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The Veterans Health Administration (VHA) provides care for more than 80,000 veterans with cirrhosis. This longitudinal, multimethod evaluation of a cirrhosis care quality improvement program aimed to (1) identify implementation strategies associated with evidence-based, guideline-concordant cirrhosis care over time, and (2) use qualitative interviews to operationalize strategies for a manualized intervention.VHA providers were surveyed annually about the use of 73 implementation strategies to improve cirrhosis care in fiscal years 2018 (FY18) and 2019 (FY19). Implementation strategies linked to guideline-concordant cirrhosis care were identified using bivariate statistics and comparative configurational methods. Semistructured interviews were conducted with 12 facilities in the highest quartile of cirrhosis care to specify the successful implementation strategies and their mechanisms of change. A total of 106 VHA facilities (82%) responded at least once over the 2-year period (FY18, n = 63; FY19, n = 100). Facilities reported using a median of 12 (interquartile range [IQR] 20) implementation strategies in FY18 and 10 (IQR 19) in FY19. Of the 73 strategies, 35 (48%) were positively correlated with provision of evidence-based cirrhosis care. Configurational analysis identified multiple strategy pathways directly linked to more guideline-concordant cirrhosis care. Across both methods, a subset of eight strategies was determined to be core to cirrhosis care improvement and specified using qualitative interviews.In a national cirrhosis care improvement initiative, a multimethod approach identified a core subset of successful implementation strategy combinations. This process of empirically identifying and specifying implementation strategies may be applicable to other implementation challenges in hepatology.

Missing data problems are ubiquitous in data collection. In surveys, these problems may arise from unit response, item nonresponse, and panel attrition. Building on the Dominitz and Manski (2017) study of choice between two or more sampling processes that differ in cost and quality, we study minimax-regret sample design in anticipation of missing data, where the collected data will be used for prediction under square loss of the values of functions of two variables. The analysis imposes no assumptions that restrict unobserved outcomes. Findings are reported for prediction of the values of linear and indicator functions using panel data with attrition. We also consider choice between a panel and repeated cross sections.

This document is a focused update to the 2017 colorectal cancer (CRC) screening recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer, which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. This update is restricted to addressing the age to start and stop CRC screening in average-risk individuals and the recommended screening modalities. Although there is no literature demonstrating that CRC screening in individuals under age 50 improves health outcomes such as CRC incidence or CRC-related mortality, sufficient data support the U.S. Multi-Society Task Force to suggest average-risk CRC screening begin at age 45. This recommendation is based on the increasing disease burden among individuals under age 50, emerging data that the prevalence of advanced colorectal neoplasia in individuals ages 45 to 49 approaches rates in individuals 50 to 59, and modeling studies that demonstrate the benefits of screening outweigh the potential harms and costs. For individuals ages 76 to 85, the decision to start or continue screening should be individualized and based on prior screening history, life expectancy, CRC risk, and personal preference. Screening is not recommended after age 85.

Introduction: Clostridiodes difficile infection is the leading cause of infectious diarrhea in the United States, with substantial morbidity and mortality. Recurrent infection is especially challenging, with each recurrence increasing the likelihood of a successive recurrence, leading to cycles of prolonged symptoms, frequent antimicrobial use, and decreased quality of life. Fecal microbiota transplantation to prevent recurrent infection is a promising intervention with a large effect size in observational studies, but with conflicting results from randomized controlled trials. We are conducting a Veterans Affairs-wide randomized controlled trial utilizing centralized case identification, with enrollment and fecal microbiota transplant administration occurring at the participant’s home. This type of trial design significantly improves trial efficiency, greatly decreases trial cost, increases consistency of trial administration, and most importantly makes nationwide clinical trials in less-common diseases possible. Methods: This is a randomized comparison of capsule-delivered fecal microbiota transplant for the prevention of recurrent Clostridiodes difficile infection, administered after successful initial treatment of recurrent C. difficile infection with standard therapy. The primary endpoint is the incidence of recurrent C. difficile infection or death. Cases are identified by searching the Veterans Affairs Corporate Data Warehouse, with central study coordinators then reaching out to potential participants. Individuals meeting inclusion criteria and interested in participation are scheduled for in-home consent, randomization, and capsule administration, followed by telephone follow-up for 6 months. To mitigate risks of COVID-19, enrollment via video visits has been implemented. Results: A total of 102 participants have been enrolled through January 2021. Centralized case identification and in-home enrollment has facilitated enrollment from 34 unique states, with 38% being from rural or highly rural areas. Discussion: Centralized case identification and in-home enrollment is a feasible and innovative method of conducting randomized controlled trials in the Veterans Affairs system, improving access to clinical research for populations who may have difficulty engaging with the traditional model of clinical trials where enrollment is based at large hospitals in major metropolitan areas.

BACKGROUND AND AIMS: Whether patients with cirrhosis have increased risk of SARS-CoV-2 infection and the extent to which infection and cirrhosis increase the risk of adverse patient outcomes remain unclear. APPROACH AND RESULTS: We identified 88,747 patients tested for SARS-CoV-2 between 3/1/20-5/14/20 in the Veterans Affairs (VA) national healthcare system, including 75,315 with no cirrhosis-SARS-CoV-2 negative (C0-S0), 9826 with no cirrhosis-SARS-CoV-2 positive (C0-S1); 3301 with cirrhosis-SARS-CoV-2 negative (C1-S0); and 305 with cirrhosis-SARS-CoV-2 positive (C1-S1). Patients were followed through 6/22/20. Hospitalization, mechanical ventilation and death were modeled in time-to-event analyses using Cox proportional hazards regression. Patients with cirrhosis were less likely to test positive than patients without cirrhosis (8.5% vs. 11.5%, adjusted odds ratio 0.83, 95% CI 0.69-0.99). Thirty-day mortality and ventilation rates increased progressively from C0-S0 (2.3% and 1.6%), to C1-S0 (5.2% and 3.6%), to C0-S1 (10.6% and 6.5%), to C1-S1(17.1% and 13.0%). Among patients with cirrhosis, those who tested positive for SARS-CoV-2 were 4.1 times more likely to undergo mechanical ventilation (adjusted hazard ratio [aHR] 4.12, 95% CI 2.79-6.10) and 3.5 times more likely to die (aHR 3.54, 95% CI 2.55-4.90) than those who tested negative. Among patients with SARS-CoV-2 infection, those with cirrhosis were more likely to be hospitalized (aHR 1.37, 95% CI 1.12-1.66), undergo ventilation (aHR 1.61, 95% CI 1.05-2.46) or die (aHR 1.65, 95% CI 1.18-2.30) than patients without cirrhosis. Among patients with cirrhosis and SARS-CoV-2 infection, the most important predictors of mortality were advanced age, cirrhosis decompensation and high MELD score. CONCLUSIONS: SARS-CoV-2 infection was associated with a 3.5-fold increase in mortality in patients with cirrhosis. Cirrhosis was associated with a 1.7-fold increase in mortality in patients with SARS-CoV-2 infection.

The gut microbiome is an environmental driver of colorectal cancer (CRC). Although multiple gut bacterial species have been linked to CRC, each is detectable in a minority of CRC cases. Therefore, we postulated the existence of CRC-associated microbes more numerous and diverse than what is currently recognized. We performed a large-scale meta-analysis of metagenomic datasets from global gut microbiome surveys of CRC cohorts. By performing de novo clustering of co-abundant genes (CAG), we identified CRC-associated organisms with sub-species level resolution without the confounding effects of presupposed taxonomic hierarchies. This gene-level analysis disclosed 2,319 CAGs comprised of 427,261 bacterial genes significantly enriched or depleted in CRC that are widely encoded in genomes of diverse commensal organisms (an estimated 23-40% of gut bacteria), including taxa not previously linked to CRC. We demonstrated causality in gnotobiotic ApcMin/+ mice using defined bacterial consortia and human fecal samples: microbiomes harboring CRC-associated CAGs were more tumorigenic than microbiomes with health-associated genomic signatures. Bulk and single-cell RNA sequencing disclosed that tumorigenicity of the microbiome can be mediated through effects on the microenvironment rather than direct intestinal epithelial cell growth promotion. Together, these data offer proof-of-principle for microbiome-based personalized CRC risk profiling.

Background We aimed to describe trends in adverse outcomes among patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between February and September 2020 within a national healthcare system. Methods We identified enrollees in the national United States Veterans Affairs healthcare system who tested positive for SARS-CoV-2 between 28 February 2020 and 30 September 2020 (n = 55 952), with follow-up extending to 19 November 2020. We determined trends over time in incidence of the following outcomes that occurred within 30 days of testing positive: hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and death. Results Between February and July 2020, there were marked downward trends in the 30-day incidence of hospitalization (44.2% to 15.8%), ICU admission (20.3% to 5.3%), mechanical ventilation (12.7% to 2.2%), and death (12.5% to 4.4%), which subsequently plateaued between July and September 2020. These trends persisted after adjustment for sociodemographic characteristics, comorbid conditions, documented symptoms, and laboratory tests, including among subgroups of patients hospitalized, admitted to the ICU, or treated with mechanical ventilation. From February to September, there were decreases in the use of hydroxychloroquine (56.5% to 0%), azithromycin (48.3% to 16.6%), vasopressors (20.6% to 8.7%), and dialysis (11.6% to 3.8%) and increases in the use of dexamethasone (3.4% to 53.1%), other corticosteroids (4.9% to 29.0%), and remdesivir (1.7% to 45.4%) among hospitalized patients. Conclusions The risk of adverse outcomes in SARS-CoV-2–positive patients decreased markedly between February and July, with subsequent stabilization from July to September. These trends were not explained by changes in measured baseline patient characteristics and may reflect changing treatment practices or viral pathogenicity.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

Studies suggest that nonsteroidal anti-inflammatory drugs (NSAID) may contribute to inflammatory bowel disease (IBD) exacerbations. We examined whether variation in the likelihood of IBD exacerbations is attributable to NSAID.In a cohort of patients with IBD (2004-2015), we used 3 analytic methods to examine the likelihood of an exacerbation after an NSAID exposure. First, we matched patients by propensity for NSAID use and examined the association between NSAID exposure and IBD exacerbation using an adjusted Cox proportional hazards model. To assess for residual confounding, we estimated a previous event rate ratio and used a self-controlled case series analysis to further explore the relationship between NSAID and IBD exacerbations.We identified 15,705 (44.8%) and 19,326 (55.2%) IBD patients with and without an NSAID exposure, respectively. Findings from the Cox proportional hazards model suggested an association between NSAID and IBD exacerbation (hazard ratio 1.24; 95% confidence interval 1.16-1.33). However, the likelihood of an IBD exacerbation in the NSAID-exposed arm preceding NSAID exposure was similar (hazard ratio 1.30; 95% confidence interval 1.21-1.39). A self-controlled case series analysis of 3,968 patients who had both an NSAID exposure and IBD exacerbation demonstrated similar exacerbation rates in the 1 year preceding exposure, 2-6 weeks postexposure, and 6 weeks to 6 months postexposure, but a higher incidence in 0-2 weeks postexposure, suggesting potential confounding by reverse causality.While we see an association between NSAID and IBD exacerbations using traditional methods, further analysis suggests this may be secondary to residual bias. These findings may reassure patients and clinicians considering NSAID as a nonopioid pain management option.