ORCID Profile
0000-0001-5256-7672
Current Organisations
Yale University School of Public Health
,
Mater Health Services
,
Mater Research Institute The University of Queensland
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 06-2016
Publisher: BMJ
Date: 03-02-2018
DOI: 10.1136/GUTJNL-2017-315655
Abstract: Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework.
Publisher: Georg Thieme Verlag KG
Date: 10-06-2015
Publisher: American Society of Hematology
Date: 05-05-2021
Abstract: Immunopathology and intestinal stem cell (ISC) loss in the gastrointestinal (GI) tract is the prima facie manifestation of graft-versus-host disease (GVHD) and is responsible for significant mortality after allogeneic bone marrow transplantation (BMT). Approaches to prevent GVHD to date focus on immune suppression. Here, we identify interferon-λ (IFN-λ interleukin-28 [IL-28]/IL-29) as a key protector of GI GVHD immunopathology, notably within the ISC compartment. Ifnlr1−/− mice displayed exaggerated GI GVHD and mortality independent of Paneth cells and alterations to the microbiome. Ifnlr1−/− intestinal organoid growth was significantly impaired, and targeted Ifnlr1 deficiency exhibited effects intrinsic to recipient Lgr5+ ISCs and natural killer cells. PEGylated recombinant IL-29 (PEG-rIL-29) treatment of naive mice enhanced Lgr5+ ISC numbers and organoid growth independent of both IL-22 and type I IFN and modulated proliferative and apoptosis gene sets in Lgr5+ ISCs. PEG-rIL-29 treatment improved survival, reduced GVHD severity, and enhanced epithelial proliferation and ISC-derived organoid growth after BMT. The preservation of ISC numbers in response to PEG-rIL-29 after BMT occurred both in the presence and absence of IFN-λ–signaling in recipient natural killer cells. IFN-λ is therefore an attractive and rapidly testable approach to prevent ISC loss and immunopathology during GVHD.
Publisher: Cold Spring Harbor Laboratory
Date: 03-03-2018
DOI: 10.1101/275719
Abstract: Enterococcus faecalis is an early coloniser of the human infant gut and contributes to the development of intestinal immunity. To better understand the functional capacity of E. faecalis we constructed a broad host range RP4 mobilisable vector, pEHR513112, that confers chlor henicol resistance and used a metaparental mating approach to isolate E. faecalis AHG0090 from a faecal s le collected from a healthy human infant. We demonstrated that E. faecalis AHG0090 is genetically tractable and could be manipulated using traditional molecular microbiology approaches. E. faecalis AHG0090 was comparable to the gold-standard anti-inflammatory bacterium Faecalibacterium prausnitzii A2-165 in its ability to suppress cytokine mediated NF-КB activation in human gut derived LS174T goblet cell-like and Caco-2 enterocyte-like cell lines. E. faecalis AHG0090 and F. prausnitzii A2-165 produced secreted low molecular weight NF-КB suppressive peptidic bioactives. Both bioactives were sensitive to heat and proteinase K treatments although the E. faecalis AHG0090 bioactive was more resilient to both forms of treatment. As expected, E. faecalis AHG0090 suppressed IL-1β induced NF-КB-p65 subunit nuclear translocation and expression of the NF-КB regulated genes IL-6, IL-8 and CXCL-10. Finally, we determined that E. faecalis AHG0090 is distantly related to other commensal strains and likely encodes niche factors that support effective colonisation of the infant gut.
Publisher: Elsevier BV
Date: 10-2001
DOI: 10.1016/S0969-2126(01)00662-1
Abstract: Adrenaline is localized to specific regions of the central nervous system (CNS), but its role therein is unclear because of a lack of suitable pharmacologic agents. Ideally, a chemical is required that crosses the blood-brain barrier, potently inhibits the adrenaline-synthesizing enzyme PNMT, and does not affect other catecholamine processes. Currently available PNMT inhibitors do not meet these criteria. We aim to produce potent, selective, and CNS-active PNMT inhibitors by structure-based design methods. The first step is the structure determination of PNMT. We have solved the crystal structure of human PNMT complexed with a cofactor product and a submicromolar inhibitor at a resolution of 2.4 A. The structure reveals a highly decorated methyltransferase fold, with an active site protected from solvent by an extensive cover formed from several discrete structural motifs. The structure of PNMT shows that the inhibitor interacts with the enzyme in a different mode from the (modeled) substrate noradrenaline. Specifically, the position and orientation of the amines is not equivalent. An unexpected finding is that the structure of PNMT provides independent evidence of both backward evolution and fold recruitment in the evolution of a complex enzyme from a simple fold. The proposed evolutionary pathway implies that adrenaline, the product of PNMT catalysis, is a relative newcomer in the catecholamine family. The PNMT structure reported here enables the design of potent and selective inhibitors with which to characterize the role of adrenaline in the CNS. Such chemical probes could potentially be useful as novel therapeutics.
Publisher: Oxford University Press (OUP)
Date: 12-2012
Publisher: MDPI AG
Date: 02-08-2023
DOI: 10.3390/BIOMEDICINES11082179
Abstract: Background: There are limited treatment options for mental health comorbidities associated with Inflammatory Bowel Disease (IBD), although they have been shown to negatively affect the course of IBD and multiple important areas of functioning. Photobiomodulation (PBM) is a new therapeutic intervention using laser-generated low-powered light therapy that has shown early promise in alleviating fatigue, depression, and pain in chronic illness. Methods: This prospective, single-arm pilot study aims to assess the feasibility and efficacy of PBM in the treatment of fatigue, depression, and pain in youth with IBD. We will recruit 28 young adults with IBD who will receive PBM in addition to treatment as usual. The primary outcome will be fatigue, while secondary outcomes will include depression, pain, quality of life, inflammatory markers, alterations in microbiome composition, physical activity, and functioning. Outcome measures will be assessed at baseline, after a 10-week control period (pre-PBM), at 20 weeks (post-PBM), and at 30 weeks. Feasibility will be assessed by attendance, recruitment rates, and participants’ views of PBM. Mixed-effects linear regression modelling will be used to assess the PBM effect on continuous outcomes (fatigue, depression, anxiety and stress scores, and inflammation levels). Results: The study will provide preliminary indicators of PBM feasibility and efficacy in IBD.
Publisher: Public Library of Science (PLoS)
Date: 12-09-2013
Publisher: Elsevier BV
Date: 12-2012
Publisher: Wiley
Date: 27-09-2020
DOI: 10.1111/APT.16102
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1334
Abstract: Adoptive regulatory T cell (Treg) therapy is being trialled for the treatment of different autoimmune disorders, including inflammatory bowel diseases (IBD). In‐depth understanding of the biological variability of Treg in the human blood may be required to improve IBD immune monitoring and treatment strategies. Through a combination of quantitative proteomic, multiparametric flow cytometry, RNA‐sequencing data analysis and functional assays on Treg enriched from the blood of ulcerative colitis (UC) patients and healthy controls, we investigated the association between CD49f expression, Treg phenotype and function, and UC disease activity. High‐dimensional analysis and filtering defined two distinct subsets of human Treg based on the presence or absence of CD49f with ergent transcriptional landscape and functional activities. CD49f negative (CD49f − ) Treg are enriched for functional Treg markers and present significantly increased suppressive capacity. In contrast, CD49f high Treg display a pro‐inflammatory Th17‐like phenotype and accumulate in the blood of patients with UC. Dysregulation on CD49f Treg subsets in patients with UC correlate with disease activity. Overall, our findings uncover the importance of CD49f expression on Treg in physiological immunity and in pathological autoimmunity.
Publisher: Wiley
Date: 16-01-2023
DOI: 10.1111/JGH.16102
Abstract: Prevention of liver failure arising from accidental or deliberate paracetamol (acetaminophen [APAP]) overdose remains a vexed health problem despite well‐publicized guidelines for its early detection and treatment. It is recognized that the gut may aggravate liver pathology, via the gut–liver axis. The main aim of this study was to assess the role of the colon in APAP‐induced liver toxicity. Liver necrosis and colitis were studied following sublethal doses of APAP administered intraperitoneally to C57Bl/6 wild‐type (WT) mice, as well as to C57Bl/6 Winnie mice, which develop a spontaneous colitis caused by a SNP in Muc2 , and WT mice with acute DSS‐induced colitis. Repeated APAP exposure was studied in WT and Rag1 ko mice that lack mature T and B lymphocytes. APAP overdose resulted in significant colonic injury in WT mice ( P 0.05), which resolved by 24 h. Underlying colitis was not associated with liver necrosis, but colitis exacerbated APAP‐induced liver injury and extended APAP‐colonic injury. Prior APAP exposure exacerbated both APAP‐liver and APAP‐colonic injury more so in WT than Rag1 ko mice. APAP impaired barrier function with increased intestinal permeability and associated bacterial translocation to the liver and spleen in mice with the Winnie phenotype. This study identifies novel roles for APAP in causing colitis, the lification of APAP‐liver toxicity where there is underlying colitis, and involvement of immune memory in APAP‐toxicity. The latter could be key for decoding the poorly understood but important clinical entity of chronic APAP liver failure.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2009
Publisher: Wiley
Date: 2018
DOI: 10.1002/CTI2.1017
Publisher: JMIR Publications Inc.
Date: 24-07-2019
DOI: 10.2196/14432
Publisher: Wiley
Date: 04-2021
DOI: 10.1111/JGH.15450
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.CGH.2021.07.053
Abstract: Higher anti-tumor necrosis factor-α (TNF) drug levels are associated with improved clinical healing of Crohn's perianal fistulas. It is unclear whether this leads to improved healing on radiologic assessment. We aimed to evaluate the association between anti-TNF drug levels and radiologic outcomes in perianal fistulising Crohn's disease. A cross-sectional retrospective multicenter study was undertaken. Patients with perianal fistulising Crohn's disease on maintenance infliximab or adalimumab, with drug levels within 6 months of perianal magnetic resonance imaging were included. Patients receiving dose changes or fistula surgery between drug level and imaging were excluded. Radiologic disease activity was scored using the Van Assche Index, with an inflammatory subscore calculated using indices: T2-weighted imaging hyperintensity, collections >3 mm diameter, rectal wall involvement. Primary endpoint was radiologic healing (inflammatory subscore ≤6). Secondary endpoint was radiologic remission (inflammatory subscore = 0). Of 193 patients (infliximab, n = 117 adalimumab, n = 76), patients with radiologic healing had higher median drug levels compared with those with active disease (infliximab 6.0 vs 3.9 μg/mL adalimumab 9.1 vs 6.2 μg/mL both P < .05). Patients with radiologic remission also had higher median drug levels compared with those with active disease (infliximab 7.4 vs 3.9 μg/mL P < .05 adalimumab 9.8 vs 6.2 μg/mL P = .07). There was a significant incremental reduction in median inflammatory subscores with higher anti-TNF drug level tertiles. Higher anti-TNF drug levels were associated with improved radiologic outcomes on magnetic resonance imaging in perianal fistulising Crohn's disease, with an incremental improvement at higher drug level tertiles for both infliximab and adalimumab.
Publisher: American Society for Microbiology
Date: 04-2003
DOI: 10.1128/IAI.71.4.2208-2217.2003
Abstract: Staphylococcus aureus , an important pathogen of humans and other warm-blooded animals, is also capable of killing the nematode Caenorhabditis elegans . Here, we show that C. elegans organisms that are fed S. aureus die over the course of several days in a process that is correlated with the accumulation of bacteria within the nematode digestive tract. Several S. aureus virulence determinants known or speculated to be important in mammalian pathogenesis, including the quorum-sensing global virulence regulatory system agr and the global virulence regulator sarA , the alternative sigma factor σ B , alpha-hemolysin, and V8 serine protease, are required for full pathogenicity in nematodes. In addition, several defined C. elegans mutants were examined for susceptibility to S. aureus infection. Enhanced susceptibility to S. aureus killing was observed with loss-of-function mutations in the C. elegans genes esp-2 / sek-1 and esp-8 / nsy-1 , which encode components of a conserved p38 MAP kinase signaling pathway involved in nematode defense against multiple pathogens. These results suggest that key aspects of S. aureus pathogenesis have been conserved, irrespective of the host, and that specific C. elegans host factors can alter susceptibility to this gram-positive human pathogen.
Publisher: Proceedings of the National Academy of Sciences
Date: 18-02-2014
Abstract: Chronic granulomatous disease (CGD) has an immunodeficiency component and, in addition, an autoinflammatory component in which autophagy and inflammasome activation are linked and amenable to IL-1 blockade. This study provides a rationale to perform clinical trials to investigate the efficacy of blocking IL-1 in CGD colitis and expands the therapeutic potential of IL-1 antagonists to inflammatory diseases with defective autophagy.
Publisher: Elsevier BV
Date: 11-2019
Publisher: Hindawi Limited
Date: 07-2021
DOI: 10.1002/YGH2.473
Publisher: Oxford University Press (OUP)
Date: 28-04-2020
Abstract: Inflammatory bowel disease [IBD] affects women during their childbearing years. Gastrointestinal ultrasonography [GIUS] accurately identifies disease activity in non-pregnant patients with IBD. The utility of GIUS in pregnancy has not been established. We aimed to determine the feasibility and accuracy of GIUS in the assessment of IBD during pregnancy progression. A multicentre observational study of women with IBD undergoing GIUS during pregnancy. Clinicians assessed the adequacy of bowel views and disease activity in four colonic segments and the terminal ileum. Location[s] in which views were impeded by the uterus were documented. GIUS disease activity [bowel wall thickness & mm] was compared with biochemical disease activity [faecal calprotectin & μg/g]. Ninety patients and 127 GIUS examinations were included [median gestation 19 weeks, range 4–33]. Adequate colonic views were obtained in 116/127 [91%] scans. Adequate ileal views were obtained in 62/67 [93%] scans & weeks and 30/51 [59%] scans at 20–26 weeks. There was a positive correlation between bowel wall thickness and calprotectin [r = 0.26, p = 0.03]. GIUS delivered a specificity of 83%, sensitivity of 74%, and negative predictive value of 90% compared with calprotectin. GIUS is a feasible and accurate modality for monitoring IBD in pregnancy. Adequate GIUS views of the colon and terminal ileum can be obtained in the majority of patients up to 20 weeks of gestation. Beyond 20 weeks, GIUS provides good views of the colon but the terminal ileum becomes difficult to assess.
Publisher: Oxford University Press (OUP)
Date: 06-10-2021
Abstract: No consensus exists on defining intestinal ultrasound response, transmural healing, or transmural remission in inflammatory bowel disease, nor clear guidance for optimal timing of assessment during treatment. This systematic review and expert consensus study aimed to define such recommendations, along with key parameters included in response reporting. Electronic databases were searched from inception to July 26, 2021, using pre-defined terms. Studies were eligible if at least two intestinal ultrasound [IUS] assessments at different time points during treatment were reported, along with an appropriate reference standard. The QUADAS-2 tool was used to examine study-level risk of bias. An international panel of experts [n = 18] rated an initial 196 statements [RAND/UCLA process, scale 1–9]. Two videoconferences were conducted, resulting in additional ratings of 149 and 13 statements, respectively. Out of 5826 records, 31 full-text articles, 16 abstracts, and one research letter were included 83% [40/48] of included studies showed a low concern of applicability, and 96% [46/48] had a high risk of bias. A consensus was reached on 41 statements, with clear definitions of IUS treatment response, transmural healing, transmural remission, timing of assessment, and general considerations when using intestinal ultrasound in inflammatory bowel disease. Response criteria and time points of response assessment varied between studies, complicating direct comparison of parameter changes and their relation to treatment outcomes. To ensure a unified approach in routine care and clinical trials, we provide recommendations and definitions for key parameters for intestinal ultrasound response, to incorporate into future prospective studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2013
Publisher: The American Association of Immunologists
Date: 10-2019
Abstract: The clear role of autophagy in human inflammatory diseases such as Crohn disease was first identified by genome-wide association studies and subsequently dissected in multiple mechanistic studies. ATG16L1 has been particularly well studied in knockout and hypomorph settings as well as models recapitulating the Crohn disease–associated T300A polymorphism. Interestingly, ATG16L1 has a single homolog, ATG16L2, which is independently implicated in diseases, including Crohn disease and systemic lupus erythematosus. However, the contribution of ATG16L2 to canonical autophagy pathways and other cellular functions is poorly understood. To better understand its role, we generated and analyzed the first, to our knowledge, ATG16L2 knockout mouse. Our results show that ATG16L1 and ATG16L2 contribute very distinctly to autophagy and cellular ontogeny in myeloid, lymphoid, and epithelial lineages. Dysregulation of any of these lineages could contribute to complex diseases like Crohn disease and systemic lupus erythematosus, highlighting the value of examining cell-specific effects. We also identify a novel genetic interaction between ATG16L2 and epithelial ATG16L1. These findings are discussed in the context of how these genes may contribute distinctly to human disease.
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1330
Abstract: Tumor‐associated autoantibodies (AAbs) in in iduals with cancer can precede clinical diagnosis by several months to years. The objective of this study was to determine whether the primary immune response in form of IgM and gut mucosa‐associated IgA can aid IgG AAbs in the detection of early‐stage colorectal cancer (CRC). We developed a novel protein array comprising 492 antigens seropositive in CRC. The array was used to profile IgG, IgM and IgA antibody signatures in 99 CRC patients and 99 sex‐ and age‐matched non‐cancer controls. A receiver operating curve (ROC), Kaplan–Meier survival analysis and univariate and multivariate Cox regression analyses were conducted. We identified a panel of 16 multi‐isotype AAbs with a cumulative sensitivity of 91% and specificity of 74% (AUC 0.90, 95% CI: 0.850–0.940) across all CRC stages. IgM and IgG isotypes were conversely associated with disease stage with IgM contributing significantly to improved stage I and II sensitivity of 96% at 78% specificity (AUC 0.928, 95% CI: 0.884–0.973). A single identified IgA AAb reached an overall sensitivity of 5% at 99% specificity (AUC 0.520, 95% CI: 0.440–0.601) balanced across all CRC stages. Kaplan–Meier analysis revealed that se33‐1 (ZNF638) IgG AAbs were associated with reduced 5‐year overall survival (log‐rank test, P = 0.012), whereas cumulative IgM isotype signatures were associated with improved 5‐year overall survival (log‐rank test, P = 0.024). IgM AAbs are associated with early‐stage colorectal cancer. Combining IgG, IgM and IgA AAbs is a novel strategy to improve early diagnosis of cancers.
Publisher: Cold Spring Harbor Laboratory
Date: 16-12-2019
DOI: 10.1101/2019.12.16.861872
Abstract: Evidence is emerging that microbiome–immune system crosstalk regulates the tenor of host intestinal immunity and predisposition to inflammatory bowel disease (IBD). We identified five NF-κB suppressive strains affiliated with Clostridium clusters IV, XIVa and XV that independently suppressed secretion of the chemokine IL-8 by peripheral blood mononuclear cells and gut epithelial organoids from healthy human subjects, as well as patients with the predominant IBD subtypes, Crohn’s disease and ulcerative colitis. The NF-κB suppressive Clostridium bolteae AHG0001, but not C. bolteae BAA-613, suppressed cytokine-driven inflammatory responses and endoplasmic reticulum stress in gut epithelial organoids derived from Winnie mice that develop spontaneous colitis. This predicted in vivo responses thereby validating a precision medicine approach to treat Winnie colitis and suggesting the microbiome may function as an extrinsic regulator of host immunity. Finally, we identified a novel molecule associated with NF-κB suppression indicating gut bacteria could be harnessed to develop new therapeutics.
Publisher: Wiley
Date: 07-03-2019
DOI: 10.1111/APT.15209
Abstract: Decision support tools may facilitate shared decision-making and improve quality of care. To assess the effectiveness of a decision support tool on improving quality of care in ulcerative colitis. A prospective quality of care intervention was conducted at two Australian hospitals comparing out-patient-based ulcerative colitis care with, and without, a tablet-based decision support tool. This included questions on disease activity management psychological well-being and preventive care, with 13 process indicators relevant to each domain. Participants included adult out-patients with mild-to-moderate ulcerative colitis and their clinicians who were ided into two cohorts. The first cohort were followed up immediately after their clinical review to check whether their clinician had discussed the 13 process indicators during the consultation. The second cohort of patients used the decision support tool immediately prior to their consultation which then generated a suggested management plan for the patient and clinician to discuss during the consultation. Management between the 2 cohorts was compared to assess the effectiveness of the decision support tool in improving the primary outcome, defined as the proportion of quality process indicators used for ulcerative colitis care, with and without the decision support tool. Thirteen physicians and 100 patients participated. Fifty patients were managed without the decision support tool using standard care (median age 40 44% male), and 50 patients used the decision support tool (median age 40 46% male) over a 20-week period. Increase in the median use of process indicators overall was observed following use of the decision support tool (27% vs 100% P < 0.001). Improvements were seen in psychological well-being management (30% vs 100% P < 0.001), preventive care (16% vs 100% P < 0.001) and process indicators related to disease activity management (50% vs 100% P < 0.001). The decision support tool was found to be usable and acceptable. Shared decision-making was greater in the post-intervention group (mean decision conflict score of 18.0 vs 33.5 P = 0.002). The decision support tool substantially improved the quality of the delivery of care. Decision support tools have the potential to minimise errors of omission via a standardised approach to care.
Publisher: Wiley
Date: 14-12-2021
DOI: 10.1111/APT.16739
Abstract: Ustekinumab is increasingly used in pregnant women with inflammatory bowel disease (IBD). Existing safety data are reassuring, but the stability of ustekinumab levels in pregnancy, degree of transfer to the infant and time to infant clearance are unknown. In this prospective observational study, ustekinumab‐exposed women with IBD had trough levels measured in each trimester of pregnancy and at delivery. Infant ustekinumab levels were measured at delivery and ongoing until clearance was achieved. Trough ustekinumab level stability in in iduals across pregnancy was compared by Skillings‐Mack test. Spearman coefficients were used to correlate maternal and infant delivery levels, and median time to infant ustekinumab clearance was defined. 19 pregnant women receiving ustekinumab were included. There was no difference in ustekinumab levels across pregnancy in those with two or more representative trough levels ( P = 0.83, n = 11). Infant delivery ustekinumab levels were higher than maternal levels, with a median infant:maternal ratio of 1.79 (IQR 1.26‐3.1). There was a positive correlation between maternal and infant delivery ustekinumab levels ( r = 0.75, P = 0.001) and an inverse correlation between the number of days from final antenatal dose and delivery infant ustekinumab level ( r = −0.65, P = 0.006). Median time of infant ustekinumab clearance was 9 (range 6‐19) weeks (n = 9). Ustekinumab drug levels appear stable in pregnancy, with a delivery infant:maternal ratio similar to that of anti‐TNFs. Infant ustekinumab clearance was complete by 20 weeks post‐partum, however, infants exposed in utero should avoid live vaccination before 12 months of age until further clearance data are obtained.
Publisher: Wiley
Date: 07-2020
DOI: 10.1111/IMJ.14889
Publisher: Elsevier BV
Date: 2018
Publisher: Wiley
Date: 09-2018
DOI: 10.1111/JGH.14415
Publisher: American Society for Microbiology
Date: 02-2005
DOI: 10.1128/IAI.73.2.872-877.2005
Abstract: Staphylococcus aureus is an important human pathogen that is also able to kill the model nematode Caenorhabditis elegans . We constructed a 2,950-member Tn 917 transposon insertion library in S. aureus strain NCTC 8325. Twenty-one of these insertions exhibited attenuated C. elegans killing, and of these, 12 contained insertions in different genes or chromosomal locations. Ten of these 12 insertions showed attenuated killing phenotypes when transduced into two different S. aureus strains, and 5 of the 10 mutants correspond to genes that have not been previously identified in signature-tagged mutagenesis studies. These latter five mutants were tested in a murine renal abscess model, and one mutant harboring an insertion in nagD exhibited attenuated virulence. Interestingly, Tn 917 was shown to have a very strong bias for insertions near the terminus of DNA replication.
Publisher: Wiley
Date: 09-2018
DOI: 10.1111/JGH.14414
Publisher: JMIR Publications Inc.
Date: 17-04-2019
Abstract: indfulness-based programs are increasingly used as a part of integrated treatment for inflammatory bowel disease (IBD). However, the majority of research has been quantitative with limited qualitative exploration of patients’ experiences of mindfulness programs and no studies among adolescents and young adults with IBD. Furthermore, there has been a paucity of research exploring the role of common psychotherapy and group factors within mindfulness programs. his study aims to explore the experiences of adolescents and young adults with IBD and depression who completed a mindfulness-based cognitive therapy (MBCT) group program, as well as the role of therapeutic alliance, group affiliation, and other common psychotherapy and group factors. his mixed methods qualitative study, nested within a randomized controlled trial (RCT) of MBCT for adolescents and young adults with IBD, will obtain qualitative data from focus groups and open-ended survey questions. The study aims to conduct three to four focus groups with 6-8 participants in each group. It will employ data and investigator triangulation as well as thematic analysis of the qualitative data. he study was approved by the Mater Hospital Human Research Ethics Committee and recruitment commenced in May 2019 study completion is anticipated by early 2020. he study will contribute to the assessment of acceptability and feasibility of the MBCT program for adolescents and young adults with IBD. It will also elucidate the role of previously unexplored common psychotherapy and group factors within mindfulness training and help inform the design of a future large-scale RCT of MBCT in this cohort. ustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12617000876392 www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373115 RR1-10.2196/14432
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.ANAEROBE.2017.06.002
Abstract: The gut microbiota is increasingly implicated in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) although the identity of the bacteria that underpin these diseases has remained elusive. The pathobiont Bacteroides vulgatus has been associated with both diseases although relatively little is known about how its growth and functional activity might drive the host inflammatory response. We identified an ATP Binding Cassette (ABC) export system and lipoprotein in B. vulgatus ATCC 8482 and B. vulgatus PC510 that displayed significant sequence similarity to an NF-κB immunomodulatory regulon previously identified on a CD-derived metagenomic fosmid clone. Interestingly, the ABC export system was specifically enriched in CD subjects suggesting that it may be important for colonization and persistence in the CD gut environment. Both B. vulgatus ATCC 8482 and PC510 activated NF-κB in a strain and growth phase specific manner in a HT-29/kb-seap-25 enterocyte like cell line. B. vulgatus ATCC 8482 also activated NF-κB in a Caco-2-NF-κBluc enterocyte like and an LS174T-NF-κBluc goblet cell like cell lines, and induced NF-κB-p65 subunit nuclear translocation and IL-6, IL-8, CXCL-10 and MCP-1 gene expression. Despite this, NF-κB activation was not coincident with maximal expression of the ABC exporter or lipoprotein in B. vulgatus PC510 suggesting that the regulon may be necessary but not sufficient for the immunomodulatory effects.
Publisher: Springer Science and Business Media LLC
Date: 09-07-2022
DOI: 10.1038/S43856-022-00147-Y
Abstract: Rapid antigen (RA) tests are being increasingly employed to detect SARS-CoV-2 infections in quarantine and surveillance. Prior research has focused on RT-PCR testing, a single RA test, or generic diagnostic characteristics of RA tests in assessing testing strategies. We have conducted a comparative analysis of the post-quarantine transmission, the effective reproduction number during serial testing, and the false-positive rates for 18 RA tests with emergency use authorization from The United States Food and Drug Administration and an RT-PCR test. To quantify the extent of transmission, we developed an analytical mathematical framework informed by COVID-19 infectiousness, test specificity, and temporal diagnostic sensitivity data. We demonstrate that the relative effectiveness of RA tests and RT-PCR testing in reducing post-quarantine transmission depends on the quarantine duration and the turnaround time of testing results. For quarantines of two days or shorter, conducting a RA test on exit from quarantine reduces onward transmission more than a single RT-PCR test (with a 24-h delay) conducted upon exit. Applied to a complementary approach of performing serial testing at a specified frequency paired with isolation of positives, we have shown that RA tests outperform RT-PCR with a 24-h delay. The results from our modeling framework are consistent with quarantine and serial testing data collected from a remote industry setting. These RA test-specific results are an important component of the tool set for policy decision-making, and demonstrate that judicious selection of an appropriate RA test can supply a viable alternative to RT-PCR in efforts to control the spread of disease.
Publisher: Wiley
Date: 09-03-2021
DOI: 10.1111/IMCB.12447
Abstract: The endothelial adhesion protein E‐selectin/CD62E is not required for leukocyte homing, unlike closely related family member P‐selectin/CD62P. As transmigration through the endothelium is one of the first steps in generating a local immune response, we hypothesized that E‐selectin may play additional roles in the early stages of immune activation. We found contact with E‐selectin, but not P‐selectin or vascular cell adhesion molecule 1 (CD106), induced phosphorylation of protein kinase B (AKT) and nuclear factor‐κB in mouse bone marrow‐derived macrophages (BMDMs) in vitro . This occurred within 15 min of E‐selectin contact and was dependent on phosphatidylinositol‐3 kinase activity. Binding to E‐selectin activated downstream proteins including mammalian target of rapamycin, p70 ribosomal protein S6 kinase and eukaryotic translation initiation factor 4E‐binding protein 1. Functionally, adhesion to E‐selectin induced upregulation of CD86 expression and CCL2 secretion. We next asked whether contact with E‐selectin impacts further BMDM stimulation. We found enhanced secretion of both interleukin (IL)‐10 and CCL2, but not tumor necrosis factor or IL‐6 in response to lipopolysaccharide (LPS) stimulation after adhesion to E‐selectin. Importantly, adhesion to E‐selectin did not polarize BMDMs to one type of response but enhanced both arginase activity and nitric oxide production following IL‐4 or LPS stimulation, respectively. In cultured human monocytes, adhesion to E‐selectin similarly induced phosphorylation of AKT. Finally, when E‐selectin was blocked in vivo in mice, thioglycollate‐elicited macrophages showed reduced CD86 expression, validating our in vitro studies. Our results imply functions for E‐selectin beyond homing and suggest that E‐selectin plays an early role in priming and lifying innate immune responses.
Publisher: BMJ
Date: 11-02-2020
DOI: 10.1136/GUTJNL-2019-320260
Abstract: Faecal microbiota transplantation (FMT) has proved to be an extremely effective treatment for recurrent Clostridioides difficile infection, and there is interest in its potential application in other gastrointestinal and systemic diseases. However, the recent death and episode of septicaemia following FMT highlights the need for further appraisal and guidelines on donor evaluation, production standards, treatment facilities and acceptable clinical indications. For these consensus statements, a 24-member multidisciplinary working group voted online and then convened in-person, using a modified Delphi approach to formulate and refine a series of recommendations based on best evidence and expert opinion. Invitations to participate were directed to Australian experts, with an international delegate assisting the development. The following issues regarding the use of FMT in clinical practice were addressed: donor selection and screening, clinical indications, requirements of FMT centres and future directions. Evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Consensus was reached on 27 statements to provide guidance on best practice in FMT. These include: (1) minimum standards for donor screening with recommended clinical selection criteria, blood and stool testing (2) accepted routes of administration (3) clinical indications (4) minimum standards for FMT production and requirements for treatment facilities acknowledging distinction between single-site centres (eg, hospital-based) and stool banks and (5) recommendations on future research and product development. These FMT consensus statements provide comprehensive recommendations around the production and use of FMT in clinical practice with relevance to clinicians, researchers and policy makers.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1BM01352A
Abstract: Interleukin (IL)-22 is a multifunctional cytokine with a very short half-life that activates STAT3 and can elicit an anti-inflammatory response. We show encapsulation of IL-22 in LPMSN enhances its biological activity and stability in in vitro and human colonic organoids.
Publisher: Springer Science and Business Media LLC
Date: 12-11-2001
DOI: 10.1038/NSB725
Publisher: BMJ
Date: 02-2022
DOI: 10.1136/BMJGAST-2021-000853
Abstract: 5-aminosalicylate (mesalazine 5-ASA) is an established first-line treatment for mild-to-moderate ulcerative colitis (UC). This study aimed to model the benefits of optimising 5-ASA therapy. A decision tree model followed 10 000 newly diagnosed patients with mild-to-moderately active UC through induction and 1 year of maintenance treatment. Optimised treatment (maximising dose of 5-ASA and use of combined oral and rectal therapy before treatment escalation) was compared with standard treatment (standard doses of 5-ASA without optimisation). Modelled data were derived from published meta-analyses. The primary outcomes were patient numbers achieving and maintaining remission, with an analysis of treatment costs for each strategy conducted as a secondary outcome (using UK reference costs). During induction, there was a 39% increase in patients achieving remission through the optimised pathway without requiring systemic steroids and/or biologics (6565 vs 4725 for standard). Potential steroidal/biological adverse events avoided included: seven venous thromboembolisms and eight serious infections. Out of the 6565 patients entering maintenance following successful induction on 5-ASA, there was a 21% reduction in relapses when optimised (1830 vs 2311 for standard). This translated into 297 patients avoiding further systemic steroids and 214 biologics. Optimisation led to an average net saving of £272 per patient entering the model for the induction and maintenance of remission over 1 year. Modelling suggests that optimising 5-ASA therapy (both the inclusion of rectal 5-ASA into a combined oral and rectal regimen and maximisation of 5-ASA dose) has clinical and cost benefits that supports wider adoption in clinical practice.
Publisher: International Union of Crystallography (IUCr)
Date: 24-01-2002
DOI: 10.1107/S090744490101962X
Abstract: Phenylethanolamine N-methyltransferase, PNMT, utilizes the methylating cofactor S-adenosyl-L-methionine to catalyse the synthesis of adrenaline. Human PNMT has been crystallized in complex with an inhibitor and the cofactor product S-adenosyl-L-homocysteine using the hanging-drop technique with PEG 6000 and lithium chloride as precipitant. A critical requirement for crystallization was a high enzyme concentration (>90 mg ml(-1)) and cryocrystallography was used for high-quality data measurement. Diffraction data measured from a cryocooled crystal extend to a resolution of 2.3 A. Cryocooled crystals belong to space group P4(3)2(1)2 and have unit-cell parameters a = b = 94.3, c = 187.7 A.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Informa UK Limited
Date: 17-10-2017
Publisher: BMJ
Date: 04-2019
DOI: 10.1136/BMJOPEN-2018-025568
Abstract: Inflammatory bowel disease (IBD) is a chronic autoinflammatory disease of the gastrointestinal tract with peak age of onset during adolescence and young adulthood. Adolescents and young adults (AYAs) with IBD experience higher depression rates compared with peers who are well or have other chronic conditions. Mindfulness-based interventions are of particular interest because of their potential to improve both the course of IBD and depression. This study is a parallel design, single-blind, pilot randomised controlled trial (RCT) of mindfulness-based cognitive therapy (MBCT) in AYAs with IBD and depression. The trial aims to recruit 64 participants who will be randomly allocated to MBCT or treatment as usual. The primary outcome measure is the depression subscale score from the Depression, Anxiety and Stress Scale. Secondary outcomes include anxiety, stress, post-traumatic growth, IBD-related quality of life, illness knowledge, medication adherence, mindfulness, IBD activity, inflammatory markers, microbiome and brain neuroconnectivity changes. All outcomes other than neuroimaging will be collected at three time points: at baseline, at therapy completion and at 20 weeks. Neuroimaging will be conducted at baseline and at therapy completion. Mixed-effects linear and logistic regression modelling will be used to analyse continuous and dichotomous outcomes, respectively. Participants’ experiences will be explored through focus groups, and thematic analysis will be used to generate relevant themes. The protocol has been approved by the Mater Hospital Human Research Ethics Committee (HREC) and University of Queensland HREC. Trial findings will be published in peer-reviewed journals and will be presented at scientific conferences. ACTRN12617000876392, U1111-1197-7370 Pre-results.
Publisher: Cold Spring Harbor Laboratory
Date: 20-01-2021
DOI: 10.1101/2021.01.19.21250059
Abstract: Pouchitis is a common complication after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). Although antibiotics are the primary therapy for acute pouchitis, a proportion of patients developed chronic antibiotic-dependent pouchitis (CADP) or antibiotic-refractory pouchitis (CARP). The efficacy of second line immunomodulator and biologic therapies for chronic pouchitis remain undefined. We performed a systematic review and metanalysis of published studies to assess their efficacy. The online EMBASE database was searched for full-text articles describing the treatment of chronic pouchitis meeting our criteria. Post-induction clinical and endoscopic response and remission rates were extracted and combined for meta-analyses. The rate of treatment discontinuation and safety profiles were also assessed. A total of 21 full-text articles were included in this meta-analysis representing 491 patients. The overall clinical response rate was 49% with clinical remission rate of 34%. The overall endoscopic response and remission rates were 53% and 36% respectively. The safety profile of in idual agents was reassuring, but vedolizumab appears to have a more favorable safety profile. This review and meta-analysis identified the effectiveness of vedolizumab and ustekinumab in achieving clinical and endoscopic response in chronic pouchitis, with a reassuring safety profile. There is limited data regarding use of immunomodulators and no conclusion can be drawn. Further studies are required to define the comparative effectiveness of available treatments of CADP or CARP.
Publisher: Informa UK Limited
Date: 21-12-2022
DOI: 10.1080/00365521.2021.2015801
Abstract: To understand current thinking and clinical decision-making in the treatment and management of patients with mild-to-moderate ulcerative colitis (UC). This multinational, survey-based study was conducted in 2021. Two meetings were held, involving 11 IBD specialists, that used a series of questions and discussion to identify all factors possibly related to the management of UC. The importance of identified factors was assessed using an online questionnaire covering three scenarios - active disease, remission and patient empowerment. Each factor was scored on a scale of 0 (very-unimportant) to 100 (very-important) within each scenario, by a separate group of healthcare professionals working in IBD. A total of 157 in idual factors were identified by the 11 IBD specialists and scored in the three scenarios by 56 respondents (52 93% specialist gastroenterologists) from Europe and North America (25 45%), South America (19 34%) and the Middle East, Asia and Australia (12 21%). For all scenarios, factors related to educating patients regarding UC and its treatment and understanding of patient goals ranked highest, ahead of clinical considerations regarding disease activity and treatment history. Setting realistic short-term treatment targets was a key consideration. 5-ASA optimisation and use of faecal calprotectin monitoring were core strategies across the three scenarios tested. Support for patients during longer-term management of their disease, starting from initial flare, was an important recurring theme. The current management approach for mild-to-moderate UC was found to be guided primarily by the patient's perspectives and goals, alongside assessment of their medical and disease history.
Publisher: Frontiers Media SA
Date: 18-04-2018
Publisher: Wiley
Date: 09-10-2020
DOI: 10.1002/JGH3.12268
Publisher: AMPCo
Date: 17-10-2020
DOI: 10.5694/MJA2.50824
Publisher: BMJ
Date: 06-2021
DOI: 10.1136/BMJOPEN-2020-044463
Abstract: The perinatal–postnatal family environment is associated with childhood outcomes including impacts on physical and mental health and educational attainment. Family longitudinal cohort studies collect in-depth data that can capture the influence of an era on family lifestyle, mental health, chronic disease, education and financial stability to enable identification of gaps in society and provide the evidence for changes in government in policy and practice. The Queensland Family Cohort (QFC) is a prospective, observational, longitudinal study that will recruit 12 500 pregnant families across the state of Queensland (QLD), Australia and intends to follow-up families and children for three decades. To identify the immediate and future health requirements of the QLD population pregnant participants and their partners will be enrolled by 24 weeks of gestation and followed up at 24, 28 and 36 weeks of gestation, during delivery, on-ward, 6 weeks postpartum and then every 12 months where questionnaires, biological s les and physical measures will be collected from parents and children. To examine the impact of environmental exposures on families, data related to environmental pollution, household pollution and employment exposures will be linked to pregnancy and health outcomes. Where feasible, data linkage of state and federal government databases will be used to follow the participants long term. Biological s les will be stored long term for future discoveries of biomarkers of health and disease. Ethical approval has been obtained from the Mater Research Ethics (HREC/16/MHS/113). Findings will be reported to (1) QFC participating families (2) funding bodies, institutes and hospitals supporting the QFC (3) federal, state and local governments to inform policy (4) presented at local, national and international conferences and (5) disseminated by peer-review publications.
Publisher: Oxford University Press (OUP)
Date: 16-09-2022
Abstract: Ulcerative colitis [UC] is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of disease severity remains poorly understood. To further investigate this, we performed a genome wide association [GWA] study using an extremes of phenotype strategy. We conducted GWA analyses in 311 patients with medically refractory UC [MRUC], 287 with non-medically refractory UC [non-MRUC] and 583 controls. Odds ratios [ORs] were calculated for known risk variants comparing MRUC and non-MRUC, and controls. MRUC–control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms [SNPs] [2018], including lead SNP = rs111838972 [OR = 1.82, p = 6.28 × 10−9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10−19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p & 9.0 × 10−6]. No SNPs reached significance in the non-MRUC–control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 × 10−8). We replicate findings for rs4151651 in the Complement Factor B [CFB] gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC. Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of in iduals with severe disease.
Publisher: American Chemical Society (ACS)
Date: 06-1999
DOI: 10.1021/BI990174X
Publisher: Elsevier BV
Date: 05-2021
Publisher: Baishideng Publishing Group Inc.
Date: 14-08-2020
Publisher: Korean Association for the Study of Intestinal Diseases
Date: 31-01-2023
Publisher: Wiley
Date: 09-2018
DOI: 10.1111/JGH.14423
Publisher: Elsevier BV
Date: 03-2005
DOI: 10.1016/J.TIM.2005.01.003
Abstract: The nematode Caenorhabditis elegans is emerging as a facile and economical model host for the study of evolutionarily conserved mechanisms of microbial pathogenesis and innate immunity. A rapidly growing number of human and animal microbial pathogens have been shown to injure and kill nematodes. In many cases, microbial genes known to be important for full virulence in mammalian models have been shown to be similarly required for maximum pathogenicity in nematodes. C. elegans has been used in mutation-based screening systems to identify novel virulence-related microbial genes and immune-related host genes, many of which have been validated in mammalian models of disease. C. elegans-based pathogenesis systems hold the potential to simultaneously explore the molecular genetic determinants of both pathogen virulence and host defense.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.IJPHARM.2016.12.030
Abstract: With the recent quantum leap in chemoprevention by dietary products, their use as cancer therapeutics is garnering worldwide attention. The concept of effortlessly fighting this deadly disease by gulping cups of green tea or swallowing green tea extract capsules is appreciated universally. Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, has generated significant interest in controlling carcinogenesis due to its growth-inhibitory efficacy against a variety of cancers by targeting multiple signaling pathways. However, the success of EGCG in preclinical studies is difficult to translate into clinical trials due to issues of low solubility, bioavailability and an uncertain therapeutic window. The laborious and expensive journey of drugs from the laboratory to commercialization can be improved by utilizing nanoparticles as anti-cancer drug carriers. Exploitation of biopolymeric nanoparticles in recent years has improved EGCG's biodistribution, stability and tumor selectivity, revealing its superior chemopreventive effects. This review briefly summarizes recent developments regarding the targets and side effects of EGCG, complications associated with its low bioavailability and critically analyses the application of biopolymeric nanoparticles encapsulating EGCG as a next generation delivery systems.
Publisher: Public Library of Science (PLoS)
Date: 20-04-2007
Publisher: American Chemical Society (ACS)
Date: 1996
DOI: 10.1021/JA953790Z
Publisher: Wiley
Date: 28-11-2018
DOI: 10.1111/APT.15027
Publisher: Wiley
Date: 05-2020
DOI: 10.1111/IMJ.14822
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5FO01196E
Abstract: The therapeutic effects associated with EEN may be mediated by co-ordinate effects on the host gut mucosa and microbiota.
Publisher: Public Library of Science (PLoS)
Date: 10-01-2022
DOI: 10.1371/JOURNAL.PPAT.1010166
Abstract: A hallmark of Listeria (L . ) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L . monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L . monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria -containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L . monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L . monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L . monocytogenes in macrophages is not inevitably tied to bacterial persistence.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.SEMCDB.2016.08.018
Abstract: Intestinal homeostasis is maintained through the interplay of the intestinal mucosa, local and systemic immune factors, and the microbial content of the gut. The cellular processes of autophagy, endoplasmic reticulum stress, the unfolded protein response and regulation of reactive oxygen species production are required to maintain a balance between pro-inflammatory responses against potential pathogens and a tolerogenic response towards commensal bacteria. Intestinally active cytokines regulate innate immune pathways and cellular pathways within the gut mucosa. Disruption of these processes, or alterations in the cytokine milieu, can result in an improper response to the commensal gut microbial community leading to inappropriate inflammation characteristic of conditions such as inflammatory bowel disease.
Publisher: Wiley
Date: 06-2016
DOI: 10.1111/JGH.13348
Publisher: Wiley
Date: 14-11-2020
DOI: 10.1002/JGH3.12278
Publisher: AMPCo
Date: 11-2019
DOI: 10.5694/MJA2.50384
Abstract: To assess the clinical effectiveness of faecal calprotectin (FC) testing for distinguishing between organic gastrointestinal diseases (organic GID), such as inflammatory bowel disease (IBD), and functional gastrointestinal disorders (functional GIDs). Studies that assessed the accuracy of FC testing for differentiating between IBD or organic GID and functional GIDs were reviewed. Articles published in English during January 1998 - June 2018 that compared diagnostic FC testing in primary care and outpatient hospital settings with a reference test and employed the standard enzyme-linked immunosorbent FC assay method with a cut-off of 50 or 100 μg/g faeces were included. Study quality was assessed with QUADAS-2, an evidence-based quality assessment tool for diagnostic accuracy studies. MEDLINE and EMBASE reference lists of screened articles. Eighteen relevant studies were identified. For distinguishing patients with organic GID (including IBD) from those with functional GIDs (16 studies), the estimated sensitivity of FC testing was 81% (95% CI, 74-86%), the specificity 81% (95% CI, 71-88%) area under the curve (AUC) was 0.87. For distinguishing IBD from functional GIDs (ten studies), sensitivity was 88% (95% CI, 80-93%), specificity 72% (95% CI, 59-82%), and AUC 0.89. Assuming a population prevalence of organic GID of 1%, the positive predictive value was 4.2%, the negative predictive value 100%. The difference in sensitivity and specificity between FC testing cut-offs of 50 μg/g and 100 μg/g faeces was not statistically significant (P = 0.77). FC testing is clinically useful for distinguishing organic GID (including IBD) from functional GIDs, and its incorporation into clinical practice for evaluating patients with lower gastrointestinal symptoms could lead to fewer patients with functional GIDs undergoing colonoscopy, reducing costs for both patients and the health system. CRD4201810507.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2019
DOI: 10.1038/S41388-019-0951-Y
Abstract: Many adenocarcinomas, including colorectal cancer (CRC), overexpress the MUC13 cell surface mucin, but the functional significance and mechanisms are unknown. Here, we report the roles of MUC13 in colonic tumorigenesis and tumor progression. High-MUC13 expression is associated with poor survival in two independent patient cohorts. In a comprehensive series of in vivo experiments, we identified a critical role for MUC13 in the development of this malignancy, by promoting survival and proliferation of tumor-initiating cells and driving an immunosuppressive environment that protects tumors from checkpoint inhibitor immunotherapy. In Muc13-deficient mice, fewer tumors are generated after exposure to carcinogens and inflammation, they have markedly reduced β-catenin signaling, have more tumor-infiltrating CD103
Publisher: Informa UK Limited
Date: 08-11-2020
Publisher: Informa UK Limited
Date: 2021
Publisher: Wiley
Date: 12-2021
DOI: 10.1111/IMJ.15034
Abstract: This study examined the psychosocial burden of inflammatory bowel disease (IBD) in young people aged 15–25 years attending a tertiary specialist health centre for adolescents and young adults in Brisbane. To describe the impact of IBD on psychosocial well‐being in young people and to compare well‐being in the IBD cohort to well‐being among young people with other chronic conditions, with a view to identifying characteristics and challenges unique to those with IBD. Young people with IBD provided demographic information and psychosocial data through a cross‐sectional self‐report survey. Psychosocial data included the Kessler Psychological Distress Scale, Perceived Stress Scale, Brief Illness Perception Questionnaire, World Health Organisation Well‐being Index, Paediatric Quality of Life Inventory, Short Quality of Life Questionnaire for IBD, Multidimensional Scale of Perceived Social Support, Connor Davidson Resilience Scale 2 and the Multidimensional Health Locus of Control Scale. Surveys were collected from 51 young people with IBD and compared with surveys from 210 young people with juvenile rheumatic disease ( n = 31), phenylketonuria ( n = 21), cystic fibrosis ( n = 33), renal transplants ( n = 14) and craniomaxillofacial conditions ( n = 111). On the psychosocial domains, 41% of young people with IBD had poor well‐being and 37% were at risk of depression. When assessed against the comparison group, young people with IBD reported higher depressive symptoms ( P = 0.04), worse illness perceptions ( P 0.01) and lower internal locus of control ( P 0.01). Early recognition and treatment of depression and other psychosocial comorbidities within integrated pathways of care is crucial in adolescents and young adults with IBD and likely to improve the course of IBD and their overall health and well‐being. Interventions aimed at enhancing self‐efficacy and increasing public awareness are also likely to be helpful.
Publisher: BMJ
Date: 11-2020
DOI: 10.1136/BMJOPEN-2020-041140
Abstract: Mindfulness-based cognitive therapy (MBCT) is effective in treating psychosocial comorbidities in inflammatory bowel disease (IBD) however, there have been no qualitative studies of MBCT experiences among youth with IBD. We aimed to examine the experiences of youth with IBD and depression who completed an adapted MBCT group programme, and the impact of common psychotherapy and group factors. This mixed method qualitative study, nested within a randomised controlled trial (RCT) of MBCT for youth with IBD, employed thematic analysis of qualitative data from three focus groups and open-ended survey questions. The study was conducted in the outpatient department of a tertiary hospital for young adults in Brisbane, Australia. Out of sixty-four adolescents and young adults recruited to the RCT of MBCT for youth with IBD and depression, 29 completed the MBCT evaluation survey and 19 attended the focus groups. Four key themes emerged: ‘connectedness and shared understanding’, ‘growing in wisdom’, ‘therapeutic alliance’ and ‘barriers to mindfulness practice’. Participants described MBCT experiences as healing and transformative with the themes of connectedness, growing in wisdom and therapeutic alliance laying the foundation for therapeutic change. Main barriers included fatigue, depression, time and travel constraints. The study identified key themes facilitating the process of therapeutic change within the MBCT programme for youth with IBD and elucidated common and group psychotherapy factors underlying the key themes. Participants perceived connecting with peers as essential for learning mindfulness skills which in turn strengthened the connection. Study findings will facilitate interpretation of the results of the RCT of MBCT in youth with IBD and inform the design of future studies of MBCT in this cohort. ACTRN12617000876392 Results.
Publisher: Elsevier BV
Date: 2020
Publisher: Wiley
Date: 09-2018
DOI: 10.1111/JGH.14430
Publisher: Cold Spring Harbor Laboratory
Date: 12-10-2021
DOI: 10.1101/2021.10.04.462982
Abstract: Ulcerative colitis (UC) is a major form of inflammatory bowel disease with increasing global incidence. There is significant phenotypic heterogeneity defined by a range of clinical variables including age of onset and disease extent. Clinical outcomes range from long-term remission on minimal therapy to surgical resection. Close to 70% of UC risk can be attributed to genetics and understanding the genetic mechanisms contributing to this risk and disease heterogeneity is vital for understanding disease pathogenesis and improving patient outcomes through targeted screening and therapies. This study aims to characterise the genetic heterogeneity of UC by identifying genomic risk variants specific to mild and/or severe forms of UC, exploring variations in the effect size of known risk variants and assessing the clinical value of a genetic risk score (GRS). We conducted genome-wide association (GWA) analyses in 287 patients with mild UC, 311 patients with severe UC and 583 age- and gender-matched controls. Odds ratios (OR) for mild vs control, severe vs control and combined mild and severe UC vs control were calculated. Using the combined UC data, two independent loci in the HLA region reached genome-wide significance. An additional genome-wide significant signal on chromosome 1 was identified in severe cases only. OR for known risk loci varied between mild and severe patients and were similar to previously published results. Effect estimates from the most recent UC GWA meta-analysis were used to calculate a GRS for each in idual. A higher mean GRS was observed in both mild and severe UC cases compared to controls however, there was no difference between the mean GRS for mild and severe UC. Heterogeneity in effect sizes of UC associated variants between mild and severe disease burden suggests the presence of genetically distinct signatures. While large consortium data are needed to identify genome-wide significant variants, additional risk loci may be identified by targeted recruitment of in iduals with a history of severe disease. Ulcerative colitis (UC) is a chronic and often debilitating form of inflammatory bowel disease affecting approximately 0.3% of the population in industrialized economies. The disease displays significant clinical heterogeneity including age at presentation, disease severity, and the propensity to develop disease-related complications. Several previous studies have demonstrated the heritability of UC, identifying over 30 loci specific to the disease. The majority of these loci have small to modest effect sizes other than those within the Human Leucocyte Antigen (HLA) region on chromosome 6. Using stringent clinical criteria for defining mild and severe forms of UC in an extremes of phenotype approach, we undertook a genome wide association study in a dataset of 1222 participants to investigate genetic heterogeneity in this disease. We demonstrated substantial differences in genetic associations in severe UC as compared to mild UC. While over 2,000 SNPs achieved genome-wide significance in the severe UC analysis, none reached significance for mild UC. These results were reflected in significant differences in odds ratios. We identified Complement Factor B (CFB) as a potential susceptibility gene for severe UC in the Caucasian population with additional tissue gene expression demonstrating a positive correlation with disease severity.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-06-2003
Publisher: BMJ
Date: 07-2021
DOI: 10.1136/BMJOPEN-2020-043921
Abstract: Perianal fistulising Crohn’s disease (pfCD) can be somewhat treatment refractory. Higher infliximab trough levels (TLIs) may improve fistula healing rates however, it remains unclear whether escalating infliximab therapy to meet higher TLI targets using proactive, or routine, therapeutic drug monitoring (TDM) improves outcomes. This randomised controlled trial aimed to assess whether infliximab therapy targeting higher TLIs guided by proactive TDM improves outcomes compared with standard therapy. Patients with active pfCD will be randomised 1:1 to either the proactive TDM arm or standard dosing arm and followed up for 54 weeks. Patients in the proactive TDM arm will have infliximab dosing optimised to target higher TLIs. The targets will be TLI ≥ 25 µg/mL at week 2, ≥ 20 µg/mL at week 6 and ≥ 10 µg/mL during maintenance therapy. The primary objective will be fistula healing at week 32. Secondary objectives will include fistula healing, fistula closure, radiological fistula healing, patient-reported outcomes and economic costs up to 54 weeks. Patients in the standard dosing arm will receive conventional infliximab dosing not guided by TLIs (5 mg/kg at weeks 0, 2 and 6, and 5 mg/kg 8 weekly thereafter). Patients aged 18–80 years with pfCD with single or multiple externally draining complex perianal fistulas who are relatively naïve to infliximab treatment will be included. Patients with erting ileostomies or colostomies and pregnant or breast feeding will be excluded. Fifty-eight patients per arm will be required to detect a 25% difference in the primary outcome measure, with 138 patients needed to account for an estimated 6.1% primary non-response rate and 10% dropout rate. Results will be presented in peer-reviewed journals and international conferences. Ethics approval has been granted by the South Western Sydney Local Health District Human Research Ethics Committee in Australia. Australian New Zealand Clinical Trials Registry (ACTRN12621000023853) Pre-results.
Publisher: Cold Spring Harbor Laboratory
Date: 23-02-2021
DOI: 10.1101/2021.02.22.432185
Abstract: Adoptive regulatory T cell (Treg) therapy is being trialled for treatment of different autoimmune disorders, including inflammatory bowel diseases (IBD). In-depth understanding of the biological variability of Treg in the human blood may be required to improve IBD immune monitoring and treatment strategies. Through a combination of quantitative proteomic, multiparametric flow cytometry, RNA-sequencing data analysis and functional assays on Treg enriched from the blood of ulcerative colitis (UC) patients and healthy controls, we investigated the association between CD49f expression, Treg phenotype and function, and UC disease activity. High-dimensional analysis and filtering defined two distinct subsets of human Treg based on the presence or absence of CD49f with ergent transcriptional landscape and functional activities. CD49f negative Treg are enriched for functional Treg markers and present significantly increased suppressive capacity. In contrast, CD49f high Treg display a pro-inflammatory Th17-like phenotype and accumulate in the blood of UC patients. Dysregulation on CD49f Treg subsets in UC patients correlate with disease activity. Overall our findings uncover the importance of CD49f expression on Treg in physiological immunity and in pathological autoimmunity.
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.JPSYCHORES.2021.110594
Abstract: Mindfulness-based cognitive therapy (MBCT) is a promising adjunctive treatment for adolescents and young adults (AYAs) with Inflammatory Bowel Disease (IBD) and comorbid depression. This pilot randomised controlled trial (RCT) aimed to evaluate feasibility and efficacy of an adapted MBCT program for AYA, aged 16-29, with IBD. Sixty-four AYAs were randomly allocated to MBCT (n = 33) or treatment as usual (TAU) (n = 31). Primary outcome measure was the depression score on Depression, Anxiety and Stress Scale. Secondary outcomes included anxiety, stress, IBD-related quality of life, coping, mindfulness, post-traumatic growth, medication adherence, IBD activity, inflammatory markers, microbiome characteristics and brain functional connectivity. Study recruitment rate was 75%, retention rate 70%, and session attendance 92%. Intention to treat analyses revealed that, compared to TAU group, MBCT group had significantly lower depression (∆ = -6.0 95%CI = -10.8 to -1.2 P = 0.015) and stress (∆ = -5.1 95%CI = -10.1 to -0.0 P = 0.049), higher active coping (∆ = 1.0 %CI = 0.1-1.9 P = 0.022), and total mindfulness scores (∆ = 10.9 %CI = 1.1-20.8 P = 0.030) at 8 weeks (post-therapy), and improved coping by positive reframing (∆ = 1.1 %CI = 0.0-2.2 P = 0.043) and planning (∆ = 0.9 %CI = 0.0-1.9 P = 0.045), mindful awareness (∆ = 5.2. %CI = 2.0-8.5 P = 0.002) and total mindfulness scores (∆ = 10.8. %CI = 0.4-21.1 P = 0.042) at 20 weeks. On per protocol analysis, MBCT group had significantly lower depression (∆ = -6.3 95%CI = -11.4 to -1.2 P = 0.015), stress (∆ = -6.0 95%CI = -11.2 to -0.5 P = 0.032), increased active coping (∆ = 0.9 %CI = 0-1.7 P = 0.05) at 8 weeks, and mindful awareness (∆ = 5.4 95%CI = 2.1-8.6 P = 0.001) at 20 weeks. In AYAs with IBD, MBCT is feasible and beneficial in improving depression, stress, mindfulness and adaptive coping. It holds promise as an important component of integrated IBD care. Trial registration number ACTRN12617000876392, U1111-1197-7370 Pre-results.
Publisher: Oxford University Press (OUP)
Date: 02-2008
DOI: 10.1534/GENETICS.107.083923
Abstract: To further understand how the nematode Caenorhabditis elegans defends itself against pathogen attack, we analyzed enhanced pathogen resistance (epr) mutants obtained from a forward genetic screen. We also examined several well-characterized sterile mutants that exhibit an Epr phenotype. We found that sterility and pathogen resistance are highly correlated and that resistance in both epr and sterile mutants is dependent on DAF-16 activity. Our data indicate that a DAF-16-dependent signaling pathway distinct from previously described pathways is involved in the activation of genes that confer resistance to bacterial pathogens. The timing of DAF-16-dependent gene activation in sterile mutants coincides with the onset of embryonic development in wild-type animals, suggesting that signals from developing embryos normally downregulate the immune response.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JPSYCHORES.2018.11.010
Abstract: Mindfulness interventions are increasingly used as a part of integrated treatment in inflammatory bowel disease (IBD) but there are limited data and a lack of consensus regarding effectiveness. We explored the efficacy of mindfulness interventions compared to treatment as usual (TAU), or other psychotherapeutic interventions, in treating physical and psychosocial symptoms associated with IBD. We conducted a systematic review and meta-analysis of relevant randomized controlled trials (RCTs). We included a broad range of mindfulness interventions including mindfulness-based interventions and yoga, with no restrictions on date of publication, participants' age, language or publication type. We searched the following electronic databases: MEDLINE, EMBASE, PsycINFO, CINAHL and WHO ICTRP database. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines in conducting the review. We included eight studies in the meta-analysis. Mindfulness interventions showed a statistically significant effect on stress in both the short(SMD = -0.48 95%CI:-0.97, 0.00 P = .05), and long term(SMD = -0.55 95%CI:-0.78, -0.32 P < .00001), significant long term effects on depression (SMD = -0.36 95%CI:-0.66, -0.07 P = .02) and quality of life (SMD = 0.38 95%CI:0.08, 0.68 P = .01),and small but not statistically significant improvements in anxiety (SMD = -0.27 95%CI:-0.65, 0.11 P = .16).Effects on physical outcomes were equivocal and not statistically significant. Mindfulness interventions are effective in reducing stress and depression and improving quality of life and anxiety, but do not lead to significant improvements in the physical symptoms of IBD. Further research involving IBD-tailored interventions and more rigorously designed trials is warranted.
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: Australia
Start Date: 2012
End Date: 2013
Funder: Crohn's and Colitis Foundation of America
View Funded Activity