Effects of empagliflozin on liver fat in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus: A randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: We investigated whether empagliflozin reduces hepatic steatosis in patients with metabolic dysfunction-associated steatotic liver disease without diabetes mellitus. APPROACH AND RESULTS: This was an investigator-initiated, double-blind, randomized, placebo-controlled trial recruiting adult subjects from the community. Eligible subjects without diabetes mellitus (fasting plasma glucose < 7 mmol/L and HbA1c < 6.5%) who had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 5% were randomly allocated to receive empagliflozin 10 mg daily or placebo (1:1 ratio) for 52 weeks (end of treatment, EOT). MRI-PDFF was conducted at baseline and EOT. The primary outcome was the difference in change of MRI-PDFF between the 2 groups at EOT. Secondary outcomes were hepatic steatosis resolution (MRI-PDFF < 5%), alanine aminotransferase drop ≥ 17 U/L, MRI-PDFF decline ≥ 30%, a combination of both, and changes of anthropometric and laboratory parameters at EOT. All outcomes were based on intention-to-treat analysis. Of 98 recruited subjects (median age: 55.7 y [IQR:49.5-63.4]; male:54 [55.1%]), 97 (empagliflozin:49, placebo:48; median MRI-PDFF:9.7% vs 9.0%) had MRI-PDFF repeated at EOT. The Empagliflozin group had a greater reduction in median MRI-PDFF compared to the placebo group (-2.49% vs. -1.43%; p = 0.025), with a nonsignificant trend of resolution of hepatic steatosis (44.9% vs. 28.6%; p = 0.094). There was no significant difference in alanine aminotransferase drop ≥ 17 U/L (16.3% vs. 12.2%; p = 0.564), MRI-PDFF drop ≥ 30% (49.0% vs. 40.8%; p = 0.417), and composite outcome (8.2% vs. 8.2%; p = 1.000). Empagliflozin group had a greater drop in body weight (-2.7 vs. -0.2 kg), waist circumference (-2.0 vs. 0 cm), fasting glucose (-0.3 vs. 0 mmol/L), and ferritin (-126 vs. -22 pmol/L) (all p < 0.05). CONCLUSIONS: Empagliflozin for 52 weeks reduces hepatic fat content in subjects with nondiabetic metabolic dysfunction-associated steatotic liver disease. (ClinicalTrials.gov Identifier: NCT04642261).

Benefit and Harm of Aspirin on Mortality From Gastrointestinal Cancers Vs Bleeding in Helicobacter pylori-Eradicated Patients.

BACKGROUND & AIMS: We investigated the benefit-risk profile of aspirin on mortality reduction from chemoprevention of gastrointestinal (GI) cancer vs excess mortality from bleeding among Helicobacter pylori-eradicated patients, and its interaction with proton pump inhibitors (PPIs). METHODS: H pylori-eradicated patients (between 2003 and 2016), identified from a territory-wide database, were observed from the date of H pylori therapy until death or the end of the study (July 2020). Primary exposure was aspirin use as time-varying variable. The primary outcome was GI cancer-related (gastrointestinal, hepatobiliary, or pancreatic cancer) death and the secondary outcome was bleeding-related (gastrointestinal bleeding or intracranial bleeding) death. The adjusted hazard ratio (aHR) of outcomes was calculated by multivariable Cox model after adjusting for age, sex, comorbidities, and concomitant medications. The benefit-risk profile was expressed as the adjusted absolute risk difference of cancer-related deaths and bleeding-related deaths between aspirin users and nonusers. RESULTS: A total of 87,967 subjects were followed up for a median of 10.1 years, with 1294 (1.5%) GI cancer-related deaths and 304 (0.3%) bleeding-related deaths. Aspirin was associated with lower GI cancer-related mortality (aHR, 0.51; 95% CI, 0.42-0.61), but higher bleeding-related mortality (aHR, 1.52; 95% CI, 1.11-2.08). Among PPI users, the aHR of bleeding-related mortality with aspirin was 1.06 (95% CI, 0.70-1.63). For the whole cohort, the adjusted absolute risk difference between aspirin users and nonusers was 7 (95% CI, 5-8) fewer cancer-related and 1 (95% CI, 0.3-3) more bleeding-related death per 10,000 person-years. Among concomitant PPI-aspirin use, there were 9 (95% CI, 8-10) fewer cancer-related deaths per 10,000 person-years without an increase in bleeding-related deaths. CONCLUSIONS: GI cancer mortality benefit from aspirin outweighs bleeding-related mortality in H pylori-eradicated subjects, which is enhanced further by PPI use.

Endocuff With or Without Artificial Intelligence-Assisted Colonoscopy in Detection of Colorectal Adenoma: A Randomized Colonoscopy Trial.

INTRODUCTION: Both artificial intelligence (AI) and distal attachment devices have been shown to improve adenoma detection rate and reduce miss rate during colonoscopy. We studied the combined effect of Endocuff and AI on enhancing detection rates of various colonic lesions. METHODS: This was a 3-arm prospective randomized colonoscopy study involving patients aged 40 years or older. Participants were randomly assigned in a 1:1:1 ratio to undergo Endocuff with AI, AI alone, or standard high-definition (HD) colonoscopy. The primary outcome was adenoma detection rate (ADR) between the Endocuff-AI and AI groups while secondary outcomes included detection rates of polyp (PDR), sessile serrated lesion (sessile detection rate [SDR]), and advanced adenoma (advanced adenoma detection rate) between the 2 groups. RESULTS: A total of 682 patients were included (mean age 65.4 years, 52.3% male), with 53.7% undergoing diagnostic colonoscopy. The ADR for the Endocuff-AI, AI, and HD groups was 58.7%, 53.8%, and 46.3%, respectively, while the corresponding PDR was 77.0%, 74.0%, and 61.2%. A significant increase in ADR, PDR, and SDR was observed between the Endocuff-AI and AI groups (ADR difference: 4.9%, 95% CI: 1.4%-8.2%, P = 0.03; PDR difference: 3.0%, 95% CI: 0.4%-5.8%, P = 0.04; SDR difference: 6.4%, 95% CI: 3.4%-9.7%, P < 0.01). Both Endocuff-AI and AI groups had a higher ADR, PDR, SDR, and advanced adenoma detection rate than the HD group (all P < 0.01). DISCUSSION: Endocuff in combination with AI further improves various colonic lesion detection rates when compared with AI alone.

Real-world efficacy of second-line therapies for Helicobacter pylori: a population-based study.

BACKGROUND: With the increasing prevalence of antibiotic resistance, real-world data on the optimal empirical second-line therapy for Helicobacter pylori are still limited. OBJECTIVES: To evaluate the real-world efficacy of various second-line therapies for H. pylori. PATIENTS AND METHODS: This was a retrospective population-based cohort study of all H. pylori-infected patients who had received the second-line treatment after the failure of primary clarithromycin triple therapy in Hong Kong between 2003 and 2018. The retreatment success rates of different second-line therapies were evaluated. RESULTS: A total of 7591 patients who received second-line treatment were included. Notably, the most commonly prescribed regimen was still clarithromycin triple therapy, but the frequency of use had decreased from 59.5% in 2003-06 to 28.7% in 2015-18. Concomitant non-bismuth quadruple therapy had emerged as the commonest regimen (from 3.3% to 43.9%). In a validation analysis, the sensitivity and specificity of retreatment-inferred second-line treatment failure were 88.3% and 97.1%, respectively. The overall success rate of second-line therapies was 73.6%. Bismuth quadruple therapy had the highest success rate of 85.6%, while clarithromycin triple therapy had the lowest success rate of 63.5%. Specifically, bismuth/metronidazole/tetracycline quadruple, metronidazole/tetracycline triple, levofloxacin/metronidazole/tetracycline quadruple, rifabutin/amoxicillin triple and amoxicillin/levofloxacin triple therapies had relatively higher success rates over 80%. Age, treatment duration, baseline conditions and first-line treatment used were associated with success rate. CONCLUSIONS: Bismuth quadruple therapy was the most effective second-line regimen for H. pylori in this real-world study. Despite a very low success rate, clarithromycin-containing triple therapies were still commonly used as second-line regimens.

Artificial intelligence-assisted real-time monitoring of effective withdrawal time during colonoscopy: a novel quality marker of colonoscopy.

BACKGROUND AND AIMS: The importance of withdrawal time during colonoscopy cannot be overstated in mitigating the risk of missed lesions and postcolonoscopy colorectal cancer. We evaluated a novel colonoscopy quality metric called the effective withdrawal time (EWT), which is an artificial intelligence (AI)-derived quantitative measure of quality withdrawal time, and its association with various colonic lesion detection rates as compared with standard withdrawal time (SWT). METHODS: Three hundred fifty video recordings of colonoscopy withdrawal (from the cecum to the anus) were assessed by the new AI model. The primary outcome was adenoma detection rate (ADR) according to different quintiles of EWT. Multivariate logistic regression, adjusting for baseline covariates, was used to determine the adjusted odd ratios (ORs) for EWT on lesion detection rates, with the lowest quintile as reference. The area under the receiver-operating characteristic curve of EWT was compared with SWT. RESULTS: The crude ADR in different quintiles of EWT, from lowest to highest, was 10.0%, 31.4%, 33.3%, 53.5%, and 85.7%. The ORs of detecting adenomas and polyps were significantly higher in all top 4 quintiles when compared with the lowest quintile. Each minute increase in EWT was associated with a 49% increase in ADR (aOR, 1.49; 95% confidence interval [CI], 1.36-1.65). The area under the receiver-operating characteristic curve of EWT was also significantly higher than SWT on adenoma detection (.80 [95% CI, .75-.84] vs .70 [95% CI, .64-.74], P < .01). CONCLUSIONS: AI-derived monitoring of EWT is a promising novel quality indicator for colonoscopy, which is more associated with ADR than SWT.

Global burden of young-onset gastric cancer: a systematic trend analysis of the global burden of disease study 2019.

BACKGROUND: While gastric cancer is generally declining globally, the temporal trend of young-onset (< 40 years) gastric cancer remains uncertain. We performed this analysis to determine the temporal trends of young-onset gastric cancer compared to late-onset cancer (≥ 40 years). METHODS: We extracted cross-sectional data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. The burden of gastric cancer from 1990 to 2019 was assessed through indicators including incidence and mortality rates, which were classified at global, national, and regional levels, and according to socio-demographic indexes (SDI) and age or sex groups. Joinpoint regression analysis was used to identify specific years with significant changes. The correlation between AAPC with countries' average SDI was tested by Pearson's Test. RESULTS: The global incidence rate of young-onset gastric cancer decreased from 2.20 (per 100,000) in 1990 to 1.65 in 2019 (AAPC: - 0.95; 95% confidence interval [CI] - 1.25 to - 0.65; P < 0.001). Late-onset cancer incidence also decreased from 59.53 (per 100,000) in 1990 to 41.26 in 2019 (AAPC: - 1.23; 95% CI - 1.39 to - 1.06, P < 0.001). Despite an overall decreasing trend, the incidence rate of young-onset cancer demonstrated a significant increase from 2015 to 2019 (annual percentage change [APC]: 1.39; 95% CI 0.06 to 2.74; P = 0.041), whereas no upward trend was observed in late-onset cancer. Mortality rates of young- and late-onset cancer both exhibited a significant decline during this period (AAPC: - 1.82; 95% CI - 2.15 to - 1.56; P < 0.001 and AAPC: - 1.69, 95% CI - 1.79 to - 1.59; P < 0.001). The male-to-female rate ratio for incidence and mortality in both age groups have been increasing since 1990. While countries with high SDI have had a greater decline in the incidence of late-onset gastric cancer (slope of AAPC change: - 0.20, P = 0.004), it was not observed in young-onset cancer (slope of AAPC change: - 0.11, P = 0.13). CONCLUSIONS: The global incidence and mortality rates of both young- and late-onset gastric cancer have decreased since 1990. However, the incidence rate of young-onset cancer has demonstrated a small but significant upward trend since 2015. There was disparity in the decline in young-onset gastric cancer among male and high SDI countries. These findings could help to inform future strategies in preventing gastric cancer in younger individuals.

Proton pump inhibitors associated with severe COVID-19 among two-dose but not three-dose vaccine recipients.

BACKGROUND AND AIM: Proton pump inhibitors (PPIs) may increase the risk of COVID-19 among non-vaccinated subjects via various mechanisms, including gut dysbiosis. We aimed to investigate whether PPIs also affect the clinical outcomes of COVID-19 among vaccine recipients. METHODS: This was a territory-wide cohort study of 3 272 286 vaccine recipients (aged ≥ 18 years) of ≥ 2 doses of either BNT162b2 or CoronaVac. Exclusion criteria included prior gastrointestinal surgery, immunocompromised status, and prior COVID-19. The primary outcome was COVID-19, and secondary outcomes included COVID-19-related hospitalization and severe infection (composite of intensive care unit admission, ventilatory support, and/or death). Covariates include age, sex, the Charlson Comorbidity Index, comorbidities, and concomitant medication use. Subjects were followed from index date (first dose of vaccination) until outcome occurrence, death, additional dose of vaccination, or March 31, 2022. Exposure was pre-vaccination PPI use (any prescription within 90 days before the index date). Propensity score (PS) matching and a Poisson regression model were used to estimate the adjusted incidence rate ratio (aIRR) of outcomes with PPI use. RESULTS: Among 439 154 PS-matched two-dose vaccine recipients (mean age: 65.3 years; male: 45.7%) with a median follow-up of 6.8 months (interquartile range: 2.6-7.9), PPI exposure was associated with a higher risk of COVID-19 (aIRR: 1.08; 95% confidence interval [95% CI]: 1.05-1.10), hospitalization (aIRR: 1.20; 95% CI: 1.08-1.33), and severe infection (aIRR: 1.57; 95% CI: 1.24-1.98). Among 188 360 PS-matched three-dose vaccine recipients (mean age: 62.5 years; male: 49.0%; median follow-up: 9.1 months [interquartile range: 8.0-10.9]), PPIs were associated with higher infection risk (aIRR: 1.11; 95% CI: 1.08-1.15) but not other outcomes. CONCLUSIONS: Although PPI use was associated with a higher COVID-19 risk, severe infection was limited to two-dose but not three-dose vaccine recipients.

Ten missteps in the management of inflammatory bowel disease in Asia: An expert report by the Asian Pacific Association of Gastroenterology Working Group on Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is rapidly emerging in the Asia Pacific region. However, there are many challenges in the diagnosis and management of this condition. The Asian Pacific Association of Gastroenterology (APAGE) Working Group on IBD conducted a round table meeting to identify 10 common mistakes in the management of IBD in Asia. To summarize, many physicians still over rely on a definitive histological diagnosis before starting treatment and do not fully establish disease extent such as perianal and proximal gastrointestinal involvement in Crohn's disease (CD) or extent of involvement in ulcerative colitis (UC). It is also essential to actively look for evidence of extra-intestinal manifestations, which may influence choice of therapy. In terms of conventional therapy, underuse of topical 5 aminosalicylates (5-ASAs) in UC and inappropriate dosing of corticosteroids are also important considerations. Acute severe UC remains a life-threatening condition and delay in starting rescue therapy after inadequate response to intravenous steroids is still common. Anti-tumor necrosis factors should be considered first line in all cases of complex perianal fistulizing CD. Most patients with IBD are on potent immunosuppressive therapy and should be screened for latent infections and offered vaccinations according to guidelines. Under-recognition and management of significant complications such as anemia, osteoporosis, malnutrition, and thromboembolism should also be addressed. Colonoscopy is still not properly performed for dysplasia/cancer surveillance and for evaluating post-op recurrence of CD. Another common misstep is inappropriate withdrawal of medications during pregnancy leading to increased complications for the mother and the newborn.

Comparison of Over-the-Scope Clips to Standard Endoscopic Treatment as the Initial Treatment in Patients With Bleeding From a Nonvariceal Upper Gastrointestinal Cause : A Randomized Controlled Trial.

BACKGROUND: Current endoscopic methods in the control of acute nonvariceal bleeding have a small but clinically significant failure rate. The role of over-the-scope clips (OTSCs) as the first treatment has not been defined. OBJECTIVE: To compare OTSCs with standard endoscopic hemostatic treatments in the control of bleeding from nonvariceal upper gastrointestinal causes. DESIGN: A multicenter, randomized controlled trial. (ClinicalTrials.gov: NCT03216395). SETTING: University teaching hospitals in Hong Kong, China, and Australia. PATIENTS: 190 adult patients with active bleeding or a nonbleeding visible vessel from a nonvariceal cause on upper gastrointestinal endoscopy. INTERVENTION: Standard hemostatic treatment (n = 97) or OTSC (n = 93). MEASUREMENTS: The primary outcome was 30-day probability of further bleeds. Other outcomes included failure to control bleeding after assigned endoscopic treatment, recurrent bleeding after initial hemostasis, further intervention, blood transfusion, and hospitalization. RESULTS: The 30-day probability of further bleeding in the standard treatment and OTSC groups was 14.6% (14 of 97) and 3.2% (3 of 93), respectively (risk difference, 11.4 percentage points [95% CI, 3.3 to 20.0 percentage points]; P = 0.006). Failure to control bleeding after assigned endoscopic treatment in the standard treatment and OTSC groups was 6 versus 1 (risk difference, 5.1 percentage points [CI, 0.7 to 11.8 percentage points]), respectively, and 30-day recurrent bleeding was 8 versus 2 (risk difference, 6.6 percentage points [CI, -0.3 to 14.4 percentage points]), respectively. The need for further interventions was 8 versus 2, respectively. Thirty-day mortality was 4 versus 2, respectively. In a post hoc analysis with a composite end point of failure to successfully apply assigned treatment and further bleeds, the event rate was 15 of 97 (15.6%) and 6 of 93 (6.5%) in the standard and OTSC groups, respectively (risk difference, 9.1 percentage points [CI, 0.004 to 18.3 percentage points]). LIMITATION: Clinicians were not blinded to treatment and the option of crossover treatment. CONCLUSION: Over-the-scope clips, as an initial treatment, may be better than standard treatment in reducing the risk for further bleeding from nonvariceal upper gastrointestinal causes that are amenable to OTSC placement. PRIMARY FUNDING SOURCE: General Research Fund to the University Grant Committee, Hong Kong SAR Government.

The Predictive Value of Gut Microbiota Composition for Sustained Immunogenicity following Two Doses of CoronaVac.

CoronaVac immunogenicity decreases with time, and we aimed to investigate whether gut microbiota associate with longer-term immunogenicity of CoronaVac. This was a prospective cohort study recruiting two-dose CoronaVac recipients from three centres in Hong Kong. We collected blood samples at baseline and day 180 after the first dose and used chemiluminescence immunoassay to test for neutralizing antibodies (NAbs) against the receptor-binding domain (RBD) of wild-type SARS-CoV-2 virus. We performed shotgun metagenomic sequencing performed on baseline stool samples. The primary outcome was the NAb seroconversion rate (seropositivity defined as NAb ≥ 15AU/mL) at day 180. Linear discriminant analysis [LDA] effect size analysis was used to identify putative bacterial species and metabolic pathways. A univariate logistic regression model was used to derive the odds ratio (OR) of seropositivity with bacterial species. Of 119 CoronaVac recipients (median age: 53.4 years [IQR: 47.8-61.3]; male: 39 [32.8%]), only 8 (6.7%) remained seropositive at 6 months after vaccination. Bacteroides uniformis (log10LDA score = 4.39) and Bacteroides eggerthii (log10LDA score = 3.89) were significantly enriched in seropositive than seronegative participants. Seropositivity was associated with B. eggerthii (OR: 5.73; 95% CI: 1.32-29.55; p = 0.022) and B. uniformis with borderline significance (OR: 3.27; 95% CI: 0.73-14.72; p = 0.110). Additionally, B. uniformis was positively correlated with most enriched metabolic pathways in seropositive vaccinees, including the superpathway of adenosine nucleotide de novo biosynthesis I (log10LDA score = 2.88) and II (log10LDA score = 2.91), as well as pathways related to vitamin B biosynthesis, all of which are known to promote immune functions. In conclusion, certain gut bacterial species (B. eggerthii and B. uniformis) and metabolic pathways were associated with longer-term CoronaVac immunogenicity.

Risk of Postcolonoscopy Thromboembolic Events: A Real-World Cohort Study.

BACKGROUND& AIMS: Although antithrombotic agents could increase the risk of postpolypectomy bleeding, interruption of these agents also increases the risk of thromboembolism (TE). We assessed the risks of postcolonoscopy TE events and their association with the interruption of antithrombotic agents. METHODS: This was a retrospective cohort study including consecutive patients undergoing colonoscopy between January 2016 and March 2021. We determined the rates of postcolonoscopy TE events in patients taking various antithrombotic agents (with or without interruption), and in different patient groups according to indications for colonoscopy, underlying TE, and bleeding risks. RESULTS: Of the 6220 patients, 1755 (28.2%) were on antithrombotics. Overall, 20 patients (0.32%) developed TE events, and 25 (0.80%) of 3134 patients with polypectomy experienced major episodes of bleeding. Among all patients on antithrombotic agents, the highest rates of TE events were observed in patients on dual-antiplatelet therapy (4.65%; adjusted odds ratio [aOR], 28.0; 95% CI, 3.77-142.1) and clopidogrel (2.78%; aOR, 12.2; 95% CI, 2.10-57.0), compared with 0.11% among those not on antithrombotics. In patients interrupting anti-thrombotic agents, the risk of TE was increased compared to those on no agent as follows: stopping 2 or more antithrombotic agents (4.55%; aOR, 22.5; 95% CI, 1.09-158.0), monotherapy with clopidogrel (3.06%; aOR, 15.5; 95% CI, 2.86-69.6), warfarin (1.33%; aOR, 6.96; 95% CI, 1.14-33.5), or direct-acting oral anticoagulants (0.87%; aOR, 6.23; 95% CI, 1.22-26.8). Having an underlying high TE risk (aOR, 16.8; 95% CI, 6.33-46.6) was associated with higher postcolonoscopy TE events. CONCLUSIONS: The risk of post-colonoscopy thromboembolic events is low. However, the temporary interruption of antithrombotic agents, particularly stopping 2 or more agents, clopidogrel, warfarin, or direct-acting oral anticoagulants was associated with higher postcolonoscopy TE events, particularly in high-risk patients.

Low-dose aspirin does not lower the risk of colorectal cancer in patients with type 2 diabetes taking metformin.

BACKGROUND: Low-dose aspirin and metformin have been individually associated with a reduced risk of cancer. Whether their concurrent use in adults with type 2 diabetes mellitus (T2DM) is associated with a reduced risk of colorectal cancer (CRC) is unclear. OBJECTIVE: Among individuals with T2DM taking metformin, we sought to evaluate the association between low-dose aspirin versus no aspirin and the risk of CRC. METHODS: A multiple-database new-user cohort study of patients with T2DM taking metformin was conducted between 2007 and 2010 (Clinical Data Analysis and Reporting System [CDARS], Hong Kong) and 2007-2016 (The Health Improvement Network [THIN], UK). The primary outcome was incident CRC. Patients were followed from index date of prescription until the earliest occurrence of an outcome of interest, an incident diagnosis of any cancer, death, or until 31 December 2019. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Estimates were pooled using an inverse variance random effects model, and heterogeneity was assessed using I2 . RESULTS: After one-to-one propensity-score matching, 57,534 patients were included (CDARS = 16,276; THIN = 41,258). The median (IQR) follow-up was 9.3 (6.5-10.7) years in CDARS and 3.2 (1.1-5.8) years in THIN. The concurrent use of low-dose aspirin and metformin was not associated with a lower risk of CRC compared to metformin only (HR = 0.89, 95% CI 0.75-1.05, I2  = 0%). CONCLUSION: Low-dose aspirin was not associated with a lower risk of CRC in patients with T2DM taking metformin. Our study does not support the routine use of low-dose aspirin in this population.

Computer-assisted detection versus conventional colonoscopy for proximal colonic lesions: a multicenter, randomized, tandem-colonoscopy study.

BACKGROUND AND AIMS: Computer-assisted detection (CADe) is a promising technologic advance that enhances adenoma detection during colonoscopy. However, the role of CADe in reducing missed colonic lesions is uncertain. The aim of this study was to determine the miss rates of proximal colonic lesions by CADe and conventional colonoscopy. METHODS: This was a prospective, multicenter, randomized, tandem-colonoscopy study conducted in 3 Asian centers. Patients were randomized to receive CADe or conventional white-light colonoscopy during the first withdrawal of the proximal colon (cecum to splenic flexure), immediately followed by tandem examination of the proximal colon with white light in both groups. The primary outcome was adenoma/polyp miss rate, which was defined as any adenoma/polyp detected during the second examination. RESULTS: Of 223 patients (48.6% men; median age, 63 years) enrolled, 7 patients did not have tandem examination, leaving 108 patients in each group. There was no difference in the miss rate for proximal adenomas (CADe vs conventional: 20.0% vs 14.0%, P = .07) and polyps (26.7% vs 19.6%, P = .06). The CADe group, however, had significantly higher proximal polyp (58.0% vs 46.7%, P = .03) and adenoma (44.7% vs 34.6%, P = .04) detection rates than the conventional group. The mean number of proximal polyps and adenomas detected per patient during the first examination was also significantly higher in the CADe group (polyp: 1.20 vs .86, P = .03; adenoma, .91 vs .61, P = .03). Subgroup analysis showed that CADe enhanced proximal adenoma detection in patients with fair bowel preparation, shorter withdrawal time, and endoscopists with lower adenoma detection rate. CONCLUSIONS: This multicenter trial from Asia confirmed that CADe can further enhance proximal adenoma and polyp detection but may not be able to reduce the number of missed proximal colonic lesions. (Clinical trial registration number: NCT04294355.).

Blue-light imaging or narrow-band imaging for proximal colonic lesions: a prospective randomized tandem colonoscopy study.

BACKGROUND AND AIMS: Blue-light imaging (BLI) is a new image-enhanced endoscopy with a wavelength filter similar to narrow-band imaging (NBI). We compared the 2 with white-light imaging (WLI) on proximal colonic lesion detection and miss rates. METHODS: In this 3-arm prospective randomized study with tandem examination of the proximal colon, we enrolled patients aged ≥40 years. Eligible patients were randomized in 1:1:1 ratio to receive BLI, NBI, or WLI during the first withdrawal from the proximal colon. The second withdrawal was performed using WLI in all patients. Primary outcomes were proximal polyp (pPDRs) and adenoma (pADRs) detection rates. Secondary outcomes were miss rates of proximal lesions found on tandem examination. RESULTS: Of 901 patients included (mean age, 64.7 years; 52.9% men), 48.1% underwent colonoscopy for screening or surveillance. The corresponding pPDRs of the BLI, NBI, and WLI groups were 45.8%, 41.6, and 36.6%, whereas the corresponding pADRs were 36.6%, 33.8%, and 28.3%. There was a significant difference in pPDR and pADR between BLI and WLI groups (difference, 9.2% [95% confidence interval {CI}, 3.3-16.9] and 8.3% [95% CI, 2.7-15.9]) and between NBI and WLI groups (difference, 5.0% [95% CI, 1.4-12.9] and 5.6% [95% CI, 2.1-13.3]). Proximal adenoma miss rates were significantly lower with BLI (19.4%) than with WLI (27.4%; difference, -8.0%; 95% CI, -15.8 to -.1) but not between NBI (27.2%) and WLI. CONCLUSIONS: Both BLI and NBI were superior to WLI on detecting proximal colonic lesions, but only BLI had lower proximal adenoma miss rates than WLI. (Clinical trial registration number: NCT03696992.).

Risk of hospitalization for upper gastrointestinal bleeding in Helicobacter pylori eradicated patients newly started on warfarin or direct oral anticoagulants: A population-based cohort study.

BACKGROUND: To investigate risks of hospitalization for upper gastrointestinal bleeding (UGIB) in H. pylori-eradicated patients newly started on warfarin or direct oral anti-coagulants (DOACs). METHODS: We identified all patients who had previously received H. pylori eradication therapy or were found to have no H. pylori on endoscopy and were then newly started on warfarin or DOACs from a population-based electronic healthcare database. Primary analysis was the risk of UGIB between warfarin and DOACs users in H. pylori-eradicated patients. Secondary analysis included the UGIB risk between H. pylori-eradicated and H. pylori-negative patients who were newly started on warfarin or DOACs. The hazard ratio (HR) of UGIB was approximated by pooled logistic regression model incorporating the inverse propensity of treatment weightings with time-varying covariables. RESULTS: Among H. pylori-eradicated patients, DOACs had a significantly lower risk of UGIB (HR: 0.26, 95% CI 0.09-0.71) compared with warfarin. In particular, lower UGIB risks with DOACs were observed among older (≥65 years) patients, female, those without a history of UGIB or peptic ulcer, or ischemic heart disease, and non-users of acid-suppressive agents or aspirin. Secondary analysis showed no significant difference in UGIB risk between H. pylori-eradicated and H. pylori-negative patients newly started on warfarin (HR: 0.63,95% CI 0.33-1.19) or DOACs (HR: 1.37, 95% CI 0.45-4.22). CONCLUSIONS: In H. pylori-eradicated patients, new users of DOACs had a significantly lower risk of UGIB than new warfarin users. Furthermore, the risk of UGIB in new warfarin or DOACs users was comparable between H. pylori-eradicated and H. pylori-negative patients.

Whole genome sequencing reveals novel genetic mutations of Helicobacter pylori associating with resistance to clarithromycin and levofloxacin.

BACKGROUND: Detection of mutations in one or a couple of genes may not provide enough data or cover all the genomic DNA variance related to antibiotic resistance of Helicobacter pylori to clarithromycin (CLA) and levofloxacin (LVX). We aimed to perform whole genome sequencing to explore novel antibiotic resistance-related genes to increase predictive accuracy for future targeted sequencing tests. METHODS: Gastric mucosal biopsies were taken during upper endoscopy in 27 H. pylori-infected patients. According to culture-based antibacterial susceptibility test, H. pylori strains were divided into three groups, with nine strains in each group: CLA single-drug resistance (group C), LVX single-drug resistance (group L), and strains sensitive to all antibacterial drugs (group S). Based on whole genome sequencing with group S being the control, group C and group L group-specific single nucleotide variants and amino acid mutations were screened, and potential candidate genes related to CLA and LVX resistance were identified. RESULTS: The median age of study subjects was 35 years (IQR: 31-40), and 17 (63.0%) were male. All nine CLA-resistant strains had A2143G mutations in 23S rRNA, while none of nine sensitive strains had the mutation. Six of nine strains in group L and six of nine strains in group S had 87th or 91st mutation in gyrA. After comparing sequencing data of strains among the three groups, we identified five mutated positions belonging to four genes related to CLA resistance, and 31 mutated positions belonging to 20 genes related to LVX resistance. Novel genetic mutations were detected for CLA resistance (including fliJ and clpX) and LVX resistance (including fliJ, cheA, hemE, Val360Ile, and HP0568). Missense mutations in fliJ and cheA gene were mainly involved in chemotaxis and flagellar motility to facilitate bacterial escape of antibiotics, while the functions of other novel gene mutations underpinning antibiotic resistance remain to be investigated. CONCLUSION: Whole genome sequencing detected potential novel genetic mutations conferring resistance of H. pylori to CLA and LVX including fliJ and cheA. Further studies to correlate these findings with treatment outcome should be performed.

Antibiotic Resistance, Susceptibility Testing and Stewardship in Helicobacter pylori Infection.

Despite the declining trend of Helicobacter pylori (H. pylori) prevalence around the globe, ongoing efforts are still needed to optimize current and future regimens in view of the increasing antibiotic resistance. The resistance of H. pylori to different antibiotics is caused by different molecular mechanisms, and advancements in sequencing technology have come a far way in broadening our understanding and in facilitating the testing of antibiotic susceptibility to H. pylori. In this literature review, we give an overview of the molecular mechanisms behind resistance, as well as discuss and compare different antibiotic susceptibility tests based on the latest research. We also discuss the principles of antibiotic stewardship and compare the performance of empirical therapies based on up-to-date resistance patterns and susceptibility-guided therapies in providing effective H. pylori treatment. Studies and clinical guidelines should ensure that the treatment being tested or recommended can reliably achieve a pre-agreed acceptable level of eradication rate and take into account the variations in antibiotic resistance across populations. Local, regional and international organizations must work together to establish routine antibiotic susceptibility surveillance programs and enforce antibiotic stewardship in the treatment of H. pylori, so that it can be managed in a sustainable and efficient manner.

Timing of prior exposure to antibiotics and failure of Helicobacter pylori eradication: a population-based study.

BACKGROUND: The success rate of conventional Helicobacter pylori eradication therapy is declining, due to rising antibiotic resistance. OBJECTIVES: To determine the temporal effects of prior antibiotic exposure on eradication outcome. PATIENTS AND METHODS: This is a retrospective cohort study including all H. pylori-infected patients who received their first course of clarithromycin-containing triple therapy in 2003-18. Prior antibiotic exposures before H. pylori eradication therapy (up to 180 days, 1 year or 3 years) were retrieved. A logistic regression model was used to evaluate the association between different timings of previous antibiotic exposure, recent (within 30/60 days) or distant period, and the need for retreatment for H. pylori. RESULTS: A total of 120 787 H. pylori-infected patients were included. Prior exposure to any antibiotics within 180 days was associated with a higher risk of retreatment (OR 1.18, 95% CI 1.13-1.24) and the risk progressively increased with longer duration of antibiotic use. The results were consistent for prior exposure up to 1 year (OR 1.26, 95% CI 1.20-1.31) or 3 years (OR 1.30, 95% CI 1.25-1.35). However, when compared with those without prior antibiotic exposure, recent exposure (within 30 days) did not increase the risk of retreatment, which was consistent for analysis with prior antibiotic exposure up to 3 years. Notably, recent use of cephalosporins within 30/60 days and nitroimidazole within 30 days had significantly lower risks of retreatment. CONCLUSIONS: Any prior antibiotic exposure increased the risk of treatment failure of clarithromycin-containing triple therapy. Recent exposures to some classes of antibiotics may paradoxically increase treatment success.

Age of eradication and failure rates of clarithromycin-containing triple therapy for Helicobacter pylori: A 15-year population-based study.

BACKGROUND: Failure rates of clarithromycin-containing triple therapy for H. pylori are rising. To determine the trend of failure rates of clarithromycin-containing triple therapy in different age groups in Hong Kong over the past 15 years. MATERIALS AND METHODS: This is a population-based retrospective age-period-cohort study involving all adult H. pylori-infected patients who had received the first course of clarithromycin-containing triple therapy in 2003-2017. Failed eradication was identified by the need of retreatment within 2 years of eradication. Logistic regression model was used to characterize the risk of retreatment. RESULTS: 113,526 H. pylori-infected patients were included. The overall failure rate increased from 4.83% in 2003 to 10.2% in 2016 (p for linear trend <0.001). When stratified by age of eradication, patients 75 years or above had the lowest retreatment rate of 5.11%, which progressively increased in younger patients (60-74 years: OR 1.26, 95% CI 1.15-1.38; 45-59 years: OR 1.36, 95% CI 1.24-1.48; 18-44 years: OR 1.55, 95% CI 1.41-1.69). The results remained consistent when stratified by year of birth, and period of eradication. Other risk factors for retreatment included female (OR 1.24, 95% CI 1.18-1.30), triple therapy containing metronidazole (OR 2.30, 95% CI 2.12-2.50), and shorter duration of therapy (10 days: OR 0.88, 95% CI 0.79-0.97; 14 days: OR 0.67, 95% CI 0.58-0.77 vs 7 days). CONCLUSIONS: While failure rates of clarithromycin-containing triple therapy progressively increased over the past 15 years, the failure rate was particularly high among younger patients, which could undermine the potential benefits of early H. pylori eradication.

Dynamic changes in antibiotic resistance genes and gut microbiota after Helicobacter pylori eradication therapies.

BACKGROUND: Short-term antibiotics exposure is associated with alterations in microbiota and antibiotic resistance genes (ARGs) in the human gut. While antibiotics are critical in the successful eradication of Helicobacter pylori, the short-term and long-term impacts on the composition and quantity of antibiotics resistance genes after H. pylori eradication are unclear. This study used whole-genome shotgun metagenomic of stool samples to characterize the gut microbiota and ARGs, before and after H. pylori eradication therapy. RESULTS: Forty-four H. pylori-infected patients were recruited, including 21 treatment naïve patients who received clarithromycin-based triple therapy (CLA group) and 23 patients who failed previous therapies, in which 10 received levofloxacin-based quadruple therapy (LEVO group) and 13 received other combinations (OTHER group). Stool samples were collected at baseline (before current treatment), 6 week and 6 month after eradication therapy. At baseline, there was only a slight difference among the three groups on ARGs and gut microbiota. After eradication therapy, there was a transient but significant increase in gut ARGs 6 week post-therapy, among which the LEVO group had the most significant ARGs alteration compared to other two groups. For treatment naïve patients, those with higher ErmF abundance were prone to fail CLA eradication and gain more ARGs after treatment. For gut microbiota, the bacteria richness decreased at 6 week and there was a significant difference in microbiota community among the three groups at 6 week. CONCLUSIONS: Our findings demonstrated the dynamic alterations in gut microbiota and ARGs induced by different eradication therapies, which could influence the choices of antibiotics in eradication therapy.