Variation in responses to incretin therapy: Modifiable and non-modifiable factors.

Type 2 diabetes (T2D) and obesity have reached epidemic proportions. Incretin therapy is the second line of treatment for T2D, improving both blood glucose regulation and weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-stimulated insulinotropic polypeptide (GIP) are the incretin hormones that provide the foundations for these drugs. While these therapies have been highly effective for some, the results are variable. Incretin therapies target the class B G protein-coupled receptors GLP-1R and GIPR, expressed mainly in the pancreas and the hypothalamus, while some therapeutical approaches include additional targeting of the related glucagon receptor (GCGR) in the liver. The proper functioning of these receptors is crucial for incretin therapy success and here we review several mechanisms at the cellular and molecular level that influence an individual's response to incretin therapy.

The Contribution of the Human Oral Microbiome to Oral Disease: A Review.

The oral microbiome is an emerging field that has been a topic of discussion since the development of next generation sequencing and the implementation of the human microbiome project. This article reviews the current literature surrounding the oral microbiome, briefly highlighting most recent methods of microbiome characterization including cutting edge omics, databases for the microbiome, and areas with current gaps in knowledge. This article also describes reports on microorganisms contained in the oral microbiome which include viruses, archaea, fungi, and bacteria, and provides an in-depth analysis of their significant roles in tissue homeostasis. Finally, we detail key bacteria involved in oral disease, including oral cancer, and the current research surrounding their role in stimulation of inflammatory cytokines, the role of gingival crevicular fluid in periodontal disease, the creation of a network of interactions between microorganisms, the influence of the planktonic microbiome and cospecies biofilms, and the implications of antibiotic resistance. This paper provides a comprehensive literature analysis while also identifying gaps in knowledge to enable future studies to be conducted.

Leveraging electronic medical record functionality to capture adenoma detection rate.

Measuring the adenoma detection rate (ADR) is critical to providing quality care, however it is also challenging. We aimed to develop a tool using pre-existing electronic health record (EHR) functions to accurately and easily measure total ADR and to provide real-time feedback for endoscopists. We utilized the Epic EHR. With the help of an Epic analyst, using existing tools, we developed a method by which endoscopy staff could mark whether an adenoma was detected for a given colonoscopy. Using these responses and all colonoscopies performed by the endoscopist recorded in the EHR, ADR was calculated in a report and displayed to endoscopists within the EHR. One endoscopist piloted the tool, and results of the tool were validated against a manual chart review. Over the pilot period the endoscopist performed 145 colonoscopies, of which 78 had adenomas. The tool correctly identified 76/78 colonoscopies with an adenoma and 67/67 of colonoscopies with no adenomas (97.4% sensitivity, 100% specificity, 98% accuracy). There was no difference in ADR as determined by the tool compared to manual review (53.1% vs. 53.8%, p = 0.912). We successfully developed and pilot tested a tool to measure ADR using existing EHR functionality.

Histology, Size, and Number of Advanced Polyps are Associated With Guideline-Discordant Surveillance Recommendations.

Surveillance guidelines following polypectomy promote cost-effective reductions in future colorectal cancer (CRC) risk, but high nonadherence rates1 can have negative consequences on costs and effectiveness. Professional societies recommend a 3-year interval for patients with advanced colorectal polyps (ACPs), although few studies report provider adherence to surveillance intervals.2 This study evaluated rates and predictors of guideline-discordant recommendations for patients with ACPs.

Poor Knowledge of Personal and Familial Colorectal Cancer Risk and Screening Recommendations Associated with Advanced Colorectal Polyps.

BACKGROUND AND AIMS: Advanced colorectal polyps (adenoma or sessile serrated polyp ≥ 1 cm, adenoma with villous features, adenoma with high-grade dysplasia, or any sessile serrated polyps with dysplasia) are associated with an increased risk of future advanced colorectal neoplasia and confer an increased risk of advanced neoplasia to first-degree family members. Professional societies therefore recommend more intensive surveillance of these polyps and earlier screening for first-degree relatives. The aim of this study was to assess knowledge of personal and familial risk and recommendations among patients with advanced colorectal polyps and identify predictors of knowledge. METHODS: An online survey was designed to assess the domains of knowledge and risk perception regarding personal and familial colorectal cancer risk and screening recommendations. After expert review and pilot testing, the 37-item survey was electronically sent to all patients diagnosed with an advanced colon or rectal polyp under the age of 60. Patient report of polyp findings was compared to documented findings in the medical record. Univariable and multivariable regressions were performed to evaluate predictors of knowledge. RESULTS: One hundred thirty-seven out of 344 (39.8%) eligible patients responded to the survey. 28.5% of participants reported that the polyp they had removed was precancerous. 54.8% of participants reported that they have a higher risk of CRC, and 65.2% reported that they should be undergoing colonoscopy surveillance in 3 years or less. 40.1% reported that their first-degree family members are at increased CRC risk, and 38.0% reported that first-degree family members should get earlier screening. Participants reported their endoscopists as their top source of information about risk and recommendations, though only 7.3% of endoscopists made recommendations for family members. Female gender and higher income were predictors of accurate knowledge, as endoscopist was the main source of knowledge. CONCLUSIONS: Patients with advanced colorectal polyps have poor knowledge of personal and familial CRC risk and recommendations. Endoscopists who remove advanced polyps are in an ideal position to educate their patients about their personal risk and the risk and recommendations for first-degree family members.

Predictors of Failed Conscious Sedation in Patients Undergoing an Outpatient Colonoscopy and Implications for the Adenoma Detection Rate.

Guidelines to triage patients to conscious sedation (CS) or monitored anaesthesia care (MAC) for colonoscopy do not exist. We aimed to identify the CS failure rate, predictors of failure, and its impact on the adenoma detection rate (ADR). Strict (based on patient experience) and expanded (based on doses of sedative medications) definitions of CS failure were used. Patient and procedure-related variables were extracted. Multivariable logistic regression identified predictors for CS failure and the ADR. Among 766 patients, 29 (3.8%) and 175 (22.8%) patients failed CS by strict and expanded definitions, respectively. Female gender (OR 3.50; 95% CI: 1.37-8.94) and fellow involvement (OR 4.15; 95% CI: 1.79-9.58) were associated with failed CS by the strict definition. Younger age (OR 1.27, 95% CI: 1.07-1.49), outpatient opiate use (OR 1.71; 95% CI 1.03-2.84), use of an adjunct medication (OR 3.34; 95% CI: 1.94-5.73), and fellow involvement (OR 2.20; 95% CI: 1.31-3.71) were associated with failed CS by the expanded definition. Patients meeting strict failure criteria had a lower ADR (OR 0.30; 95% CI: 0.12-0.77). Several clinical factors may be useful for triaging to MAC. The ADR is lower in patients meeting strict criteria for failed CS.

A compartmentalized type I interferon response in the gut during chronic HIV-1 infection is associated with immunopathogenesis.

OBJECTIVE(S): Type I interferon (IFN-I) responses confer both protective and pathogenic effects in persistent virus infections. IFN-I diversity, stage of infection and tissue compartment may account for this dichotomy. The gut is a major site of early HIV-1 replication and microbial translocation, but the nature of the IFN-I response in this compartment remains unclear. DESIGN: Samples were obtained from two IRB-approved cross-sectional studies. The first study included individuals with chronic, untreated HIV-1 infection (n = 24) and age/sex-balanced uninfected controls (n = 14). The second study included antiretroviral-treated, HIV-1-infected individuals (n = 15) and uninfected controls (n = 15). METHODS: The expression of 12 IFNα subtypes, IFNß and antiviral IFN-stimulated genes (ISGs) were quantified in peripheral blood mononuclear cells (PBMCs) and colon biopsies using real-time PCR and next-generation sequencing. In untreated HIV-1-infected individuals, associations between IFN-I responses and gut HIV-1 RNA levels as well as previously established measures of colonic and systemic immunological indices were determined. RESULTS: IFNα1, IFNα2, IFNα4, IFNα5 and IFNα8 were upregulated in PBMCs during untreated chronic HIV-1 infection, but IFNß was undetectable. By contrast, IFNß was upregulated and all IFNα subtypes were downregulated in gut tissue. Gut ISG levels positively correlated with gut HIV-1 RNA and immune activation, microbial translocation and inflammation markers. Gut IFN-I responses were not significantly different between HIV-1-infected individuals on antiretroviral treatment and uninfected controls. CONCLUSION: The IFN-I response is compartmentalized during chronic untreated HIV-1 infection, with IFNß being more predominant in the gut. Gut IFN-I responses are associated with immunopathogenesis, and viral replication is likely a major driver of this response.

A low-volume polyethylene glycol solution was associated with an increased suboptimal bowel preparation rate but had similar recommendations for an early repeat colonoscopy, procedure times, and adenoma detection rates.

BACKGROUND/AIMS: Low-volume polyethylene glycol (PEG) bowel preparations are better tolerated by patients than high-volume preparations and may achieve similar preparation quality. However, there is little data comparing their effects on a recommendation for an early repeat colonoscopy (because of a suboptimal preparation), procedure times, adenoma detection rate (ADR), and advanced adenoma detection rate (AADR). METHODS: This is a retrospective cohort study of outpatient colonoscopies performed during a one-year period at a single academic medical center in which low-volume MoviPrep® (n = 1841) or high-volume Colyte® (n = 1337) was used. All preparations were split-dosed. Appropriate covariates were included in regression models assessing suboptimal preparation quality (fair, poor, or inadequate), procedure times, recommendation for an early repeat colonoscopy, ADR, and AADR. RESULTS: MoviPrep® was associated with an increase in having a suboptimal bowel preparation (OR 1.36; 95% CI: 1.06-1.76), but it was not associated with differences in insertion (p = 0.43), withdrawal (p = 0.22), or total procedure times (p = 0.10). The adjusted percentage with a suboptimal preparation was 11.7% for patients using MoviPrep® and 8.8% for patients using Colyte®. MoviPrep® was not associated with a significant difference in overall ADR (OR 0.93; 95% CI: 0.78-1.11), AADR (OR 1.18; 95% CI: 0.87-1.62), or recommendation for early repeat colonoscopy (OR 1.16; 95% CI: 0.72-1.88). CONCLUSIONS: MoviPrep® was associated with a small absolute increase in having a suboptimal preparation, but did not affect recommendations for an early repeat colonoscopy, procedure times, or adenoma detection rates. Mechanisms to reduce financial barriers limiting low-volume preparations should be considered because of their favorable tolerability profile.

Per-oral video cholangiopancreatoscopy with narrow-band imaging for the evaluation of indeterminate pancreaticobiliary disease.

BACKGROUND AND AIMS: Cholangiopancreatoscopy for evaluating pancreaticobiliary pathology is currently limited by suboptimal optics. The aim of this study was to characterize the operating characteristics of per-oral video cholangiopancreatoscopy with narrow-band imaging (POVCP) findings in indeterminate pancreaticobiliary disease and to describe their association with neoplasia. METHODS: Data from consecutive patients undergoing POVCP for the evaluation of indeterminate pancreaticobiliary disease at a single tertiary care center were analyzed. Two experienced investigators had previously agreed on POVCP findings and terminology that were documented in endoscopy reports. Endoscopic procedural data from POVCPs performed between January 2006 and April 2015 and clinical data were abstracted from the endoscopic database and electronic medical records. Study endpoints included tissue-proven neoplasia or benign disease with ≥1 year of follow-up. RESULTS: A total of 109 patients were identified; 13 were excluded because of the presence of stone disease, known pancreaticobiliary malignancy, or presumed benign disease with ≤1 year of follow-up. Most patients (85%) underwent POVCP for biliary disease and 15% underwent POVCP for a pancreatic cause. Tortuous and dilated vessels (P < .001), infiltrative stricture (P < .001), polypoid mass (P = .003), and the presence of fish-egg lesions (P = .04) were found to be significantly associated with neoplasia. The overall POVCP impression had a high sensitivity (85%) and negative predictive value (89%) in assessing for the presence of neoplasia. CONCLUSIONS: Per-oral video cholangiopancreatoscopy is effective in the evaluation of indeterminate pancreaticobiliary disease. Tortuous and dilated vessels, infiltrative stricture, polypoid mass, and the presence of fish-egg lesions are significantly associated with neoplasia.

Intracellular Tenofovir and Emtricitabine Anabolites in Genital, Rectal, and Blood Compartments from First Dose to Steady State.

The pharmacokinetics (PK) of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP), the active anabolites of tenofovir disoproxil fumarate (TDF), and emtricitabine (FTC) in blood, genital, and rectal compartments was determined in HIV-positive and seronegative adults who undertook a 60-day intensive PK study of daily TDF/FTC (plus efavirenz in HIV positives). Lymphocyte cell sorting, genital, and rectal sampling occurred once per subject, at staggered visits. Among 19 HIV-positive (3 female) and 21 seronegative (10 female) adults, TFV-DP in peripheral blood mononuclear cells (PBMC) accumulated 8.6-fold [95% confidence interval (CI): 7.2-10] from first-dose to steady-state concentration (Css) versus 1.7-fold (95% CI: 1.5-1.9) for FTC-TP. Css was reached in ∼11 and 3 days, respectively. Css values were similar between HIV-negative and HIV-positive individuals. Css TFV-DP in rectal mononuclear cells (1,450 fmol/106 cells, 898-2,340) was achieved in 5 days and was >10 times higher than PBMC (95 fmol/106 cells, 85-106), seminal cells (22 fmol/106 cells, 6-79), and cervical cells (111 fmol/106 cells, 64-194). FTC-TP Css was highest in PBMC (5.7 pmol/106 cells, 5.2-6.1) and cervical cells (7 pmol/106 cells, 2-19) versus rectal (0.8 pmol/106 cells, 0.6-1.1) and seminal cells (0.3 pmol/106 cells, 0.2-0.5). Genital drug concentrations on days 1-7 overlapped with estimated Css, but accumulation characteristics were based on limited data. TFV-DP and FTC-TP in cell sorted samples were highest and achieved most rapidly in CD14+ compared with CD4+, CD8+, and CD19+ cells. Together, these findings demonstrate cell-type and tissue-dependent cellular pharmacology, preferential accumulation of TFV-DP in rectal mononuclear cells, and rapid distribution into rectal and genital compartments.

Medicare Under Age 65 and Medicaid Patients Have Poorer Bowel Preparations: Implications for Recommendations for an Early Repeat Colonoscopy.

BACKGROUND/AIMS: Colonoscopy is performed on patients across a broad spectrum of demographic characteristics. These characteristics may aggregate by patient insurance provider and influence bowel preparation quality and the prevalence of adenomas. The purpose of this study was to evaluate the association of insurance status and suboptimal bowel preparation, recommendation for an early repeat colonoscopy due to suboptimal bowel preparation, adenoma detection rate (ADR), and advanced ADR (AADR). METHODS: This is a cohort study of outpatient colonoscopies (n = 3113) at a single academic medical center. Patient insurance status was categorized into five groups: 1) Medicare < 65y; 2) Medicare ≥ 65y; 3) Tricare/VA; 4) Medicaid/Colorado Indigent Care Program (CICP); and 5) commercial insurance. We used multivariable logistic or linear regression modeling to estimate the risks for the association between patient insurance and suboptimal bowel preparation, recommendation for an early repeat colonoscopy due to suboptimal bowel preparation, ADR, and AADR. Models were adjusted for appropriate covariates. RESULTS: Medicare patients < 65y (OR 4.91; 95% CI: 3.25-7.43) and Medicaid/CICP patients (OR 4.23; 95% CI: 2.65-7.65) were more likely to have a suboptimal preparation compared to commercial insurance patients. Medicare patients < 65y (OR 5.58; 95% CI: 2.85-10.92) and Medicaid/CICP patients (OR 3.64; CI: 1.60-8.28) were more likely to receive a recommendation for an early repeat colonoscopy compared to commercial insurance patients. Medicare patients < 65y had a significantly higher adjusted ADR (OR 1.50; 95% CI: 1.03-2.18) and adjusted AADR (OR 1.99; 95% CI: 1.15-3.44) compared to commercial insurance patients. CONCLUSIONS: Understanding the reasons for the higher rate of a suboptimal bowel preparation in Medicare < 65y and Medicaid/CICP patients and reducing this rate is critical to improving colonoscopy outcomes and reducing healthcare costs in these populations.

Antidepressant Use is Associated with Increased Energy Intake and Similar Levels of Physical Activity.

Antidepressants have been associated with weight gain, but the causes are unclear. The aims of this study were to assess the association of antidepressant use with energy intake, macronutrient diet composition, and physical activity. We used data on medication use, energy intake, diet composition, and physical activity for 3073 eligible adults from the 2005-2006 National Health and Nutrition Examination Survey (NHANES). Potential confounding variables, including depression symptoms, were included in the models assessing energy intake, physical activity, and sedentary behavior. Antidepressant users reported consuming an additional (mean ± S.E.) 215 ± 73 kcal/day compared to non-users (p = 0.01). There were no differences in percent calories from sugar, fat, or alcohol between the two groups. Antidepressant users had similar frequencies of walking or biking, engaging in muscle-strengthening activities, and engaging in moderate or vigorous physical activity. Antidepressant users were more likely to use a computer for ≥2 h/day (OR 1.77; 95% CI: 1.09-2.90), but TV watching was similar between the two groups. These results suggest increased energy intake and sedentary behavior may contribute to weight gain associated with antidepressant use. Focusing on limiting food intake and sedentary behaviors may be important in mitigating the weight gain associated with antidepressant use.

Association of Proton Pump Inhibitor (PPI) Use with Energy Intake, Physical Activity, and Weight Gain.

Studies suggest proton pump inhibitor (PPI) use impacts body weight regulation, though the effect of PPIs on energy intake, energy extraction, and energy expenditure is unknown. We used data on 3073 eligible adults from the National Health and Nutrition Examination Survey (NHANES). Medication use, energy intake, diet composition, and physical activity were extracted from NHANES. Multivariate regression models included confounding variables. Daily energy intake was similar between PPI users and non-users (p = 0.41). Diet composition was similar between the two groups, except that PPI users consumed a slightly greater proportion of calories from fat (34.5% vs. 33.2%; p = 0.02). PPI users rated themselves as being as physically active as their age/gender-matched peers and reported similar frequencies of walking or biking. However, PPI users were less likely to have participated in muscle-strengthening activities (OR: 0.53; 95% CI: 0.30-0.95). PPI users reported similar sedentary behaviors to non-users. Male PPI users had an increase in weight (of 1.52 ± 0.59 kg; p = 0.021) over the previous year compared to non-users, while female PPI users had a non-significant increase in weight. The potential mechanisms for PPI-associated weight gain are unclear as we did not find evidence for significant differences in energy intake or markers of energy expenditure.

Acid suppression medications are associated with suboptimal weight loss after laparoscopic Roux-en-Y gastric bypass in patients older than 40 years.

BACKGROUND: Bariatric surgery, including laparoscopic Roux-en-Y gastric bypass (LRYGB), achieves the greatest long-term weight loss in severe obesity. Approximately 50%-60% of severely obese patients have gastroesophageal reflux disease, and a substantial proportion is taking a proton pump inhibitor (PPI) or histamine-2 blocker (H2 B) at the time of LRYGB. The objective of this study was to explore the association of PPI/H2 B use before LRYGB with suboptimal percent weight loss (PWL) after LRYGB. METHODS: This was a cohort study of 472 consecutive patients who underwent LRYGB at a single center from 2004-2011. Suboptimal PWL was defined as<14% at 2 months,<25% at 6 months, and<30% at 12 months. Because of effect modification by age, stratified analyses (by median age of 40 yr) were performed. All models were adjusted for appropriate covariates, including obesity-associated co-morbidities. RESULTS: For patients aged ≤40 years, PPI/H2 B use leading up to LRYGB was not associated with suboptimal PWL at 2 months (P = .86), 6 months (P = .47), or 12 months (P = .66). However, for patients aged>40 years, PPI/H2 B use leading up to LRYGB was associated with a nonsignificant increase in suboptimal PWL at 2 months (odds ratio [OR] 2.23; P = .08) and significant increases in suboptimal PWL at 6 months (OR 7.23; P = .002) and 12 months (OR 11.1; P = .02). Results were independent of GERD. CONCLUSIONS: Mechanisms for the poorer weight loss in patients aged>40 years who were using a PPI/H2 B just before LRYGB should be explored.

The effect of Medicaid status on weight loss, hospital length of stay, and 30-day readmission after laparoscopic Roux-en-Y gastric bypass surgery.

BACKGROUND: Patients with Medicaid are much less likely to undergo bariatric surgery compared to those with commercial insurance. The aims of this study were to compare outcomes after laparoscopic Roux-en-Y gastric bypass (LRYGB) for patients covered by Medicaid, other (non-Medicaid) government insurance, and commercial insurance. METHODS: This was a retrospective cohort study of all eligible patients who underwent LRYGB between July 2004 and October 2011 at a single university hospital (n = 450). Multivariable regression analysis was used to compare percent weight loss (PWL), absolute weight loss (AWL), hospital length of stay (LOS) ≥3 days, and 30-day readmission rates. Analyses were adjusted for appropriate covariates. RESULTS: There was a nonsignificant increase in PWL in Medicaid patients at 2 months (p = 0.08), 6 months (p = 0.09), and 12 months (p = 0.17) compared to commercial insurance patients. Similarly, there was a nonsignificant increase in AWL in Medicaid patients at 2 months (p = 0.054), 6 months (p = 0.08), and 12 months (p = 0.14) compared to commercial insurance patients. Medicaid patients had similar PWL and AWL compared to those with other government insurance (p ≥ 0.29 at all time points). Medicaid patients were more likely to have a hospital LOS ≥ 3 days (OR 2.03; 95 % confidence interval (CI) 1.09-3.77) and a hospital readmission within 30 days of discharge (odds ratio (OR) 2.84; 95 % CI 1.15-6.96) compared to commercial insurance patients. CONCLUSIONS: These data should be considered as states expand Medicaid and make decisions regarding treatment of severe obesity. Interventions to decrease hospital LOS and the 30-day readmission rate, particularly in Medicaid patients, should be explored.

The effect of PPI use on human gut microbiota and weight loss in patients undergoing laparoscopic Roux-en-Y gastric bypass.

Laparoscopic Roux-en-Y gastric bypass (LRYGB) achieves sustainable weight loss possibly by altering the gut microbiota. The effect of a proton pump inhibitor (PPI) on weight loss and the gut microbiota has not been explored. PPI use and the gut microbiota were assessed before and 6 months after LRYGB in eight patients. Bacterial profiles were generated by 16S ribosomal RNA (rRNA) gene sequencing. Prior to LRYGB, PPI users had a higher percent relative abundance (PRA) of Firmicutes compared to nonusers. PPI users at 6 months post-LRYGB had a higher PRA of Firmicutes [48.6 versus 35.6%, p = nonsignificant (NS)] and a trend toward significantly lower percent excess weight loss (49.3 versus 61.4%, p = 0.067) compared to nonusers. PPI use post-LRYGB may impair weight loss by modifying gut microbiota.