Bismuth-Containing Quadruple Therapy for Helicobacter pylori Eradication: A Randomized Clinical Trial of 10 and 14 Days.

BACKGROUND: Bismuth-containing quadruple therapy is the first-line treatment for eradicating Helicobacter pylori (H. pylori). The optimal duration for H. pylori eradication using bismuth-containing quadruple therapy remains controversial. Therefore, we aimed to compare the clinical effects of the 10- and 14-day bismuth-containing quadruple treatment regimen to eradicate H. pylori. METHODS: Treatment-naïve patients with H. pylori infection (n = 1300) were enrolled in this multicenter randomized controlled study across five hospitals in China. They were randomized into 10- or 14-day treatment groups to receive bismuth-containing quadruple therapy as follows: vonoprazan 20 mg twice daily; bismuth 220 mg twice daily; amoxicillin 1000 mg twice daily; and either clarithromycin 500 mg twice daily or tetracycline 500 mg four times daily. At least 6 weeks after treatment, we performed a 13C-urea breath test to evaluate H. pylori eradication. RESULTS: The per-protocol eradication rates were 93.22% (564/605) and 93.74% (569/607) (p < 0.001) and the intention-to-treat eradication rates were 88.62% (576/650) and 89.38% (581/650) (p = 0.007) for the 10- and 14-day regimens, respectively. Incidence of adverse effects was lower in patients who received 10- vs. 14 days of treatment (22.59% vs. 28.50%, p = 0.016). We observed no significant differences in the compliance to treatment or the discontinuation of therapy because of severe adverse effects between the groups. CONCLUSION: Compared with the 14-day bismuth-containing quadruple regimens, the 10-day regimen demonstrated a non-inferior efficacy and lower incidence of adverse effects. Therefore, the 10-day regimen is safe and tolerated and could be recommended for H. pylori eradication (NCT05049902).

Efficacy and safety of a 14-day modified concomitant therapy for refractory Helicobacter pylori infection: a pilot study.

BACKGROUND AND AIM: After three treatment failures, Helicobacter pylori infection is deemed refractory as antibiotic treatment options become significantly limited. This study evaluated the efficacy and safety of a 14-day modified concomitant therapy for managing refractory H. pylori infection. METHODS: Patients who had failed to respond to three or more rounds of H. pylori therapies were recruited for this study. They received a 14-day modified concomitant therapy, including esomeprazole 40 mg, amoxicillin 1000 mg, and furazolidone 100 mg twice daily and tetracycline 500 mg four times daily. Demographic data, adverse events, and patient compliance were recorded. The presence of H. pylori was reevaluated 6 weeks following treatment. Eradication rate was assessed as the primary outcome. RESULTS: Overall, 59 participants received the 14-day modified concomitant therapy. In the intention-to-treat and per-protocol analyses, the eradication rate was 84.7% (50/59) and 89.3% (50/56), respectively. H. pylori was successfully isolated from 75.0% (12/16) of patients. The resistance rate of H. pylori to metronidazole, levofloxacin, and clarithromycin was 91.7% (11/12), 58.3% (7/12), and 50.0% (6/12), respectively. Resistance to amoxicillin, furazolidone, or tetracycline was not observed. The frequency of adverse events was 35.6% (21/59), with no serious adverse events reported. CONCLUSION: The 14-day modified concomitant therapy appears to be appropriate for refractory H. pylori infection and is particularly promising for the Chinese population. A randomized controlled trial is warranted to verify its efficacy, especially in the current environment of increasing antibiotic resistance.

Vonoprazan is noninferior to proton pump inhibitors in bismuth-containing quadruple therapy for the treatment of Helicobacter pylori infection: A propensity score matching analysis.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of vonoprazan (VPZ) versus proton pump inhibitor (PPI) in clarithromycin-based bismuth-containing quadruple therapy (C-BQT) for the treatment of Helicobacter pylori (H. pylori) eradication. METHODS: Medical records of patients in whom H. pylori was eradicated between 1 July 2018 and 31 December 2021 were retrieved retrospectively from the Outpatient Unit of Qilu Hospital. Efficacy, safety, and compliance were compared between VPZ-based and PPI-based C-BQT, containing vonoprazan 20 mg or proton pump inhibitors (lansoprazole 30 mg or esomeprazole 20 mg), bismuth 220 or 200 mg, amoxicillin 1000 mg, and clarithromycin 500 mg, twice daily for 2 weeks by 1:1 propensity score matching analysis. The trial was registed on ClinicalTrials.gov (registration no. NCT05301725). RESULTS: The H. pylori eradication rates of VPZ-based and PPI-based therapies were 88.8% (151/170) and 87.6% (149/170) in the intention-to-treat analysis, 94.1% (144/153) and 91.1% (144/158) in the per-protocol analysis, respectively. The noninferiority of VPZ to PPI was confirmed in all analyses (P < 0.001). The incidence of adverse events was 30.0% (51/170) and 27.1% (46/170) in the VPZ-based and PPI-based groups, respectively. VPZ-based and PPI-based therapies were well tolerated and showed good patient compliance without significant differences. CONCLUSIONS: VPZ-based therapy resulted in a satisfactory eradication rate and was well tolerated for H. pylori eradication, which are comparable to PPIs in C-BQT as a first-line treatment for H. pylori infection.

The cure rate of 10-day bismuth-containing quadruple therapy for Helicobacter pylori eradication is equivalent to 14-day: a systematic review and meta-analysis.

Helicobacter pylori (H. pylori) infection is a major cause of duodenal ulcers, gastric ulcers, and gastric cancer. However, the optimal duration for H. pylori eradication therapy remains controversial. Most studies have mainly focused on triple therapy, and there is insufficient research on bismuth-containing quadruple therapy. The aim of this study was to compare the clinical effect of the 10-day bismuth-containing quadruple treatment regimen with the 14-day regime in eradicating H. pylori. We searched PubMed, Embase, Web of Science, and the Cochrane Library for randomized controlled trials published in English until May 2022 according to the eligibility criteria. Summary risk ratios (RRs) and 95% confidence intervals (CIs) for eradication rates, adverse effects, and compliance were calculated for included studies. Four studies, involving 1173 patients, were eligible for inclusion. The eradication rate was similar in the 10-day treatment group and the 14-day treatment group in the intention-to-treat analysis (RR 0.97, 95% CI 0.93 to 1.01). Meanwhile, the incidence of adverse effects was lower in patients who received 10 days of treatment than in those who received 14 days of treatment and patients' compliance was almost the same between two groups. Compared to the 14-day bismuth-containing quadruple regimens, 10-day regimens had similar efficacy and lower incidence of adverse effects. Therefore, the 10-day regimen is safe and well-tolerated and should be recommended for H. pylori infection.

Implementation of WeChat-based patient-doctor interaction in the management of Helicobacter pylori infection: A propensity score matching analysis.

OBJECTIVE: We aimed to investigate if the WeChat-based patient-doctor interaction could affect treatment outcomes of Helicobacter pylori (H. pylori) eradication compared with conventional patient education (CPE) alone. METHODS: Patients treated for H. pylori infection for the first time at our clinic from 1 July 2019 to 31 July 2021 were retrospectively included and divided into the CPE and WeChat groups. Both groups received CPE including verbal education and a specifically designed printout with detailed instructions. Those in the WeChat group were required to join a physician-managed WeChat group chat and they were encouraged to ask questions for clarification. Baseline characteristics were matched using propensity score matching between the two groups. Relevant knowledge and instructions were occasionally shared. Eradication rate, compliance, and adverse events in the two groups were evaluated. RESULTS: A total of 348 patients were included after propensity score matching. Intention-to-treat analysis revealed eradication rate of 85.6% in the WeChat group and 80.5% in the CPE group (P = 0.199), whereas the per-protocol eradication rate was 91.1% and 88.2% (P = 0.399), respectively. Compliance did not differ between the two groups (WeChat group vs CPE group: 92.5% vs 91.4%, P = 0.693). The incidences of adverse events were also comparable between the two groups. CONCLUSIONS: CPE utilization already yields fair H. pylori eradication rate; however, the WeChat-based patient-doctor interaction did not yield better results. More appropriate managements are needed in the future to explore the impact of the WeChat platform on H. pylori eradication.

Clinical practice of Helicobacter pylori infection management by gastroenterologists in secondary and tertiary hospitals: A stratified sampling cross-sectional survey.

OBJECTIVE: To investigate the management of Helicobacter pylori (H. pylori) infection by gastroenterologists from secondary and tertiary hospitals in Shandong Province, China, where there is a high prevalence of H. pylori infection. METHODS: A questionnaire-based, stratified sampling survey was conducted from June 1 to August 30, 2021. The ratio of secondary to tertiary hospitals was set at 2:1. An electronic questionnaire was sent to the gastroenterologists via the WeChat platform. RESULTS: A total of 89.09% (1053/1182) gastroenterologists were included. Overall, 34.19% and 60.59% of gastroenterologists recommended screening for and treating H. pylori infection in patients without any competing factors. The most preferred testing method in secondary and tertiary hospitals was the 13 C-urea breath test (53.92% and 80.48%), but the reexamination rate of results close to the cut-off value was low (55.10% and 59.48%). Gastroenterologists preferred bismuth-containing quadruple therapy (secondary and tertiary hospitals: 96.67% and 98.53%), but the antibiotic combination prescribed for patients with penicillin allergy was suboptimal in secondary hospitals. The overall post-treatment follow-up rate was 64.58%, and gastroenterologists in secondary hospitals were more proactive than those in tertiary hospitals (69.41% vs 60.04%, P = 0.001). Less than 80% of gastroenterologists emphasized the importance of post-treatment reexamination to their patients. Only a minority of gastroenterologists in secondary and tertiary hospitals (30.79% and 34.36%) achieved acceptable eradication rates (exceeding 80%). CONCLUSIONS: Deficiencies exist in gastroenterologists from secondary and tertiary hospitals, and the H. pylori eradication rate is relatively low. Training programs for gastroenterologists are warranted to strengthen their comprehension of guidelines.

Two Different 1-Week Quadruple Therapies Given Back-to-Back Consecutive Therapy for Difficult-to-Treat Helicobacter pylori Infection: A Pilot Study.

INTRODUCTION: We aim to evaluate the efficacy of 2 different 1-week quadruple therapies given back-to-back consecutive therapy in patients with difficult-to-treat Helicobacter pylori infection. METHODS: Patients with proven H. pylori infection were recruited after >3 failed standard quadruple eradication. They received consecutive therapy consisting of esomeprazole 40 mg or rabeprazole 20 mg twice daily, amoxicillin 1,000 mg twice daily, tetracycline 500 mg 4 times daily, and furazolidone 100 mg 3 times daily for the first 7 days, followed by colloidal bismuth pectin 200 mg twice daily in place of furazolidone 100 mg for another 7 days. Eradication rates, treatment-emergent adverse events (TEAEs), and compliance were assessed. RESULTS: Sixty-five patients were enrolled. The mean number of previous eradications was 3.6 (range: 3-7). The intention-to-treat and per-protocol eradication rates were 90.8% (59/65) and 95.1% (58/61). In total, 23.4% (15/64) of patients experienced drug-related TEAEs. No serious adverse events were observed. None of the patients required treatment for TEAEs, and 95.3% (61/64) showed good compliance. Overall, 51 patients (78.5%) were with the available antimicrobial susceptibility testing results. The resistance rates to clarithromycin, metronidazole, levofloxacin, and amoxicillin were 60.8% (31/51), 100% (51/51), 70.6% (36/51), and 2.0% (1/51), respectively. No resistance was detected to either furazolidone or tetracycline. However, in 54.9% of patients (28/51), H. pylori was resistant to 3 antibiotics (metronidazole, levofloxacin, and clarithromycin). DISCUSSION: Consecutive therapy, including amoxicillin, tetracycline, and furazolidone, achieved a good eradication rate (>90%), with desirable compliance and tolerability in difficult-to-treat H. pylori infection.

Susceptibility-guided quadruple therapy is not superior to medication history-guided therapy for the rescue treatment of Helicobacter pylori infection: A randomized controlled trial.

OBJECTIVE: In this study we aimed to compare the efficacy and safety of two personalized rescue therapies for Helicobacter pylori infection. METHODS: An open-label, single-center, randomized controlled trial was conducted. Patients who had failed one or two regimens for H. pylori infection were randomized to receive a 14-day bismuth-containing quadruple therapy guided by antimicrobial susceptibility testing (AST) or personal medication history (PMH). In the AST group, either two of amoxicillin, clarithromycin, metronidazole or levofloxacin were prescribed according to the AST. In the PMH group, amoxicillin plus either levofloxacin or furazolidone were prescribed based on the patient's history of quinolone use. The primary outcomes were eradication rates confirmed by an urea breath test 6 weeks after treatment. The secondary outcomes were adherence, incidence of adverse events (AE) and cost-effectiveness. RESULTS: Altogether 164 with a positive culture received AST-guided therapy and 192 received PMH-guided therapy, respectively. Both AST- and PMH-guided therapies achieved comparable eradication rate (intention-to-treat analysis: 78.10% vs 74.29%, P = 0.42; per-protocol analysis: 87.10% vs 88.64%, P = 0.80). The AST clarithromycin regimen had a lower per-protocol eradication rate than the levofloxacin (75.47% vs 96.30%, P = 0.03) or furazolidone-containing regimen (75.47% vs 92.75%, P = 0.02). Both groups had high compliance with low incidences of AE, and PMH-guided therapy had a lower medical cost. CONCLUSIONS: AST-guided therapy was not superior to PMH-guided therapy as a second- or third-line treatment for H. pylori infection. Considering the cost-effectiveness, PMH therapy is clinically more favorable.

The complex jujube genome provides insights into fruit tree biology.

The jujube (Ziziphus jujuba Mill.), a member of family Rhamnaceae, is a major dry fruit and a traditional herbal medicine for more than one billion people. Here we present a high-quality sequence for the complex jujube genome, the first genome sequence of Rhamnaceae, using an integrated strategy. The final assembly spans 437.65 Mb (98.6% of the estimated) with 321.45 Mb anchored to the 12 pseudo-chromosomes and contains 32,808 genes. The jujube genome has undergone frequent inter-chromosome fusions and segmental duplications, but no recent whole-genome duplication. Further analyses of the jujube-specific genes and transcriptome data from 15 tissues reveal the molecular mechanisms underlying some specific properties of the jujube. Its high vitamin C content can be attributed to a unique high level expression of genes involved in both biosynthesis and regeneration. Our study provides insights into jujube-specific biology and valuable genomic resources for the improvement of Rhamnaceae plants and other fruit trees.

Leukemia inhibitory factor in the neuroimmune communication pathways in allergic asthma.

In the pathogenesis of asthma, central sensitization is suggested to be an important neural mechanism, and neurotrophins and cytokines are likely to be the major mediators in the neuroimmune communication pathways of asthma. However, their impact on the central nervous system in allergic asthma remains unclear. We hypothesize that central neurogenic inflammation develops in the pathogenesis of allergic asthma, and nerve growth factor (NGF) and leukemia inhibitory factor (LIF) are important mediators in its development. An asthma model of rats was established by sensitization and challenged with ovalbumin (OVA). For further confirmation of the role of LIF in neurogenic inflammation, a subgroup was pretreated with intraperitoneally (i.p.) LIF antibody before OVA challenge. The levels of LIF and NGF were measured with reverse transcription and polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemistry stain in lung tissue, airway-specific dorsal root ganglia (DRG, C7-T5) and brain stem of asthmatic rats, anti-LIF pretreated rats and controls. A significantly increased number of LIF- and NGF-immunoreactive cells were detected in lung tissue, DRG and the brain stem of asthmatic rats. In the asthma group a significantly increase level of mRNA encoding LIF and NGF in lung tissue was detected, but not in DRG and the brain stem. Pretreatment with LIF antibody decreased the level of LIF and NGF in all tissues. LIF is an important mediator in the crosstalk between nerve and immune systems. Our study demonstrate that the increased level of LIF and NGF in DRG and brain stem may be not based on result from de novo synthesis, but rather on result from retrograde nerve transport or passage across the blood-brain-barrier.

[Experimental study on the mechanisms of regulating airway neurogenic inflammation in asthma by never growth factor and leukemia inhibitory factor].

OBJECTIVE: To study the mechanisms of regulating airway neurogenic inflammation in asthma by never growth factor (NGF) and leukemia inhibitory factor (LIF), and then to explore new targets in treating asthma. METHODS: Adult male SD rats (n 36) were divided into the normal group, the asthmatic group and the anti-NGF group at random. There were 12 rats in each group. The asthma models were established by sensitization and challenge with ovalbumin, and the asthma model was treated with anti-NGF. The expression of NGF, LIF and substance P (SP) in lung tissue or in doral root ganglion of each rat were detected by immunohistochemistry and hybridisation in situ. RESULTS: (1) The gray-levels of NGF protein/NGF mRNA, LIF protein/LIF mRNA in the lungs were 157 +/- 7, 138 +/- 8, 156 +/- 6, 141 +/- 10 for the asthmatic group respectively, 183 +/- 7, 190 +/- 7, 187 +/- 7, 181 +/- 8 for the normal control group respectively, and 177 +/- 6, 169 +/- 9, 178 +/- 7, 172 +/- 9 for the asthmatic group with anti-NGF treatment. There were significant differences in gray-level of NGF protein/NGF mRNA, LIF protein/LIF mRNA among those three groups (t = 19.40, 15.80, 20.38, [corrected] 14.79, all P < 0.01). (2) The gray-levels of NGF protein/LIF protein, SP protein/SP mRNA in the doral root ganglions were 136 +/- 8, 148 +/- 6, 140 +/- 8, 128 +/- 8 for the asthmatic group respectively, 185 +/- 7, 187 +/- 8, 174 +/- 7, 180 +/- 8 for the normal control group respectively, and 164 +/- 6, 170 +/- 8, 163 +/- 9, 157 +/- 7 for the asthmatic group with anti-NGF treatment. There were also significant differences in gray-level of NGF protein/LIF protein, SP protein/SP mRNA among those three groups (t = 29.50, 22.65, 23.12, 28.71, all P < 0.01). CONCLUSION: Enhancing the synthesis and release of SP in doral root ganglion may be one of the mechanisms by which NGF and LIF regulate airway neurogenic inflammation in asthmatic rats, and this mechanism can be depressed by the intervention of anti-NGF.

[Regulation effect of nerve growth factor on Ras-MAPK signal transduction pathway in neurogenic inflammation of asthma].

OBJECTIVE: To investigate the regulatory effect of nerve growth factor (NGF) on Ras-MAPK signal transduction pathway in neurogenic inflammation of asthma. METHODS: Thirty-six Sprague-Dawley rats were randomly divided into 3 groups (control group, asthma group and anti-NGF group). The asthmatic model was established by ovalbumin inhalation and injection. The protein expressions of pan-Ras, pERK and c-fos in the dorsal root ganglion and lung of the asthma group and the control group were examined by immunohischemical method. Anti-NGF antibody was used to investigate how it affected the protein expression of pan-Ras, pERK and c-fos in the dorsal root ganglion and the lung of the asthma group. PD98059 (the inhibitor of MAPK) and PMA (the enhancer of PKC) were used to culture the NHBEC. Cell extracts were analyzed for pERK, total-ERK and c-fos by Western blot. RESULTS: The protein expressions of pan-Ras, pERK and c-fos in the lung and dorsal root ganglion of the asthma group were significantly higher than those of the control group (P < 0.01). The protein expressions of pan-Ras, pERK and c-fos were decreased by the anti-NGF treatment (P < 0.01) . The expressions of epithelial pERK and c-fos in the NGF group were significantly higher than those in the control group, and PD98059 could inhibit NGF inducing NHBEC to produce pERK and c-fos. PMA could enhance the effects of NGF. CONCLUSION: NGF may play a role in the pathogenesis of neurogenic inflammation in asthma through Ras-MAPK signal transduction pathway.

LIF upregulates expression of NK-1R in NHBE cells.

Leukemia inhibitory factor (LIF), a cytokine at the interface between neurobiology and immunology, is mainly mediated through JAK/STAT pathway and MAPK/ERK pathway. Evidence suggested LIF is related to the higher expression of neurokinin-1 receptor (NK-1R) in asthma. In this study, the immunohistochemistry stain showed the expressions of NK-1R, LIF, p-STAT3, and p-ERK1/2 in the lung tissues of allergic rats were increased compared with the controls, and the main positive cell type was airway epithelial cell. Normal human bronchial epithelial cells were treated with LIF in the presence or absence of AG490 (JAK2 inhibitor), PD98059 (MEK inhibitor), and the siRNA against STAT3. Western blot and RT-PCR indicated that LIF induced the expression of NK-1R, which was inhibited by the inhibitors mentioned above. No significant interaction was found between JAK/STAT pathway and MAPK/ERK pathway. In summary, bronchial epithelial cell changes in asthma are induced by LIF which promotes the expression of NK-1R, and JAK/STAT pathway and MAPK/ERK pathway may participate in this process.

[The relationship between leukemia inhibitory factor and neurokinin receptors in a rat model of asthma].

OBJECTIVE: To study the expression of leukemia inhibitory factor (LIF) and neurokinin receptors (NKR) in the lungs of asthmatic rats, and to evaluate the role of LIF in airway neurogenic inflammation. METHODS: Twenty-four Wistar rats were randomly divided into a control group (group A, n = 8), an asthma group (group B, n = 8) and a dexamethasone treated group (group C, n = 8). The rat asthmatic model was made by intraperitoneal injection and nebulized aspiration of ovalbumin (OVA) at the concentrations of 10% and 1% respectively. Expression levels of lung LIF, NK-1R and NK-2R were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot two weeks after challenge, and the localization of NK-1R was determined by immunohistochemistry. RESULTS: After challenge, the expressions of lung LIF mRNA in group A, B and C were 0.240 +/- 0.020, 0.510 +/- 0.130, 0.180 +/- 0.050, and protein levels were 23 110 +/- 8 018, 40 832 +/- 12 964, 16 160 +/- 2 108 respectively. The expressions of lung NK-1R mRNA in group A, B and C were 0.240 +/- 0.020, 1.040 +/- 0.480, 0.170 +/- 0.040, and protein levels were 16 538 +/- 4 342, 32 292 +/- 4 564, 15 018 +/- 1 488 respectively. The mRNA and protein levels of LIF and NK-1R in group B were significantly elevated as compared with group A and C (all P < 0.01). The expressions of lung NK-2R mRNA in group A, B and C were 0.240 +/- 0.040, 0.200 +/- 0.030 and 0.210 +/- 0.040, and no difference was found among three groups (all P > 0.05). In group B, there was a positive correlation between LIF and NK-1R at mRNA (r = 0.850, P < 0.01) and protein (r = 0.868, P < 0.01) levels respectively. NK-1R immunoreactivity was observed primarily in bronchial epithelial cells. CONCLUSION: LIF and NK-1R were excessively expressed and closely correlated in lungs of the rat asthmatic model, suggesting that LIF may be involved in modulating airway neurogenic inflammation.