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Abstract The gut microbiome is implicated in the pathogenesis of colorectal cancer (CRC), but the full scope of this dialogue is unknown. Here we aimed to define the scale and membership of the body of CRC- and health-associated gut bacteria in global populations. We performed a microbiome-CRC correlation analysis of published ultra-deep shotgun metagenomic sequencing data from global microbiome surveys, utilizing a de novo (reference-agnostic) gene-level clustering approach to identify protein-coding co-abundant gene (CAGs) clusters. We link an unprecedented ~ 23–40% of gut bacteria to CRC or health, split nearly evenly as CRC- or health-associated. These microbes encode 2319 CAGs encompassing 427,261 bacterial genes significantly enriched or depleted in CRC. We identified many microbes that had not previously been linked to CRC, thus expanding the scope of “known unknowns” of CRC-associated microbes. We performed an agnostic CAG-based screen of bacterial isolates and validated predicted effects of previously unimplicated bacteria in preclinical models, in which we observed differential induction of precancerous adenomas and field effects. Single-cell RNA sequencing disclosed microbiome-induced senescence-associated gene expression signatures in discrete colonic populations including fibroblasts. In organoid co-cultures, primary colon fibroblasts from mice with microbiomes promoted significantly greater growth than fibroblasts from microbiome-depleted mice. These results offer proof-of-principle for gene-level metagenomic analysis enabling discovery of microbiome links to health and demonstrate that the microbiome can drive precancer states, thereby potentially revealing novel cancer prevention opportunities.

BACKGROUND: Low-value use of screening colonoscopy is wasteful and potentially harmful to patients. Decreasing low-value colonoscopy prevents procedural complications, saves patient time and reduces patient discomfort, and can improve access by reducing procedural demand. The objective of this study was to develop and validate an electronic measure of screening colonoscopy overuse using International Classification of Diseases, Tenth Edition codes and then apply this measure to estimate facility-level overuse to target quality improvement initiatives to reduce overuse in a large integrated healthcare system. METHODS: Retrospective national observational study of US Veterans undergoing screening colonoscopy at 119 Veterans Health Administration (VHA) endoscopy facilities in 2017. A measure of screening colonoscopy overuse was specified by an expert workgroup, and electronic approximation of the measure numerator and denominator was performed (electronic measure). The electronic measure was then validated via manual record review (n=511). Reliability statistics (n=100) were calculated along with diagnostic test characteristics of the electronic measure. The measure was then applied to estimate overall rates of overuse and facility-level variation in overuse among all eligible patients. RESULTS: The electronic measure had high specificity (99%) and moderate sensitivity (46%). Adjusted positive predictive value and negative predictive value were 33% and 95%, respectively. Inter-rater reliability testing revealed near perfect agreement between raters (k=0.81). 269 572 colonoscopies were performed in VHA in 2017 (88 143 classified as screening procedures). Applying the measure to these 88 143 screening colonoscopies, 24.5% were identified as potential overuse. Median facility-level overuse was 22.5%, with substantial variability across facilities (IQR 19.1%-27.0%). CONCLUSIONS: An International Classification of Diseases, Tenth Edition based electronic measure of screening colonoscopy overuse has high specificity and improved sensitivity compared with a previous International Classification of Diseases, Ninth Edition based measure. Despite increased focus on reducing low-value care and improving access, a quarter of VHA screening colonoscopies in 2017 were identified as potential low-value procedures, with substantial facility-level variability.

Delays in colonoscopy work-up for red flag signs or symptoms of colorectal cancer (CRC) during the COVID-19 pandemic are not well characterized. To examine colonoscopy uptake and time to colonoscopy after red flag diagnosis, before and during the COVID-19 pandemic. Cohort study of adults ages 50-75 with iron deficiency anemia (IDA), hematochezia, or abnormal stool blood test receiving Veterans Health Administration (VHA) care from April 2019 to December 2020. Index date was first red flag diagnosis date, categorized into "pre" (April-December 2019) and "intra" (April-December 2020) policy implementation prioritizing diagnostic procedures, allowing for a 3-month "washout" (January-March 2020) period. Outcomes were colonoscopy completion and time to colonoscopy pre- vs. intra-COVID-19, examined using multivariable Cox models with hazard ratios (aHRs) and 95% confidence intervals (CIs). There were 52,539 adults with red flag signs or symptoms (pre-COVID: 25,154; washout: 7527; intra-COVID: 19,858). Proportion completing colonoscopy was similar pre- vs. intra-COVID-19 (27.0% vs. 26.5%; p = 0.24). Median time to colonoscopy among colonoscopy completers was similar for pre- vs. intra-COVID-19 (46 vs. 42 days), but longer for individuals with IDA (60 vs. 49 days). There was no association between time period and colonoscopy completion (aHR: 0.99, 95% CI 0.95-1.03). Colonoscopy work-up of CRC red flag signs and symptoms was not delayed within VHA during the COVID-19 pandemic, possibly due to VHA policies supporting prioritization and completion. Further work is needed to understand how COVID-19 policies on screening and surveillance impact CRC-related outcomes, and how to optimize colonoscopy completion after a red flag diagnosis.

Sensory neurons specialize in detecting and signaling the presence of diverse environmental stimuli. Neuronal injury or disease may undermine such signaling, diminishing the availability of crucial information. Can animals distinguish between a stimulus not being present and the inability to sense that stimulus in the first place? To address this question, we studied Caenorhabditis elegans nematode worms that lack gentle body touch sensation due to genetic mechanoreceptor dysfunction. We previously showed that worms can compensate for the loss of touch by enhancing their sense of smell, via an FLP-20 neuropeptide pathway. Here, we find that touch-deficient worms exhibit, in addition to sensory compensation, also cautious-like behavior, as if preemptively avoiding potential undetectable hazards. Intriguingly, these behavioral adjustments are abolished when the touch neurons are removed, suggesting that touch neurons are required for signaling the unavailability of touch information, in addition to their conventional role of signaling touch stimulation. Furthermore, we found that the ASE taste neurons, which similarly to the touch neurons, express the FLP-20 neuropeptide, exhibit altered FLP-20 expression levels in a touch-dependent manner, thus cooperating with the touch circuit. These results imply a novel form of neuronal signaling that enables C. elegans to distinguish between lack of touch stimulation and loss of touch sensation, producing adaptive behavioral adjustments that could overcome the inability to detect potential threats.

Background and Aims: Colorectal cancer (CRC) polygenic risk scores (PRS) may help personalize CRC prevention strategies. We investigated whether an existing PRS was associated with advanced neoplasia (AN) in a population undergoing screening and follow-up colonoscopy. Methods: We evaluated 10-year outcomes in the Cooperative Studies Program #380 screening colonoscopy cohort, which includes a biorepository of selected individuals with baseline AN (defined as CRC or adenoma ≥10 mm or villous histology, or high-grade dysplasia) and matched individuals without AN. A PRS was constructed from 136 prespecified CRC-risk single nucleotide polymorphisms. Multivariate logistic regression was used to evaluate the PRS for associations with AN prevalence at baseline screening colonoscopy or incident AN in participants with at least one follow-up colonoscopy. Results: The PRS was associated with AN risk at baseline screening colonoscopy (P = .004). Participants in the lowest PRS quintile had more than a 70% decreased risk of AN at baseline (odds ratio 0.29, 95% confidence interval 0.14–0.58; P < .001) compared to participants with a PRS in the middle quintile. Using a PRS cut-off of more than the first quintile to indicate need for colonoscopy as primary screening, the sensitivity for detecting AN at baseline is 91.8%. We did not observe a relationship between the PRS and incident AN during follow-up (P = .28). Conclusion: A PRS could identify individuals at low risk for prevalent AN. Ongoing work will determine whether this PRS can identify a subset of individuals at sufficiently low risk who could safely delay or be reassured about noninvasive screening. Otherwise, more research is needed to augment these genetic tools to predict incident AN during long-term follow-up.

BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.

IntroductionThe Veterans Health Administration introduced a clinical reminder system in 2018 to help address process gaps in colorectal cancer screening, including the diagnostic evaluation of positive fecal immunochemical test (FIT) results. We conducted a qualitative study to explore the differences between facilities who performed in the top vs bottom decile for follow-up colonoscopy.MethodsSeventeen semistructured interviews with gastroenterology (GI) providers and staff were conducted at 9 high-performing and 8 low-performing sites.ResultsWe identified 2 domains, current practices and perceived barriers, and most findings were described by both high- and low-performing sites. Findings exclusive to 1 group mainly pertained to current practices, especially arranging colonoscopy for FIT-positive patients. We observed only 1 difference in the perceived barriers domain, which pertained to primary care providers.DiscussionThese results suggest that what primarily distinguishes high- and low-performing sites is not a difference in barriers but rather in the GI clinical care process. Developing and disseminating patient education materials about the importance of diagnostic colonoscopy, eliminating in-person precolonoscopy visits when clinically appropriate, and involving GI in missed colonoscopy appointments and outside referrals should all be considered to increase follow-up colonoscopy rates. Our study illustrates the challenges of performing a timely colonoscopy after a positive FIT result and provides insights on improving the clinical care process for patients who are at substantially increased risk for colorectal cancer.

After implementing a successful hepatitis C elimination program, the Veterans Health Administration's (VHA) Hepatic Innovation Team (HIT) Collaborative pivoted to focus on improving cirrhosis care. This national program developed teams of providers across the country and engaged them in using systems redesign methods and population health approaches to improve care. The HIT Collaborative developed an Advanced Liver Disease (ALD) Dashboard to identify Veterans with cirrhosis who were due for surveillance for hepatocellular carcinoma (HCC) and other liver care, promoted the use of an HCC Clinical Reminder in the electronic health record, and provided training and networking opportunities. This evaluation aimed to describe the VHA's approach to improving cirrhosis care and identify the facility factors and HIT activities associated with HCC surveillance rates, using a quasi-experimental design. Across all VHA facilities, as the HIT focused on cirrhosis between 2018-2019, HCC surveillance rates increased from 46% (IQR 37-53%) to 51% (IQR 42-60%, p < 0.001). The median HCC surveillance rate was 57% in facilities with high ALD Dashboard utilization compared with 45% in facilities with lower utilization (p < 0.001) and 58% in facilities using the HCC Clinical Reminder compared with 47% in facilities not using this tool (p < 0.001) in FY19. Increased use of the ALD Dashboard and adoption of the HCC Clinical Reminder were independently, significantly associated with HCC surveillance rates in multivariate models, controlling for other facility characteristics. In conclusion, the VHA's HIT Collaborative is a national healthcare initiative associated with significant improvement in HCC surveillance rates.

BackgroundCirrhosis is a rapidly increasing cause of global mortality. To improve cirrhosis care, the Veterans Health Administration (VHA) developed the Hepatic Innovation Team (HIT) Collaborative to support VA Medical Centers (VAMCs) to deliver evidence-based cirrhosis care. This randomized HIT program evaluation aims to develop and assess a novel approach for choosing and applying implementation strategies to improve the quality of cirrhosis care.MethodsEvaluation aims are to (1) empirically determine which combinations of implementation strategies are associated with successful implementation of evidence-based practices (EBPs) for Veterans with cirrhosis, (2) manualize these "data-driven" implementation strategies, and (3) assess the effectiveness of data-driven implementation strategies in increasing cirrhosis EBP uptake. Aim 1 will include an online survey of all VAMCs' use of 73 implementations strategies to improve cirrhosis care, as defined by the Expert Recommendations for Implementing Change taxonomy. Traditional statistical as well as configurational comparative methods will both be employed to determine which combinations of implementation strategies are associated with site-level adherence to EBPs for cirrhosis. In aim 2, semi-structured interviews with high-performing VAMCs will be conducted to operationalize successful implementation strategies for cirrhosis care. These data will be used to inform the creation of a step-by-step guide to tailoring and applying the implementation strategies identified in aim 1. In aim 3, this manualized implementation intervention will be assessed using a hybrid type III stepped-wedge cluster randomized design. This evaluation will be conducted in 12 VAMCs, with four VAMCs crossing from control to intervention every 6 months, in order to assess the effectiveness of using data-driven implementation strategies to improve guideline-concordant cirrhosis care.DiscussionSuccessful completion of this innovative evaluation will establish the feasibility of using early evaluation data to inform a manualized, user-friendly implementation intervention for VAMCs with opportunities to improve care. This evaluation will provide implementation support tools that can be applied to enhance the implementation of other evidence-based practices.Trial registrationThis project was registered at ClinicalTrials.Gov ( NCT04178096 ) on 4/29/20.

Uptake of colorectal cancer screening remains suboptimal. Mailed fecal immunochemical testing (FIT) offers promise for increasing screening rates, but optimal strategies for implementation have not been well synthesized. In June 2019, the Centers for Disease Control and Prevention convened a meeting of subject matter experts and stakeholders to answer key questions regarding mailed FIT implementation in the United States. Points of agreement included: 1) primers, such as texts, telephone calls, and printed mailings before mailed FIT, appear to contribute to effectiveness; 2) invitation letters should be brief and easy to read, and the signatory should be tailored based on setting; 3) instructions for FIT completion should be simple and address challenges that may lead to failed laboratory processing, such as notation of collection date; 4) reminders delivered to initial noncompleters should be used to increase the FIT return rate; 5) data infrastructure should identify eligible patients and track each step in the outreach process, from primer delivery through abnormal FIT follow-up; 6) protocols and procedures such as navigation should be in place to promote colonoscopy after abnormal FIT; 7) a high-quality, 1-sample FIT should be used; 8) sustainability requires a program champion and organizational support for the work, including sufficient funding and external policies (such as quality reporting requirements) to drive commitment to program investment; and 9) the cost effectiveness of mailed FIT has been established. Participants concluded that mailed FIT is an effective and efficient strategy with great potential for increasing colorectal cancer screening in diverse health care settings if more widely implemented.

When interacting with the environment, the sensorimotor system faces temporal and spatial discrepancies between sensory inputs, such as delay in sensory information transmission, and asymmetrical visual inputs across space. These discrepancies can affect motor control and the representation of space. We recently showed that adaptation to a laterally asymmetric delay in the visual feedback induces neglect-like effects in blind drawing movements, expressed by asymmetrical elongation of circles that are drawn in different workspaces and directions; this establishes a possible connection between delayed feedback and asymmetrical spatial processing in the control of action. In the current study, we investigate whether such adaptation also influences visual perception. In addition, we examined transfer to another motor task - a line bisection task that is commonly used to detect spatial disorders, and extend these results to examine the mapping of these neglect-like effects. We performed two sets of experiments in which participants executed lateral reaching movements, and were exposed to visual feedback delay only in the left workspace. We examined transfer of adaptation to a perceptual line bisection task - answers about the perceived midline of lines that were presented in different directions and workspaces, and to a blind motor line bisection task - reaching movements toward the centers of similar lines. We found that the adaptation to the asymmetrical delay transferred to the control of lateral movements, but did not affect the perceived location of the midlines. Our results clarify the effect of asymmetrical delayed visual feedback on perception and action, and provide potential insights on the link between visuomotor delay and neurological disorders such as the hemispatial neglect syndrome.

Abstract Background There is significant variability in the performance and outcomes of invasive medical procedures such as percutaneous coronary intervention, endoscopy, and bronchoscopy. Peer evaluation is a common mechanism for assessment of clinician performance and care quality, and may be ideally suited for the evaluation of medical procedures. We therefore sought to perform a systematic review to identify and characterize peer evaluation tools for practicing clinicians, assess evidence supporting the validity of peer evaluation, and describe best practices of peer evaluation programs across multiple invasive medical procedures. Methods A systematic search of Medline and Embase (through September 7, 2021) was conducted to identify studies of peer evaluation and feedback relating to procedures in the field of internal medicine and related subspecialties. The methodological quality of the studies was assessed. Data were extracted on peer evaluation methods, feedback structures, and the validity and reproducibility of peer evaluations, including inter-observer agreement and associations with other quality measures when available. Results Of 2,135 retrieved references, 32 studies met inclusion criteria. Of these, 21 were from the field of gastroenterology, 5 from cardiology, 3 from pulmonology, and 3 from interventional radiology. Overall, 22 studies described the development or testing of peer scoring systems and 18 reported inter-observer agreement, which was good or excellent in all but 2 studies. Only 4 studies, all from gastroenterology, tested the association of scoring systems with other quality measures, and no studies tested the impact of peer evaluation on patient outcomes. Best practices included standardized scoring systems, prospective criteria for case selection, and collaborative and non-judgmental review. Conclusions Peer evaluation of invasive medical procedures is feasible and generally demonstrates good or excellent inter-observer agreement when performed with structured tools. Our review identifies common elements of successful interventions across specialties. However, there is limited evidence that peer-evaluated performance is linked to other quality measures or that feedback to clinicians improves patient care or outcomes. Additional research is needed to develop and test peer evaluation and feedback interventions.

Background Screening for colorectal cancer (CRC) with faecal immunochemical test (FIT) is effective at reducing CRC mortality. Unfortunately, the COVID-19 pandemic has been associated with deferred care, especially screening for CRC.Aim We sought to develop a mailed FIT programme (MFP) to increase CRC screening and make recommendations for adoption across the Veterans Health Administration (VHA) and for other large healthcare systems.Setting 2 regional VA medical centres in California and Washington state.Participants 5667 average risk veterans aged 50–75 overdue or due within 90 days for CRC screening.Programme description A multidisciplinary implementation team collaborated to mail an FIT kit to eligible veterans. Both sites mailed a primer postcard, and one site added an automated reminder call.Programme evaluation We monitored FIT return and positivity rate, as well as impact of the programme on clinical staff. 34% of FIT kits were returned within 90 days and 7.8% were abnormal.Discussion We successfully implemented a population-based MFP at multiple regional VA sites and recommend that these efforts be spread across VA. Our model of regional leadership, facility champions and using centralised resources can be adaptable to other large healthcare systems. MFPs support catch-up from disrupted care by addressing access to CRC screening, unburden primary care visits and conserve limited procedural resources.

Abstract Background Older age and comorbid burden are both associated with adverse outcomes in SARS-CoV-2, but it is not known whether the association between comorbid burden and adverse outcomes differs in older and younger adults. Objective To compare the relationship between comorbid burden and adverse outcomes in adults with SARS-CoV-2 of different ages (18–64, 65–79 and ≥ 80 years). Design, setting, and participants Observational longitudinal cohort study of 170,528 patients who tested positive for SARS-CoV-2 in the US Department of Veterans Affairs (VA) Health Care System between 2/28/20 and 12/31/2020 who were followed through 01/31/2021. Measurements Charlson Comorbidity Index (CCI); Incidence of hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and death within 30 days of a positive SARS-CoV-2 test. Results The cumulative 30-day incidence of death was 0.8% in cohort members

In 2016, the Veterans Health Administration (VHA) held a Weight Management State of the Art conference to identify evidence gaps and develop a research agenda for population-based weight management for veterans. Included were behavioral, pharmacologic, and bariatric surgery workgroups. This article summarizes the bariatric surgery workgroup (BSWG) findings and recommendations for future research. The BSWG agreed that there is evidence from randomized trials and large observational studies suggesting that bariatric surgery is superior to medical therapy for short- and intermediate-term remission of type 2 diabetes, long-term weight loss, and long-term survival. Priority evidence gaps include long-term comorbidity remission, mental health, substance abuse, and health care costs. Evidence of the role of endoscopic weight loss options is also lacking. The BSWG also noted the limited evidence regarding optimal timing for bariatric surgery referral, barriers to bariatric surgery itself, and management of high-risk bariatric surgery patients. Clinical trials of pre- and post-surgery interventions may help to optimize patient outcomes. A registry of overweight and obese veterans and a workforce assessment to determine the VHA's capacity to increase bariatric surgery access were recommended. These will help inform policy modifications and focus the research agenda to improve the ability of the VHA to deliver population-based weight management.

Sensory neurons specialize in detecting and signaling the presence of diverse environmental stimuli. Neuronal injury or disease may undermine such signaling, diminishing the availability of crucial information. Can animals distinguish between a stimulus not being present and the inability to sense that stimulus in the first place? To address this question, we studied Caenorhabditis elegans nematode worms that lack gentle body touch sensation due to genetic mechanoreceptor dysfunction. We previously showed that worms can compensate for the loss of touch by enhancing their sense of smell, via an FLP-20 neuropeptide pathway. Here, we find that touch-deficient worms exhibit, in addition to sensory compensation, also cautious-like behavior, as if preemptively avoiding potential undetectable hazards. Intriguingly, these behavioral adjustments are abolished when the touch neurons are removed, suggesting that touch neurons are required for signaling the unavailability of touch information, in addition to their conventional role of signaling touch stimulation. Furthermore, we found that the ASE taste neurons, which similarly to the touch neurons, express the FLP-20 neuropeptide, exhibit altered FLP-20 expression levels in a touch-dependent manner, thus cooperating with the touch circuit. These results imply a novel form of neuronal signaling that enables C. elegans to distinguish between lack of touch stimulation and loss of touch sensation, producing adaptive behavioral adjustments that could overcome the inability to detect potential threats. Sensory loss deprives animals of important information. This study shows that Caenorhabditis elegans worms lacking touch sensation show cautious-like behaviors, indicating that the touch neurons provide not only information about the presence or absence of touch stimuli, but also about the unavailability of touch information. [ABSTRACT FROM AUTHOR]