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DescriptionThe purpose of this best practice advice (BPA) article from the Clinical Practice Update Committee of the American Gastroenterological Association is to provide an update on advances and innovation regarding the screening and surveillance of Barrett's esophagus.MethodsThe BPA statements presented here were developed from expert review of existing literature combined with discussion and expert opinion to provide practical advice. Formal rating of the quality of evidence or strength of BPAs was not the intent of this clinical practice update. This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. BEST PRACTICE ADVICE 1: Screening with standard upper endoscopy may be considered in individuals with at least 3 established risk factors for Barrett's esophagus (BE) and esophageal adenocarcinoma, including individuals who are male, non-Hispanic white, age >50 years, have a history of smoking, chronic gastroesophageal reflux disease, obesity, or a family history of BE or esophageal adenocarcinoma. BEST PRACTICE ADVICE 2: Nonendoscopic cell-collection devices may be considered as an option to screen for BE. BEST PRACTICE ADVICE 3: Screening and surveillance endoscopic examination should be performed using high-definition white light endoscopy and virtual chromoendoscopy, with endoscopists spending adequate time inspecting the Barrett's segment. BEST PRACTICE ADVICE 4: Screening and surveillance exams should define the extent of BE using a standardized grading system documenting the circumferential and maximal extent of the columnar lined esophagus (Prague classification) with a clear description of landmarks and the location and characteristics of visible lesions (nodularity, ulceration), when present. BEST PRACTICE ADVICE 5: Advanced imaging technologies such as endomicroscopy may be used as adjunctive techniques to identify dysplasia. BEST PRACTICE ADVICE 6: Sampling during screening and surveillance exams should be performed using the Seattle biopsy protocol (4-quadrant biopsies every 1-2 cm and target biopsies from any visible lesion). BEST PRACTICE ADVICE 7: Wide-area transepithelial sampling may be used as an adjunctive technique to sample the suspected or established Barrett's segment (in addition to the Seattle biopsy protocol). BEST PRACTICE ADVICE 8: Patients with erosive esophagitis should be biopsied when concern of dysplasia or malignancy exists. A repeat endoscopy should be performed after 8 weeks of twice a day proton pump inhibitor therapy. BEST PRACTICE ADVICE 9: Tissue systems pathology-based prediction assay may be utilized for risk stratification of patients with nondysplastic BE. BEST PRACTICE ADVICE 10: Risk stratification models may be utilized to selectively identify individuals at risk for Barrett's associated neoplasia. BEST PRACTICE ADVICE 11: Given the significant interobserver variability among pathologists, the diagnosis of BE-related neoplasia should be confirmed by an expert pathology review. BEST PRACTICE ADVICE 12: Patients with BE-related neoplasia should be referred to endoscopists with expertise in advanced imaging, resection, and ablation. BEST PRACTICE ADVICE 13: All patients with BE should be placed on at least daily proton pump inhibitor therapy. BEST PRACTICE ADVICE 14: Patients with nondysplastic BE should undergo surveillance endoscopy in 3 to 5 years. BEST PRACTICE ADVICE 15: In patients undergoing surveillance after endoscopic eradication therapy, random biopsies should be taken of the esophagogastric junction, gastric cardia, and the distal 2 cm of the neosquamous epithelium as well as from all visible lesions, independent of the length of the original BE segment.

BackgroundGlobal efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies.MethodsIn the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders).ResultsSeveral studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes.ConclusionsIn this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

BackgroundUp to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored.MethodsTo characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers.ResultsWe identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer.ConclusionsOverall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.

Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

The Cancer Research Network (CRN) is a consortium of 12 research groups, each affiliated with a nonprofit integrated health care delivery system, that was first funded in 1998. The overall goal of the CRN is to support and facilitate collaborative cancer research within its component delivery systems. This paper describes the CRN's 20-year experience and evolution. The network combined its members' scientific capabilities and data resources to create an infrastructure that has ultimately supported over 275 projects. Insights about the strengths and limitations of electronic health data for research, approaches to optimizing multidisciplinary collaboration, and the role of a health services research infrastructure to complement traditional clinical trials and large observational datasets are described, along with recommendations for other research consortia.

OBJECTIVES:The effectiveness of fecal immunochemical test (FIT) screening for colorectal cancer depends on timely colonoscopy follow-up of positive tests, although limited data exist regarding effective system-level strategies for improving follow-up rates. METHODS:Using a mixed-methods design (qualitative and quantitative), we first identified system-level strategies that were implemented for improving timely follow-up after a positive FIT test in a large community-based setting between 2006 and 2016. We then evaluated changes in time to colonoscopy among FIT-positive patients across 3 periods during the study interval, controlling for screening participant age, sex, race/ethnicity, comorbidity, FIT date, and previous screening history. RESULTS:Implemented strategies over the study period included setting a goal of colonoscopy follow-up within 30 days of a positive FIT, tracking FIT-positive patients, early telephone contact to directly schedule follow-up colonoscopies, assigning the responsibility for follow-up tracking and scheduling to gastroenterology departments (vs primary care), and increasing colonoscopy capacity. Among 160,051 patients who had a positive FIT between 2006 and 2016, 126,420 (79%) had a follow-up colonoscopy within 180 days, including 67% in 2006-2008, 79% in 2009-2012, and 83% in 2013-2016 (P < 0.001). Follow-up within 180 days in 2016 varied moderately across service areas, between 72% (95% CI 70-75) and 88% (95% CI 86-91), but there were no obvious differences in the pattern of strategies implemented in higher- vs lower-performing service areas. CONCLUSIONS:The implementation of system-level strategies coincided with substantial improvements in timely colonoscopy follow-up after a positive FIT. Intervention studies are needed to identify the most effective strategies for promoting timely follow-up.

BackgroundThe risk of hepatotoxicity with antiretroviral therapy (ART) remains unknown. We determined the comparative risk of acute liver injury (ALI) for antiretroviral drugs, classes, and regimens, by viral hepatitis status.MethodsWe followed a cohort of 10 083 human immunodeficiency virus (HIV)-infected persons in Kaiser Permanente Northern California (n = 2099) from 2004 to 2010 and the Veterans Aging Cohort Study (n = 7984) from 2004 to 2012. Within the first year of ART, we determined occurrence of (1) liver aminotransferases >200 U/L and (2) severe ALI (coagulopathy with hyperbilirubinemia). We used Cox regression to determine hazard ratios (HRs) with 95% confidence intervals (CIs) of endpoints among initiators of nucleos(t)ide analogue combinations, antiretroviral classes, and ART regimens, all stratified by viral hepatitis status.ResultsLiver aminotransferases >200 U/L developed in 206 (2%) persons and occurred more frequently among HIV/viral hepatitis-coinfected than HIV-monoinfected persons (116.1 vs 20.7 events/1000 person-years; P < .001). No evidence of differential risk was found between initiators of abacavir/lamivudine versus tenofovir/emtricitabine among coinfected (HR, 0.68; 95% CI, .29-1.57) or HIV-monoinfected (HR, 1.19; 95% CI, .47-2.97) groups. Coinfected patients had a higher risk of aminotransferases >200 U/L after initiation with a protease inhibitor than nonnucleoside reverse-transcriptase inhibitor (HR, 2.01; 95% CI, 1.36-2.96). Severe ALI (30 events; 0.3%) occurred more frequently in coinfected persons (15.9 vs 3.1 events/1000 person-years; P < .001) but was too uncommon to evaluate in adjusted analyses.ConclusionsWithin the year after ART initiation, aminotransferase elevations were infrequently observed and rarely led to severe ALI. Protease inhibitor use was associated with a higher risk of aminotransferase elevations among viral hepatitis-coinfected patients.

Background: Understanding the relative contributions of SARS-CoV-2 infection-induced and vaccine-induced seroprevalence is key to measuring overall population-level seroprevalence and help guide policy decisions. Methods: Using a series of six population-based cross-sectional surveys conducted among persons aged ≥7 years in a large health system with over 4.5 million members between May 2021 and April 2022, we combined data from the electronic health record (EHR), an electronic survey and SARS-CoV-2 spike antibody binding assay, to assess the relative contributions of infection and vaccination to population-level SARS-CoV-2 seroprevalence. EHR and survey data were incorporated to determine spike antibody positivity due to SARS-CoV-2 infection and COVID-19 vaccination. We used sampling and non-response weighting to create population-level estimates. Results: We enrolled 4,319 persons over six recruitment waves. SARS-CoV-2 spike antibody seroprevalence increased from 83.3% (CI 77.0–88.9) in May 2021 to 93.5% (CI 89.5–97.5) in April 2022. By April 2022, 68.5% (CI 61.9–74.3) of the population was seropositive from COVID-19 vaccination only, 13.9% (10.7–17.9) from COVID-19 vaccination and prior diagnosed SARS-CoV-2 infection, 8.2% (CI 4.5–14.5) from prior diagnosed SARS-CoV-2 infection only and 2.9% (CI 1.1–7.6) from prior undiagnosed SARS-CoV-2 infection only. We found high agreement (≥97%) between EHR and survey data for ascertaining COVID-19 vaccination and SARS-CoV-2 infection status. Conclusions: By April 2022, 93.5% of persons had detectable SARS-CoV-2 spike antibody, predominantly from COVID-19 vaccination. In this highly vaccinated population and over 18 months into the pandemic, SARS-CoV-2 infection without COVID-19 vaccination was a small contributor to overall population-level seroprevalence. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusions Ongoing crises in the quality, affordability, sustainability, value, and equity of U.S. healthcare call for rapid, massive‐scale innovations across multiple specialties. Physician groups and healthcare organizations commit significant monetary and personnel investments for innovation and improvement efforts, but most lack over‐arching systems theory‐supported conceptual frameworks for efficiently coordinating the timely, large‐volume idea generation, refinement, prioritization, evidence development, implementation, and re‐evaluation strategies needed for rapid‐cycle improvements in health care delivery, outcomes, and value.This article describes one large‐scale, generalizable model: The Permanente Medical Group's (TPMG) Delivery Science and Applied Research (DARE) program within Kaiser Permanente Northern California. This organization‐level initiative was designed to: (1) elicit clinical innovation and quality concerns across clinical specialties; (2) prioritize these questions for next‐step evaluations; (3) create dedicated analytic, research, and clinical expertise to rapidly study the questions generated; (4) develop communities of clinician‐researchers, embedded within their specialties' clinical operations, who gather ideas for evaluation, generate evidence, and facilitate implementation of research results (a.k.a. evidence‐based innovators); and (5) broadly disseminate findings, to connect results with potential next‐step implementation.The DARE program and its components rapidly led to more than 200 recently completed or ongoing projects, informed care changes, influenced national guidelines, developed communities of evidence‐based clinician innovators in 15 specialties, and empowered new paths for career diversity and physician wellness. Key factors in the DARE program's success include explicitly defining high‐impact ideas; engaging researchers with analysts experienced with large clinical data systems; developing several research funding mechanisms scaled to project size; prioritizing rapid and efficient project completion; supporting clinician‐investigators embedded within their specialties; and structured organization‐wide dissemination of findings for informing potential implementation.High‐volume, evidence‐based innovation programs can be important, scale‐able, reproducible models for different settings for increasing quality, affordability, sustainability, value, and equity in healthcare and furthering the difficult‐to‐achieve concept of developing sustainable learning healthcare systems. [ABSTRACT FROM AUTHOR]

BackgroundAbdominal obesity is a risk factor for Barrett's esophagus independent of GERD symptoms, but little is understood about the biological mechanisms between obesity and the carcinogenic pathway of esophageal adenocarcinoma.AimsTo evaluate whether ghrelin and leptin may partially explain the association between obesity and Barrett's esophagus.MethodsWe conducted a case-control study using patients with a new diagnosis of Barrett's esophagus (cases) and two control groups frequency matched to cases for age, gender, and geographic region: (1) patients with gastroesophageal reflux disease (GERD) and (2) a sample of the general population. We generated odds ratios using logistic regressions to evaluate quartiles of serum ghrelin or serum leptin, adjusting for known risk factors for Barrett's esophagus. We evaluated potential interaction variables using cross products and ran stratified analyses to generate stratum-specific odds ratios.ResultsA total of 886 participants were included in the analysis. Higher ghrelin concentrations were associated with an increased risk of Barrett's esophagus, when compared to the population controls, but not the GERD controls. Ghrelin concentrations were not associated with the frequency of GERD symptoms, but ghrelin's relationship with Barrett's esophagus varied significantly with the frequency of GERD symptoms. Leptin concentrations were positively associated with at least weekly GERD symptoms among the population controls and were inversely associated with Barrett's esophagus only among the GERD controls. Adjusting for waist circumference did not change the main associations.ConclusionHigher levels of ghrelin were associated with an increased risk of Barrett's esophagus among the general population. In contrast, leptin was positively associated with frequent GERD symptoms, but inversely associated with the risk of Barrett's esophagus among the GERD controls.