BACKGROUND:IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a protein that serves as a transcriptional regulator of bowel epithelium regeneration. We aimed to evaluate the safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856 in healthy participants and in patients with coeliac disease. METHODS:This study reports the results from a completed first-in-human, three-part, double-blind, randomised, placebo-controlled, clinical trial of IMU-856 in healthy participants and patients with coeliac disease done in Australia and New Zealand. In part A, healthy participants were enrolled in six cohorts and randomly assigned (3:1) using a block randomisation algorithm to receive single ascending doses of IMU-856 ranging from 10 mg to 160 mg or matching placebo. Based on the results from part A, three doses were selected for part B to evaluate the safety, tolerability, and pharmacokinetics of IMU-856 once daily for 14 days using the same randomisation algorithm. Part C enrolled patients with well controlled coeliac disease. Participants were centrally randomised 1:1:1 using an interactive web response system to receive either low dose or high dose of IMU-856 or placebo once daily for 28 days that included a 15-day gluten challenge starting on day 14. The primary objective was safety and tolerability of IMU-856. Safety analyses were done on all patients who received at least one dose of the study drug. The trial is registered with the ANZCTR registry (ACTRN12620000901909). FINDINGS:Between July 27, 2020, and Oct 28, 2022, 71 healthy participants were enrolled in part A and B and assigned to either placebo (n=19) or IMU-856 (n=52). In part A and B, the IMU-856 doses were 10 mg (n=6), 20 mg (n=6), 40 mg (n=13), 80 mg (n=12), 120 mg (n=4), 160 mg (n=11). 43 patients with coeliac disease were enrolled in part C and assigned to either placebo (n=14), IMU-856 80 mg (n=14), or IMU-856 160 mg (n=15). Treatment-emergent adverse events (TEAEs) occurred in 24 (73%) of 33 participants in part A and 15 (79%) of 19 participants in part B receiving any dose of IMU-856 compared with six (50%) of 12 participants in part A and five (71%) of seven participants in part B with placebo. TEAEs were mainly mild in severity. In part C, TEAEs occured in 26 (90%) of 29 patients on any dose of IMU-856 and ten (71%) of 14 receiving placebo; the most common TEAEs with any dose of IMU-856 by preferred term were headache (13 [45%] of 29), nausea (nine [31%]), diarrhoea (eight [28%]), and abdominal distension (seven [24%]). Two serious adverse events occurred with IMU-856 treatment (one in part B [bacterial myocarditis] and one in part C [biliary colic]), both of which were unrelated to IMU-856. No dose-limiting toxicities, systematic safety laboratory changes, or deaths occurred during the study. In part C, mean decrease in villous height was -20·9 μm (SD 34·8) among patients who received IMU-856 80 mg, -22·5 μm (51·1) among those who received IMU-856 160 mg, and -60·3 μm (52·2) among those who received placebo. INTERPRETATION:The favourable safety profile, along with preliminary activity, suggests that IMU-856 should be studied in future trials of coeliac disease. FUNDING:Immunic Australia.

Although not a technically challenging procedure, the correct insertion of a naso-enteric feeding tube is an important skill for the surgeon. The described technique has been refined over two decades, and is well tolerated, reliable and reproducible.

In order for any endoscopic procedure to be safe and successful, appropriate informed consent, correct patient preparation, and awareness of patient-specific factors must be taken into account. Although informed consent varies from country to country, most would agree that the consent process should include a detailed explanation of indications, potential risks, and benefits of the procedure. The endoscopist's knowledge of procedural indication not only determines what procedure is performed but also what interventions or treatment might be required during the procedure. Understanding the patient-specific factors will enable the endoscopist to determine the proper preparation and any specific modifications that might be required for an individual patient. This information, in turn, allows the endoscopist to select the most appropriate type of sedation, bowel preparation, need for antibiotics, and discontinuation of antiplatelet and anticoagulation therapies for the patient. There are special circumstances where specific preparations are required to ensure the safety and success of the procedure, which include endoscopies for foreign body removal or food bolus impaction, as well as acute upper and lower gastrointestinal bleeding. The decision to discontinue antithrombotic or anticoagulation therapy is primarily based on a comparison of the risk of bleeding from an endoscopic intervention to the risk of a thromboembolic event. Preparation for patients with hemostasis disorders should be individualized and performed in close collaboration with an experienced hematologist. This chapter aims to outline important key steps in preparing patients for various endoscopic procedures, with detailed discussions regarding the use of prophylactic antibiotics and the management of antithrombotic and anticoagulation medications.

IMPORTANCE High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity. OBJECTIVE To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool. DESIGN, SETTING, AND PARTICIPANTS A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017. INTERVENTIONS Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months. MAIN OUTCOMES AND MEASURES The primary outcome was steroid-free remission of UC, defined as a total Mayo score of <= 2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events. RESULTS Among 73 patients who were randomized (mean age, 39 years; women, 33 [45%]), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23%[95% CI, 4%-42%]; odds ratio, 5.0 [95% CI, 1.2-20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group. CONCLUSIONS AND RELEVANCE In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety.

A “treat‐to‐target” approach has been proposed for ulcerative colitis (UC), with a target of combined clinical and endoscopic remission. The aim of the study was to evaluate the extent to which proposed targets are achieved in real‐world care, along with clinician perceptions and potential challenges.

Background: A dysregulated tissue hypoxia response is central to ulcerative colitis (UC) pathogenesis.Hyperbaric oxygen therapy (HBOT) markedly increases tissue oxygen delivery and case series suggest a potential therapeutic benefit in UC.Hospitalized UC patients often require 2 nd line therapy (colectomy or anti-TNF therapy) for non-responsiveness to steroids.We investigated the therapeutic potential of HBOT as an adjunct to steroids for UC patients hospitalized for moderate-severe flares.Methods: UC patients hospitalized for moderatesevere flares (Mayo score ≥ 6, endoscopic sub-score ≥ 2) were block randomized across 3 sites in a 1:1 fashion to either steroids + daily HBOT (2.4 ATA @ 100% oxygen, 90 minute, 10 sessions) or steroids + daily sham hyperbaric air (1.2 ATA @ 21% oxygen, 90 minutes, 10 sessions).Sham patients were pressurized to 1.34 ATA to mimic pressure changes observed with HBOT, and then decompressed to 1.2 ATA for the remainder of the treatment.Patient blinding was maintained by covering all consoles and valves, and the hyperbaric teams followed an a priori established script to ensure similarity when treating both groups.The treating medical team, gastroenterologist, and surgeon were blinded to study assignment.Clinical assessments were performed by a blinded gastroenterologist.The primary outcome was the clinical remission rate at study day 5 (partial Mayo score ≤ 2 with no sub-score > 1).Secondary outcomes were: clinical response (reduction in partial Mayo score ≥ 2, rectal bleeding sub-score of 0-1) and progression to 2 nd line therapy (colectomy, anti-TNF therapy, cyclosporine).Results: A total of 18 patients (10 HBOT, 8 Sham) were randomized and treated.HBOT patients had a higher median baseline CRP level (81 vs. 10, p=0.07) with comparable mean baseline Mayo scores (9.9 vs. 10.9, p=0.14).The study met its primary end-point of clinical remission at study day 5 for HBOT vs sham (50% vs. 0%, p=0.04).Response to HBOT was observed as early as day 3 (60% vs. 13%, p=0.07), and a significantly higher proportion of HBOT patients achieved day 10 response (80% vs. 25%, p=0.05) and remission (50% vs. 0%, p=0.04).HBOT patients less often required progression to 2 nd line therapy (10% vs. 63%, p=0.04), or colectomy specifically (0% vs. 38%, p=0.07) while hospitalized.There were no adverse events.Conclusion: The use of HBOT as an adjunct to steroids for hospitalized UC patients suffering from moderate-severe flares resulted in higher rates of response and remission, and a reduction in rates of colectomy or progression to anti-TNF therapy while hospitalized.HBOT is safe and well tolerated, and further randomized trials are needed to confirm our findings.

Background: A “Treat to Target” (T2T) approach has been proposed for ulcerative colitis (UC), with a target of combined clinical and endoscopic remission. This has yet to be evaluated in real-world care. Methods: A multicentre, retrospective, cross-sectional review of patients with UC attending outpatient services in South Australia between Jul 2013 and Nov 2015 was conducted. Clinician assessment of disease activity and objective assessment (endoscopy, histology, and/or biomarkers) were recorded. An on-line survey of local Gastroenterologists evaluated their perceptions of T2T in UC. Multivariate logistic regression, Fisher's exact tests and Kappa statistics were performed. Results: Of 246 patients with UC, 61% were documented to be in clinical remission (normal bowel habit and no rectal bleeding), 35% documented to be in clinical and endoscopic remission (Mayo endoscopic sub-score ≤1), and 16% documented to be in concordant clinical, endoscopic and histological (Truelove and Richards' Index) remission. Figure 1. UC treatment targets achieved in real-world practice. *Clinical remission: normal stool frequency and absence of rectal bleeding. Endoscopic remission: Mayo endoscopic sub-scores of ≤1. Histological remission: Truelove and Richards Index remission. Table 1. UC treatment targets achieved in real-world practice. Overall proportions of patients in UC cohort (n=246) documented to attaining remission Rather than disease-related factors (extent/activity), clinician-related factors dominated outcome. The hospital location at which care was delivered and choice of therapy predicted combined clinical and endoscopic remission (OR 3.6, 95% CI 1.6–8.7, p<0.001; OR 3.3, 95% CI 1.1–12.5, p=0.04, respectively) Table 2. Clinical factors associated with documentation of combined clinical and endoscopic remission. Logistic regression analyses, n=218 (endoscopy during follow-up).*p<0.05 statistical significance; ^Any therapy analysed in a separate model Clinicians used C-reactive protein (CRP) more often than endoscopy as a biomarker for disease activity (75% vs 47%, p<0.001), despite observed random discordance between CRP and endoscopy (kappa 0.13, 95% CI 0.0–0.27). In the survey, 45/61 Gastroenterologists responded, with significant disparity between clinician estimates of targets achieved in practice and real-world data (p<0.001 for clinical and endoscopic remission) Figure 2. Clinician reported achievement of treatment targets in UC vs. real world data. Actual vs. expected proportions compared using a Fisher's exact test. ***p value ≤0.001. Conclusions: Most patients with UC do not achieve composite clinical and endoscopic remission in real-world practice. Clinicians overestimate their achievements and practice behaviour is a barrier to achieving stipulated targets.

Background and Aims: This study aims to evaluate the role of unsedated, ultrathin disposable gastroscopy (TDG) against conventional gastroscopy (CG) in the screening and surveillance of gastroesophageal varices (GEVs) in patients with liver cirrhosis.Method: Forty-eight patients (56.4 +/- 1.3 years; 38 male, 10 female) with liver cirrhosis referred for screening (n = 12) or surveillance (n = 36) of GEVs were prospectively enrolled. Unsedated gastroscopy was initially performed with TDG, followed by CG with conscious sedation. The 2 gastroscopies were performed by different endoscopists blinded to the results of the previous examination. Video recordings of both gastroscopies were validated by an independent investigator in a random, blinded fashion. Endpoints were accuracy and interobserver agreement of detecting GEVs, safety, and potential cost saving.Results: CG identified GEVs in 26 (54%) patients, 10 of whom (21%) had high-risk esophageal varices (HREV). Compared with CG, TDG had an accuracy of 92% for the detection of all GEVs, which increased to 100% for high-risk GEVs. The interobserver agreement for detecting all GEVs on TDG was 88% (kappa = 0.74). This increased to 94% (kappa = 0.82) for high-risk GEVs. There were no serious adverse events.Conclusions: Unsedated TDG is safe and has high diagnostic accuracy and interobserver reliability for the detection of GEVs. The use of clinic-based TDG would allow immediate determination of a follow-up plan, making it attractive for variceal screening and surveillance programs. (Clinical trial (ANZCTR) registration number: ACTRN12616001103459.)

Glasgow-Blatchford score (GBS) is the most widely validated scoring tool in predicting the risk of adverse clinical outcomes following an upper gastrointestinal haemorrhage (UGIH). Our recent study observed that no patients with a GBS ≤3 required endoscopic management, experienced rebleeding or death secondary to UGIH (Bryant et al. GIE 2013).

Although capsule endoscopy (CE) has proven to be superior to all of the diagnostic modalities in the evaluation of obscure gastrointestinal (GI) bleeding, it has no ability to obtain histology or to perform endoscopic interventions. Single balloon enteroscopy (SBE), on the other hand, has excellent therapeutic capacity but lower diagnostic yield given the success rate for retrograde approach is between 20-30%. Data on the outcomes of combined use of ante-grade SBE and CE for obscure GI bleeding in a single session are lacking.

Recurrent or refractory Clostridium difficile infection (CDI) has become an increasing problem in the past decade. Fecal microbiota transplant (FMT) is a highly efficacious treatment for recurrent CDI; however, a number of technical, logistical, and regulatory issues have hampered the development of an FMT capability at many hospitals. The development of a frozen stool bank of screened donor stool is an important step in the standardization of the procedure. This gives clinicians rapid access to thoroughly screened donor stool when needed, without the ethical and logistical problems associated with patient-selected donors. We describe the practicalities of establishing such a service using a stool bank of prescreened donor stool including detail regarding donor recruitment and screening, stool preparation, and delivery of the FMT.

In the treatment of Parkinson's disease (PD) Levodopa-carbidopa intestinal gel (LCIG) has been shown to have a higher efficacy when compared to an optimized oral regime. This is commonly administered to the jejunum via a percutaneous gastrostomy tube with a jejunal extension tube (PEG-J). The commonest complications of LCIG infusion are related to the tubing of the deliver system, which can result in cessation of PD treatment. We therefore trialed direct endoscopic jejunostomy (DEJ) in these patients.

Study aim: To assess the clinical outcomes of patients who received direct percutaneous endoscopic jejunostomy (DPEJ) for enteral feeding. Materials and methods: This is a 10-year cohort study in a single tertiary center. Main outcome measurements were technical success, and short- and long-term outcomes. DPEJ was attempted in 83 patients (51 men; 55 ± 2 years) for dysphagia (n = 35), gastroparesis with recurrent aspiration (n = 30), and levodopa drug infusion for severe Parkinson’s disease (n = 18). Results: DPEJ was successful in 75 (90 %) patients. All technical failures were related to the inability to find adequate trans-illumination, and were not influenced by BMI, age, gender, or indication. Peri-operative (30-day) adverse events occurred in 11 (13 %) patients, including wound infection (3), leakage around the stoma (4), minor bleeding requiring no intervention (2), and aspiration (1). There was one case (1.2 %) of gastric perforation after PEJ insertion for levodopa drug infusion trial. This 60-year-old woman required an emergency laparotomy with nil complications, and levodopa drug infusion recommenced successfully. One case of intestinal perforation (1.2 %) occurred after jejunostomy tube replacement at 6 months of insertion, which was successfully managed with surgery. There were no peri-operative deaths. Adequate delivery of enteral feeding or Duodopa drug was achieved in 66/73 (90 %) patients, with evidence of weight gain or improvement in Parkinson’s disease. Seven (8 %) continued to have clinical regurgitation but not aspiration. After a median follow-up of 84 months, 27 (33 %) patients died of their underlying diseases. Seven (8 %) had marked improvement in their underlying disease and had PEJ removed after 5 months (range 1 – 8 months). Limitations: Single center study. Conclusions: DPEJ is associated with a high technical success rate (90 %), a relatively low rate of peri-operative adverse events (13 %) and an improvement in long-term nutritional support in the majority of patients (90 %). DPEJ should be the procedure of choice to gain enteral access for feeding or drug delivery prior to considering surgery.

BACKGROUND AND STUDY AIMS:Colonoscopy with inhaled methoxyflurane (Penthrox) is well tolerated in unselected subjects and is not associated with respiratory depression. The aim of this prospective study was to compare the feasibility, safety, and post-procedural outcomes of portable methoxyflurane used as an analgesic agent during colonoscopy with those of anesthesia-assisted deep sedation (AADS) in subjects with morbid obesity and/or obstructive sleep apnea (OSA).PATIENTS AND METHODS:The outcomes of 140 patients with morbid obesity/OSA who underwent colonoscopy with either Penthrox inhalation (n = 85; 46 men, 39 women; mean age 57.2 ± 1.1 years) or AADS (n = 55; 27 men, 28 women; mean age, 54.9 ± 1.1 years) were prospectively assessed.RESULTS:All Penthrox-assisted colonoscopies were successful, without any requirement for additional intravenous sedation. Compared with AADS, Penthrox was associated with a shorter total procedural time (24 ± 1 vs. 52 ± 1 minutes, P < 0.001), a lower incidence of hypotension (3 /85 vs. 23 /55, P < 0.001), and a lower incidence of respiratory desaturation (0 /85 vs. 14 /55, P < 0.001). The patients in the Penthrox group recovered more rapidly and were discharged much earlier than those in the AADS group (27 ± 2 vs. 97 ± 5 minutes, P < 0.0001). Of those who underwent colonoscopy with Penthrox, 90 % were willing to receive Penthrox again for colonoscopy. More importantly, of the patients who underwent colonoscopy with Penthrox and had had AADS for previous colonoscopy, 82 % (28 /34) preferred to receive Penthrox for future colonoscopies. Penthrox-assisted colonoscopy cost significantly less than colonoscopy with AADS ($ 332 vs. $ 725, P < 0.001), with a cost saving of approximately $ 400 for each additional complication avoided.CONCLUSIONS:Compared with AADS, Penthrox is highly feasible and safe in patients with morbid obesity/OSA undergoing colonoscopy and is associated with fewer cardiorespiratory complications. Because of the advantages of this approach in regard to procedural time, recovery time, and cost benefit in comparison with AADS, further evaluation in a randomized trial is warranted.

AIMTo examine the available evidence on safety, competency and cost-effectiveness of nursing staff providing gastrointestinal (GI) endoscopy services.METHODSThe literature was searched for publications reporting nurse endoscopy using several databases and specific search terms. Studies were screened against eligibility criteria and for relevance. Initial searches yielded 74 eligible and relevant articles; 26 of these studies were primary research articles using original datasets relating to the ability of non-physician endoscopists. These publications included a total of 28883 procedures performed by non-physician endoscopists.RESULTSThe number of publications in the field of non-specialist gastrointestinal endoscopy reached a peak between 1999 and 2001 and has decreased thereafter. 17/26 studies related to flexible sigmoidoscopies, 5 to upper GI endoscopy and 6 to colonoscopy. All studies were from metropolitan centres with nurses working under strict supervision and guidance by specialist gastroenterologists. Geographic distribution of publications showed the majority of research was conducted in the United States (43%), the United Kingdom (39%) and the Netherlands (7%). Most studies conclude that after appropriate training nurse endoscopists safely perform procedures. However, in relation to endoscopic competency, safety or patient satisfaction, all studies had major methodological limitations. Patients were often not randomized (21/26 studies) and not appropriately controlled. In relation to cost-efficiency, nurse endoscopists were less cost-effective per procedure at year 1 when compared to services provided by physicians, due largely to the increased need for subsequent endoscopies, specialist follow-up and primary care consultations.CONCLUSIONContrary to general beliefs, endoscopic services provided by nurse endoscopists are not more cost effective compared to standard service models and evidence suggests the opposite. Overall significant shortcomings and biases limit the validity and generalizability of studies that have explored safety and quality of services delivered by non-medical endoscopists.

Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE as most people with BE never develop EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of BE and early EAC; prevalence, incidence, natural history, and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.