Glucagon-like peptide-1 receptor agonists do not increase aspiration during upper endoscopy in patients with diabetes.

BACKGROUND AND AIMS: Glucagon-like peptide-1 receptor agonists (GLP1-RA) have been associated with greater retention of gastric contents, however there have been no controlled, population-based studies performed to evaluate the potential adverse effects of GLP1-RA in the periprocedural setting. We aimed to determine if there is increased risk of aspiration and aspiration-related complications after upper endoscopy in patients using GLP1-RA. METHODS: We used a nationwide commercial administrative claims database to conduct a retrospective cohort study of patients aged 18-64 with type 2 diabetes who underwent outpatient upper endoscopy from 2005-2021. We identified 6,806,046 unique upper endoscopy procedures. We compared claims for aspiration and associated pulmonary adverse events in the 14 days following upper endoscopy between users of GLP1-RA, dipeptidyl peptidase 4 inhibitors (DPP4i), and chronic opioids. We adjusted for age, sex, Charlson Comorbidity score, underlying respiratory disease, and gastroparesis. RESULTS: We found that pulmonary adverse events following upper endoscopy are rare, ranging from 6-25 events per 10,000 procedures. When comparing GLP1-RA to DPP4i, crude relative risks of aspiration (0.67 95%CI 0.25,1.75), aspiration pneumonia (0.95 95%CI 0.40,2.29), pneumonia (1.07 95%CI 0.62,1.86), or respiratory failure (0.75 95%CI 0.38,1.48) were not higher in patients prescribed GLP1-RA. When comparing GLP1-RA to opioids, crude relative risks (95%CI) were 0.42 (0.15,1.16) for aspiration, 0.60 (0.24,1.52) for aspiration pneumonia, 0.30 (0.19,0.49) for pneumonia, and 0.24 (0.13,0.45) for respiratory failure. These results were consistent across several sensitivity analyses. CONCLUSIONS: GLP1-RA use is not associated with increased risk of pulmonary complications after upper endoscopy compared to DPP4i use in patients with type 2 diabetes.

Offline Two-Dimensional Liquid Chromatography-Mass Spectrometry for Deep Annotation of the Fecal Metabolome Following Fecal Microbiota Transplantation.

Biological interpretation of untargeted LC-MS-based metabolomics data depends on accurate compound identification, but current techniques fall short of identifying most features that can be detected. The human fecal metabolome is complex, variable, incompletely annotated, and serves as an ideal matrix to evaluate novel compound identification methods. We devised an experimental strategy for compound annotation using multidimensional chromatography and semiautomated feature alignment and applied these methods to study the fecal metabolome in the context of fecal microbiota transplantation (FMT) for recurrent C. difficile infection. Pooled fecal samples were fractionated using semipreparative liquid chromatography and analyzed by an orthogonal LC-MS/MS method. The resulting spectra were searched against commercial, public, and local spectral libraries, and annotations were vetted using retention time alignment and prediction. Multidimensional chromatography yielded more than a 2-fold improvement in identified compounds compared to conventional LC-MS/MS and successfully identified several rare and previously unreported compounds, including novel fatty-acid conjugated bile acid species. Using an automated software-based feature alignment strategy, most metabolites identified by the new approach could be matched to features that were detected but not identified in single-dimensional LC-MS/MS data. Overall, our approach represents a powerful strategy to enhance compound identification and biological insight from untargeted metabolomics data.

Metagenomic, metabolomic, and lipidomic shifts associated with fecal microbiota transplantation for recurrent Clostridioides difficile infection.

Recurrent C. difficile infection (rCDI) is an urgent public health threat for which the last resort and lifesaving treatment is a fecal microbiota transplant (FMT). However, the exact mechanisms which mediate a successful FMT are not well understood. Here we use longitudinal stool samples collected from patients undergoing FMT to evaluate changes in the microbiome, metabolome, and lipidome after successful FMTs. We show changes in the abundance of many lipids, specifically acylcarnitines and bile acids, in response to FMT. These changes correlate with Enterobacteriaceae, which encode carnitine metabolism genes, and Lachnospiraceae, which encode bile salt hydrolases and baiA genes. LC-IMS-MS revealed a shift from microbial conjugation of primary bile acids pre-FMT to secondary bile acids post-FMT. Here we define the structural and functional changes in successful FMTs. This information will help guide targeted Live Biotherapeutic Product development for the treatment of rCDI and other intestinal diseases.

Using Multidimensional Separations to Distinguish Isomeric Amino Acid-Bile Acid Conjugates and Assess Their Presence and Perturbations in Model Systems.

Bile acids play key roles in nutrient uptake, inflammation, signaling, and microbiome composition. While previous bile acid analyses have primarily focused on profiling 5 canonical primary and secondary bile acids and their glycine and taurine amino acid-bile acid (AA-BA) conjugates, recent studies suggest that many other microbial conjugated bile acids (or MCBAs) exist. MCBAs are produced by the gut microbiota and serve as biomarkers, providing information about early disease onset and gut health. Here we analyzed 8 core bile acids synthetically conjugated with 22 proteinogenic and nonproteogenic amino acids totaling 176 MCBAs. Since many of the conjugates were isomeric and only 42 different m/z values resulted from the 176 MCBAs, a platform coupling liquid chromatography, ion mobility spectrometry, and mass spectrometry (LC-IMS-MS) was used for their separation. Their molecular characteristics were then used to create an in-house extended bile acid library for a combined total of 182 unique compounds. Additionally, ∼250 rare bile acid extracts were also assessed to provide additional resources for bile acid profiling and identification. This library was then applied to healthy mice dosed with antibiotics and humans having fecal microbiota transplantation (FMT) to assess the MCBA presence and changes in the gut before and after each perturbation.

Offline Two-dimensional Liquid Chromatography-Mass Spectrometry for Deep Annotation of the Fecal Metabolome.

Compound identification is an essential task in the workflow of untargeted metabolomics since the interpretation of the data in a biological context depends on the correct assignment of chemical identities to the features it contains. Current techniques fall short of identifying all or even most observable features in untargeted metabolomics data, even after rigorous data cleaning approaches to remove degenerate features are applied. Hence, new strategies are required to annotate the metabolome more deeply and accurately. The human fecal metabolome, which is the focus of substantial biomedical interest, is a more complex, more variable, yet lesser-investigated sample matrix compared to widely studied sample types like human plasma. This manuscript describes a novel experimental strategy using multidimensional chromatography to facilitate compound identification in untargeted metabolomics. Pooled fecal metabolite extract samples were fractionated using offline semi-preparative liquid chromatography. The resulting fractions were analyzed by an orthogonal LC-MS/MS method, and the data were searched against commercial, public, and local spectral libraries. Multidimensional chromatography yielded more than a 3-fold improvement in identified compounds compared to the typical single-dimensional LC-MS/MS approach and successfully identified several rare and novel compounds, including atypical conjugated bile acid species. Most features identified by the new approach could be matched to features that were detectable but not identifiable in the original single-dimension LC-MS data. Overall, our approach represents a powerful strategy for deeper annotation of the metabolome that can be implemented with commercially-available instrumentation, and should apply to any dataset requiring deeper annotation of the metabolome.

Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut.

Bile acids (BAs) mediate the crosstalk between human and microbial cells and influence diseases including Clostridioides difficile infection (CDI). While bile salt hydrolases (BSHs) shape the BA pool by deconjugating conjugated BAs, the basis for their substrate selectivity and impact on C. difficile remain elusive. Here we survey the diversity of BSHs in the gut commensals Lactobacillaceae, which are commonly used as probiotics, and other members of the human gut microbiome. We structurally pinpoint a loop that predicts BSH preferences for either glycine or taurine substrates. BSHs with varying specificities were shown to restrict C. difficile spore germination and growth in vitro and colonization in pre-clinical in vivo models of CDI. Furthermore, BSHs reshape the pool of microbial conjugated bile acids (MCBAs) in the murine gut, and these MCBAs can further restrict C. difficile virulence in vitro. The recognition of conjugated BAs by BSHs defines the resulting BA pool, including the expansive MCBAs. This work provides insights into the structural basis of BSH mechanisms that shape the BA landscape and promote colonization resistance against C. difficile.

Association between eosinophilic esophagitis and esophageal dysmotility: A systematic review and meta-analysis.

BACKGROUND: There is conflicting evidence about the association between eosinophilic esophagitis (EoE) and esophageal motility disorders. The aim of this study was to evaluate esophageal manometry findings in EoE. METHODS: We conducted a systematic review using PubMed, EMBASE, and Web of Science. All articles from 1990 to 2021 with EoE patients who underwent esophageal manometry were eligible. We also included pertinent abstracts from national conferences from 2015 to 2020. The primary outcomes were the prevalence of specific Chicago 3 Classification (CCv3) diagnoses in EoE, as well as broader categories of non-relaxing lower esophageal sphincter, and major and minor peristaltic disorders. When multiple studies reported a specific outcome, we performed random effects meta-analysis to obtain pooled prevalence of each outcome. To reduce heterogeneity, we restricted meta-analysis to high-resolution manometry (HRM) studies only. KEY RESULTS: Of 763 publications identified, 27 original studies met criteria for inclusion, encompassing 706 EoE patients; 14 studies (425 patients) had HRM and underwent meta-analysis. The pooled prevalence of any motility abnormality was 53% (95% CI: 43%-63%), largely comprised of minor motility disorders such as ineffective esophageal motility and fragmented peristalsis. Major motility disorders, classified by CCv3, were less common in EoE, with pooled prevalence of 2% (0%-7%), 10% (5%-16%), and 1% (0%-3%), for achalasia, esophagogastric-junction outflow obstruction, and hypercontractile disorders, respectively. CONCLUSION AND INFERENCES: Non-specific motility disorders were common in patients with EoE, but major motility disorders were rare. Further studies are needed to determine the relationship between eosinophilic infiltration and the clinical relevance of abnormal esophageal motility findings in this population.

Decreased Rate of Presentation, but Worsened Racial-Ethnic Disparity in Acute Gastrointestinal Bleeding During Coronavirus 2019 Shutdown: A Retrospective Cohort Study.

Purpose: In spring 2020, Coronavirus Disease 2019 (COVID-19) "stay-at-home" orders may have led to later, more acute disease presentations of emergent conditions such as gastrointestinal bleeding (GIB). In this retrospective cohort study, we compared incidence and severity of GIB during the strictest COVID shutdown to pre-COVID periods. Patients and methods: We compared weekly counts of emergency department (ED) visits for GIB between March 27 and May 7, 2020 (COVID period) and pre-COVID periods in 2019 and 2020 in a US statewide network of hospitals. We compared the severity of GIB presentations using incident rate ratios (IRR) of "severe" GIB (requiring ≥4 units of blood, endoscopic therapy, interventional radiology or surgical procedure), intensive care (ICU) admission and shock. We also looked for effect modification of demographic covariates on associations between year and GIB outcomes. Results: Fewer patients presented to ED for GIB during COVID than during the same dates in 2019 (534 versus 904; IRR 0.59, 95% CI 0.53-0.66). A greater proportion of COVID-period ED visits required inpatient admission (73.6% vs 67.8%, p = 0.02) and had severe GIB (19.3% vs 14.9%, p = 0.03). Proportion of patients requiring transfusion (p < 0.001), with shock (p < 0.01), or with critical hemoglobin (p = 0.003) or lactate (p = 0.02) were worse during COVID. Non-white patients experienced disproportionately worse outcomes during COVID than in 2019, with greater absolute counts of shock (65 vs 62, p = 0.01 for interaction) or ICU admission (40 vs 35, p = 0.01 for interaction). Conclusion: Fewer acute GIB presented during the pandemic period compared to the year prior. The severity of pandemic presentations was greater, driven by disproportionately worse outcomes in minorities.

Gastrointestinal and hepatic manifestations of COVID-19: A systematic review and meta-analysis.

Background and Aim: This review investigates the role of gastrointestinal and hepatic manifestations in COVID-19, particularly with regard to the prevalence of isolated gastrointestinal (GI) symptoms. Methods: We searched PubMed, Embase, and Cochrane library for COVID-19 publications from 1 December 2019 to 18 May 2020. We included any study that reported the presence of GI symptoms in a sample of >5 COVID-19 patients. Data collection and risk of bias assessment were performed independently by two reviewers. Where ≥3 studies reported data sufficiently similar to allow calculation of a pooled prevalence, we performed random effects meta-analysis. Results: This review included 17 776 COVID-19 patients from 108 studies. Isolated GI symptoms only occurred in 1% (95% confidence interval [CI] 0-6%) of patients. GI symptoms were reported in 20% (95% CI 15-24%) of patients. The most common were anorexia (21%, 95% CI 15-27%), diarrhea (13%, 95% CI 11-16%), nausea or vomiting (8%, 95% CI 6-11%), and abdominal pain (4%, 95% CI 2-6%). Transaminase elevations were present in 24% (95% CI 17-31%) of patients. Higher prevalence of GI symptoms were reported in studies published after 1st April, with prevalence of diarrhea 16% (95% CI 13-20), nausea or vomiting 12% (95% CI 8-16%), and any GI symptoms 24% (95% CI 18-34%). GI symptoms were associated with severe COVID-19 disease (odds ratio [OR] 2.1, 95% CI 1.3-3.2), but not mortality (OR 0.90, 95% CI 0.52-1.54). Conclusions: Patients with isolated GI symptoms may represent a small but significant portion of COVID-19 cases. When testing resources are abundant, clinicians should still consider testing patients with isolated GI symptoms or unexplained transaminase elevations for COVID-19. More recent studies estimate higher overall GI involvement in COVID-19 than was previously recognized.

Prevalence and Associated Dietary Factors of Rome IV Functional Gastrointestinal Disorders in Rural Western Honduras.

BACKGROUND: The literature is limited regarding the prevalence of functional gastrointestinal disorders (FGIDs) in Central America, and the role of dietary factors. METHODS: The Rome IV diagnostic questionnaire and National Cancer Institute Diet History questionnaire were administered in one-on-one interviews to a distributed cross section of the general adult population of Western Honduras. Our aim was to estimate prevalence of common FGIDs and symptoms and their relationships to dietary habits. RESULTS: In total, 815 subjects were interviewed, of whom 151 fulfilled criteria for an FGID (18.5%). Gastroduodenal FGIDs were noted in 9.4%, with epigastric pain syndrome (EPS) more common than postprandial distress syndrome, 8.5% versus 1.6%. Among bowel disorders, functional abdominal bloating (FAB) was most prevalent (6.3%), followed by irritable bowel syndrome (3.6%), functional diarrhea (FDr; 3.4%), and functional constipation (1.1%). A significant inverse association was noted between regular bean intake and any FGID (OR 0.41, 95% CI 0.27-0.63), driven by IBS and FDr. Vegetable consumption was associated with lower prevalence of functional diarrhea (OR 0.12; 95% CI 0.04-0.35) and any diarrheal disorder (OR 0.11; 95% CI 0.04-0.31). Subjects with a median daily intake of ≥ 4 corn tortillas had 1.75 (95% CI 1.22-2.50) times the odds of having any FGID. CONCLUSIONS: FGIDs were common in this rural low-resource setting in Central America, with an intriguing distribution of specific FGIDs. EPS and FAB were common, but IBS was not. Local dietary factors were associated with specific FGIDs, suggesting that diet may play a role in global variations of FGIDs.

The potential for malignancy from atopic disorders and allergic inflammation: A systematic review and meta-analysis.

OBJECTIVE: While chronic inflammation is a well-established risk factor for malignancy, studies evaluating the relationship between allergic inflammation and cancer have revealed conflicting results. Here, we aimed to assess the association between allergic inflammation in the lung (asthma), skin (eczema) or oesophagus (eosinophilic oesophagitis; EoE) and cancer at the organ site. DESIGN: We conducted a systematic review of the literature to identify observational studies (case-control, cohort and cross-sectional) evaluating the association between asthma and lung cancer, eczema and skin cancer, or EoE and oesophageal cancer. Random-effects meta-analysis was performed to define pooled estimates of effects. DATA SOURCES: PubMed, EMBASE and Web of Science. ELIGIBILITY CRITERIA FOR SELECTION: Included studies evaluated the incidence of cancer. RESULTS: Thirty-two studies met the inclusion criteria, 27 in the lung, four in the skin and one in the oesophagus. Meta-analysis of the three studies with prospective data collection of asthma diagnosis revealed a positive association with incident lung cancer (OR 1.27, 95% CI 1.09-1.44); however, this result was not consistently supported by the larger dataset of retrospective studies (OR 1.37, 95% CI 0.90-1.83). Overall, studies in the lung displayed significant heterogeneity (I2 98%, P < .0001), but no significant effect modification on the association between asthma and lung cancer was identified for the variables of sex, smoking or study design. Meta-analysis could not be applied to the four papers reviewed in the skin, but three suggested an association between eczema and non-melanoma skin cancer, while the remaining study failed to identify an association between melanoma and eczema. A single study meeting inclusion criteria showed no association between EoE and oesophageal malignancy. CONCLUSIONS: The current data cannot exclude the possibility of an association between atopy and malignancy the lung, skin and oesophagus. The relationship between allergy and cancer should be explored further in prospective studies that any association identified between these conditions has the potential for significant public health implications.

High-throughput amplicon sequencing of the full-length 16S rRNA gene with single-nucleotide resolution.

Targeted PCR amplification and high-throughput sequencing (amplicon sequencing) of 16S rRNA gene fragments is widely used to profile microbial communities. New long-read sequencing technologies can sequence the entire 16S rRNA gene, but higher error rates have limited their attractiveness when accuracy is important. Here we present a high-throughput amplicon sequencing methodology based on PacBio circular consensus sequencing and the DADA2 sample inference method that measures the full-length 16S rRNA gene with single-nucleotide resolution and a near-zero error rate. In two artificial communities of known composition, our method recovered the full complement of full-length 16S sequence variants from expected community members without residual errors. The measured abundances of intra-genomic sequence variants were in the integral ratios expected from the genuine allelic variants within a genome. The full-length 16S gene sequences recovered by our approach allowed Escherichia coli strains to be correctly classified to the O157:H7 and K12 sub-species clades. In human fecal samples, our method showed strong technical replication and was able to recover the full complement of 16S rRNA alleles in several E. coli strains. There are likely many applications beyond microbial profiling for which high-throughput amplicon sequencing of complete genes with single-nucleotide resolution will be of use.

Evaluation of Interventions Intended to Increase Colorectal Cancer Screening Rates in the United States: A Systematic Review and Meta-analysis.

Importance: Colorectal cancer screening (CRC) is recommended by all major US medical organizations but remains underused. Objective: To identify interventions associated with increasing CRC screening rates and their effect sizes. Data Sources: PubMed, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, and ClinicalTrials.gov were searched from January 1, 1996, to August 31, 2017. Key search terms included colorectal cancer and screening. Study Selection: Randomized clinical trials of US-based interventions in clinical settings designed to improve CRC screening test completion in average-risk adults. Data Extraction and Synthesis: At least 2 investigators independently extracted data and appraised each study's risk of bias. Where sufficient data were available, random-effects meta-analysis was used to obtain either a pooled risk ratio (RR) or risk difference (RD) for screening completion for each type of intervention. Main Outcomes and Measures: The main outcome was completion of CRC screening. Examination included interventions to increase completion of (1) initial CRC screening by any recommended modality, (2) colonoscopy after an abnormal initial screening test result, and (3) continued rounds of annual fecal blood tests (FBTs). Results: The main review included 73 randomized clinical trials comprising 366 766 patients at low or medium risk of bias. Interventions that were associated with increased CRC screening completion rates compared with usual care included FBT outreach (RR, 2.26; 95% CI, 1.81-2.81; RD, 22%; 95% CI, 17%-27%), patient navigation (RR, 2.01; 95% CI, 1.64-2.46; RD, 18%; 95% CI, 13%-23%), patient education (RR, 1.20; 95% CI, 1.06-1.36; RD, 4%; 95% CI, 1%-6%), patient reminders (RR, 1.20; 95% CI, 1.02-1.41; RD, 3%; 95% CI, 0%-5%), clinician interventions of academic detailing (RD, 10%; 95% CI, 3%-17%), and clinician reminders (RD, 13%; 95% CI, 8%-19%). Combinations of interventions (clinician interventions or navigation added to FBT outreach) were associated with greater increases than single components (RR, 1.18; 95% CI, 1.09-1.29; RD, 7%; 95% CI, 3%-11%). Repeated mailed FBTs with navigation were associated with increased annual FBT completion (RR, 2.09; 95% CI, 1.91-2.29; RD, 39%; 95% CI, 29%-49%). Patient navigation was not associated with colonoscopy completion after an initial abnormal screening test result (RR, 1.21; 95% CI, 0.92-1.60; RD, 14%; 95% CI, 0%-29%). Conclusions and Relevance: Fecal blood test outreach and patient navigation, particularly in the context of multicomponent interventions, were associated with increased CRC screening rates in US trials. Fecal blood test outreach should be incorporated into population-based screening programs. More research is needed on interventions to increase adherence to continued FBTs, follow-up of abnormal initial screening test results, and cost-effectiveness and other implementation barriers for more intensive interventions, such as navigation.

Low yield for non-targeted biopsies of the stomach and esophagus during elective esophagogastroduodenoscopy.

BACKGROUND AND STUDY AIMS: Biopsies of non-specific mucosal findings are often performed during esophagogastroduodenoscopy (EGD). We sought to determine the prevalence and clinical utility of non-targeted biopsies of the stomach and esophagus. PATIENTS AND METHODS: We conducted a retrospective review of 949 outpatient EGDs performed at a US tertiary referral center. Non-targeted biopsies of the stomach were defined as either "normal" or "mild" to "moderate" "erythema" or "inflammation" without other endoscopic features. Non-targeted biopsies of the esophagus and gastroesophageal junction (GEJ) were defined as endoscopically "normal" mucosa. The primary outcome was the proportion of non-targeted biopsies resulting in "definite management change." Secondary outcomes included histopathologic diagnoses of Helicobacter pylori, intestinal metaplasia and esophageal eosinophilia. RESULTS: Of 949 EGDs, 332 (35.0 %, 95 % CI 31.9 - 38.1 %) had a non-targeted biopsy taken at any site. Erythema in the gastric body and antrum was biopsied at a rate of 83 - 86 %, while biopsies of "normal"-appearing mucosa occurred at rates from 3 % (GEJ) to 15 % (body and antrum). The percentage of non-targeted biopsies that led to definite management change ranged from 5 % in the GEJ and esophagus to 9 % in the antrum, but did not significantly differ by mucosal appearance. Multivariable regression analyses suggested associations of language and age > 50 with management change from non-targeted gastric biopsy. CONCLUSIONS: Non-targeted biopsies of the stomach and esophagus led to definite management change in a small proportion of patients. Further studies are needed to identify patient and/or endoscopic characteristics and techniques to improve the yield of this practice.

Differences in subcortical structures in young adolescents at familial risk for schizophrenia: a preliminary study.

Schizophrenia has been associated with reduced volumes of subcortical structures on magnetic resonance imaging (MRI), but the relation of these reductions to familial risk for the disorder is unclear. We investigated the effect of familial risk for schizophrenia on regional subcortical volumes during adolescence, a period marked by steep maturational changes in brain structure and the emergence of psychotic symptoms. A group of 26 non-help-seeking, first-degree relatives of patients with schizophrenia and 43 matched healthy comparisons, between 9 and 18 years of age, underwent MRI scanning and were rated for the presence of prodromal symptoms. Five subcortical regions-of-interest were tested for group differences and group by age interactions, as well as correlations with low-level prodromal symptoms in the familial risk group. Relative to comparisons, familial risk subjects demonstrated greater positive volume-age relationships in hippocampus, putamen, and globus pallidus. These results suggest that relatives of individuals with schizophrenia exhibit structural abnormalities in the subcortex as early as pre-adolescence, which may reflect altered neurodevelopment of these regions.