Faecal microbiota transplantation for sleep disturbance in post-acute COVID-19 syndrome.

BACKGROUND & AIMS: Post-acute COVID-19 syndrome (PACS) is associated with sleep disturbance but treatment options are limited. The aetiology of PACS may be secondary to alterations in the gut microbiome. Here, we report the efficacy of faecal microbiota transplantation (FMT) in alleviating post-COVID insomnia symptoms in a non-randomised, open-label prospective interventional study. METHODS: Between September 22, 2022 and May 22, 2023, we recruited 60 PACS patients with insomnia defined as Insomnia Severity Index (ISI) ≥ 8 and assigned them to the FMT group (FMT at weeks 0, 2, 4 and 8; n=30) or the control group (n=30). The primary outcome was clinical remission defined by an ISI of less than eight at 12 weeks. Secondary outcomes included changes in the Pittsburgh Sleep Quality Index (PSQI), Generalised Anxiety Disorder-7 scale (GAD-7), Epworth Sleepiness Scale (ESS), Multidimensional Fatigue Inventory (MFI), blood cortisol and melatonin, and gut microbiome analysis on metagenomic sequencing. RESULTS: At week 12, more patients in the FMT than the control group had insomnia remission (37.9% vs 10.0%; p=0.018). The FMT group showed a decrease in ISI score (p<0.0001), PSQI (p<0.0001), GAD-7 (p=0.0019), ESS (p=0.0057) and blood cortisol concentration (p=0.035) from baseline to week 12, but there was no significant change in the control group. There was enrichment of bacteria such as Gemmiger formicilis and depletion of microbial pathways producing menaquinol derivatives after FMT. Gut microbiome profile resembled that of the donor in FMT responders but not in non-responders at week 12. There was no serious adverse event. CONCLUSION: This pilot study showed that FMT could be effective and safe in alleviating post-COVID insomnia and further clinical trials are warranted. CLINICALTRIALS: gov identifier: NCT05556733.

Effect of Real-Time Computer-Aided Polyp Detection System (ENDO-AID) on Adenoma Detection in Endoscopists-in-Training: A Randomized Trial.

BACKGROUND: The effect of computer-aided polyp detection (CADe) on adenoma detection rate (ADR) among endoscopists-in-training remains unknown. METHODS: We performed a single-blind, parallel-group, randomized controlled trial in Hong Kong between April 2021 and July 2022 (NCT04838951). Eligible subjects undergoing screening/surveillance/diagnostic colonoscopies were randomized 1:1 to receive colonoscopies with CADe (ENDO-AID[OIP-1]) or not (control) during withdrawal. Procedures were performed by endoscopists-in-training with <500 procedures and <3 years' experience. Randomization was stratified by patient age, sex, and endoscopist experience (beginner vs intermediate level, <200 vs 200-500 procedures). Image enhancement and distal attachment devices were disallowed. Subjects with incomplete colonoscopies or inadequate bowel preparation were excluded. Treatment allocation was blinded to outcome assessors. The primary outcome was ADR. Secondary outcomes were ADR for different adenoma sizes and locations, mean number of adenomas, and non-neoplastic resection rate. RESULTS: A total of 386 and 380 subjects were randomized to CADe and control groups, respectively. The overall ADR was significantly higher in the CADe group than in the control group (57.5% vs 44.5%; adjusted relative risk, 1.41; 95% CI, 1.17-1.72; P < .001). The ADRs for <5 mm (40.4% vs 25.0%) and 5- to 10-mm adenomas (36.8% vs 29.2%) were higher in the CADe group. The ADRs were higher in the CADe group in both the right colon (42.0% vs 30.8%) and left colon (34.5% vs 27.6%), but there was no significant difference in advanced ADR. The ADRs were higher in the CADe group among beginner (60.0% vs 41.9%) and intermediate-level (56.5% vs 45.5%) endoscopists. Mean number of adenomas (1.48 vs 0.86) and non-neoplastic resection rate (52.1% vs 35.0%) were higher in the CADe group. CONCLUSIONS: Among endoscopists-in-training, the use of CADe during colonoscopies was associated with increased overall ADR. (ClinicalTrials.gov, Number: NCT04838951).

Timing of Endoscopy for Acute Upper Gastrointestinal Bleeding.

BACKGROUND: It is recommended that patients with acute upper gastrointestinal bleeding undergo endoscopy within 24 hours after gastroenterologic consultation. The role of endoscopy performed within time frames shorter than 24 hours has not been adequately defined. METHODS: To evaluate whether urgent endoscopy improves outcomes in patients predicted to be at high risk for further bleeding or death, we randomly assigned patients with overt signs of acute upper gastrointestinal bleeding and a Glasgow-Blatchford score of 12 or higher (scores range from 0 to 23, with higher scores indicating a higher risk of further bleeding or death) to undergo endoscopy within 6 hours (urgent-endoscopy group) or between 6 and 24 hours (early-endoscopy group) after gastroenterologic consultation. The primary end point was death from any cause within 30 days after randomization. RESULTS: A total of 516 patients were enrolled. The 30-day mortality was 8.9% (23 of 258 patients) in the urgent-endoscopy group and 6.6% (17 of 258) in the early-endoscopy group (difference, 2.3 percentage points; 95% confidence interval [CI], -2.3 to 6.9). Further bleeding within 30 days occurred in 28 patients (10.9%) in the urgent-endoscopy group and in 20 (7.8%) in the early-endoscopy group (difference, 3.1 percentage points; 95% CI, -1.9 to 8.1). Ulcers with active bleeding or visible vessels were found on initial endoscopy in 105 of the 158 patients (66.4%) with peptic ulcers in the urgent-endoscopy group and in 76 of 159 (47.8%) in the early-endoscopy group. Endoscopic hemostatic treatment was administered at initial endoscopy for 155 patients (60.1%) in the urgent-endoscopy group and for 125 (48.4%) in the early-endoscopy group. CONCLUSIONS: In patients with acute upper gastrointestinal bleeding who were at high risk for further bleeding or death, endoscopy performed within 6 hours after gastroenterologic consultation was not associated with lower 30-day mortality than endoscopy performed between 6 and 24 hours after consultation. (Funded by the Health and Medical Fund of the Food and Health Bureau, Government of Hong Kong Special Administrative Region; ClinicalTrials.gov number, NCT01675856.).

Effectiveness of prophylactic clipping in preventing postpolypectomy bleeding in aspirin users: a propensity-score analysis.

BACKGROUND AND AIMS: Antithrombotic use is a significant risk factor of postpolypectomy bleeding (PPB). Evidence of prophylactic clipping is only available for proximal and large colonic lesions in the general population. Dedicated studies to examine the benefit of prophylactic clipping in patients on aspirin remain scarce. METHODS: A propensity score-weighted retrospective cohort study was performed in a tertiary referral center from January 2018 to September 2021. Patients who received aspirin and underwent colonoscopic polypectomy, EMR, or endoscopic submucosal dissection were included. Data on baseline demographics, medications, and endoscopic factors (polyp number, size, location, and morphology; resection method; and prophylactic clipping) were captured. Propensity score-weighted models were developed between prophylactic clipping and no clipping groups. The primary outcome was delayed PPB within 30 days, with a composite endpoint consisting of repeated colonoscopy for hemostasis, requirement of blood transfusion, or hemoglobin drop >2 g/dL. RESULTS: A total of 1373 patients with 3952 polyps were included. Baseline characteristics were balanced between the 2 groups. In the multivariate analysis, the largest polyp size was a significant risk factor for PPB (odds ratio, 1.07; 95% confidence interval, 1.02-1.11; P = .002). Prophylactic clipping was not associated with a reduced risk of PPB (odds ratio, 1.34; 95% confidence interval, .83-2.18; P = .240) and did not show any risk reduction in subgroups with different polyp sizes and locations and endoscopic resection techniques. CONCLUSIONS: Prophylactic clipping was not associated with a lower risk of PPB in aspirin users after endoscopic resection of colorectal polyps. Aspirin use should not be regarded as the only factor for the routine use of prophylactic clips.

Timing of endoscopy for acute upper gastrointestinal bleeding: a territory-wide cohort study.

OBJECTIVE: While it is recommended that patients presenting with acute upper gastrointestinal bleeding (AUGIB) should receive endoscopic intervention within 24 hours, the optimal timing is still uncertain. We aimed to assess whether endoscopy timing postadmission would affect outcomes. DESIGN: We conducted a retrospective, territory-wide, cohort study with healthcare data from all public hospitals in Hong Kong. Adult patients (age ≥18) that presented with AUGIB between 2013 and 2019 and received therapeutic endoscopy within 48 hours (n=6474) were recruited. Patients were classified based on endoscopic timing postadmission: urgent (t≤6), early (6

Effectiveness of prophylactic clipping in preventing postpolypectomy bleeding in oral anticoagulant users: a propensity-score analysis.

BACKGROUND AND AIMS: Evidence of prophylactic clipping is inconsistent except for proximal and large colonic lesions in the general population. Although warfarin and direct oral anticoagulants (DOACs) are significant risk factors of postpolypectomy bleeding (PPB), dedicated studies to examine the benefit of prophylactic clipping in these high-risk patients remain limited. METHODS: We performed a propensity score-weighted retrospective cohort study from 2012 to 2020. Patients who received an oral anticoagulant and underwent colonoscopic polypectomy were included. Data were collected on baseline demographics, medications (anticoagulant, antiplatelet, and heparin bridging), and endoscopies (polyp number, location, size, morphology, histopathology, resection method and prophylactic clipping). Propensity-score models with inverse probability of treatment weighting were developed between prophylactic clipping and no clipping groups. Unbalanced variables were included in a doubly robust model with multivariate analysis. The primary outcome was clinically significant delayed PPB, defined as a composite endpoint of hemoglobin drop ≥2 g/dL, blood transfusion, or repeat colonoscopy for hemostasis within 30 days. RESULTS: Five hundred forty-seven patients with 1485 polyps were included. Prophylactic clipping was not associated with a reduced risk of PPB (odds ratio [OR], 1.19; 95% confidence interval [CI], .73-1.95; P = .497). The hot resection method was associated with a significantly higher risk of PPB (OR, 9.76; 95% CI, 3.94-32.60; P < .001) compared with cold biopsy or snare polypectomy. In a subgroup analysis, prophylactic clipping was associated with a lower PPB risk in patients on DOACs (OR, .36; 95% CI, .16-.82; P = .015). CONCLUSIONS: Prophylactic clipping was not associated with an overall reduced risk of PPB in patients on oral anticoagulants. The use of cold snare polypectomy should be maximized in anticoagulated patients.

Efficacy of international web-based educational intervention in the detection of high-risk flat and depressed colorectal lesions higher (CATCH project) with a video: Randomized trial.

OBJECTIVES: Three subcategories of high-risk flat and depressed lesions (FDLs), laterally spreading tumors non-granular type (LST-NG), depressed lesions, and large sessile serrated lesions (SSLs), are highly attributable to post-colonoscopy colorectal cancer (CRC). Efficient and organized educational programs on detecting high-risk FDLs are lacking. We aimed to explore whether a web-based educational intervention with training on FIND clues (fold deformation, intensive stool/mucus attachment, no vessel visibility, and demarcated reddish area) may improve the ability to detect high-risk FDLs. METHODS: This was an international web-based randomized control trial that enrolled non-expert endoscopists in 13 Asian countries. The participants were randomized into either education or non-education group. All participants took the pre-test and post-test to read 60 endoscopic images (40 high-risk FDLs, five polypoid, 15 no lesions) and answered whether there was a lesion. Only the education group received a self-education program (video and training questions and answers) between the tests. The primary outcome was a detection rate of high-risk FDLs. RESULTS: In total, 284 participants were randomized. After excluding non-responders, the final data analyses were based on 139 participants in the education group and 130 in the non-education group. The detection rate of high-risk FDLs in the education group significantly improved by 14.7% (66.6-81.3%) compared with -0.8% (70.8-70.0%) in the non-education group. Similarly, the detection rate of LST-NG, depressed lesions, and large SSLs significantly increased only in the education group by 12.7%, 12.0%, and 21.6%, respectively. CONCLUSION: Short self-education focusing on detecting high-risk FDLs was effective for Asian non-expert endoscopists. (UMIN000042348).

Treatment of upper gastrointestinal bleeding in 2020: New techniques and outcomes.

The clinical outcome of upper gastrointestinal bleeding has improved due to advances in endoscopic therapy and standardized peri-endoscopy care. Apart from validating clinical scores, artificial intelligence-assisted machine learning models may play an important role in risk stratification. While standard endoscopic treatments remain irreplaceable, novel endoscopic modalities have changed the landscape of management. Over-the-scope clips have high success rates as rescue or even first-line treatments in difficult-to-treat cases. Hemostatic powder is safe and easy to use, which can be useful as temporary control with its high immediate hemostatic ability. After endoscopic hemostasis, Doppler endoscopic probe can offer an objective measure to guide the treatment endpoint. In refractory bleeding, angiographic embolization should be considered before salvage surgery. In variceal hemorrhage, banding ligation and glue injection are first-line treatment options. Endoscopic ultrasound-guided therapy is gaining popularity due to its capability of precise localization for treatment targets. A self-expandable metal stent may be considered as an alternative option to balloon tamponade in refractory bleeding. Transjugular intrahepatic portosystemic shunting should be reserved as salvage therapy. In this article, we aim to provide an evidence-based comprehensive review of the major advancements in endoscopic hemostatic techniques and clinical outcomes.

Prevention of recurrent idiopathic gastroduodenal ulcer bleeding: a double-blind, randomised trial.

OBJECTIVE: Patients with a history of Helicobacter pylori-negative idiopathic bleeding ulcers have a considerable risk of recurrent ulcer complications. We hypothesised that a proton pump inhibitor (lansoprazole) is superior to a histamine 2 receptor antagonist (famotidine) for the prevention of recurrent ulcer bleeding in such patients. DESIGN: In this industry-independent, double-blind, randomised trial, we recruited patients with a history of idiopathic bleeding ulcers. After ulcer healing, we randomly assigned (1:1) patients to receive oral lansoprazole 30 mg or famotidine 40 mg daily for 24 months. The primary endpoint was recurrent upper GI bleeding within 24 months, analysed in the intention-to-treat population as determined by an independent adjudication committee. RESULTS: Between 2010 and 2018, we enrolled 228 patients (114 patients in each study group). Recurrent upper GI bleeding occurred in one patient receiving lansoprazole (duodenal ulcer) and three receiving famotidine (two gastric ulcers and one duodenal ulcer). The cumulative incidence of recurrent upper GI bleeding in 24 months was 0.88% (95% CI 0.08% to 4.37%) in the lansoprazole arm and 2.63% (95% CI 0.71% to 6.91%) in the famotidine arm (p=0.313; crude HR 0.33, 95% CI 0.03 to 3.16, p=0.336). None of the patients who rebled used aspirin, non-steroidal anti-inflammatory drugs or other antithrombotic drugs. CONCLUSION: This 2-year, double-blind randomised trial showed that among patients with a history of H. pylori-negative idiopathic ulcer bleeding, recurrent bleeding rates were comparable between users of lansoprazole and famotidine, although a small difference in efficacy cannot be excluded. TRIAL REGISTRATION NUMBER: NCT01180179; Results.

Microbiota, Obesity and NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly important cause of chronic liver disease globally. Similar to metabolic syndrome and obesity, NAFLD is associated with alternations in the gut microbiota and its related biological pathways. While the exact pathophysiology of NAFLD remains largely unknown, changes in intestinal inflammation, gut permeability, energy harvest, anaerobic fermentation and insulin resistance have been described. In this chapter, we review the relationship between the gut microbiota, obesity and NAFLD, and highlight potential ways to modify the gut microbiota to help managing NAFLD patients.

The gut microbiome associates with phenotypic manifestations of post-acute COVID-19 syndrome.

The mechanisms underlying the many phenotypic manifestations of post-acute COVID-19 syndrome (PACS) are poorly understood. Herein, we characterized the gut microbiome in heterogeneous cohorts of subjects with PACS and developed a multi-label machine learning model for using the microbiome to predict specific symptoms. Our processed data covered 585 bacterial species and 500 microbial pathways, explaining 12.7% of the inter-individual variability in PACS. Three gut-microbiome-based enterotypes were identified in subjects with PACS and associated with different phenotypic manifestations. The trained model showed an accuracy of 0.89 in predicting individual symptoms of PACS in the test set and maintained a sensitivity of 86% and a specificity of 82% in predicting upcoming symptoms in an independent longitudinal cohort of subjects before they developed PACS. This study demonstrates that the gut microbiome is associated with phenotypic manifestations of PACS, which has potential clinical utility for the prediction and diagnosis of PACS.

A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Post-acute COVID-19 syndrome (PACS) affects over 65 million individuals worldwide but treatment options are scarce. We aimed to assess a synbiotic preparation (SIM01) for the alleviation of PACS symptoms. METHODS: In this randomised, double-blind, placebo-controlled trial at a tertiary referral centre in Hong Kong, patients with PACS according to the US Centers for Disease Control and Prevention criteria were randomly assigned (1:1) by random permuted blocks to receive SIM01 (10 billion colony-forming units in sachets twice daily) or placebo orally for 6 months. Inclusion criterion was the presence of at least one of 14 PACS symptoms for 4 weeks or more after confirmed SARS-CoV-2 infection, including fatigue, memory loss, difficulty in concentration, insomnia, mood disturbance, hair loss, shortness of breath, coughing, inability to exercise, chest pain, muscle pain, joint pain, gastrointestinal upset, or general unwellness. Individuals were excluded if they were immunocompromised, were pregnant or breastfeeding, were unable to receive oral fluids, or if they had received gastrointestinal surgery in the 30 days before randomisation. Participants, care providers, and investigators were masked to group assignment. The primary outcome was alleviation of PACS symptoms by 6 months, assessed by an interviewer-administered 14-item questionnaire in the intention-to-treat population. Forward stepwise multivariable logistical regression was performed to identify predictors of symptom alleviation. The trial is registered with ClinicalTrials.gov, NCT04950803. FINDINGS: Between June 25, 2021, and Aug 12, 2022, 463 patients were randomly assigned to receive SIM01 (n=232) or placebo (n=231). At 6 months, significantly higher proportions of the SIM01 group had alleviation of fatigue (OR 2·273, 95% CI 1·520-3·397, p=0·0001), memory loss (1·967, 1·271-3·044, p=0·0024), difficulty in concentration (2·644, 1·687-4·143, p<0·0001), gastrointestinal upset (1·995, 1·304-3·051, p=0·0014), and general unwellness (2·360, 1·428-3·900, p=0·0008) compared with the placebo group. Adverse event rates were similar between groups during treatment (SIM01 22 [10%] of 232 vs placebo 25 [11%] of 231; p=0·63). Treatment with SIM01, infection with omicron variants, vaccination before COVID-19, and mild acute COVID-19, were predictors of symptom alleviation (p<0·0036). INTERPRETATION: Treatment with SIM01 alleviates multiple symptoms of PACS. Our findings have implications on the management of PACS through gut microbiome modulation. Further studies are warranted to explore the beneficial effects of SIM01 in other chronic or post-infection conditions. FUNDING: Health and Medical Research Fund of Hong Kong, Hui Hoy and Chow Sin Lan Charity Fund, and InnoHK of the HKSAR Government. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Longitudinal Evaluation of Gut Bacteriomes and Viromes after Fecal Microbiota Transplantation for Eradication of Carbapenem-Resistant Enterobacteriaceae.

Understanding the role of fecal microbiota transplantation (FMT) in the decolonization of multidrug-resistant organisms (MDRO) is critical. Specifically, little is known about virome changes in MDRO-infected subjects treated with FMT. Using shotgun metagenomic sequencing, we characterized longitudinal dynamics of the gut virome and bacteriome in three recipients who successfully decolonized carbapenem-resistant Enterobacteriaceae (CRE), including Klebsiella spp. and Escherichia coli, after FMT. We observed large shifts of the fecal bacterial microbiota resembling a donor-like community after transfer of a fecal microbiota dominated by the genus Ruminococcus. We found a substantial expansion of Klebsiella phages after FMT with a concordant decrease of Klebsiella spp. and striking increase of Escherichia phages in CRE E. coli carriers after FMT. We also observed the CRE elimination and similar evolution of Klebsiella phage in mice, which may play a role in the collapse of the Klebsiella population after FMT. In summary, our pilot study documented bacteriome and virome alterations after FMT which mediate many of the effects of FMT on the gut microbiome community. IMPORTANCE Fecal microbiota transplantation (FMT) is an effective treatment for multidrug-resistant organisms; however, introducing a complex mixture of microbes also has unknown consequences for landscape features of gut microbiome. We sought to understand bacteriome and virome alterations in patients undergoing FMT to treat infection with carbapenem-resistant Enterobacteriaceae. This finding indicates that transkingdom interactions between the virome and bacteriome communities may have evolved in part to support efficient FMT for treating CRE.

Endoscopic Diagnosis and Treatment of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a deadly disease, partly because it is often diagnosed late in disease stage. An accurate early diagnosis by endoscopy could detect advanced carcinoma as well as curable dysplasia and early ESCC. This could save patients from incurable advanced malignancy. Important progress has been made in high-quality endoscopic diagnosis, including magnifying endoscopy, narrowband imaging, and other image enhancement, as well as in techniques in endoscopic resection. These emerging techniques will aid the early diagnosis of ESCC that lead to higher chance of curing the cancer.