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Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression.

Summary Background Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial. Funding UK National Institute for Health Research Health Technology Assessment Programme.

Background & aims Endoscopic ultrasound guided-biliary drainage (EUS-BD) is a promising alternative to endoscopic retrograde cholangiopancreatography (ERCP); however, its growth has been limited by a lack of multicenter randomized controlled trials (RCT) and dedicated devices. A dedicated EUS-BD lumen- apposing metal stent (LAMS) has recently been developed with the potential to greatly facilitate the technique and safety of the procedure. We aim to compare a first intent approach with EUS-guided choledochoduodenostomy with a dedicated biliary LAMS vs. standard ERCP in the management of malignant distal biliary obstruction. Methods The ELEMENT trial is a multicenter single-blinded RCT involving 130 patients in nine Canadian centers. Patients with unresectable, locally advanced, or borderline resectable malignant distal biliary obstruction meeting the inclusion and exclusion criteria will be randomized to EUS-choledochoduodenostomy using a LAMS or ERCP with traditional metal stent insertion in a 1:1 proportion in blocks of four. Patients with hilar obstruction, resectable cancer, or benign disease are excluded. The primary endpoint is the rate of stent dysfunction needing re-intervention. Secondary outcomes include technical and clinical success, interruptions in chemotherapy, rate of surgical resection, time to stent dysfunction, and adverse events. Discussion The ELEMENT trial is designed to assess whether EUS-guided choledochoduodenostomy using a dedicated LAMS is superior to conventional ERCP as a first-line endoscopic drainage approach in malignant distal biliary obstruction, which is an important and timely question that has not been addressed using an RCT study design. Trial registration Registry name: ClinicalTrials.gov. Registration number: NCT03870386. Date of registration: 03/12/2019.

Background: Both subjective cognitive decline (SCD) and a family history of Alzheimer's disease (AD) portend risk of brain abnormalities and progression to dementia. Posterior default mode network (pDMN) connectivity is altered early in the course of AD. It is unclear whether SCD predicts similar outcomes in cognitively normal individuals with a family history of AD. Methods: We studied 124 asymptomatic individuals with a family history of AD (age 64 ± 5 years). Participants were categorized as having SCD if they reported that their memory was becoming worse (SCD+). We used extensive neuropsychological assessment to investigate five different cognitive domain performances at baseline (n = 124) and 1 year later (n = 59). We assessed interconnectivity among three a priori defined ROIs: pDMN, anterior ventral DMN, medial temporal memory system (MTMS), and the connectivity of each with the rest of brain. Results: Sixty-eight (55%) participants reported SCD. Baseline cognitive performance was comparable between groups (all false discovery rate-adjusted p values >.05). At follow-up, immediate and delayed memory improved across groups, but the improvement in immediate memory was reduced in SCD+ compared with SCD− (all false discovery rate–adjusted p values −, SCD+ subjects showed increased pDMN–MTMS connectivity (false discovery rate–adjusted p

AIM:To use current evidence-based recommendations to provide a user-friendly clinical algorithm for the management of upper gastrointestinal bleeding, adapted to the Canadian environment.METHODS:A multidisciplinary consensus group of 25 participants representing 11 national societies used a seven-step approach to develop recommendations according to accepted standards. Sources of data included narrative and systematic reviews as well as published and new meta-analyses. A small writing subgroup subsequently created the algorithm.RESULTS:Recommendations emphasize appropriate initial resuscitation of the patient and a multidisciplinary approach to clinical risk stratification that determines the need for early endoscopy. Early endoscopy allows safe and prompt discharge of selected patients classified as low risk. Endoscopic hemostasis is reserved for patients with high-risk endoscopic lesions. Although monotherapy with injection or thermal coagulation is effective, the combination is superior to either treatment alone. High-dose intravenous proton-pump inhibition is recommended in patients who have undergone successful endoscopic therapy. Routine second-look endoscopy is not recommended. Patients with upper gastrointestinal bleeding secondary to ulcer disease should be tested and treated forHelicobacter pyloriinfection.CONCLUSIONS:This algorithm should facilitate appropriate risk stratification, use of endoscopic therapy and the appropriate utilization of proton-pump inhibition to optimize the care of patients with upper gastrointestinal bleeding. The algorithm should be customized to the resources of individual medical centres. Its application should be studied with appropriate outcomes recorded and validation performed.

OBJECTIVE: To assessHelicobacter pylorieradication after one week dual ranitidine bismuth citrate-clarithromycin (RBC-C) or triple omeprazole, clarithromycin and amoxicillin (OCA) therapy.METHODS: In this multicentre Canadian trial,H pylori-positive patients with functional dyspepsia or inactive peptic ulcer disease were randomized to open-label treatment with RBC-C (ranitidine bismuth citrate 400 mg plus clarithromycin 500 mg) or OCA (omezaprole 20 mg, clarithromycin 500 mg and amoxicillin 1000 mg), given twice a day for seven days. Treatment allocation was randomly assigned.H pyloriinfection was confirmed by positive13C-urea breath test (13C-UBT).H pyloristatus was reassessed by UBT at least four and 12 weeks after treatment (negative: δ13CO2below 3.5 per mil). Intention-to-treat (ITT) eradication rates were determined for all patients with confirmedH pyloriinfection. Per protocol (PP) rate was determined for all patients treated with at least two evaluable follow-up visits.RESULTS: Three hundred five patients were included in the ITT and 222 in the PP analysis. The ITT eradication rates were 66% for RBC-C and 78% for OCA. The PP success rates were 84% for RBC-C and 96% for OCA. The difference for both ITT 12% (95% CI 2 to 22) and PP 12% (95% CI 4 to 19) were statistically significant, P=0.030 and P=0.007, respectively. Treatment was generally well tolerated.CONCLUSION: The eradication rate for the seven-day dual RBC-C regimen was lower than that for OCA.

BACKGROUND: Patients with upper gastrointestinal bleeding (UGIB) require an early, tailored approach best guided by knowledge of the bleeding lesion, especially a variceal versus a nonvariceal source.OBJECTIVE: To identify, by investigating a large national registry, variables that would be predictive of a variceal origin of UGIB using clinical parameters before endoscopic evaluation.METHODS: A retrospective study was conducted in 21 Canadian hospitals during the period from January 2004 until the end of May 2005. Consecutive charts for hospitalized patients with a primary or secondary discharge diagnosis of UGIB were reviewed. Data regarding demographics, including historical, physical examination, initial laboratory investigations, endoscopic and pharmacological therapies administered, as well as clinical outcomes, were collected. Multivariable logistic regression modelling was performed to identify clinical predictors of a variceal source of bleeding.RESULTS: The patient population included 2020 patients (mean [± SD] age 66.3±16.4 years; 38.4% female). Overall, 215 (10.6%) were found to be bleeding from upper gastrointestinal varices. Among 26 patient characteristics, variables predicting a variceal source of bleeding included history of liver disease (OR 6.36 [95% CI 3.59 to 11.3]), excessive alcohol use (OR 2.28 [95% CI 1.37 to 3.77]), hematemesis (OR 2.65 [95% CI 1.61 to 4.36]), hematochezia (OR 3.02 [95% CI 1.46 to 6.22]) and stigmata of chronic liver disease (OR 2.49 [95% CI 1.46 to 4.25]). Patients treated with antithrombotic therapy were more likely to experience other causes of hemorrhage (OR 0.44 [95% CI 0.35 to 0.78]).CONCLUSION: Presenting historical and physical examination data, and initial laboratory tests carry significant predictive ability in discriminating variceal versus nonvariceal sources of bleeding.

Several organizations worldwide have developed procedure-based guidelines and/or position statements regarding various aspects of quality and safety indicators, and credentialing for endoscopy. Although important, they do not specifically address patient needs or provide a framework for their adoption in the context of endoscopy services. The consensus guidelines reported in this article, however, aimed to identify processes and indicators relevant to the provision of high-quality endoscopy services that will support ongoing quality improvement across many jurisdictions, specifically in the areas of ethics, facility standards and policies, quality assurance, training and education, reporting standards and patient perceptions.BACKGROUND: Increasing use of gastrointestinal endoscopy, particularly for colorectal cancer screening, and increasing emphasis on health care quality, highlight the need for clearly defined, evidence-based processes to support quality improvement in endoscopy.OBJECTIVE: To identify processes and indicators of quality and safety relevant to high-quality endoscopy service delivery.METHODS: A multidisciplinary group of 35 voting participants developed recommendation statements and performance indicators. Systematic literature searches generated 50 initial statements that were revised iteratively following a modified Delphi approach using a web-based evaluation and voting tool. Statement development and evidence evaluation followed the AGREE (Appraisal of Guidelines, REsearch and Evaluation) and GRADE (Grading of Recommendations, Assessment, Development and Evaluation) guidelines. At the consensus conference, participants voted anonymously on all statements using a 6-point scale. Subsequent web-based voting evaluated recommendations for specific, individual quality indicators, safety indicators and mandatory endoscopy reporting fields. Consensus was defined a priori as agreement by 80% of participants.RESULTS: Consensus was reached on 23 recommendation statements addressing the following: ethics (statement 1: agreement 100%), facility standards and policies (statements 2 to 9: 90% to 100%), qual: 97% to 100%) and patient perceptions ( statements 22 and 23: 100%). Additionally, 18 quality indicators (agreement 83% to 100%), 20 safety indicators (agreement 77% to 100%) and 23 recommended endoscopy-reporting elements (agreement 91% to 100%) were identified.DISCUSSION: The consensus process identified a clear need for high-quality clinical and outcomes research to support quality improvement in the delivery of endoscopy services.CONCLUSIONS: The guidelines support quality improvement in endoscopy by providing explicit recommendations on systematic monitoring, assessment and modification of endoscopy service delivery to yield benefits for all patients affected by the practice of gastrointestinal endoscopy.

The growth in the use of endoscopy to diagnose and treat many gastointestinal disorders, and its central role in cancer screening programs, has led to a significant increase in the number of procedures performed. This growth, however, has also led to many variations in, among others, the provision of services, the choice of sedative medications and the training of providers. The recognition of the significance of quality in endoscopy has prompted several countries, including Canada, to initiate efforts to adopt nationwide quality improvement programs. The Canadian Association of Gastroenterology formed a committee to review endoscopy and quality with the aim of stimulating improvement. This article focuses specifically on patient safety indicators that were developed at a consensus conference aimed at generating a broad range of recommendations for selected endoscopic procedures, which if adopted, could lead to significant changes in how endoscopy services are provided.INTRODUCTION: The importance of quality indicators has become increasingly recognized in gastrointestinal endoscopy. Patient safety requires the identification and monitoring of occurrences associated with harm or the potential for harm. The identification of relevant indicators of safety compromise is, therefore, a critical element that is key to the effective implementation of endoscopy quality improvement programs.OBJECTIVE: To identify key indicators of safety compromise in gastrointestinal endoscopy.METHODS: The Canadian Association of Gastroenterology Safety and Quality Indicators in Endoscopy Consensus Group was formed to address issues of quality in endoscopy. A subcommittee was formed to identify key safety indicators. A systematic literature review was undertaken, and articles pertinent to safety in endoscopy were identified and reviewed. All complications and measures used to document safety were recorded. From this, a preliminary list of 16 indicators was compiled and presented to the 35-person consensus group during a three-day meeting. A revised list of 20 items was subsequently put to the consensus group for vote for inclusion on the final list of safety indicators. Items were retained only if the consensus group highly agreed on their importance.RESULTS: A total of 19 indicators of safety compromise were retained and grouped into the three following categories: medication-related – the need for CPR, use of reversal agents, hypoxia, hypotension, hypertension, sedation doses in patients older than 70 years of age, allergic reactions and laryngospasm/bronchospasm; procedure-related early – perforation, immediate postpolypectomy bleeding, need for hospital admission or transfer to emergency department from the gastroenterology unit, instrument impaction, severe persistent abdominal pain requiring evaluation proven to not be perforation; and procedure-related delayed – death within 30 days of procedure, 14-day unplanned hospitalization, 14-day unplanned contact with a health provider, gastrointestinal bleeding within 14 days of procedure, infection or symptomatic metabolic complications.CONCLUSIONS: The 19 indicators of safety compromise in endoscopy, identified by a rigorous, evidence-based consensus process, provide clear outcomes to be recorded by all facilities as part of their continuing quality improvement programs.

Purpose: The aim of this study was to review the indications, success rate, and complications of endoscopic retrograde cholangiopancreatography (ERCP) in the pediatric age group. Methods: From 1990 to 1999, 21 ERCP procedures were attempted in 20 patients. They consisted of 8 boys and 12 girls whose age ranged from 4 to 17 years (mean, 11.3 years). Fourteen were performed under deep sedation (mean age, 12.8 years), and 7 were done under general anesthesia (mean age, 7.6 years). All ERCP procedures were performed by experienced adult endoscopists. Results: The indication for ERCP was biliary in 15 patients. Eleven had suspected choledocholithiasis by either ultrasound scan, intraoperative cholangiogram or magnetic resonance imaging (MRI). In 6 cases, the ERCP was done for pancreatic pathology. In 11 patients, the ERCP was diagnostic only, and in 10 a therapeutic procedure was done. The overall success rate was 90.5%. Post-ERCP complications consisted of 6 episodes of pancreatitis (28.5%), 4 of which followed a therapeutic procedure, and 1 episode of bleeding. Pancreatitis resolved 2 to 6 days post-ERCP. The patients underwent follow-up between 2 and 56 months after the ERCP (mean, 11 months). Conclusions: The authors conclude that even in experienced hands, ERCP in the pediatric population has a much higher complication rate than in adults (33.3%). We recommend that very specific indications be met before subjecting a pediatric patient to an endoscopic retrograde cholangiopancreatography. J Pediatr Surg 36:733-735. Copyright © 2001 by W.B. Saunders Company.