Outcomes of colon self-expandable metal stents for malignant vs benign indications at a tertiary care center and review of literature.

BACKGROUND: Endoscopic placement of a self-expandable metal stent (SEMS) is a minimally invasive treatment for use in malignant and benign colonic obstruction. However, their widespread use is still limited with a nationwide analysis showing only 5.4% of patients with colon obstruction undergoing stent placement. This underutilization could be due to perceived increase risk of complications with stent placement. AIM: To review long- and short-term clinical success of SEMS use for colonic obstruction at our center. METHODS: We retrospectively reviewed all the patients who underwent colonic SEMS placement over a eighteen year period (August 2004 through August 2022) at our academic center. Demographics including age, gender, indication (malignant and benign), technical success, clinical success, complications (perforation, stent migration), mortality, and outcomes were recorded. RESULTS: Sixty three patients underwent colon SEMS over an 18-year period. Fifty-five cases were for malignant indications, 8 were for benign conditions. The benign strictures included diverticular disease stricturing (n = 4), fistula closure (n = 2), extrinsic fibroid compression (n = 1), and ischemic stricture (n = 1). Forty-three of the malignant cases were due to intrinsic obstruction from primary or recurrent colon cancer; 12 were from extrinsic compression. Fifty-four strictures occurred on the left side, 3 occurred on the right and the rest in transverse colon. The total malignant case (n = 55) procedural success rate was 95% vs 100% for benign cases (P = 1.0, NS). Overall complication rate was significantly higher for benign group: Four complications were observed in the malignant group (stent migration, restenosis) vs 2 of 8 (25%) for benign obstruction (1-perforation, 1-stent migration) (P = 0.02). When stratifying complications of perforation and stent migration there was no significant difference between the two groups (P = 0.14, NS). CONCLUSION: Colon SEMS remains a worthwhile option for colonic obstruction related to malignancy and has a high procedural and clinical success rate. Benign indications for SEMS placement appear to have similar success to malignant. While there appears to be a higher overall complication rate in benign cases, our study is limited by sample size. When evaluating for perforation alone there does not appear to be any significant difference between the two groups. SEMS placement may be a practical option for indications other that malignant obstruction. Interventional endoscopists should be aware and discuss the risk for complications in setting of benign conditions. Indications in these cases should be discussed in a multi-disciplinary fashion with colorectal surgery.

Protein Markers of Diabetes Discovered in an African American Cohort.

Proteomics has been used to study type 2 diabetes, but the majority of available data are from White participants. Here, we extend prior work by analyzing a large cohort of self-identified African Americans in the Jackson Heart Study (n = 1,313). We found 325 proteins associated with incident diabetes after adjusting for age, sex, and sample batch (false discovery rate q < 0.05) measured using a single-stranded DNA aptamer affinity-based method on fasting plasma samples. A subset was independent of established markers of diabetes development pathways, such as adiposity, glycemia, and/or insulin resistance, suggesting potential novel biological processes associated with disease development. Thirty-six associations remained significant after additional adjustments for BMI, fasting plasma glucose, cholesterol levels, hypertension, statin use, and renal function. Twelve associations, including the top associations of complement factor H, formimidoyltransferase cyclodeaminase, serine/threonine-protein kinase 17B, and high-mobility group protein B1, were replicated in a meta-analysis of two self-identified White cohorts-the Framingham Heart Study and the Malmö Diet and Cancer Study-supporting the generalizability of these biomarkers. A selection of these diabetes-associated proteins also improved risk prediction. Thus, we uncovered both novel and broadly generalizable associations by studying a diverse population, providing a more complete understanding of the diabetes-associated proteome.

Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals.

Integrating genetic information with metabolomics has provided new insights into genes affecting human metabolism. However, gene-metabolite integration has been primarily studied in individuals of European Ancestry, limiting the opportunity to leverage genomic diversity for discovery. In addition, these analyses have principally involved known metabolites, with the majority of the profiled peaks left unannotated. Here, we perform a whole genome association study of 2,291 metabolite peaks (known and unknown features) in 2,466 Black individuals from the Jackson Heart Study. We identify 519 locus-metabolite associations for 427 metabolite peaks and validate our findings in two multi-ethnic cohorts. A significant proportion of these associations are in ancestry specific alleles including findings in APOE, TTR and CD36. We leverage tandem mass spectrometry to annotate unknown metabolites, providing new insight into hereditary diseases including transthyretin amyloidosis and sickle cell disease. Our integrative omics approach leverages genomic diversity to provide novel insights into diverse cardiometabolic diseases.

Individualized feedback on colonoscopy skills improves group colonoscopy quality in providers with lower adenoma detection rates.

Background and study aims Colonoscopy inspection quality (CIQ) assesses skills (fold examination, cleaning, and luminal distension) during inspection for polyps and correlates with adenoma detection rate (ADR) and serrated detection rate (SDR). We aimed to determine whether providing individualized CIQ feedback with instructional videos improves quality metrics performance. Methods We prospectively studied 16 colonoscopists who already received semiannual benchmarked reports of quality metrics (ADR, SDR, and withdrawal time [WT]). We randomly selected seven colonoscopies/colonoscopist for evaluation. Six gastroenterologists graded CIQ using an established scale. We created instructional videos demonstrating optimal and poor inspection techniques. Colonoscopists received the instructional videos and benchmarked CIQ performance. We compared ADR, SDR, and WT in the 12 months preceding ("baseline") and following CIQ feedback. Colonoscopists were stratified by baseline ADR into lower (≤ 34 %) and higher-performing (> 34 %) groups. Results Baseline ADR was 38.5 % (range 26.8 %-53.8 %) and SDR was 11.2 % (2.8 %-24.3 %). The proportion of colonoscopies performed by lower-performing colonoscopists was unchanged from baseline to post-CIQ feedback. All colonoscopists reviewed their CIQ report cards. Post-feedback, ADR (40.1 % vs 38.5 %, P  = 0.1) and SDR (12.2 % vs. 11.2 %, P  = 0.1) did not significantly improve; WT significantly increased (11.4 vs 12.4 min, P  < 0.01). Among the eight lower-performing colonoscopists, group ADR (31.1 % vs 34.3 %, P  = 0.02) and SDR (7.2 % vs 9.1 %, P  = 0.02) significantly increased post-feedback. In higher-performing colonoscopists, ADR and SDR did not change. Conclusions CIQ feedback modestly improves ADR and SDR among colonoscopists with lower baseline ADR but has no effect on higher-performing colonoscopists. Individualized feedback on colonoscopy skills could be used to improve polyp detection by lower-performing colonoscopists.

Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease.

BACKGROUND: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. METHODS: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). RESULTS: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10-11. These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, ß=0.61±0.05, P=3.27×10-30) and MMP-3 (ß=-0.60±0.05, P=1.67×10-32), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, ß=0.34±0.04, P=1.34×10-17) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. CONCLUSIONS: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

Cecal retroflexion is infrequently performed in routine practice and the retroflexed view is of poor quality.

BACKGROUND: As right colon polyps are challenging to detect, a retroflexed view of right colon (RV) may be useful. However, cecal retroflexion (CR) without a RV to the hepatic flexure (HF) is inadequate. We aimed to determine the frequency of CR and quality of the RV in routine practice. METHODS: This prospective observational study performed at an academic medical center assessed colonoscopy inspection technique of endoscopists who had performed ≥ 100 annual screening colonoscopies. We video recorded ≥ 28 screening/surveillance colonoscopies per endoscopist and randomly evaluated 7 videos per endoscopist. Six gastroenterologists blindly reviewed the videos to determine if CR was performed and HF withdrawal time (cecum to HF time, excluding ileal/polypectomy time). RESULTS: Reviewers assessed 119 colonoscopies performed by 17 endoscopists. The median HF withdrawal time was 3 min and 46 s. CR was performed in 31% of colonoscopies. CR frequency varied between endoscopists with 9 never performing CR and 2 performing CR in all colonoscopies. When performed, nearly half (43%) of RVs did not extend to the HF with median RV duration of 16 s (IQR 9-30 s). Three polyps were identified in the RV (polyp detection rate of 8.1%), all identified prior to a forward view. CONCLUSIONS: CR is performed infrequently in routine practice. When CR is performed, the RV is of low quality with a very short inspection duration and insufficient ascending colon examination. Further education is required to educate endoscopists in optimal technique to improve overall colonoscopy quality.

Colorectal Cancer Screening After Changes in US Preventive Services Task Force Guidelines With Increased Screening Options.

INTRODUCTION: In 2016, the US Preventive Services Task Force (USPSTF) added multitarget stool DNA and computed tomography colonography (CTC) as accepted colorectal cancer screening modalities to the already recommended tests: fecal immunochemical test (FIT), sigmoidoscopy, and colonoscopy. The aim of our study was to determine trends in screening after the USPSTF update, with the effect of additional tests on the use of existing colorectal cancer screening modalities and overall screening rates. METHODS: We prospectively compared monthly colorectal cancer overall screening rates and the mean total numbers of patients screened by multitarget stool DNA, colonoscopy, sigmoidoscopy, CTC, and FIT 6 months prior to the new USPSTF guidelines until 30 months after. RESULTS: At completion of the study, 72,202 patients were eligible for screening. The overall rate of eligible patients screened for colorectal cancer did not change (80.9% vs 81.3%; P = 0.287). There was a significant increase in the percent of patients screened with multitarget stool DNA (1.6% to 15.6%; P = .001) and a significant decrease in the percent of patients screened using CTC (3.8 % to 1.5%; P = .004), FIT (9.3% to 4.9%; P = .003), and sigmoidoscopy (2.4% to 1.5%, P = .024). There was a nonsignificant decrease in the percent use of screening colonoscopy, from 82.9 % to 76.5% (P = .313). CONCLUSION: While the overall colorectal cancer screening rate did not increase after the USPSTF update with additional recommended screening tests, practice patterns did change with a shift in the type of screening test used.

Medication management for complex patients in primary care: application of a remote, asynchronous clinical pharmacist model.

Purpose: Drug therapy problems impact about one-third of US adults, and these issues are likely to continue to worsen as the population of aging Americans increases. The objective of this study is to assess the feasibility of a remotely delivered Comprehensive Medication Management (CMM) for primary practice patients who are polypharmatic and at high risk for drug therapy problems.Methods: Using medical and prescription claims data, a list of Medicare Advantage beneficiaries at high risk for drug therapy problems was identified. Participants were enrolled in a 6-month CMM program from February - November 2020. In the program, their existing drug therapy was assessed by a pharmacist, Drug therapy problems were identified and resolved. A Collaborative Practice Agreement allowed the pharmacists to make prescription changes as needed.Results: Eighty-three percent (202) of contacted individuals agreed to participate in the study. All participants were on five medications or more, and 71% were on more than eight. A clinical pharmacist found that 86% of participants had a drug therapy problem according to classification criteria. Seventy-nine percent of all drug therapy problems identified were resolved upon completion of the study.Conclusion: The findings of this study suggest that engagement of a remote clinical pharmacist can contribute to efficient resolution of most drug therapy problems identified in a primary care population. A service model using remote pharmacist services may be an effective means of improving team-based primary care medication management for this population.

Multiomic Profiling in Black and White Populations Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Adults.

BACKGROUND: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort. METHODS: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women). RESULTS: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; ß=0.04; P=2×10-8; hazard ratio, 1.48; P=0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; ß=0.05; P=5×10-15). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; P=0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups. CONCLUSIONS: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.

Safety and Efficacy of Moderate Sedation in Super Obese Patients Undergoing Lower and Upper GI Endoscopy: a Case-Control Study.

PURPOSE: Obesity is a disease of increasing prevalence. There is minimal research on the safety of sedation for general endoscopic procedures among super obese patients (BMI ≥ 50). The aim of our study was to evaluate the safety of moderate sedation and endoscopic procedural outcomes for super obese patients in a case-control study. MATERIALS AND METHODS: We completed an age and sex-matched case-control study comparing 132 super obese patients with 132 non-obese controls. We assessed intra-procedure adverse events, delayed adverse events, doses of sedation medication used, and procedure duration at a tertiary care setting. RESULTS: The mean BMI for the obese cohort was 55.6 compared with 22.5 for the controls (P < 0.001). The mean intra-procedure fentanyl and midazolam dose was higher for the obese patients compared with the controls, fentanyl 180 mcg, midazolam 7.7 mg vs fentanyl 148 mcg, midazolam 6.4 mg, respectively (P < 0.001). There was a significantly higher percentage of brief intra-procedure hypoxia (oxygen blood saturation < 90%) for the obese patients compared with the controls, 5% vs 0% (P = 0.02). There was no difference in delayed adverse events with 2% of the cases and 2% of the controls having delayed adverse events (P = 1.0). Procedure completion rates were 100% for both cases and controls. CONCLUSION: General endoscopic procedures can be safely and effectively performed in super obese patients with moderate sedation. Brief intra-procedure hypoxia more commonly occurs in super obese patients, and higher medication doses are required.

Colonoscopy-Naïve Raters Can Be Trained to Assess Colonoscopy Quality.

The ability of a colonoscopist to detect colon polyps is commonly measured by the adenoma detection rate (ADR). The outcome of colonoscopy varies based on ADR, and the relationship between decreasing provider ADR and the increased risk of subsequent fatal colorectal cancer has been clearly established.1 Despite the importance of provider ADR, it is of limited value at lower provider volumes due to imprecise measurements. We have previously shown that ratings of colonoscopy inspection quality (CIQ) from video-taped colonoscopies by experts highly correlate with provider ADR, and can provide colonoscopists with specific techniques in need of remediation.2 It is unclear, however, whether these video-based evaluations are a feasible method of assessing colonoscopy quality due to a reliance upon expert evaluations. The primary aim of this study was to determine whether video-based assessments of colonoscopy inspection quality by colonoscopy-naïve raters (novice raters) correlate with assessments by expert raters and with established colonoscopy quality metrics.

Induction of metabolic quiescence defines the transitional to follicular B cell switch.

Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this transition was also associated with increased extracellular adenosine salvage. Follicular B cells increased the abundance of the cell surface ectonucleotidase CD73, which coincided with adenosine 5'-monophosphate-activated protein kinase (AMPK) activation. Differentiation to the follicular B cell stage in vitro correlated with surface acquisition of CD73 on human transitional B cells and was augmented with the AMPK agonist, AICAR. Last, individuals with gain-of-function PIK3CD (PI3Kδ) mutations and increased pS6 activation exhibited a near absence of circulating follicular B cells. Together, our data suggest that mTORC1 attenuation may be necessary for human follicular B cell development. These data identify a distinct metabolic switch during human B cell development at the transitional to follicular stages, which is characterized by an induction of extracellular adenosine salvage, AMPK activation, and the acquisition of metabolic quiescence.

Cytology with rapid on-site examination (ROSE) does not improve diagnostic yield of EUS-FNA of pancreatic cystic lesions.

BACKGROUND: Cytology with rapid on-site evaluation (ROSE) has been shown to increase the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for solid pancreatic lesions. No data exists on the need for rapid onsite cytology in the evaluation of pancreatic cystic lesions (PCLs). The purpose of this study is to determine whether onsite cytology impacts the diagnostic yield of EUS-FNA of PCLs. METHODS: We prospectively examined all patients with PCLs who underwent EUS-FNA without onsite cytology over a 6-month period and compared this to a historical cohort of patients with PCLs who underwent EUS-FNA with ROSE in the previous 6 months. Comparison was made between the two groups based upon patient demographics, EUS cyst characteristics, and FNA fluid & cytopathology results. RESULTS: A total of 100 EUS-FNA exams for PCLs were identified: 46 with ROSE and 54 without onsite cytology. The majority of cytology findings were negative or nondiagnostic, 87.0% in the ROSE group, 77.8% in the group without onsite cytology. There was no difference using EUS-FNA without onsite cytology compared to ROSE when measuring total diagnostic yield (22.2% vs 13.0%, P = .30), number of nondiagnostic specimens (50% vs 54%, P = .69), and number of needle passes (1.51 vs 1.57, P = .68). CONCLUSIONS: (a) The majority of cytology results from EUS-FNA of cystic lesions are negative or nondiagnostic. (b) Having rapid onsite cytology evaluation of cystic lesions does not affect the number of needle passes nor diagnostic yield and is thus not recommended.

Video-Based Assessments of Colonoscopy Inspection Quality Correlate With Quality Metrics and Highlight Areas for Improvement.

BACKGROUND & AIMS: Adenoma detection rate (ADR) and serrated polyp detection rate (SDR) vary significantly among colonoscopists. Colonoscopy inspection quality (CIQ) is the quality with which a colonoscopist inspects for polyps and may explain some of this variation. We aimed to determine the relationship between CIQ and historical ADRs and SDRs in a cohort of colonoscopists and assess whether there is variation in CIQ components (fold examination, cleaning, and luminal distension) among colonoscopists with similar ADRs and SDRs. METHODS: We conducted a prospective observational study to assess CIQ among 17 high-volume colonoscopists at an academic medical center. Over 6 weeks, we video-recorded >28 colonoscopies per colonoscopist and randomly selected 7 colonoscopies per colonoscopist for evaluation. Six raters graded CIQ using an established scale, with a maximum whole colon score of 75. RESULTS: We evaluated 119 colonoscopies. The median whole-colon CIQ score was 50.1/75. Whole-colon CIQ score (r=0.71; P<.01) and component scores (fold examination r=0.74; cleaning r=0.67; distension r=0.77; all P<.01) correlated with ADR. Proximal colon CIQ score (r=0.67; P<.01) and component scores (fold examination r=0.71; cleaning r=0.62; distension r=0.65; all P<.05) correlated with SDR. CIQ component scores differed significantly between colonoscopists with similar ADRs and SDRs for most of the CIQ skills. CONCLUSION: In a prospective observational study, we found CIQ and CIQ components to correlate with ADR and SDR. Colonoscopists with similar ADRs and SDRs differ in their performance of the 3 CIQ components-specific, actionable feedback might improve colonoscopy technique.

Probing the Virtual Proteome to Identify Novel Disease Biomarkers.

BACKGROUND: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a "virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. METHODS: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651). RESULTS: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-ß predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-ß. CONCLUSIONS: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.

A tertiary care hospital's 10 years' experience with rectal ultrasound in early rectal cancer.

BACKGROUND AND OBJECTIVES: Rectal endoscopic ultrasound (RUS) has become an essential tool in the management of rectal adenocarcinoma because of the ability to accurately stage lesions. The aim of this study was to identify the staging agreement of early RUS-staged rectal adenocarcinoma with surgical resected pathology and ultimately determine how this impacts the management of early rectal cancer (T1-T2). METHODS: Retrospective chart review was performed from November 2002 to November 2013 to identify procedure indication, RUS staging data, surgical management, and postoperative surgical pathology data. RESULTS: There were a total of 693 RUS examinations available for review and 282 of these were performed for a new diagnosis of rectal adenocarcinoma. There was staging agreement between RUS and surgical pathology in 19 out of 20 (95%) RUS-staged T1 cases. There was staging agreement between RUS and surgical pathology in 3 out of 9 (33%) RUS-staged T2 cases. There was significantly better staging agreement for RUS-staged T1 lesions compared to RUS staged T2 lesions (P = 0.002). Nearly 60% of T1N0 cancers were referred for transanal excisions (TAEs), and 78% of T2N0 cancers underwent low anterior resection. CONCLUSIONS: This study identified only a small number of T1-T2 adenocarcinomas. There was good staging agreement between RUS and surgical pathology among RUS-staged T1 lesions whereas poor staging agreement among RUS-staged T2 lesions. Although TAE is largely indicated by the staging of a T1 lesion, this approach may be less appropriate for T2 lesions due to high reported local recurrence.

Genetic Architecture of the Cardiovascular Risk Proteome.

BACKGROUND: We recently identified 156 proteins in human plasma that were each associated with the net Framingham Cardiovascular Disease Risk Score using an aptamer-based proteomic platform in Framingham Heart Study Offspring participants. Here we hypothesized that performing genome-wide association studies and exome array analyses on the levels of each of these 156 proteins might identify genetic determinants of risk-associated circulating factors and provide insights into early cardiovascular pathophysiology. METHODS: We studied the association of genetic variants with the plasma levels of each of the 156 Framingham Cardiovascular Disease Risk Score-associated proteins using linear mixed-effects models in 2 population-based cohorts. We performed discovery analyses on plasma samples from 759 participants of the Framingham Heart Study Offspring cohort, an observational study of the offspring of the original Framingham Heart Study and their spouses, and validated these findings in plasma samples from 1421 participants of the MDCS (Malmö Diet and Cancer Study). To evaluate the utility of this strategy in identifying new biological pathways relevant to cardiovascular disease pathophysiology, we performed studies in a cell-model system to experimentally validate the functional significance of an especially novel genetic association with circulating apolipoprotein E levels. RESULTS: We identified 120 locus-protein associations in genome-wide analyses and 41 associations in exome array analyses, the majority of which have not been described previously. These loci explained up to 66% of interindividual plasma protein-level variation and, on average, accounted for 3 times the amount of variation explained by common clinical factors, such as age, sex, and diabetes mellitus status. We described overlap among many of these loci and cardiovascular disease genetic risk variants. Finally, we experimentally validated a novel association between circulating apolipoprotein E levels and the transcription factor phosphatase 1G. Knockdown of phosphatase 1G in a human liver cell model resulted in decreased apolipoprotein E transcription and apolipoprotein E protein levels in cultured supernatants. CONCLUSIONS: We identified dozens of novel genetic determinants of proteins associated with the Framingham Cardiovascular Disease Risk Score and experimentally validated a new role for phosphatase 1G in lipoprotein biology. Further, genome-wide and exome array data for each protein have been made publicly available as a resource for cardiovascular disease research.

Application of Large-Scale Aptamer-Based Proteomic Profiling to Planned Myocardial Infarctions.

BACKGROUND: Emerging proteomic technologies using novel affinity-based reagents allow for efficient multiplexing with high-sample throughput. To identify early biomarkers of myocardial injury, we recently applied an aptamer-based proteomic profiling platform that measures 1129 proteins to samples from patients undergoing septal alcohol ablation for hypertrophic cardiomyopathy, a human model of planned myocardial injury. Here, we examined the scalability of this approach using a markedly expanded platform to study a far broader range of human proteins in the context of myocardial injury. METHODS: We applied a highly multiplexed, expanded proteomic technique that uses single-stranded DNA aptamers to assay 4783 human proteins (4137 distinct human gene targets) to derivation and validation cohorts of planned myocardial injury, individuals with spontaneous myocardial infarction, and at-risk controls. RESULTS: We found 376 target proteins that significantly changed in the blood after planned myocardial injury in a derivation cohort (n=20; P<1.05E-05, 1-way repeated measures analysis of variance, Bonferroni threshold). Two hundred forty-seven of these proteins were validated in an independent planned myocardial injury cohort (n=15; P<1.33E-04, 1-way repeated measures analysis of variance); >90% were directionally consistent and reached nominal significance in the validation cohort. Among the validated proteins that were increased within 1 hour after planned myocardial injury, 29 were also elevated in patients with spontaneous myocardial infarction (n=63; P<6.17E-04). Many of the novel markers identified in our study are intracellular proteins not previously identified in the peripheral circulation or have functional roles relevant to myocardial injury. For example, the cardiac LIM protein, cysteine- and glycine-rich protein 3, is thought to mediate cardiac mechanotransduction and stress responses, whereas the mitochondrial ATP synthase F0 subunit component is a vasoactive peptide on its release from cells. Last, we performed aptamer-affinity enrichment coupled with mass spectrometry to technically verify aptamer specificity for a subset of the new biomarkers. CONCLUSIONS: Our results demonstrate the feasibility of large-scale aptamer multiplexing at a level that has not previously been reported and with sample throughput that greatly exceeds other existing proteomic methods. The expanded aptamer-based proteomic platform provides a unique opportunity for biomarker and pathway discovery after myocardial injury.