetically modified (GM) maize target DNA at low levels of contamination (0.1-5.0% GM) using certified reference material, and compare this to RT-PCR. Results show that conventional DNA extraction methods developed for PCR may not be optimal for LAMP-BART quantification. Additionally, we demonstrate that LAMP is more tolerant to plant sample-derived inhibitors, and show this can be exploited to develop rapid extraction techniques suitable for simple field-based qualitative tests for GM status determination. We also assess the effect of total DNA assay load on LAMP-BART quantitation. Conclusions LAMP-BART is an effective and sensitive technique for GM detection with significant potential for quantification even at low levels of contamination and in samples derived from crops such as maize with a large genome size. The resilience of LAMP-BART to acidic polysaccharides makes it well suited to rapid sample preparation techniques and hence to both high throughput laboratory settings and to portable GM detection applications. The impact of the plant sample matrix and genome loading within a reaction must be controlled to ensure quantification at low target concentrations.

Abstract Background Blood is a convenient sample and increasingly used for quantitative gene expression measurements with a variety of diseases including chronic fatigue syndrome (CFS). Quantitative gene expression measurements require normalization of target genes to reference genes that are stable and independent from variables being tested in the experiment. Because there are no genes that are useful for all situations, reference gene selection is an essential step to any quantitative reverse transcription-PCR protocol. Many publications have described appropriate genes for a wide variety of tissues and experimental conditions, however, reference genes that may be suitable for the analysis of CFS, or human blood RNA derived from whole blood as well as isolated peripheral blood mononuclear cells (PBMCs), have not been described. Findings Literature review and analyses of our unpublished microarray data were used to narrow down the pool of candidate reference genes to six. We assayed whole blood RNA from Tempus tubes and cell preparation tube (CPT)-collected PBMC RNA from 46 subjects, and used the geNorm and NormFinder algorithms to select the most stable reference genes. Phosphoglycerate kinase 1 (PGK1) was one of the optimal normalization genes for both whole blood and PBMC RNA, however, additional genes differed for the two sample types; Ribosomal protein large, P0 (RPLP0) for PBMC RNA and Peptidylprolyl isomerase B (PPIB) for whole blood RNA. We also show that the use of a single reference gene is sufficient for normalization when the most stable candidates are used. Conclusions We have identified PGK1 as a stable reference gene for use with whole blood RNA and RNA derived from PBMC. When stable genes are selected it is possible to use a single gene for normalization rather than two or three. Optimal normalization will improve the ability of results from PBMC RNA to be compared with those from whole blood RNA and potentially allows comparison of gene expression results from blood RNA collected and processed by different methods with the intention of biomarker discovery. Results of this study should facilitate large-scale molecular epidemiologic studies using blood RNA as the target of quantitative gene expression measurements.