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See accompanying article on page 347In the pursuit of the eradication of H. pylori, the global medical community has made noteworthy progress. The first effective combination treatment, known as Triple Therapy or Helidac, originated in 1984 from our research in Sydney.[1] It was soon followed by Pylera which entered the US market when it was discovered that proton pump inhibitors (PPIs) enhanced eradication.[2,3] This trend has continued with Talicia, which includes the antibiotic rifabutin, having received FDA approval in late 2019. Despite the implementation of PPIs, rifabutin, and numerous combinations of antibiotic regimens, achieving complete eradication remains a challenge due to antimicrobial resistance (AMR). In particular, H.pylori's resistance to clarithromycin is growing and hinders treatment success in 10–40% of patients. The emergence of AMR in H. pylori strains has significantly reduced the efficacy of both primary and salvage/rescue therapies in many regions, with reports indicating that AMR resistance is as high as 20%, 81%, and 55% to clarithromycin, metronidazole, and levofloxacin, respectively.[4] Amid these mounting concerns, it is vital to reevaluate H. pylori treatment, optimize eradication, and prevent chronic mucosal sequelae and the spread of AMR. Subsequently, interest in various drug combinations has attempted to overtake microbial resistance to eradicate H.pylori. In particular, we reference two papers published in the journal, relevant to this discussion.[5,6] In the first of these papers, Zhang et al. conducted a comprehensive meta-analysis comprising 5604 participants from 14 RCTs to compare the first-line therapy, Bismuth-containing Quadruple Therapy (BQT), based on our original Pylera, against High-Dose Dual Therapy (HDDT) (PPIs and amoxicillin). Various PPIs were included in the study, understanding that PPIs have anti-H.pylori antibiotic effects.[7] Zhang et al.'s mixed composition study with variable doses of amoxicillin, tetracycline, levofloxacin, and bismuth found an 87.46% eradication rate in the HDDT group versus an 85.70% rate in the BQT group. The study provided some novel conclusions but could not completely debunk the use of BQT in preference of a slightly better HDDT. What the study lacked was a particular focus on acid suppression. Zhang et al.'s study is not alone, with many reviews and meta-analyses failing to recognize that antibiotics, by themselves, have almost reached their limits in further elevating eradication except for further improvements by adding rifabutin. Now, the potential for improved eradication must be shared with improved acid suppression. A discussion of more profound acid neutralization in eradication therapy must be included as it is the leading basis for why H. pylori is resistant to antibiotics. H.pylori resistance is not simply due to Darwinian selection as H. pylori bacteria have the ability to transition between two phases—the dormant and active spiral forms. The dormant "coccoid" form is metabolically inactive and encased in a thick mucus biofilm, which is resistant to both acid and antibiotics. Metabolic dormancy also means that any antibiotic targeting an active growth phase protein may be ineffective against coccoid H. pylori. When gastric conditions improve, coccoid forms of H.pylori transform into their active helical or spiral forms, and it is this form that is responsible for gastritis, ulcer formation, and inflammation. It is the spiral form that is susceptible to antibiotics therapy. Therefore, any protocol aiming to eliminate H. pylori must promote the transition of dormant forms of H. pylori into the antibiotic-susceptible active state and it is for this reason that novel Potassium-Competitive Acid Blockers (P-CABs), such as vonoprazan, play a crucial role. P-CABs, exemplified by vonoprazan fumarate, have emerged as game-changers in H.pylori treatment. Traditional acid suppressors, such as antacids, H2 antagonists, and PPIs, are effective in suppressing acid secretion but may be inconsistent with variable pH fluctuations. This is evident in the common side effect of sleep-associated acid rebound or night-time acid reflux which indicates a return of gastric acids. P-CABs, such as vonoprazan, offer rapid and sustained acid suppression, compelling dormant H. pylori to adopt the more antibiotic-susceptible spiral form without any periods of acidic rebound. Vonoprazan, however, has only recently achieved FDA approval in 2022 and, therefore, falls under the radar for many systematic reviews and meta-analyses. However, smaller more recent analyses have already demonstrated improved efficacy with its inclusion.[6] In our second special mention, Zhou et al. investigated the effectiveness of vonoprazan in H. pylori eradication in a small meta-analysis of five studies between 2020 and 2022. Among these studies were five RCTs and 1922 H. pylori-infected patients.[6] When the results of eradication rates of vonoprazan-amoxicillin dual therapy (VA) and PPI-based triple therapy (PAC) were compared, vonoprazan-inclusive therapy was 8.2% and 10.9% significantly higher by intention-to-treat analysis and per-protocol analysis, respectively, than PPI-based therapies. Nevertheless, Zhou et al., like Zhang et al.'s study also noted a plateau in eradication rates. Namely, that vonoprazan-amoxicillin eradication rates were limited to 78.6%, and even vonoprazan-amoxicillin-clarithromycin (VAC) triple therapy eradication rates were limited to 84.8% by per-protocol analysis (PP). While this direct comparison appears lower than that reported by Zhang et al., the presence of 20–24% clarithromycin resistance in some studies could explain why eradication was severely limited. While the best-in-class acid suppressor vonoprazan was used in Zhou's study, the question of whether more frequent administration might yield better results arises, as vonoprazan requires around 4 hours to reach a pH of 7, and it has yet to be studied in larger more robust clinical trials.[8] Our group explored some of these approaches in a small study in 2021, where we tested eleven different regimens of 2–5 different antibiotics in 153 patients, focusing on vonoprazan, amoxicillin, and, of particular importance, rifabutin.[9] Within this study, we achieved a total of 97% eradication overall in the 66 patients whom we confirmed through follow-up testing. A subgroup analysis identified that 100% eradication was achieved in treatment-naïve patients (n = 44), but eradication rates dropped to 91% in the non-naïve rescue therapy group (n = 20 out of n = 22) where patients received treatment even multiple times. We attribute these higher eradication rates to the effective application of the three principles described above: (i) that antibiotics must be effective against the extracellular forms of H. pylori (namely, amoxicillin), (ii) that another antibiotic effective against intracellular and dormant forms of H. pylori be used (rifabutin), (iii) and that profound acid suppression (vonoprazan) is used frequently (three times daily) to ensure dormant forms of H. pylori are coaxed out of their intracellular or coccoid niches. Our choice to add rifabutin was based on the fact that H. pylori, in addition to dormant and coccoid forms, can burrow into intracellular niches in host cytoplasmic vacuoles. Rifabutin, however, is highly lipophilic and concentrates within tissues and intracellular compartments at concentrations ~10 times greater than in plasma concentrations.[10] The advantages of rifabutin over other antibiotics were demonstrated against resistant mycobacteria, such as Mycobacterium tuberculosis. Furthermore, pharmacokinetic studies show that amoxicillin is highly effective against H. pylori and resistance against it is low, as it is for rifabutin. Unfortunately, amoxicillin's distribution is almost exclusively in extracellular spaces and is completely ineffective when transported intracellularly.[11] This might explain the reduced eradication rates in Zhou et al.'s studies. In future approaches, addressing intracellular survival mechanisms could be the key in fully eradicating H. pylori. Rifabutin, with intracellular penetration, complements amoxicillin's effectiveness against extracellular forms, and vonoprazan's synergism with amoxicillin which has been demonstrated.[12] Embracing this multi-pronged approach involving amoxicillin, rifabutin, and vonoprazan in larger pilot studies could pave the way for more effective H. pylori treatment regimens.

The objective of this study was to estimate the effectiveness of early biologics compared to conventional treatment in the management of Crohn's disease among pediatric and adolescent patients. A comprehensive literature search was conducted in four electronic databases to identify relevant studies published from inception to 2023. The inclusion criteria comprised randomized controlled trials (RCTs) and cohort studies that reported on the efficacy and clinical outcomes of early biologic therapy compared to late/conventional therapy in children with Crohn's disease. The quality of the studies was assessed using the Cochrane Risk of Bias tool and the Newcastle Ottawa scale. A total of 13 studies (2 RCTs and 11 cohort studies), involving 861 patients, were included in the meta-analysis. The results demonstrated that early biologic therapy was associated with a significantly higher rate of clinical remission (risk ratio [RR] 1.30, 95% confidence interval [CI] 1.10-1.54), lower relapse rates (RR 0.33, 95% CI 0.21-0.53), and improved mucosal healing (RR 1.47, 95% CI 1.10-1.97) compared to late/conventional therapy. However, it should be noted that there was evidence of publication bias among studies reporting clinical remission. In conclusion, early biologic therapy is significantly more effective in achieving clinical remission (within two years of diagnosis), promoting mucosal healing, and reducing relapse rates in pediatric and adolescent patients with Crohn's disease, compared to late/conventional therapy. These findings emphasize the importance of initiating biological therapy early in the treatment of Crohn's disease in this patient population.

Vonoprazan-amoxicillin (VA) dual therapy has recently been proposed to eradicate Helicobacter pylori (H. pylori) with controversial results. We, therefore, conducted a meta-analysis to assess the effect of this therapy for H. pylori eradication. We searched PubMed, Embase, Cochrane Library, and Web of Science database from inception until November 2022, collecting randomized controlled trials (RCTs) comparing VA dual therapy with other regimens for H. pylori eradication. Pooled relative risks (RRs) were calculated using random effects model. Five RCTs were ultimately included. Compared with the vonoprazan-amoxicillin-clarithromycin (VAC) triple therapy, the eradication rate of VA dual therapy was lower in intention-to-treat (ITT) analysis (n = 3 RCTs, RR = 0.94, 95% CI: 0.88-0.99, P = 0.03), but there was no significant difference between them in the per-protocol (PP) analysis (RR = 0.96, 95% CI: 0.91-1.01, P = 0.11). For clarithromycin-resistant H. pylori strains, the eradication rate of VA dual therapy was significantly higher than that of the VAC triple therapy (n = 2 RCTs, RR = 1.20, 95% CI: 1.03-1.39, P = 0.02). Compared with the PPI-based triple therapy (PAC), VA dual therapy had a superior eradication rate (n = 2 RCTs, ITT analysis: RR = 1.13, 95% CI: 1.04-1.23, P = 0.003; PP analysis: pooled RR = 1.14, 95% CI: 1.06-1.22, P = 0.0004). Compared with VAC or PAC triple therapy, VA dual therapy has a similar incidence of total adverse events and compliance. VA dual therapy had a similar effect compared to VAC triple therapy and was superior to PAC triple therapy. Future RCTs are needed to ascertain the optimal dosage and duration of vonoprazan and amoxicillin, and the effect of VA dual therapy compared with the mainstream regimens recommended by current guidelines.

Smoking poses a significant risk for colorectal cancer (CRC), considered the third leading reason for cancer-related deaths worldwide. However, there has been limited research on the relationship between smoking and CRC in the Eastern Mediterranean Regional Office (EMRO). Therefore, a meta-analysis was conducted to combine available data and gain a comprehensive understanding of the relationship between smoking and CRC in EMRO. Two independent researchers searched PubMed, Scopus, and Web of Science until December 2022. The included studies were checked for risk of bias administering the Newcastle-Ottawa scale. Heterogeneity was evaluated using I2 statistics and the Cochrane test. Publication bias was determined through funnel plot analysis and Egger's regression test. Additionally, a meta-regression analysis explored the impact of a country's Human Development Index (HDI) on the relationship between smoking and CRC. The final analysis included 26 studies, revealing a significant association between smoking and CRC (OR = 1.40; 95% CI: 1.11 - 1.78; P = 0.004). Moreover, smoking had a more pronounced adverse effect on CRC in countries with higher HDIs compared to those with lower HDIs (OR = 1.30; 95% CI: 0.99 - 1.71; P = 0.054). Our findings underscore the importance of implementing smoking cessation programs and policies in EMRO countries, as they demonstrate a positive relationship between smoking and the risk of CRC. Furthermore, the results suggest that a country's level of human development may influence the association between smoking and CRC. Further research is needed to investigate this potential connection and develop targeted public health interventions.

Inflammatory bowel disease (IBD) disk is an easy tool to use in clinical practice to measure IBD-related disability, with a score >40 correlating with high daily-life burden. Its use has been limited mainly to the western world. We aimed to estimate the prevalence of IBD-related disability and evaluate the associated risk factors in Saudi Arabia. In this cross sectional study conducted at a tertiary referral center for IBD, the English IBD disk was translated into Arabic, and patients with IBD were approached to complete it. Total IBD disk score (0 = no disability; 100 = severe disability) was documented and a score of >40 was set as a threshold to estimate the prevalence of disability. Eighty patients with a mean age of 32.5 ± 11.9 years and disease duration of 6 years, including 57% females, were analyzed. The mean IBD-disk total score was 20.70 ± 18.69. The mean subscores for each function within the disk ranged from 0.38 ± 1.69 for sexual functions to 3.61 ± 3.29 for energy. The overall prevalence of IBD-related disability was 19% (15/80 scoring >40) and was much higher in active disease, in males and in IBD of long duration (39%, 24%, and 26%, respectively). A clinically active disease, high CRP, and high calprotectin were strongly associated with higher disk scores. Although the overall mean IBD disk score was low, nearly 19% of our population had high scores signifying a high prevalence of disability. As demonstrated by other studies, active disease and high biomarkers were significantly associated with higher IBD-disk scores.

Celiac serology can be transiently elevated in patients with type 1 diabetes mellitus (T1DM) and normalized despite gluten consumption. This study aimed to identify the frequency and predictive factors of spontaneous normalization of anti-tissue transglutaminase (anti-TTG-IgA) antibodies in these patients. The charts of all patients (≤18 years) with T1DM were retrospectively reviewed from 2012 to 2021 at a tertiary care center in Riyadh, Saudi Arabia. The following data were collected: clinical characteristics of the participants, anti-TTG-IgA-immunoglobulin (Ig) A antibody, and histological findings. The outcome of positive anti-TTG-IgA-IgA in patients with T1DM and the predictive factors for spontaneous normalization were investigated. Of the 1,006 patients with T1DM, 138 (13.7%) had elevated anti-TTG-IgA antibodies, celiac disease was diagnosed in 58/138 (42%) patients, spontaneous normalization of anti-TTG-IgA was observed in 65 (47.1%) patients, and fluctuating anti-TTG-IgA antibodies were seen in 15 (10.9%) patients. The patients with anti-TTG-IgA levels at 3-10 times the upper normal limits (UNL), and those with levels ≥10 times UNL were less likely to have spontaneous normalization of anti-TTG-IgA compared to patients with levels at 1-3 times UNL (hazard ratio [HR] = 0.28, 95% confidence interval [Cl] = 0.13-0.61, P = 0.001, and HR = 0.03, 95% Cl = 0.00-0.19, P < 0.001, respectively). Asymptomatic patients with T1DM with mild elevation of anti-TTG-IgA need not be rushed for invasive endoscopy or exposed to an un-needed gluten-free diet but should rather have a regular follow-up of their celiac serology.

Endoscopic submucosal dissection (ESD) of rectal tumors involving the dentate line (RT-DL) is challenging because of the anatomical features of the anal canal. This study aimed to identify optimal techniques and sedation and to determine the clinical outcomes of ESD for RT-DL. We retrospectively collected medical records and endoscopic results of patients who underwent ESD for rectal tumors between January 2012 and April 2021. Patients were divided into RT-DL and rectal tumors not involving the dentate line (RT-NDL) groups, as per involvement of the dentate line. The treatment results and clinical outcomes of the two groups were evaluated and analyzed. Additionally, subgroup analysis was performed in the RT-DL group for the sedation method involved. In total, 225 patients were enrolled and 22 were assigned to the RT-DL group. The complete resection rate (90.9% vs. 95.6%, P =0.336), delayed bleeding (13.6% vs. 5.9%, P =0.084), perforation (0% vs. 3.9%, P = 0.343), hospital stays (4.55 vs. 4.48 days, P = 0.869), and recurrence (0% vs. 0.5%) showed no significant group differences. However, in RT-DL group, the procedure time (78.32 vs. 51.10 min, P = 0.002) was longer and there was more perianal pain (22.7% vs. 0%, P = 0.001). The subgroup analysis revealed that deep sedation using propofol reduced perianal pain during the procedure (0/14 vs. 5/8, P = 0.002). ESD of RT-DL is a safe and effective treatment despite the challenges of requiring a high level of technique and longer procedure time. In particular, ESD under deep sedation should be considered in patients with RT-DL to control perianal pain.