Publications by authors named "Simon Ghaly"

22 Publications

  • Page 1 of 1

Australia IBD Microbiome (AIM) Study: protocol for a multicentre longitudinal prospective cohort study.

BMJ Open 2021 02 16;11(2):e042493. Epub 2021 Feb 16.

Microbiome Research Centre, University of New South Wales, Sydney, New South Wales, Australia

Introduction: Crohn's disease and ulcerative colitis are common chronic idiopathic inflammatory bowel diseases (IBD), which cause considerable morbidity. Although the precise mechanisms of disease remain unclear, evidence implicates a strong multidirectional interplay between diet, environmental factors, genetic determinants/immune perturbations and the gut microbiota. IBD can be brought into remission using a number of medications, which act by suppressing the immune response. However, none of the available medications address any of the underlying potential mechanisms. As we understand more about how the microbiota drives inflammation, much interest has focused on identifying microbial signals/triggers in the search for effective therapeutic targets. We describe the establishment of the Australian IBD Microbiota (AIM) Study, Australia's first longitudinal IBD bioresource, which will identify and correlate longitudinal microbial and metagenomics signals to disease activity as evaluated by validated clinical instruments, patient-reported surveys, as well as biomarkers. The AIM Study will also gather extensive demographic, clinical, lifestyle and dietary data known to influence microbial composition in order to generate a more complete understanding of the interplay between patients with IBD and their microbiota.

Methods: The AIM Study is an Australian multicentre longitudinal prospective cohort study, which will enrol 1000 participants; 500 patients with IBD and 500 healthy controls over a 5-year period. Assessment occurs at 3 monthly intervals over a 24-month period. At each assessment oral and faecal samples are self-collected along with patient-reported outcome measures, with clinical data also collected at baseline, 12 and 24 months. Intestinal tissue will be sampled whenever a colonoscopy is performed. Dietary intake, general health and psychological state will be assessed using validated self-report questionnaires. Samples will undergo metagenomic, transcriptomic, proteomic, metabolomic and culturomic analyses. Omics data will be integrated with clinical data to identify predictive biomarkers of response to therapy, disease behaviour and environmental factors in patients with IBD.

Ethics And Dissemination: Ethical approval for this study has been obtained from the South Eastern Sydney Local Health District Research Ethics Committee (HREC 2019/ETH11443). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals.

Trial Registration Number: ACTRN12619000911190.
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http://dx.doi.org/10.1136/bmjopen-2020-042493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888320PMC
February 2021

The Role of Diet in the Pathogenesis and Management of Inflammatory Bowel Disease: A Review.

Nutrients 2020 Dec 31;13(1). Epub 2020 Dec 31.

St Vincent's Clinical School, UNSW, Sydney 2052, Australia.

Inflammatory bowel diseases, which include ulcerative colitis and Crohn's disease, are chronic relapsing and remitting inflammatory diseases of the gastrointestinal tract that are increasing in prevalence and incidence globally. They are associated with significant morbidity, reduced quality of life to individual sufferers and are an increasing burden on society through direct and indirect costs. Current treatment strategies rely on immunosuppression, which, while effective, is associated with adverse events. Epidemiological evidence suggests that diet impacts the risk of developing IBD and modulates disease activity. Using diet as a therapeutic option is attractive to patients and clinicians alike due to its availability, low cost and few side effects. Diet may influence IBD risk and disease behaviour through several mechanisms. Firstly, some components of the diet influence microbiota structure and function with downstream effects on immune activity. Secondly, dietary components act to alter the structure and permeability of the mucosal barrier, and lastly dietary elements may have direct interactions with components of the immune response. This review will summarise the mechanisms of diet-microbial-immune system interaction, outline key studies examining associations between diet and IBD and evidence demonstrating the impact of diet on disease control. Finally, this review will outline current prescribed dietary therapies for active CD.
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http://dx.doi.org/10.3390/nu13010135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823614PMC
December 2020

Switching Australian patients with moderate to severe inflammatory bowel disease from originator to biosimilar infliximab: a multicentre, parallel cohort study.

Med J Aust 2021 02 17;214(3):128-133. Epub 2020 Oct 17.

Fiona Stanley Hospital, Perth, WA.

Objective: To examine whether non-medical switching of patients with inflammatory bowel disease (IBD) from originator infliximab to a biosimilar (CT-P13, Inflectra) is safe and clinically non-inferior to continued treatment with originator infliximab.

Design: Prospective, open label, multicentre, parallel cohort, non-inferiority study in seven Australian hospitals over 48 weeks, May 2017 - October 2019.

Participants: Adults (18 years or older) with IBD receiving maintenance originator infliximab (Remicade) who had been in steroid-free clinical remission for at least 12 weeks.

Intervention: Managed program for switching patients in four hospitals from originator to biosimilar infliximab (CT-P13); patients in three other hospitals continued to receive originator infliximab (control).

Main Outcome Measures: Clinical disease worsening requiring infliximab dose escalation or change in therapy.

Results: The switch group included 204 patients, the control group 141 patients with IBD. Ten patients in the control group (7%) and 16 patients switched to CT-P13 (8%) experienced clinical deterioration; the adjusted risk difference (control v switch group) was -1.1 percentage points (95% CI, -6.1 to 8.2 percentage points), within our pre-specified non-inferiority margin of 15 percentage points. Serious adverse events leading to infliximab discontinuation were infrequent in both the switch (six, 3%) and control (six, 4%) groups.

Conclusion: Switching patients with IBD from originator to biosimilar infliximab is safe and non-inferior to continuing treatment with originator infliximab. Moreover, the introduction of biosimilar infliximab, by increasing market competition, has resulted in substantial cost savings for the Pharmaceutical Benefits Scheme.
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http://dx.doi.org/10.5694/mja2.50824DOI Listing
February 2021

Myocarditis in Crohn's disease: a case report.

Eur Heart J Case Rep 2020 Aug 8;4(4):1-6. Epub 2020 Jul 8.

Department of Cardiology, St Vincent's Hospital, 390 Victoria Street, Darlinghurst, Sydney, 2010 NSW, Australia.

Background: Mobile valvular masses are often considered pathognomonic for infective endocarditis. We present a case of a young patient with mobile valvular masses in the context of myocarditis likely secondary to active ileal Crohn's disease. Cardiac magnetic resonance (CMR) imaging was crucial in diagnosing and monitoring our patient.

Case Summary: A 27-year-old woman presented with pleuritic chest pain, dyspnoea, and a 3-day history of fevers. She also reported a 2-month history of intermittent visual loss in her right eye. She had a history of histologically proven ileal Crohn's disease, diagnosed 5 months prior. She was haemodynamically unstable on presentation. Abnormalities on a transthoracic echocardiogram necessitated a transoesophageal echocardiogram. After blood cultures were sent, the patient was commenced on empirical treatment for infective endocarditis with gentamicin and flucloxacillin. Eight days after her initial presentation, all blood cultures remained negative and she was changed to empirical treatment for culture negative endocarditis with ceftriaxone and vancomycin, according to local protocol. Despite 8 days of treatment for infective endocarditis she remained febrile. A CMR was organized on Day 9 and this showed myocarditis, which changed the treatment paradigm. She responded swiftly to steroids and anti-coagulation.

Discussion: In this case, echo-dense valvular lesions are not pathognomonic for infective endocarditis and a careful diagnostic process involving multi-modality imaging, including CMR, occurred to arrive at a diagnosis of myocarditis likely secondary to Crohn's disease.
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http://dx.doi.org/10.1093/ehjcr/ytaa120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501932PMC
August 2020

Vedolizumab for ulcerative colitis: Real world outcomes from a multicenter observational cohort of Australia and Oxford.

World J Gastroenterol 2020 Aug;26(30):4428-4441

Centre for Inflammatory Bowel Diseases, St John of God Hospital, Subiaco 6008, Western Australia, Australia.

Background: Vedolizumab (VDZ), a humanised monoclonal antibody that selectively inhibits integrins is approved for use in adult moderate to severe ulcerative colitis (UC) patients.

Aim: To assess the efficacy and safety of VDZ in the real-world management of UC in a large multicenter cohort involving two countries and to identify predictors of achieving remission.

Methods: A retrospective review of Australian and Oxford, United Kingdom data for UC patients. Clinical response at 3 mo, endoscopic remission at 6 mo and clinical remission at 3, 6 and 12 mo were assessed. Cox regression models and Kaplan Meier curves were performed to assess the time to remission, time to failure and the covariates influencing them. Safety outcomes were recorded.

Results: Three hundred and three UC patients from 14 centres in Australia and United Kingdom, [60% = 182, anti-TNF naïve] were included. The clinical response was 79% at 3 mo with more Australian patients achieving clinical response compared to Oxford (83% 70% = 0.01). Clinical remission for all patients was 56%, 62% and 60% at 3, 6 and 12 mo respectively. Anti-TNF naive patients were more likely to achieve remission than exposed patients at all the time points (3 mo 66% 40% < 0.001, 6 mo 73% 46% < 0.001, 12 mo 66% 51% = 0.03). More Australian patients achieved endoscopic remission at 6 mo compared to Oxford (69% 43% = 0.01). On multi-variate analysis, anti-TNF naïve patients were 1.8 (95%CI: 1.3-2.3) times more likely to achieve remission than anti-TNF exposed ( < 0.001). 32 patients (11%) had colectomy by 12 mo.

Conclusion: VDZ was safe and effective with 60% of UC patients achieving clinical remission at 12 mo and prior anti-TNF exposure influenced this outcome.
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http://dx.doi.org/10.3748/wjg.v26.i30.4428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438197PMC
August 2020

Practical management of inflammatory bowel disease patients during the COVID-19 pandemic: expert commentary from the Gastroenterological Society of Australia Inflammatory Bowel Disease faculty.

Intern Med J 2020 07;50(7):798-804

Department of Gastroenterology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has emerged as a public health emergency and challenged healthcare systems globally. In a minority of patients, SARS-CoV-2 manifests with a severe acute respiratory illness and currently there is insufficient data regarding the virulence of COVID-19 in inflammatory bowel disease patients taking immunosuppressive therapy. This review aims to summarise the current literature and provide guidance on the management of inflammatory bowel disease patients in the context of the COVID-19 pandemic in the Australasian setting.
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http://dx.doi.org/10.1111/imj.14889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405147PMC
July 2020

Australian consensus statements for the regulation, production and use of faecal microbiota transplantation in clinical practice.

Gut 2020 05 11;69(5):801-810. Epub 2020 Feb 11.

The University of Sydney, Sydney, New South Wales, Australia

Objective: Faecal microbiota transplantation (FMT) has proved to be an extremely effective treatment for recurrent 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.

Design: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1136/gutjnl-2019-320260DOI Listing
May 2020

Effects of UVR exposure on the gut microbiota of mice and humans.

Photochem Photobiol Sci 2020 Jan;19(1):20-28

Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.

Many alterations to the skin microbiome by exposure to UV radiation (UVR) have been postulated and may contribute to the ability of UVR phototherapy to regulate skin inflammatory diseases. Very recently, an effect of sub-erythemal narrowband UVB radiation (311 nm) on the gut microbiome of healthy individuals was reported. The relative abundance of Firmicutes and Proteobacteria increased in faecal samples of those receiving three exposures to narrowband UVB radiation; the Bacteroidetes phyla were reduced by UVB. In mice chronically exposed to sub-erythemal broadband UVR, similar faecal changes in Firmicutes and Bacteroidetes have been reported. Murine studies have allowed a further dissection of the relative ability of UVR and dietary vitamin D to modulate the gut microbiome by analysis of relative bacterial abundance in mice with similar 25-hydroxy vitamin D levels obtained by UVR exposure or from their diet, respectively. The studies of mice recovering from colitis suggested that dietary vitamin D could stimulate greater faecal abundance of Rikenellaceae, whilst exposure to UVR was necessary for changes to the abundance of Lachnospiraceae and Desulfovibrionaceae. Both human and murine studies report that multiple exposures to sub-erythemal UVR can increase the diversity of the gut microbiome, which in turn may be beneficial to the health of the host.
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http://dx.doi.org/10.1039/c9pp00443bDOI Listing
January 2020

Inflammatory bowel diseases: interrelationships between dietary vitamin D, exposure to UV radiation and the fecal microbiome.

Expert Rev Gastroenterol Hepatol 2019 Nov 7;13(11):1039-1048. Epub 2019 Nov 7.

Inflammation, Telethon Kids Institute, Nedlands, Australia.

: Environmental factors and an altered fecal microbiome are believed to be central to the pathogenesis of inflammatory bowel diseases (IBD). Vitamin D and ultraviolet radiation (UVR) are environmental factors that are associated by several pathways, including changes to the gastrointestinal microbiome, with the development and course of IBD.: This review explores the interaction of vitamin D, and UVR, with the intestinal innate and adaptive immune systems, and how they may influence the gut microbiome and the subsequent development, and progression, of IBD.: Vitamin D and UVR both regulate innate and adaptive immunity through a combination of common and independent mechanisms, with the overall effect being the promotion of immune tolerance. Vitamin D, and to a lesser extent UVR, can modify the gastrointestinal microbiome either directly, or through immune-mediated mechanisms and this may explain the effect on intestinal inflammation in animal models of IBD and some clinical studies. Thus, both vitamin D and UVR exposure can be considered potential 'master regulators' of gastrointestinal immunity, fine-tuning the complex interaction between genetics, host immunity and the gut microbiome. Further research and increased understanding of environment-host interactions is essential to achieving the ultimate goal of preventing and curing IBD.
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http://dx.doi.org/10.1080/17474124.2019.1685874DOI Listing
November 2019

Level of UV Exposure, Skin Type, and Age Are More Important than Thiopurine Use for Keratinocyte Carcinoma Development in IBD Patients.

Dig Dis Sci 2020 04 6;65(4):1172-1179. Epub 2019 Sep 6.

Centre of Inflammatory Bowel Diseases, St John of God Hospital, Subiaco, WA, Australia.

Background: Retrospective studies observe an increased risk of keratinocyte carcinomas (KCs) in patients with inflammatory bowel disease (IBD) on thiopurine (TP) medication. The role of traditional risk factors such as skin type and sun protection behavior has not been studied in this population. This study aimed to examine traditional KC risk factors and thiopurine use on skin cancer development in an IBD cohort.

Methods: Consecutive IBD patients were recruited from four specialist centers in Australia and New Zealand, each with varying UV exposure indices. Data pertaining to race, skin color, freckling and sun protection behavior, dose of TP therapy, and skin cancer development were elicited through a self-reported questionnaire.

Results: A total of 691 IBD patients were included with 62 reporting KC development. Thiopurine usage was similar among patients who developed skin cancer compared with those who did not (92% vs. 89%, p = 0.3). There was no statistically significant association between KC development and TP dose or 6-thioguanine nucleotide levels. In multivariate modeling, four factors were independently and significantly associated with KC: age over 61 years old versus less than 30 years old (OR 6.76; 95% CI 2.38-19.18), residing in Brisbane versus Christchurch (OR 3.3; 95% CI 1.6-6.8), never staying in the shade versus staying in the shade ≥ 50% of the time (OR 3.8; 95% CI 1.4-10.5), and having a skin type that never tanned versus other skin types (OR 6.9; 95% CI 2.9-16.0).

Conclusion: Skin type, age, and sun protection behavior are more important risk factors for KC development than thiopurine medication use in this IBD population.
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http://dx.doi.org/10.1007/s10620-019-05818-wDOI Listing
April 2020

Vitamin D metabolites are lower with active Crohn's disease and spontaneously recover with development of remission.

Therap Adv Gastroenterol 2019 26;12:1756284819865144. Epub 2019 Jul 26.

St Vincent's Hospital, Department of Gastroenterology, Sydney, Australia.

Background: Vitamin D deficiency is associated with active Crohn's disease (CD). However, it remains unclear if lower 25-hydroxyvitamin D [25(OH)D] concentration is the cause, or consequence, of intestinal inflammation. Existing literature has focused on circulating 25(OH)D rather than the active metabolite 1,25(OH)D, or its breakdown product, 24,25(OH)D. We aimed to characterise vitamin D metabolism in a cohort of patients with active and inactive CD.

Methods: Fifty-four patients with CD and not on corticosteroids or vitamin D supplements, were enrolled in a 6-month prospective cohort study. Sera were collected on enrolment and at 6 months and tested for 25(OH)D, 1,25(OH)D, 24,25(OH)D using liquid chromatography tandem mass spectroscopy as well as vitamin-D-binding protein.

Results: There were no differences in 25(OH)D or 1,25(OH)D levels between participants with active inactive disease. Levels of 24,25(OH)D were significantly lower in those with active compared with inactive disease (mean 3.9 6.0 µmol/l;  = 0.007) and therefore the ratio of 25(OH)D:24,25(OH)D was higher (mean 17.3 11.1;  = 0.001). In those patients with active disease who achieved remission, there was a mean increase in 25(OH)D of 32.3 nmol/l (i.e. to a level in the sufficient range) and 24,25(OH)D of 2.1 µmol/l. These increases were not seen in patients with persistently active or inactive disease.

Conclusion: Levels of 24,25(OH)D, but not 25(OH)D, were lower in patients with active CD, and spontaneously increased with resolution of underlying inflammation. The utility of 24,25(OH)D as a biomarker of disease activity and vitamin D status in CD warrants further exploration.
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http://dx.doi.org/10.1177/1756284819865144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661794PMC
July 2019

Pericardial Mesothelioma in a 35-Year-Old Male With Ulcerative Colitis.

Circ Cardiovasc Imaging 2019 12;12(1):e008659

Department of Cardiology (J.I., N.K.B., C.J.H.), University of New South Wales, Sydney, Australia.

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http://dx.doi.org/10.1161/CIRCIMAGING.118.008659DOI Listing
December 2019

Letter: vedolizumab drug concentrations in neonates following intrauterine exposure.

Aliment Pharmacol Ther 2018 12;48(11-12):1328-1330

St Vincent's Hospital, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/apt.15027DOI Listing
December 2018

Vitamin D C3-epimer levels are proportionally higher with oral vitamin D supplementation compared to ultraviolet irradiation of skin in mice but not humans.

J Steroid Biochem Mol Biol 2019 02 5;186:110-116. Epub 2018 Oct 5.

Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.

A proportion of circulating 25-hydroxy vitamin D (25(OH)D) undergoes epimerization to form C3-epi 25(OH)D and C3-epi 1,25(OH)D. These epimers have less calcaemic activity than non-epimerized metabolites and are not differentiated by many immunoassays when reporting total 25(OH)D levels. This study aimed to compare the effect of exposure to ultraviolet radiation (UVR) and oral vitamin D supplementation on vitamin D C3-epimer levels. C57Bl/6 female mice were fed either vitamin D-sufficient (vitamin D 2000 IU/kg) or -deficient diets (no vitamin D) for 4 weeks. Among the vitamin D-deficient group, the shaved backs of half were irradiated daily for 4 days with 1 kJ/m UVR, followed by twice weekly irradiation for 4 weeks. Despite similar 25(OH)D levels, the UV-irradiated group had a lower proportion of C3-epi 25(OH)D at week 7 (p < 0.05) and week 9 (p < 0.01). C3-epimer concentrations and %C3-epi 25(OH)D were also analysed in serum samples from two human clinical trials. These trials investigated the effect of high dose oral vitamin D supplementation and narrowband UVB phototherapy, respectively. Serum 25(OH)D and the %C3-epi 25(OH)D levels measured at 12 months after oral vitamin D supplementation were not significantly different to those measured at the time of maximal effect of phototherapy (2 months). Thus, the proportion of 25(OH)D that undergoes epimerization is greater with oral vitamin D supplementation than exposure to UVR in mice, but not in humans. This important difference between human and murine vitamin D metabolism warrants consideration when interpreting animal studies.
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http://dx.doi.org/10.1016/j.jsbmb.2018.10.002DOI Listing
February 2019

What is in our treasure chest? Australian pharmaceutical benefits scheme availability and criteria for prescribing biologics.

Authors:
Simon Ghaly

J Gastroenterol Hepatol 2018 Sep;33 Suppl 3:12-13

Department of Gastroenterology and Hepatology, St. Vincent's Hospital, Sydney, Australia.

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http://dx.doi.org/10.1111/jgh.14420DOI Listing
September 2018

Ultraviolet Irradiation of Skin Alters the Faecal Microbiome Independently of Vitamin D in Mice.

Nutrients 2018 Aug 11;10(8). Epub 2018 Aug 11.

Telethon Kids Institute, The University of Western Australia, Perth, WA 6008, Australia.

Reduced sunlight exposure has been associated with an increased incidence of Crohn's disease and ulcerative colitis. The effect of ultraviolet radiation (UVR) on the faecal microbiome and susceptibility to colitis has not been explored. C57Bl/6 female mice were fed three different vitamin D-containing diets for 24 days before half of the mice in each group were UV-irradiated (1 kJ/m²) for each of four days, followed by twice-weekly irradiation of shaved dorsal skin for 35 days. Faecal DNA was extracted and high-throughput sequencing of the 16S RNA gene performed. UV irradiation of skin was associated with a significant change in the beta-diversity of faeces compared to nonirradiated mice, independently of vitamin D. Specifically, members of phylum Firmicutes, including , were enriched, whereas members of phylum Bacteroidetes, such as Bacteroidales, were depleted. Expression of colonic increased by four-fold and decreased by five-fold, suggesting a UVR-induced anti-inflammatory effect. UV-irradiated mice, however, were not protected against colitis induced by dextran sodium sulfate (DSS), although distinct faecal microbiome differences were documented post-DSS between UV-irradiated and nonirradiated mice. Thus, skin exposure to UVR alters the faecal microbiome, and further investigations to explore the implications of this in health and disease are warranted.
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http://dx.doi.org/10.3390/nu10081069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116187PMC
August 2018

High Dose Vitamin D supplementation alters faecal microbiome and predisposes mice to more severe colitis.

Sci Rep 2018 07 31;8(1):11511. Epub 2018 Jul 31.

Telethon Kids Institute, The University of Western Australia, Perth, WA, Australia.

Vitamin D has been suggested as a possible adjunctive treatment to ameliorate disease severity in human inflammatory bowel disease. In this study, the effects of diets containing high (D++, 10,000 IU/kg), moderate (D+, 2,280 IU/kg) or no vitamin D (D-) on the severity of dextran sodium sulphate (DSS) colitis in female C57Bl/6 mice were investigated. The group on high dose vitamin D (D++) developed the most severe colitis as measured by blinded endoscopic (p < 0.001) and histologic (p < 0.05) assessment, weight loss (p < 0.001), drop in serum albumin (p = 0.05) and increased expression of colonic TNF-α (p < 0.05). Microbiota analysis of faecal DNA showed that the microbial composition of D++ control mice was more similar to that of DSS mice. Serum 25(OH)D levels reduced by 63% in the D++ group and 23% in the D+ group after 6 days of DSS treatment. Thus, high dose vitamin D supplementation is associated with a shift to a more inflammatory faecal microbiome and increased susceptibility to colitis, with a fall in circulating vitamin D occurring as a secondary event in response to the inflammatory process.
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http://dx.doi.org/10.1038/s41598-018-29759-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068189PMC
July 2018

UV Irradiation of Skin Enhances Glycolytic Flux and Reduces Migration Capabilities in Bone Marrow-Differentiated Dendritic Cells.

Am J Pathol 2017 Sep 11;187(9):2046-2059. Epub 2017 Jul 11.

Telethon Kids Institute, University of Western Australia, West Perth, Western Australia, Australia. Electronic address:

A systemic immunosuppression follows UV irradiation of the skin of humans and mice. In this study, dendritic cells (DCs) differentiating from the bone marrow (BM) of UV-irradiated mice had a reduced ability to migrate toward the chemokine (C-C motif) ligand 21. Fewer DCs also accumulated in the peritoneal cavity of UV-chimeric mice (ie, mice transplanted with BM from UV-irradiated mice) after injection of an inflammatory stimulus into that site. We hypothesized that different metabolic states underpin altered DC motility. Compared with DCs from the BM of nonirradiated mice, those from UV-irradiated mice produced more lactate, consumed more glucose, and had greater glycolytic flux in a bioenergetics stress test. Greater expression of 3-hydroxyanthranilate 3,4-dioxygenase was identified as a potential contributor to increased glycolysis. Inhibition of 3-hydroxyanthranilate 3,4-dioxygenase by 6-chloro-dl-tryptophan prevented both increased lactate production and reduced migration toward chemokine (C-C motif) ligand 21 by DCs differentiated from BM of UV-irradiated mice. UV-induced prostaglandin E has been implicated as an intermediary in the effects of UV radiation on BM cells. DCs differentiating from BM cells pulsed in vitro for 2 hours with dimethyl prostaglandin E were functionally similar to those from the BM of UV-irradiated mice. Reduced migration of DCs to lymph nodes associated with increased glycolytic flux may contribute to their reduced ability to initiate new immune responses in UV-irradiated mice.
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http://dx.doi.org/10.1016/j.ajpath.2017.06.003DOI Listing
September 2017

High Vitamin D-Binding Protein Concentration, Low Albumin, and Mode of Remission Predict Relapse in Crohn's Disease.

Inflamm Bowel Dis 2016 10;22(10):2456-64

*Harry Perkins Institute of Medical Research, School of Medicine and Pharmacology, University of Western Australia, Murdoch, Western Australia, Australia;†Telethon Kids Institute, University of Western Australia, Subiaco, Western Australia, Australia;‡UWA Centre for Applied Statistics, University of Western Australia, Western Australia, Crawley, Australia;§Department of Gastroenterology and Hepatology, Flinders Medical Centre, South Australia, Adelaide, Australia;‖Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Queensland, Brisbane, Australia; and¶Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco, Western Australia, Australia.

Background: Vitamin D (25(OH)D) deficiency occurs in active Crohn's disease (CD) and may be secondary to reduced sunlight exposure and oral intake. Vitamin D-binding protein (VDBP) levels, however, fluctuate less with season and sunlight. The aim, therefore, was to examine patients with CD in remission and determine any associations between VDBP, serum 25(OH)D, and the calculated free 25(OH)D concentrations with the risk of disease flare.

Methods: Subjects were identified from prospectively maintained inflammatory bowel disease databases at 3 teaching hospitals in Australia. Patients were in steroid-free clinical remission at the time of blood draw and were followed for at least 12 months. Total and epimer-25(OH)D3, VDBP concentrations, and genotypes were determined.

Results: A total of 309 patients with CD (46% men) met the inclusion criteria. A disease flare occurred in 100 (32.4%). Serum 25(OH)D3 was deficient (<50 nmol/L) in 36 (12%) and insufficient (50-75 nmol/L) in 107 (35%) patients. Total, free, and epimer-25(OH)D3 serum levels did not predict disease flare. Higher VDBP concentrations, however, significantly correlated with increased risk of disease flare (hazard ratio 1.2, 95% CI, 1.0-1.5). On multivariate analysis, VDBP concentration, low albumin, and medication-induced remission were significantly more associated with disease flare. VDBP genotypes were significantly associated with 25(OH)D and VDBP concentrations but not disease flare.

Conclusions: Vitamin D deficiency was uncommon in our patients with CD in remission, and serum 25(OH)D3 did not predict disease flare, whereas higher VDBP concentrations were significantly associated with disease flare. Further investigations to explore the possible mechanisms for this association are warranted.
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http://dx.doi.org/10.1097/MIB.0000000000000894DOI Listing
October 2016

Iron and vitamin D deficiency in inflammatory bowel disease.

Authors:
Simon Ghaly

J Gastroenterol Hepatol 2016 Jun;31 Suppl 1:27-8

Department of Gastroenterology and Hepatology, St. Vincent's Hospital, Sydney, Australia.

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http://dx.doi.org/10.1111/jgh.13359DOI Listing
June 2016

The role of vitamin D in gastrointestinal inflammation.

Expert Rev Gastroenterol Hepatol 2014 Nov 22;8(8):909-23. Epub 2014 Jul 22.

Centre for Inflammatory Bowel Diseases, Fremantle Hospital and School of Medicine and Pharmacology, University of Western Australia, Level 5, T Block, Alma St, Fremanlte, Western Australia 6159, Australia.

The emerging role of vitamin D as a regulator of both innate and adaptive immune responses has encouraged the investigation of its role in the pathogenesis of a variety of autoimmune conditions including the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Animal models consistently demonstrate that vitamin D significantly impacts on the modulation of astrointestinal inflammation, while epidemiological and observational data show an inverse relationship between vitamin D status and the onset/progression of Crohn's disease as well as the development of colorectal cancer. As vitamin D supplementation is readily available, at low cost, it is a very attractive potential therapeutic option. The biological plausibility for a role for vitamin D in inflammation modulation, the potential genetic links associated with vitamin D metabolism and the clinical aspects for it in IBD will be discussed.
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http://dx.doi.org/10.1586/17474124.2014.925796DOI Listing
November 2014

Audit of endometrial biopsy at outpatient hysteroscopy.

Aust N Z J Obstet Gynaecol 2008 Apr;48(2):202-6

Department of Endo-Gynaecology, Royal Hospital for Women, University of New South Wales, Sydney, New South Wales, Australia.

Background And Aim: Outpatient hysteroscopy (OPH) and endometrial biopsy (EMB) are less invasive alternatives to inpatient hysteroscopy and dilatation and curettage for assessment of the endometrium. Using local anaesthetic, the procedure is readily tolerated and can be completed in an ambulatory setting. This study aims to audit OPH and EMB conducted over three consecutive years with regard to the ability to complete the procedure and subsequent pathology.

Methods: Data were retrospectively collected from the medical records of patients who underwent OPH during the study period. Data collected included demography, medical history, procedure details and outcome. An indicative assessment of the resource requirements for provision of these services in an outpatient versus inpatient setting was also conducted based on published cost information.

Results: Between June 2003 to June 2006, 435 OPH were performed and 427 of these were available for audit. Four hundred and five (94.8%) of the procedures were successful. Sixty-five (18.8%) EMBs were reported to be insufficient, of which 41 (63%) were in postmenopausal women (P < 0.001). Women who presented with postmenopausal bleeding were significantly more likely to have an insufficient sample (P < 0.001). The Australian Refined Diagnosis Related Groups cost for inpatient hysteroscopy is $A1,786, including $A711 in theatre costs and $A258 in ward costs. These costs are not incurred with OPH.

Conclusion: This study indicates that hysteroscopy and EMB can be easily and successfully performed as an outpatient procedure in Australia. Pathology can be readily identified and management planned. Moreover, an opportunity exists for a reduction in resource use by utilising this procedure instead of inpatient hysteroscopy where possible.
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http://dx.doi.org/10.1111/j.1479-828X.2008.00834.xDOI Listing
April 2008