RE.GA.IN.: the Real-world Gastritis Initiative-updating the updates.

At the end of the last century, a far-sighted 'working party' held in Sydney, Australia addressed the clinicopathological issues related to gastric inflammatory diseases. A few years later, an international conference held in Houston, Texas, USA critically updated the seminal Sydney classification. In line with these initiatives, Kyoto Global Consensus Report, flanked by the Maastricht-Florence conferences, added new clinical evidence to the gastritis clinicopathological puzzle.The most relevant topics related to the gastric inflammatory diseases have been addressed by the Real-world Gastritis Initiative (RE.GA.IN.), from disease definitions to the clinical diagnosis and prognosis. This paper reports the conclusions of the RE.GA.IN. consensus process, which culminated in Venice in November 2022 after more than 8 months of intense global scientific deliberations. A forum of gastritis scholars from five continents participated in the multidisciplinary RE.GA.IN. consensus. After lively debates on the most controversial aspects of the gastritis spectrum, the RE.GA.IN. Faculty amalgamated complementary knowledge to distil patient-centred, evidence-based statements to assist health professionals in their real-world clinical practice. The sections of this report focus on: the epidemiology of gastritis; Helicobacter pylori as dominant aetiology of environmental gastritis and as the most important determinant of the gastric oncogenetic field; the evolving knowledge on gastric autoimmunity; the clinicopathological relevance of gastric microbiota; the new diagnostic horizons of endoscopy; and the clinical priority of histologically reporting gastritis in terms of staging. The ultimate goal of RE.GA.IN. was and remains the promotion of further improvement in the clinical management of patients with gastritis.

Diagnosis and Treatment of Helicobacter pylori Infection.

The last 5 years have seen major shifts in defining whom to test and how to treat Helicobacter pylori infection. Peptic ulcer has changed from a chronic disease to a one-off condition, and countries with a high incidence of gastric cancer have begun implementing population-wide screening and treatment. A proactive approach to testing and treatment of H. pylori is now recommended, including outreach to family members of individuals diagnosed with active infection as well as high-risk local populations such as immigrants from high-risk countries. Increasing antimicrobial resistance has resulted in an overall decline in treatment success, causing a rethinking of the approach to development of treatment guidelines as well as the need to adopt the principles of antibiotic usage and antimicrobial stewardship. Required changes include abandoning empiric use of clarithromycin, metronidazole, and levofloxacin triple therapies. Here, we discuss these transformations and give guidance regarding testing and use of therapies that are effective when given empirically.

A pilot study evaluating high dose esomeprazole, bismuth subcitrate and amoxicillin for eradicating Helicobacter pylori infection in Iran.

BACKGROUND: Helicobacter pylori (H. pylori) is strongly associated with peptic ulcer disease and gastric cancer. We evaluated two triple therapy regimens comprising esomeprazole, high dose bismuth, and different doses of amoxicillin for first-line H. pylori eradication. MATERIALS AND METHODS: Two hundred patients with dyspepsia and naive H. pylori infection were randomly assigned into two groups (n = 100). Both groups were treated for 14 days similarly with esomeprazole (40 mg, twice daily) and bismuth subcitrate (240 mg, three times daily), but the dose of amoxicillin was varied between Groups A (750 mg) and B (1000 mg) three times daily. Treatment compliance and side effect were evaluated following the therapies and after 8 weeks, a negative test of stool H. pylori antigen confirmed eradication. RESULTS: The two groups were comparable with respect to sex and age. According to intention to treat analysis, eradication rates were 80% (95% CI: 77.2%-82.8%) and 90% (95% CI: 84.1%-95.9%) in A and B groups, respectively (p = 0.22). Per-protocol eradication rates were 87% (95% CI: 80.4%-93.6%) and 92.8% (95% CI: 87.7%-97.9%), respectively (p = 0.23). Severe adverse effects were 3% and 2%, respectively (p = 0.34). CONCLUSION: High dose esomeprazole, amoxicillin and bismuth achieved 92.8% cure rates per protocol in a country with a high background rate of resistance. Additional studies are needed to ascertain whether this therapy can be further improved. Until then, it can be recommended as a first-line H. pylori eradication in north of Iran.

Autoimmune gastritis: long-term natural history in naïve Helicobacter pylori-negative patients.

OBJECTIVE: Autoimmune gastritis (AIG) is an immunomediated disease targeting parietal cells, eventually resulting in oxyntic-restricted atrophy. This long-term follow-up study aimed at elucidating the natural history, histological phenotype(s), and associated cancer risk of patients with AIG consistently tested H. pylori-negative (naïve H. pylori-negative subjects). DESIGN: Two-hundred eleven naïve H. pylori-negative patients (tested by serology, histology, molecular biology) with AIG (F:M=3.15:1; p<0.001) were prospectively followed up with paired biopsies (T1 vs T2; mean follow-up years:7.5 (SD:4.4); median:7). Histology distinguished non-atrophic versus atrophic AIG. Atrophy was further subtyped/scored as non-metaplastic versus metaplastic (pseudopyloric (PPM) and intestinal (IM)). Enterochromaffin-like-cell (ECL) status was categorised as diffuse versus adenomatoid hyperplasia/dysplasia, and type 1 neuroendocrine tumours (Type1-NETs). RESULTS: Over the long-term histological follow-up, AIG consistently featured oxyntic-predominant-mononuclear inflammation. At T1, PPM-score was greater than IM (200/211 vs 160/211, respectively); IM scores increased from T1 to T2 (160/211 to 179/211), with no changes in the PPM prevalence (T1=200/211; T2=201/211). At both T1/T2, the prevalence of OLGA-III-stage was <5%; no Operative Link on Gastritis Assessment (OLGA)-IV-stage occurred. ECL-cell-status progressed from diffuse to adenomatoid hyperplasia/dysplasia (T1=167/14 vs T2=151/25). Type1-NETs (T1=10; T2=11) always coexisted with extensive oxyntic-atrophy, and ECL adenomatoid-hyperplasia/dysplasia. No excess risk of gastric or other malignancies was found over a cumulative follow-up time of 10 541 person years, except for (marginally significant) thyroid cancer (SIR=3.09; 95% CI 1.001 to 7.20). CONCLUSIONS: Oxyntic-restricted inflammation, PPM (more than IM), and ECL-cell hyperplasia/neoplasia are the histological AIG hallmarks. Compared with the general population, corpus-restricted inflammation/atrophy does not increase the GC risk. The excess of GC risk reported in patients with AIG could plausibly result from unrecognised previous/current H. pylori comorbidity.

Eradicating Helicobacter pylori via 13C-urea breath screening to prevent gastric cancer in indigenous communities: a population-based study and development of a family index-case method.

OBJECTIVE: Screening and eradication of Helicobacter pylori help reduce disparities in the incidence of gastric cancer. We aimed to evaluate its acceptability and feasibility in the indigenous communities and develop a family index-case method to roll out this programme. DESIGN: We enrolled residents aged 20-60 years from Taiwanese indigenous communities to receive a course of test, treat, retest and re-treat initial treatment failures with the 13C-urea breath tests and four-drug antibiotic treatments. We also invited the family members of a participant (constituting an index case) to join the programme and evaluated whether the infection rate would be higher in the positive index cases. RESULTS: Between 24 September 2018 and 31 December 2021, 15 057 participants (8852 indigenous and 6205 non-indigenous) were enrolled, with a participation rate of 80.0% (15 057 of 18 821 invitees). The positivity rate was 44.1% (95% CI 43.3% to 44.9%). In the proof-of-concept study with 72 indigenous families (258 participants), family members of a positive index case had 1.98 times (95% CI 1.03 to 3.80) higher prevalence of H. pylori than those of a negative index case. The results were replicated in the mass screening setting (1.95 times, 95% CI 1.61 to 2.36) when 1115 indigenous and 555 non-indigenous families were included (4157 participants). Of the 6643 testing positive, 5493 (82.6%) received treatment. According to intention-to-treat and per-protocol analyses, the eradication rates were 91.7% (89.1% to 94.3%) and 92.1% (89.2% to 95.0%), respectively, after one to two courses of treatment. The rate of adverse effects leading to treatment discontinuation was low at 1.2% (0.9% to 1.5%). CONCLUSION: A high participation rate, a high eradication rate of H. pylori and an efficient rollout method indicate that a primary prevention strategy is acceptable and feasible in indigenous communities. TRIAL REGISTRATION NUMBER: NCT03900910.

Rates of Antimicrobial Resistance in Helicobacter pylori Isolates From Clinical Trial Patients Across the US and Europe.

INTRODUCTION: Guidelines recommend that proton pump inhibitor-based triple regimens with clarithromycin not be used for Helicobacter pylori infection in areas where clarithromycin resistance is ≥15%, or in patients with prior macrolide use. Up-to-date information on local resistance patterns is limited, especially in the US. Here, we report resistance rates to antibiotics commonly used to treat H. pylori from a large study conducted in the US and Europe (pHalcon-HP). METHODS: Gastric mucosal biopsies were collected from adult participants with H. pylori infection during screening. Minimum inhibitory concentrations were determined via agar dilution for clarithromycin, amoxicillin, and metronidazole, with breakpoints ≥1 µg/mL, >0.125 µg/mL, and >8 µg/mL, respectively. Resistance rates were obtained for the US and Europe, and also for US subregions and participating European countries. RESULTS: Resistance rates were established in isolates from 907 participants. Overall, 22.2% were resistant to clarithromycin, 1.2% to amoxicillin, and 69.2% to metronidazole. Resistance in the US and Europe was similar; metronidazole resistance was the most prevalent (50%-79%) and amoxicillin the least (≤5%). In all subregions, ≥15% of isolates were resistant to clarithromycin, except the UK (0/8 isolates). Among clarithromycin-resistant isolates, 75% were also metronidazole-resistant. Two US isolates were resistant to clarithromycin and amoxicillin; one of these was also metronidazole-resistant. DISCUSSION: The resistance rates observed in this study argue against the continued empiric use of proton pump inhibitor-based triple therapy containing clarithromycin, per treatment guidelines, and highlight the need for antibiotic resistance surveillance and novel treatment strategies for H. pylori infection in the US and Europe.

Hybrid, High-Dose Dual and Bismuth Quadruple Therapies for First-Line Treatment of Helicobacter pylori Infection in Taiwan: A Multicenter, Open-Label, Randomized Trial.

INTRODUCTION: The study aimed to compare the efficacies and safety of 14-day hybrid therapy, 14-day high-dose dual therapy, and 10-day bismuth quadruple therapy in the first-line treatment of Helicobacter pylori infections. METHODS: In this multicenter, open-label, randomized trial, we recruited adult H. pylori -infected patients from 9 centers in Taiwan. Subjects were randomly assigned (1:1:1) to 14-day hybrid therapy, 14-day high-dose dual therapy, or 10-day bismuth quadruple therapy. Eradication status was determined by the 13 C-urea breath test. The primary outcome was the eradication rate of H. pylori assessed in the intention-to-treat population. RESULTS: Between August 1, 2018, and December 2021, 918 patients were randomly assigned in this study. The intention-to-treat eradication rates were 91.5% (280/306; 95% confidence interval [CI] 88.4%-94.6%) for 14-day hybrid therapy, 83.3% (255/306; 95% CI 87.8%-95.0%) for 14-day high-dose dual therapy, and 90.2% (276/306; 95% CI 87.8%-95.0%) for 10-day bismuth quadruple therapy. Both hybrid therapy (difference 8.2%; 95% CI 4.5%-11.9%; P = 0.002) and bismuth quadruple therapy (difference 6.9%; 95% CI 1.6%-12.2%; P = 0.012) were superior to high-dose dual therapy and were similar to one another. The frequency of adverse events was 27% (81/303) with 14-day hybrid therapy, 13% (40/305) with 14-day high-dose dual therapy, and 32% (96/303) with 10-day bismuth quadruple therapy. Patients receiving high-dose dual therapy had the fewest adverse events (both P < 0.001). DISCUSSION: Fourteen-day hybrid therapy and 10-day bismuth quadruple therapy are more effective than 14-day high-dose dual therapy in the first-line treatment of H. pylori infection in Taiwan. However, high-dose dual therapy has fewer adverse effects than hybrid bismuth quadruple therapies.

Controversies regarding management of Helicobacter pylori infections.

PURPOSE OF REVIEW: The recognition that Helicobacter pylori should be considered and treated as an infectious disease has yet to fundamentally change diagnostic and treatment practices and has resulted in many controversies. RECENT FINDINGS: We discuss the following controversies: whether the current 'per-patient' approach to H. pylori testing based on symptoms should be expanded to include achieving population-level H. pylori eradication, whether H. pylori should be approached as an infectious gastrointestinal disease similar to that of other infectious diseases of similar severity and outcome, whether treatment of H. pylori should be primarily empiric or based on antibiotic susceptibility and locally proven successful therapies as are other infectious diseases, whether it is necessary to obtain confirmation of treatment success in every patient treated for H. pylori , and whether potassium-competitive acid blockers should replace proton pump inhibitors in H. pylori therapy. SUMMARY: Available guidelines and meta-analyses do not yet address H. pylori as an infectious disease. The diagnosis and management and treatment success of H. pylori infections trails behind that of other important infectious diseases. We provide new insights and propose changes in the traditional understanding required to modernize the management of H. pylori infections.

Current role of tailored therapy in treating Helicobacter pylori infections. A systematic review, meta-analysis and critical analysis.

BACKGROUND AND AIMS: Recent guidelines dictate that all Helicobacter pylori (H. pylori) infected subjects should receive curative therapy. The efficacy of empirical regimens for H. pylori eradication might decline with bacterial, drug, and host factors. The necessity of a tailored therapy still remains controversial. Here we provide a meta-analysis of the current status of susceptibility-based (tailored) therapy in which susceptibility-based therapies were compared to the currently accepted choice of empiric therapy. In this rapidly closing era, neither the susceptibility nor empiric therapies were routinely optimized, such that we report the outcome of comparisons on the efficacy of unoptimized tailored vs. locally preferred empiric treatments. METHODS: PubMed, Medline, and Embase databases were searched using suitable keywords. Individual and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the fixed- or random-effects model as appropriate. Heterogeneity was calculated employing the Cochrane Q test and I2 values, whereas the possibility of publication bias was examined by constructing funnel plots. Additionally, subgroup and sensitivity analyses were performed. RESULTS: Thirty-four studies were included with a total of 9613 patients. Tailored therapy proved superior to empiric treatment [OR 2.07 (95% CI 1.53-2.79)]. However, tailored therapy achieved eradication rates >90% in only 15 (44%) studies and >95% in only 6 (17.6%). CONCLUSIONS: Although tailored therapy performed better than empiric treatment, the lack of optimization of therapies failed to reliably achieve high cure rates (>90%). These results emphasize that H. pylori infection, like other infectious diseases, should utilize the principles of antimicrobial stewardship in relation to treatment guidance.

Pilot studies of vonoprazan-containing Helicobacter pylori eradication therapy suggest Thailand may be more similar to the US than Japan.

BACKGROUND: Vonoprazan-containing Helicobacter pylori eradication is reliably effective in Japan. Its effectiveness in other countries remains unclear. Here, we examined vonoprazan-H. pylori therapies in Thailand. MATERIALS AND METHODS: This was pilot study of four different vonoprazan containing therapies. Subjects were randomized to: 14-day dual therapy (500 mg amoxicillin q.i.d. plus 20 mg vonoprazan b.i.d.), 14-day triple therapy (amoxicillin 1 g b.i.d., slow release clarithromycin-MR, 1 g daily plus vonoprazan 20 mg b.i.d.), 7-day high-dose vonoprazan triple therapy (amoxicillin 1 g b.i.d., clarithromycin-MR 1 g daily and 60 mg vonoprazan once daily), and 14-day vonoprazan triple therapy plus bismuth (amoxicillin 1 g b.i.d., clarithromycin-MR 1 g daily, vonoprazan 20 mg b.i.d., and bismuth subsalicylate 1048 mg b.i.d.). Eradication was confirmed 4 weeks after therapy. Antimicrobial susceptibility and CYP3A4/5 genotyping were performed. RESULTS: One hundred H. pylori-infected patients (mean age 54.3 ± 13 years, 51% men) were randomized. All were CYP3A4 extensive metabolizers. Cure rates with both 14-day vonoprazan dual therapy and 14-day triple therapy were low: 66.7%; 95% CI = 43-85% (14/21), and 59.3%; 95% CI = 39-78%) (16/27), respectively. In contrast, 7-day high-dose vonoprazan triple therapy and 14-day vonoprazan triple plus bismuth proved effective 92.3%; 95% CI = 75%-99% (24/26) and 96.2%; 95% CI = 80%-100% (25/26), respectively. CONCLUSION: Both 14-day vonoprazan dual and triple therapy were ineffective for H. pylori eradication in Thailand. Higher dosage of vonoprazan, and/or the addition of bismuth may be required to achieve high H. pylori eradication rates. High-dose vonoprazan triple therapy and vonoprazan triple therapy adding bismuth might be used as first-line treatments in some regions with high efficacy irrespective of CYP3A4/5 genotype and clarithromycin resistance.

Why the Vonoprazan Helicobacter pylori Therapies in the US-European Trial Produced Unacceptable Cure Rates.

INTRODUCTION: Helicobacter pylori infects a large percentage of the world's population and is etiologically related to gastric cancer. The U.S. Food and Drug Administration recently approved two 14-day vonoprazan-containing regimens (vonoprazan-amoxicillin with or without clarithromycin) for H. pylori infections in the United States/Europe. METHODS: We critically reviewed the trial methods to discover why the results were unacceptable low [i.e., no regimen achieved clinically acceptable (≥ 90%) or even conditionally acceptable cure rates (≥ 85%)]. Cure rates with antibiotic susceptible strains were 84.7 for vonoprazan triple therapy, 78.5 for vonoprazan-amoxicillin, and 78.7 for lansoprazole triple therapy, respectively. As was previously shown in Japan, the benefit from adding clarithromycin to vonoprazan-amoxicillin was minimal and the majority of the clarithromycin administered was unnecessary. RESULTS: The possible reasons for failure to achieve high cure rates discussed include (a) reduced intragastric antibiotic concentrations, (b) an increase in heteroresistance, and (c) failure to achieve an intragastric pH conducive for amoxicillin to eradicate the infection. In addition, there was no pilot study or other attempt to optimize any regimen. CONCLUSION: The most likely reason for failure was failure to achieve high intragastric concentrations of antibiotics or to achieve an intragastric pH conducive for amoxicillin to be active. Importantly, vonoprazan triple therapy resulted in > 10 tons of unneeded clarithromycin/million courses of vonoprazan triple therapy. Antibiotic misuse combined with low cure rates suggest that vonoprazan-clarithromycin triple therapies should not be prescribed for H. pylori infection. Dual vonoprazan-amoxicillin therapy has proven effective elsewhere and after optimization may eventually prove useful in the U.S./Europe.

Bile acids and ceramide overcome the entry restriction for GII.3 human norovirus replication in human intestinal enteroids.

Human noroviruses (HuNoVs) cause sporadic and epidemic outbreaks of gastroenteritis in all age groups worldwide. We previously reported that stem cell-derived human intestinal enteroid (HIE) cultures support replication of multiple HuNoV strains and that some strains (e.g., GII.3) replicate only in the presence of bile. Heat- and trypsin-treatment of bile did not reduce GII.3 replication, indicating a nonproteinaceous component in bile functions as an active factor. Here we show that bile acids (BAs) are critical for GII.3 replication and replication correlates with BA hydrophobicity. Using the highly effective BA, glycochenodeoxycholic acid (GCDCA), we show BAs act during the early stage of infection, BA-dependent replication in HIEs is not mediated by detergent effects or classic farnesoid X receptor or Takeda G protein-coupled receptor 5 signaling but involves another G protein-coupled receptor, sphingosine-1-phosphate receptor 2, and BA treatment of HIEs increases particle uptake. We also demonstrate that GCDCA induces multiple cellular responses that promote GII.3 replication in HIEs, including enhancement of 1) endosomal uptake, 2) endosomal acidification and subsequent activity of endosomal/lysosomal enzyme acid sphingomyelinase (ASM), and 3) ceramide levels on the apical membrane. Inhibitors of endosomal acidification or ASM reduce GII.3 infection and exogenous addition of ceramide alone permits infection. Furthermore, inhibition of lysosomal exocytosis of ASM, which is required for ceramide production at the apical surface, decreases GII.3 infection. Together, our results support a model where GII.3 exploits rapid BA-mediated cellular endolysosomal dynamic changes and cellular ceramide to enter and replicate in jejunal HIEs.

Cross-roads for meta-analysis and network meta-analysis of H. pylori therapy.

Helicobacter pylori infections are responsible for tremendous morbidity and mortality worldwide, leading to efforts to eradicate the organism. However, the effectiveness of antimicrobial therapy has been undermined by the progressive development of antimicrobial resistance. Treatments and treatment guidelines have been based on traditional pairwise meta-analyses of randomised controlled trials. More recently, network meta-analyses have also been used in an attempt to provide useful information to the clinician regarding which therapies appear best and which to avoid as the least efficacious. However, both forms of meta-analysis have been undermined by the same problems including the poor quality of the clinical trials using unoptimised regimens and incomparable comparisons related to marked geographic and ethnic genotypic and phenotypic heterogeneity. In addition, the comparator regimens often consist of invalid strawman comparisons. New approaches concerning H. pylori treatment and analysis of therapies are needed. H. pylori therapies should be based on antimicrobial stewardship, as in other infectious diseases. This approach requires the use of only optimised therapies proven to be reliably highly effective in the local population (eg, a cure rate of >90%) for both the study and the comparator regimens. Meta-analyses should be restricted to regimens that meet these criteria and must take into account the presence of marked geographical and host genetic and phenotypic heterogeneity. In addition, to provide clinically relevant results, treatment outcomes should focus on, and present, actual cure rates in addition to odd ratios.

Primer for Development of Guidelines for Helicobacter pylori Therapy Using Antimicrobial Stewardship.

We provide a primer to assist in the difficult transition of Helicobacter pylori therapy guidelines to those that adhere to the principles of antimicrobial stewardship. This transition will entail abandonment of many of the principles that heretofore formed the basis of treatment guidelines and recommendations. The goals of antimicrobial stewardship include optimization of the use of antibiotics while reducing antimicrobial resistance. The critical outcome measure is absolute cure rate which largely restricts comparative trials to those which reliably produce high cure rates (eg, ∼95%). Therapies that fail to achieve at least a 90% cure rate should be abandoned as unacceptable. Because only optimized therapies should be prescribed, guidance on the principles and practices of optimization will we required. Therapies that contain antibiotics which do not contribute to outcome should be eliminated. Surveillance, one of the fundamental elements of antimicrobial stewardship, must be done to provide ongoing assurance that the recommended therapies remain effective. It is yet not widely recognized when utilizing otherwise highly successful therapies, the routine test of cure data is an indirect, surrogate method for susceptibility testing. To systematically guide therapy, test of cure data should be collected, shared and integrated into local antimicrobial stewardship programs to provide guidance regarding best practices to both prescribers and public health individuals. Treatment recommendations should be compatible with those of the American Society of Infectious Disease white paper on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens which include criteria for ethical active-controlled superiority studies of antibacterial agents.

Comparison of Culture With Antibiogram to Next-Generation Sequencing Using Bacterial Isolates and Formalin-Fixed, Paraffin-Embedded Gastric Biopsies.

BACKGROUND & AIMS: The decline in Helicobacter pylori cure rates emphasizes the need for readily available methods to determine antimicrobial susceptibility. Our aim was to compare targeted next-generation sequencing (NGS) and culture-based H pylori susceptibility testing using clinical isolates and paired formalin-fixed, paraffin-embedded (FFPE) gastric biopsies. METHODS: H pylori isolates and FFPE tissues were tested for susceptibility to amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and rifabutin using agar dilution and NGS targeted to 23S rRNA, gyrA, 16S rRNA, pbp1, rpoB and rdxA. Agreement was quantified using κ statistics. RESULTS: Paired comparisons included 170 isolates and FFPE tissue for amoxicillin, clarithromycin, metronidazole, and rifabutin and 57 isolates and FFPE tissue for levofloxacin and tetracycline. Agreement between agar dilution and NGS from culture isolates was very good for clarithromycin (κ = 0.90012), good for levofloxacin (κ = 0.78161) and fair for metronidazole (κ = 0.55880), and amoxicillin (κ = 0.21400). Only 1 isolate was resistant to tetracycline (culture) and 1 to rifabutin (NGS). Comparison of NGS from tissue blocks and agar dilution from isolates from the same stomachs demonstrated good accuracy to predict resistance for clarithromycin (94.1%), amoxicillin (95.9%), metronidazole (77%), levofloxacin (87.7%), and tetracycline (98.2%). Lack of resistance precluded comparisons for tetracycline and rifabutin. CONCLUSIONS: Compared with agar dilution, NGS reliably determined resistance to clarithromycin, levofloxacin, rifabutin, and tetracycline from clinical isolates and formalin-fixed gastric tissue. Consistency was fair for metronidazole and amoxicillin. Culture-based testing can predict treatment outcomes with clarithromycin and levofloxacin. Studies are needed to compare the relative ability of both methods to predict treatment outcomes for other antibiotics.

Comparative Effectiveness of Multiple Different First-Line Treatment Regimens for Helicobacter pylori Infection: A Network Meta-analysis.

BACKGROUND & AIMS: A number of double, triple, and quadruple therapies have been proposed as first-line empiric treatments for Helicobacter pylori infection. However, knowledge of their worldwide and regional comparative efficacy is lacking. We examined the comparative effectiveness of all empirically used first-line regimens tested against standard triple treatment using a network meta-analysis of published randomized controlled trials. METHODS: Data extracted from eligible randomized controlled trials were entered into a Bayesian network meta-analysis to investigate the comparative efficacy of H pylori infection empiric first-line regimens and to explore their effectiveness rank order. The ranking probability for each regimen was evaluated by means of surfaces under cumulative ranking values. RESULTS: Sixty-eight eligible randomized controlled trials were included, giving a total of 92 paired comparisons with 22,975 patients randomized to 8 first-line regimens. The overall results showed that only vonoprazan triple therapy and reverse hybrid therapy achieved cure rates of >90%. Levofloxacin triple therapy performed best in Western countries (eradication rate 88.5%). The comparative effectiveness ranking showed that vonoprazan triple therapy had the best results, whereas standard triple therapy was the least efficacious regimen (surfaces under cumulative ranking 92.4% vs 4.7% respectively; odds ratio, 3.80; 95% credible interval, 1.62-8.94). CONCLUSIONS: For first-line empiric treatment of H pylori infection, vonoprazan triple therapy and reverse hybrid therapy achieved high eradication rates of >90%. Levofloxacin triple therapy achieved the highest eradication rates in Western countries. Standard triple therapy was the least efficacious regimen in this network meta-analysis.

Helicobacter pylori.

Helicobacter pylori (H. pylori) is an important human pathogen etiologically associated with peptic ulcers and gastric cancer. The infection is present in approximately one-half of the world's population. Population-based H. pylori eradiation has confirmed that cure or prevention of the infection produces a marked reduction in gastric cancer and peptic ulcer disease. Antimicrobial therapy has become increasingly ineffective, and complexity and costs of antimicrobial therapy for infected individuals residing in and, immigrating from, the developing world combined with the cost of treatment for cancer make vaccine development a cost-effective alternative. Challenge studies allowed making a "go-no go" decision regarding vaccine effectiveness. We provide detailed protocols regarding challenge strain selection and administration as well as guidance regarding the clinical and laboratory tests used to confirm and monitor experimental infection. Experience shows that reliance of noninvasive methods led to the erroneous conclusion that some subjects were not infected. The current data suggests that histologic assessment of gastric mucosal biopsies may be one of the most sensitive and specific means of assessment of the presence of experimental infection as well as of successful H. pylori eradication. We recommend detailed recommendations for acquiring, processing, embedding, sectioning, and examining the gastric biopsies.

Management of upper gastrointestinal symptoms in patients with autoimmune gastritis.

PURPOSE OF REVIEW: Autoimmune gastritis is characterized by atrophy of acid secreting parietal cells resulting in achlorhydria. Upper gastrointestinal symptoms are common in autoimmune gastritis and frequently result in prescriptions for acid suppressant medications despite the inability of the stomach to secrete acid. Evidence-based recommendations for management of gastrointestinal symptoms in autoimmune gastritis are lacking. RECENT FINDINGS: The most common symptoms in patients with autoimmune gastritis are dyspepsia, heartburn, and regurgitation. Gastroesophageal reflux should be confirmed by pH-impedance testing and is typically weakly acid or alkaline. Therapy for reflux focuses on mechanical prevention of reflux (i.e., elevation of the head of the bed and alginates) or when severe, antireflux surgery. The etiology of dyspepsia in autoimmune gastritis is unclear and largely unstudied. In the first half of the 20th century, oral administration of acid to "aid digestion" was widely used with reported success. However, randomized, placebo-controlled trials are lacking. Here, we provide suggestions for attempting gastric acidification therapy. SUMMARY: Upper GI symptoms are common in autoimmune gastritis. Their pathogenesis and therapy remain incompletely understood. Acid suppressant medications are useless and should be discontinued. A trial of acid replacement therapy is recommended especially in the form of placebo-controlled trials.

Managing bleeding risk after cold snare polypectomy in patients receiving direct-acting oral anticoagulants.

BACKGROUND AND AIMS: The best strategy to manage direct-acting oral anticoagulants (DOACs) for patients undergoing cold snare polypectomy remains unclear. This study compared the effect of continuing versus stopping DOACs only on the day of the procedure on bleeding after cold snare polypectomy. METHODS: This prospective, observational, single-center cohort study enrolled consecutive patients receiving antithrombotic agents and undergoing cold snare polypectomy of colorectal polyps ≤10 mm in diameter. During period 1 (2017 and 2018) antithrombotic agents including DOACs were not discontinued (DOAC continued group). In period 2 (2019 and 2020) DOACs were withheld only on the day of the procedure (DOAC withheld group) and restarted the next day after the procedure. The primary outcome was delayed bleeding requiring endoscopic treatment occurring within 2 weeks after cold snare polypectomy. Secondary outcomes were immediate bleeding and the number of hemostatic clips used. RESULTS: For the 2 groups, 204 (DOAC continued group; 34% women; mean age, 75 years) and 264 (DOAC withheld group; 36% women; mean age, 74 years) patients were enrolled. Clinical features were similar between the 2 groups. Delayed bleeding after cold snare polypectomy occurred in 4 of 47 patients (8.5%) in the DOAC continued group versus 0 of 66 (0%) in the DOAC withheld group (P < .001). Immediate postpolypectomy bleeding occurred in 12 of 47 patients (25.5%) in the DOAC continued group versus 4 of 66 (6.1%) in the DOAC withheld group (P < .008). CONCLUSIONS: Cold snare polypectomy may be safely preformed if DOACs are withheld only on the day of the procedure. (Clinical trial registration number: NCT02594813.).

Spatial Characteristics of Colonic Mucosa-Associated Gut Microbiota in Humans.

Limited data exist on the spatial distribution of the colonic bacteria in humans. We collected the colonic biopsies from five segments of 27 polyp-free adults and collected feces from 13 of them. We sequenced the V4 region of the bacterial 16S rRNA gene using the MiSeq platform. The sequencing data were assigned to the amplicon sequence variant (ASV) using SILVA. Biodiversity and the relative abundance of the ASV were compared across the colonic segments and between the rectal and fecal samples. Bacterial functional capacity was assessed using Tax4fun. Each individual had a unique bacterial community composition (Weighted Bray-Curtis P value = 0.001). There were no significant differences in richness, evenness, community composition, and the taxonomic structure across the colon segments in all the samples. Firmicutes (47%), Bacteroidetes (39%), and Proteobacteria (6%) were the major phyla in all segments, followed by Verrucomicrobia, Fusobacteria, Desulfobacterota, and Actinobacteria. There were 15 genera with relative abundance > 1%, including Bacteroides, Faecalibacterium, Escherichia/Shigella, Sutterella, Akkermansia, Parabacteroides, Prevotella, Lachnoclostridium, Alistipes, Fusobacterium, Erysipelatoclostridium, and four Lachnospiraceae family members. Intra-individually, the community compositional dissimilarity was the greatest between the cecum and the rectum. There were significant differences in biodiversity and the taxonomic structure between the rectal and fecal bacteria. The bacterial community composition and structure were homogeneous across the large intestine in adults. The inter-individual variability of the bacteria was greater than inter-segment variability. The rectal and fecal bacteria differed in the community composition and structure.