Interactive training with a novel simulation model for upper gastrointestinal endoscopic hemostasis improves trainee technique and confidence.

Background and study aims Endoscopic hemostasis is a life-saving procedure for gastrointestinal bleeding; however, training for it is often performed on real patients and during urgent situations that put patients at risk. Reports of simulation-based training models for endoscopic hemostasis are scarce. Herein, we developed a novel simulator called "Medical Rising STAR-Ulcer type" to practice endoscopic hemostasis with hemoclips and coagulation graspers. This study aimed to evaluate the reproducibility of the clinical difficulty of this model and the effectiveness of simulation-based training for clipping hemostasis. Patients and methods This was a prospective educational study. Fifty gastroenterology residents from Japan and Canada were recruited to participate in a simulation-based training program. The primary outcome was the success rate for clipping hemostasis. We measured differences in trainee subjective assessment scores and evaluated the co-occurrence network based on comments after training. Results The hemostasis success rate of the trainees significantly increased after instruction (64% vs. 86%, P < 0.05). The success rate for ulcers in the upper body of the stomach (59%), a high-difficulty site, was significantly lower than that for ulcers in the antrum, even after feedback and instruction. Trainee self-perceived proficiency and confidence significantly improved after simulation-based training ( P < 0.05). Co-occurrence network analysis showed that trainees valued a structured learning approach, acknowledged simulator limitations, and recognized the need for continuous skill refinement. Conclusions Our study demonstrates the potential of our simulation-based training model as a valuable tool for improving technical skills and confidence in trainees learning to perform endoscopic hemostasis.

A Novel Dry Simulator Model for Learning Comprehensive Endoscopic Retrograde Cholangiopancreatography/Endoscopic Sphincterotomy Procedures while Minimizing Adverse Bleeding Events (with Video).

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (EST) are essential skills for performing endoscopic cholangiopancreatic procedures. However, these procedures have a high incidence of adverse events, and current training predominantly relies on patient-based approaches. Herein, we aimed to develop an ERCP/EST simulator model to address the need for safer training alternatives, especially for learners with limited ERCP experience. METHODS: The model was designed to facilitate the use of actual endoscopic devices, supporting learning objectives that align with the components of the validated Bethesda ERCP Skill Assessment Tool (BESAT). BESAT focuses on skills, such as papillary alignment, maintenance of duodenoscope position, gentle and efficient cannulation, controlled sphincterotomy in the correct trajectory, and guidewire manipulation. Thirty gastroenterology trainees used the simulator between May 2022 and March 2023, and their satisfaction was assessed using a visual analog scale (VAS) and pre- and post-training questionnaires. RESULTS: The novel simulator model comprised a disposable duodenal papillary section, suitable for incision with an electrosurgical knife, alongside washable upper gastrointestinal tract and bile duct sections for repeated use. The duodenal papillary section enabled reproduction of a realistic endoscope position and the adverse bleeding events due to improper incisions. The bile duct section allowed for the reproduction of fluoroscopic-like images, enabling learners to practice guidewire guidance and insertion of other devices. Following training, the median VAS score reflecting the expectation for model learning significantly increased from 69.5 (interquartile range [IQR]: 55.5-76.5) to 85.5 (IQR: 78.0-92.0) (p < 0.01). All participants expressed a desire for repeated simulator training sessions. CONCLUSIONS: This innovative simulator could serve as a practical educational tool, particularly beneficial for novices in ERCP. It could facilitate hands-on practice with actual devices, enhancing procedural fluency and understanding of precise incisions to minimize the risk of bleeding complications during EST.

Similar Effect of Vonoprazan and Oral Proton Pump Inhibitors for Preventing Rebleeding in Cases of Upper Gastrointestinal Bleeding.

Objective The use of a proton pump inhibitor (PPI) reduces rebleeding and mortality in patients with upper gastrointestinal bleeding (UGIB). Vonoprazan is a novel oral agent with strong and sustained acid-inhibitory activity. We clarified the effect of vonoprazan compared with oral PPIs in such patients. Methods We analyzed the Diagnosis Procedure Combination database. The primary outcome was rebleeding, and secondary outcomes were in-hospital mortality and in-hospital mortality after rebleeding. Propensity score matching was performed to balance the comparison groups, and logistic regression analyses were used to compare the outcomes between vonoprazan and oral PPIs. Patients Patients on vonoprazan or oral PPIs who underwent endoscopic hemostasis for UGIB between 2014 and 2019 were included. Results We enrolled 78,964 patients, of whom 27,101 and 51,863 were prescribed vonoprazan and a PPI, respectively. After propensity score matching, the rebleeding rate of vonoprazan did not significantly differ from that of oral PPIs [6.4% vs. 6.1%; odds ratio (OR), 1.05; 95% confidence interval (CI), 0.98-1.13]; similarly, the in-hospital mortality rate (1.4% vs. 1.5%; OR, 0.91; 95% CI, 0.79-1.05) and in-hospital mortality after rebleeding (0.3% vs. 0.2%; OR, 1.09; 95% CI, 0.78-1.54) also did not significantly differ between the groups. The acquired findings were robust across dose-restricted analyses and several sensitivity analyses. Conclusion Rebleeding and in-hospital mortality risks in patients on vonoprazan were similar to those in patients on oral PPIs. Considering the higher cost of vonoprazan, oral PPIs might be an optimal oral agent as an acid-suppressive therapy in such patients.

Investigating the implant position reproducibility of optical impressions obtained using an intraoral scanner and 3D-printed models fabricated using an intraoral scanner.

PURPOSE: This study aims to examine the effect of the size of the intraoral scanning area on implant position reproducibility and compare the implant position reproducibility of plaster models fabricated using the silicone impression technique, the digital model of an intraoral scanner, and three-dimensional (3D)-printed models fabricated using an intraoral scanner. METHODS: Scanbodies were attached to an edentulous model with six implants (master model) and were scanned using a dental laboratory scanner to obtain basic data. The plaster model was fabricated using the open-tray method (IMPM; n = 5). The master model was then scanned in various implant areas using an intraoral scanner to obtain data (IOSM; n = 5); the scanning data of six scanbodies were used to fabricate the 3D-printed models (3DPM; n = 5) using a 3D printer. Scanbodies were attached to the implant analogs of the IMPM and 3DPM models and data were obtained using a dental laboratory scanner. The basic data and IMPM, IOSM, and 3DPM data were superimposed to calculate the concordance rate of the scanbodies. RESULTS: The concordance rate of intraoral scanning decreased as the number of scanbodies increased. Significant differences were observed between the IMPM and IOSM data, and between the IOSM and 3DPM data; however, the IMPM and 3DPM data did not differ significantly. CONCLUSIONS: The implant position reproducibility of the intraoral scanner decreased with an increase in the scanning area. However, ISOM and 3DPM may provide higher implant position reproducibility than plaster models fabricated using IMPM.

Predictors for the Development of Hypoxia or Prolonged Acute Symptoms among Non-Hospitalized Mild-to-Moderate Patients with Coronavirus Disease 2019.

The coronavirus disease 2019 (COVID-19) pandemic remains a global public health concern. The clinical course and risk of developing severe illness among patients with COVID-19 who are at low-risk of severe COVID-19 remain uncertain. This retrospective cohort study from an isolation facility for low-risk COVID-19 patients in Japan evaluated the potential risks for severe disease with hypoxia (SpO2 ≤ 93%) or experiencing prolonged isolation period longer than 14 days with persistent acute symptoms. The study was performed before the spread of the alpha variant in the country and before the start of a nationwide mass vaccination campaign against COVID-19. Among the 929 participants with reliable outcome data regarding the development of hypoxia, 63 (6.8%) developed severe disease with hypoxia during their stays at the facility. Higher age [adjusted odds ratio (aOR), 1.08; 95% confidence interval (CI), 1.06-1.10] and male sex (aOR, 4.70; 95% CI, 2.39-9.22) were associated with this outcome. As for the experience of prolonged isolation period, higher age (aOR, 1.02; 95% CI, 1.01-1.04), atopic diseases (aOR, 1.69, 95% CI, 1.09-2.64), presence of cough at onset (aOR, 1.64; 95% CI, 1.09-2.48), and prescription of oral antibiotics before positive test results for COVID-19 (aOR, 2.37; 95% CI, 1.33-4.22) were associated with this outcome. In summary, 5-10% of low-risk COVID-19 patients later develop hypoxia. Older age and male sex were associated with both the development of hypoxia and prolonged acute symptoms. The unnecessary prescription of antibiotics before COVID-19 diagnosis may prolong COVID-19 symptoms.

A case of refractory bleeding from duodenal angioectasia with acquired hemophilia A.

Acquired hemophilia A (AHA) is a coagulation disorder related to the factor VIII inhibitors, which might cause intractable bleeding of gastrointestinal tracts. However, its scarcity makes it difficult to recognize AHA as a pitfall of endoscopic hemostasis failure. An 81-year-old female with a history of endoscopic treatment for colon polyps visited a local hospital with chief compliments of bloody stool and severe anemia. During several examinations for the bleeding origin, esophagogastroduodenoscopy depicted a 5 mm-sized hemorrhagic angioectasia of the duodenum, followed by treatment with argon plasma coagulation. However, hemostasis was not achieved by multiple sessions of endoscopic hemostasis and transcatheter arterial embolization, so blood transfusion was repeatedly done and she was transferred to our hospital. Laboratory data showed severe anemia with coagulation disorder. Based on the results of von Willebrand factor activity, factor VIII activity and factor VIII inhibitor, we diagnosed AHA as a comorbidity. Endoscopic hemostasis was confirmed only after improvement of APTT level and negative for the factor VIII inhibitor by hemostatic bypass treatment with recombinant active factor VII and immunosuppressive therapy with prednisolone and cyclophosphamide. In case of refractory bleeding of gastrointestinal tract, we should suspect of a comorbidity of coagulation disorder like AHA.

Discrepancy between Abdominal Symptoms and Endoscopic Findings in Patients with Gastro-duodenal Eosinophilia: A Case Series.

Some patients present gastro-duodenal eosinophilia without abdominal symptoms. Nine cases with gastro-duodenal eosinophilia were seen at the Tohoku University Hospital between January 2011 and June 2022. Seven (78%) patients had a background of allergic or hyper-eosinophilic disease. Esophagogastroduodenoscopy showed erosions (n=6), discoloration (n=4), ulcers (n=3), erythema (n=3), muskmelon-like appearance (n=2), and cracks (n=1). Two cases were asymptomatic with eosinophilic gastroenteritis (EGE)-like endoscopic findings, and two were symptomatic with normal endoscopic findings. The discrepancy between the abdominal symptoms and esophagogastroduodenoscopy findings suggests that clinicians should assess patients for background allergic disease, regardless of abdominal symptoms.

Novel simulator of endoscopic hemostasis with actual endoscope and devices.

Video 1Demonstration of novel simulator of endoscopic hemostasis.

What is the Prevalence of Clinically Significant Endoscopic Findings in Subjects With Dyspepsia? Updated Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The prevalence of clinically significant endoscopic findings in people with dyspepsia and understanding how symptoms can predict endoscopic pathology can help inform dyspepsia guidelines. We evaluated this in an updated systematic review and meta-analysis. METHODS: We searched MEDLINE, EMBASE, Cochrane CENTRAL, and the Cochrane Database of Systematic Reviews from 2010 through to January 2022 to identify relevant articles. Eligible studies enrolled adults from the community, workplace, blood donation or screening clinics, family physician offices, or internal medicine clinics. Studies were required to report prevalence of dyspepsia and perform esophagogastroduodenoscopy (EGD). Prevalence of clinically significant endoscopic findings in subjects with and without dyspepsia was pooled for all studies and compared using odds ratios and 95% confidence intervals (CIs). The data were pooled with those of the 9 studies included in the prior review. RESULTS: Of 511 papers evaluated, 184 reported prevalence of dyspepsia. Fifteen reported prevalence of endoscopic findings among 41,763 participants (40.4% with dyspepsia). Erosive esophagitis was the most common abnormality (pooled prevalence, 11.0%; 95% CI, 8.9%-13.2%) followed by peptic ulcer (pooled prevalence, 4.4%; 95% CI, 2.5%-6.7%). The only finding encountered more frequently in individuals with dyspepsia, compared with those without, was peptic ulcer (odds ratio, 1.61; 95% CI, 1.08-2.39). More than 85% of EGDs were completely normal. Gastroesophageal cancer was rare (<0.4%) and equally prevalent among those with and without dyspepsia. CONCLUSIONS: Erosive esophagitis was the most common clinically significant finding at EGD, whereas gastroesophageal cancers were rare. Most pathology, including esophagitis and cancer, were found in similar proportions in both groups. These findings support noninvasive approaches to managing dyspepsia in the community, with EGD reserved for those at high risk of malignancy.

Decreased Expression of NRF2 Target Genes after Alcohol Exposure in the Background Esophageal Mucosa of Patients with Esophageal Squamous Cell Carcinoma.

Patients with esophageal squamous cell carcinoma (ESCC) might have a specific mechanism for the carcinogenesis by alcohol consumption in the background esophageal mucosa, and nuclear factor erythroid 2-related factor 2 (NRF2), which plays a protective role against esophageal carcinogenesis, and barrier dysfunction might be associated with this phenomenon. This study aimed to confirm this hypothesis. Twenty patients with superficial ESCCs (ESCC patients) and 20 age- and sex-matched patients without ESCC (non-ESCC patients) were enrolled. Biopsy samples were obtained from non-neoplastic esophageal mucosa: one for histological evaluation, one for quantitative real-time polymerase chain reaction (PCR), and two for the mini-Ussing chamber system to measure transepithelial electrical resistance (TEER) and, thereafter, for PCR. The TEER after acetaldehyde or both acetaldehyde and ethanol exposure did not differ significantly between ESCC and non-ESCC patients. Unlike non-ESCC patients, mRNA levels of NRF2 target genes and claudin4 in ESCC patients tended to decrease after the exposure, with a significant difference between no exposure and both acetaldehyde and ethanol exposure in NRF2 target genes (p < 0.05). Furthermore, in ESCC patients, the decreased tendency of mRNA levels of NRF2 target genes after the exposure was more pronounced in high-risk states, such as aldehyde dehydrogenase 2 (ALDH2) Lys alleles (Glu/Lys + Lys/Lys), Lugol-voiding lesion grade C, and drinking history. In conclusion, the protective role of NRF2 against carcinogenesis from alcohol exposure might be disrupted in the background esophageal mucosa of ESCC patients, which might lead to a high incidence of metachronous ESCC.

Accuracy of Implant-Supported Copy Overdentures Fabricated Using Either an Intraoral Scanner and a 3D Printer or the Conventional Copy Denture Technique: A Comparative Study.

PURPOSE: To compare the 3D accuracy of copy dentures fabricated using an IOS (IOS copy denture) to that of copy dentures fabricated using the conventional method (conventional copy denture). MATERIALS AND METHODS: Maxillary and mandibular complete dentures were fabricated and scanned using a high-precision dental laboratory scanner to obtain data (basic data). Optical impressions of the dentures were recorded with the IOS to obtain data (IOS reference dentures). The IOS copy denture was fabricated using a 3D printer after configuring the data using the software. The conventional copy dentures were fabricated by making impressions of the complete dentures and pouring the room-temperature curing resin into them. The IOS copy dentures and conventional copy dentures were scanned using a high-precision dental laboratory scanner to obtain data. The data obtained were imported into 3D analysis software, and the IOS reference denture, IOS copy denture, and conventional copy denture data were each superimposed on the basic data for 3D evaluation by color mapping and calculation of the concordance rate. RESULTS: Statistically significant differences in the concordance rates were observed between the IOS reference dentures and IOS copy dentures and between IOS copy dentures and conventional copy dentures (P < .05), but not between maxillary and mandibular complete dentures (P > .05). CONCLUSION: The IOS copy dentures demonstrated greater accuracy than the conventional copy dentures.

Feasibility of Support by Family Practitioners in Reducing Colorectal Cancer-Related Death among Outpatients Who Have Not Undergone Colorectal Cancer Screening.

We aimed to clarify the effectiveness of interventions in outpatients who did not undergo colorectal cancer (CRC) screening. From September 2012 to August 2013, we conducted a project, which showed that the immunological fecal occult blood test (FOBT) was actively recommended for outpatients who were ≥40 years of age, attended the Marumori Hospital regularly, and were not screened for CRC in the previous two years. We evaluated the detection rate of CRC and the disease specific survival ratio in February 2021 among patients with positive FOBT results during the retrospective cohort study. Overall, 388 (91%) out of the 425 outpatients submitted their stool samples. Among 388 outpatients, 66 tested positive for FOBT. While both the positive rate of FOBT and the detection rate of CRC (17% and 0.77%, respectively) were significantly higher than those in the nationwide administrative examination (5.7% and 0.13%, respectively) (p < 0.05), there was no statistically significant difference in the detection rate, compared with the group aged 65 years and older in the nationwide administrative examination. The 7-year CRC-specific survival ratio was 98.5%. Active promotion of FOBT at primary care institutions for outpatients who did not undergo CRC screening may contribute to reducing the frequency of CRC-related deaths.

Refractory Chest Pain in Mild to Moderate Coronavirus Disease 2019 Successfully Treated with Saikanto, a Japanese Traditional Medicine.

Coronavirus disease 2019 (COVID-19) causes a variety of pain symptoms in the acute phase. Severe chest pain suddenly occurs even without abnormalities on examination and is sometimes refractory to analgesics. Such pain is a clinical concern in care facilities with limited resources, and this is the first report on the use of saikanto for its treatment. In Miyagi Prefecture, Japan, COVID-19 patients with mild symptoms were admitted to a hotel that operated as an isolation facility, and their symptoms were observed. In this article, we report four cases in which chest pain comorbid with mild to moderate COVID-19 was successfully treated with saikanto, a traditional Japanese (Kampo) medicine. The patients presented with chest pain and underwent medical examination at the facility. Two patients had severe chest pain refractory to acetaminophen. Critical cardiopulmonary diseases were ruled out in all the patients, and three patients had features of pneumonia on chest radiograph. Medications, including saikanto, were administered to the patients. The patients' chest pain and other symptoms improved 1-4 days after the administration of saikanto, and they left the care facility without hospitalization. The cause of the chest pain experienced by these patients is unclear, but we speculate that it could be minimal pleural inflammation or neuropathy. Previous pharmacological studies have suggested anti-inflammatory and analgesic properties of the crude drugs that constitute saikanto. This case report suggests that saikanto could be a treatment option for chest pain refractory to analgesics in patients with mild to moderate COVID-19.

Response to Glucocorticoid Therapy in Patients with Mild to Moderate Coronavirus Disease 2019 at a Japanese Care Facility.

The fifth wave of the coronavirus disease 2019 (COVID-19) pandemic caused by delta variant infection depleted medical resources, and the Japanese government announced glucocorticoid use for outpatients. An appropriate outpatient-glucocorticoid treatment for COVID-19 has not been established; therefore, we created treatment manuals with indications for glucocorticoid administration in a care facility adequately equipped to manage patients with mild to moderate COVID-19. Thirty-eight patients (24 males, 14 females; mean age 40.5 ± 11.8 years) were treated with glucocorticoids from August 1 to October 1, 2021 [COVID-19 staging, mild (n = 1), moderate I (n = 19), and moderate II (n = 18)]. Patients were treated with 6.6 mg/day d.i.v. or 6 mg/day p.o. dexamethasone, or 20-30 mg/day p.o. prednisolone. The median (25th-75th percentile) number of days from the date of onset to glucocorticoid administration was 8.0 days (7.0-11.25 days). While 24 patients were hospitalized, the condition of 14 improved without hospitalization. The median number of days from glucocorticoid administration to hospitalization was 1.0 day (range, 1.0-1.0 day). In the non-hospitalized patients, the median number of days of glucocorticoid administration was 5.0 days (5.0-5.25 days). The mean number of days from glucocorticoid administration to discharge from the care facility for non-hospitalized patients was 8.4 ± 3.3 days. The adverse reactions among non-hospitalized patients included insomnia (n = 1) and mild liver dysfunction (n = 3). The present method of glucocorticoid administration can be safely used for patients with COVID-19 in care facilities.

Recent approach for preventing complications in upper gastrointestinal endoscopic submucosal dissection.

Although endoscopic submucosal dissection (ESD) is a minimally invasive treatment method for upper gastrointestinal (GI) tumors, patients undergoing upper GI ESD sometimes fall into a serious condition from complications. Thus, it is important to fully understand how to prevent complications when performing upper GI ESD. One of the major complications in esophageal and gastric ESD is intraoperative perforation. To prevent this complication, blind dissection should be avoided. Traction-assisted ESD is a useful technique for maintaining good endoscopic view. This method was proven to reduce the incidence of intraoperative perforation, which would become a standard technique in esophageal and gastric ESD. In gastric ESD, delayed bleeding is the most common complication. Recently, a novel prediction model (BEST-J score) consisting of 10 factors with four risk categories for delayed bleeding in gastric ESD was established, and a free mobile application is now available. For reducing delayed bleeding in gastric ESD, vonoprazan ≥20 mg/day is the sole reliable method in the current status. Duodenal ESD is still challenging with a much higher frequency of complications, such as perforation and delayed bleeding, than ESD in other organs. However, with the development of improved devices and techniques, the frequency of complications in duodenal ESD has been decreasing. To prevent intraoperative perforation, some ESD techniques, such as using the distal tips of the Clutch Cutter, were developed. An endoscopic mucosal defect closure technique would be mandatory for preventing delayed complications. However, several unresolved issues, including standardization of duodenal ESD, remain and further studies are demanded.

Reliability and Validation of the Persian Version of JUICE Study Questionnaire.

BACKGROUND: This study is part of a prospective international cohort study on the composition of microbiota living in the upper gastrointestinal (GI) tract and its correlations to the patients' symptoms, and their psychological and physical health status in three different populations (JUICE Study). Our study evaluates the reliability and validity of the Persian version of a three-part questionnaire which will be used in this study. METHODS: The original English version of the questionnaire was translated to Farsi and then back translated to English by an expert Iranian English teacher. The back-translation was edited by a native English speaker and then retranslated to Farsi. The questionnaire consists of three parts; the first part includes demographic data, the second part is the EQ-5D questionnaire which is an instrument developed by the EuroQol group to measure five dimensions of quality of life and health status, and the third part is the Hospital Anxiety and Depression Scale questionnaire (HADS). By convenience sampling, 22 participants were enrolled. To check reliability, they were asked to complete the questionnaire and repeat this two weeks later. For validity, one of the researchers completed the questionnaire for each of the participants after interviewing them and this was compared with the questionnaire completed by the participant. Each participant was also asked to comment on the content and structure of the questionnaire and these points were considered for improvement of the questionnaire. RESULTS: The first six questions were demographic, and completely the same in the test and retest phases. All of the other questions in the first part of the questionnaire had Kappa values above 0.6 for both reliability and validity. Four questions in this section were assessed with percentage agreement. Percentage agreements were 0.86, 0.54, 0.66 and 0.9 for reliability and 1, 0.81, 0.81 and 1 for validity for the 8th, 12th, 13th and 14th questions, respectively. In the second part, i.e. the EQ5D questionnaire, percentage agreements of the first and second items for reliability equaled 1. Percentage agreements of the three last items were 0.90, 0.63 and 0.72, respectively. Validity of the EQ5D questionnaire was 100% for the first three items and 95% for the last one. For the HADS questionnaire, percentage agreement averaged 0.63 in the reliability phase and 0.78 in the validation phase. CONCLUSION: According to our data, this three-part questionnaire has acceptable reliability and validity to be used as an instrument in Farsi-speaking populations for the JUICE study.

Parietal Cell Dysfunction: A Rare Cause of Gastric Neuroendocrine Neoplasm with Achlorhydria and Extreme Hypergastrinemia.

A 69-year-old woman with multiple neuroendocrine neoplasms (NENs) was referred to our hospital. Although she had extreme hypergastrinemia (11,675 pg/mL), no findings that indicated types I to III gastric NENs were found. Although gastric corpus atrophy was suspected on conventional white-light imaging, findings on magnifying endoscopy with narrow-band imaging indicated no severe atrophy. A biopsy from the background fundic gland mucosa revealed no atrophic changes, parietal cells with vacuolated cytoplasm and negative findings for H+K+-ATPase. Thus, this case was diagnosed as multiple NENs with parietal cell dysfunction. Neither progression nor metastasis has been confirmed during two-year follow-up.

Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding.

BACKGROUND: Upper gastrointestinal (GI) bleeding is a common reason for emergency hospital admission. Proton pump inhibitors (PPIs) reduce gastric acid production and are used to manage upper GI bleeding. However, there is conflicting evidence regarding the clinical efficacy of proton pump inhibitors initiated before endoscopy in people with upper gastrointestinal bleeding. OBJECTIVES: To assess the effects of PPI treatment initiated prior to endoscopy in people with acute upper GI bleeding. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Embase and CINAHL databases and major conference proceedings to October 2008, for the previous versions of this review, and in April 2018, October 2019, and 3 June 2021 for this update. We also contacted experts in the field and searched trial registries and references of trials for any additional trials. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) that compared treatment with a PPI (oral or intravenous) versus control treatment with either placebo, histamine-2 receptor antagonist (H2RA) or no treatment, prior to endoscopy in hospitalised people with uninvestigated upper GI bleeding. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed study eligibility, extracted study data and assessed risk of bias. Outcomes assessed at 30 days were: mortality (our primary outcome), rebleeding, surgery, high-risk stigmata of recent haemorrhage (active bleeding, non-bleeding visible vessel or adherent clot) at index endoscopy, endoscopic haemostatic treatment at index endoscopy, time to discharge, blood transfusion requirements and adverse effects. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included six RCTs comprising 2223 participants. No new studies have been published after the literature search performed in 2008 for the previous version of this review. Of the included studies, we considered one to be at low risk of bias, two to be at unclear risk of bias, and three at high risk of bias. Our meta-analyses suggest that pre-endoscopic PPI use may not reduce mortality (OR 1.14, 95% CI 0.76 to 1.70; 5 studies; low-certainty evidence), and may reduce rebleeding (OR 0.81, 95% CI 0.62 to 1.06; 5 studies; low-certainty evidence). In addition, pre-endoscopic PPI use may not reduce the need for surgery (OR 0.91, 95% CI 0.65 to 1.26; 6 studies; low-certainty evidence), and may not reduce the proportion of participants with high-risk stigmata of recent haemorrhage at index endoscopy (OR 0.80, 95% CI 0.52 to 1.21; 4 studies; low-certainty evidence). Pre-endoscopic PPI use likely reduces the need for endoscopic haemostatic treatment at index endoscopy (OR 0.68, 95% CI 0.50 to 0.93; 3 studies; moderate-certainty evidence). There were insufficient data to determine the effect of pre-endoscopic PPI use on blood transfusions (2 studies; meta-analysis not possible; very low-certainty evidence) and time to discharge (1 study; very low-certainty evidence). There was no substantial heterogeneity amongst trials in any analysis. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that PPI treatment initiated before endoscopy for upper GI bleeding likely reduces the requirement for endoscopic haemostatic treatment at index endoscopy. However, there is insufficient evidence to conclude whether pre-endoscopic PPI treatment increases, reduces or has no effect on other clinical outcomes, including mortality, rebleeding and need for surgery. Further well-designed RCTs that conform to current standards for endoscopic haemostatic treatment and appropriate co-interventions, and that ensure high-dose PPIs are only given to people who received endoscopic haemostatic treatment, regardless of initial randomisation, are warranted. However, as it may be unrealistic to achieve the optimal information size, pragmatic multicentre trials may provide valuable evidence on this topic.

Suppressed Cellular Senescence Mediated by T-box3 in Aged Gastric Epithelial Cells may Contribute to Aging-related Carcinogenesis.

Aging is a risk factor for cancers in various organs. Recent advances in the organoid culturing system have made it viable to investigate the influence of aging utilizing these mini organs. In this study, we aimed to examine the implications of aging for gastric carcinogenesis. Gastric organoids established from aged mice grew larger, proliferated vigorously, and survived longer than that from young mice. Because Wnt/ß-catenin signaling was intensified in the aged organoids and because removal of Wnt-related factors diminished their proliferation, we investigated for Wnt target gene that contributed to enhanced proliferation and discovered that the aged organoids expressed the transcription factor T-box3 (Tbx3), which has been reported to suppress cellular senescence. Indeed, cellular senescence was suppressed in the aged organoids, and this resulted from enhanced G2-M transition. As for the mechanism involved in the intensified Wnt/ß-catenin signaling, we identified that Dickkopf3 (Dkk3) expression was reduced in the aged organoids due to methylation of the Dkk3 gene. Finally, the expression of TBX3 was enhanced in human atrophic gastritis and even more enhanced in human gastric cancers. In addition, its expression correlated positively with patients' age. These results indicated that the emergence of antisenescent property in aged gastric organoids due to enhanced Tbx3 expression led to accelerated cellular proliferation and organoid formation. Because the enhanced Tbx3 expression seen in aged gastric organoids was also observed in human gastric cancer tissues, this Dkk3-Wnt-Tbx3 pathway may be involved in aging-related gastric carcinogenesis. Significance: This work provides an insight into the mechanism involved in aging-related gastric carcinogenesis through studies utilizing organoids established from young and aged murine stomachs.