Conformational flexibility of HIV-1 envelope glycoproteins modulates transmitted/founder sensitivity to broadly neutralizing antibodies.

HIV-1 envelope glycoproteins (Envs) of most primary HIV-1 strains exist in closed conformation and infrequently sample open states, limiting access to internal epitopes. Thus, immunogen design aims to mimic the closed Env conformation as preferred target for eliciting broadly neutralizing antibodies (bnAbs). Here we identify incompletely closed Env conformations of 6 out of 13 transmitted/founder (T/F) strains that are sensitive to antibodies that recognize internal epitopes typically exposed on open Envs. A 3.6 Å cryo-electron microscopy structure of unliganded, incompletely closed T/F Envs (1059-SOSIP) reveals protomer motion that increased sampling of states with incompletely closed trimer apex. We reconstruct de novo the post-transmission evolutionary pathway of a second T/F. Evolved viruses exhibit increased Env resistance to cold, soluble CD4 and 19b, all of which correlate with closing of the adapted Env trimer. Lastly, we show that the ultra-broad N6 bnAb efficiently recognizes different Env conformations and exhibits improved antiviral breadth against VRC01-resistant Envs isolated during the first-in-humans antibody-mediated-prevention trial.

Prying the lid open: Atomic-level insights on sialoglycan-TMPRSS2 coordination in HKU1 entry.

The pre-fusion coronavirus HKU1 spike binds host sialoglycans and proteinaceous receptor TMPRSS2 for cell entry. In this issue of Cell, three papers by Fernández et al., McCallum et al., and Wang et al. provide structural information on HKU1 spike interactions with host receptors, providing insights into its multi-step opening.

SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition.

A recombinant lineage of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryoelectron microscopy (cryo-EM) structures of XBB.1.5, XBB.1.16, EG.5, and EG.5.1 spike (S) ectodomains to reveal reinforced 3-receptor binding domain (RBD)-down receptor-inaccessible closed states mediated by interprotomer RBD interactions previously observed in BA.1 and BA.2. Improved XBB.1.5 and XBB.1.16 RBD stability compensated for stability loss caused by early Omicron mutations, while the F456L substitution reduced EG.5 RBD stability. S1 subunit mutations had long-range impacts on conformation and epitope presentation in the S2 subunit. Our results reveal continued S protein evolution via simultaneous optimization of multiple parameters, including stability, receptor binding, and immune evasion, and the dramatic effects of relatively few residue substitutions in altering the S protein conformational landscape.

Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans.

A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541). Here, we report MPER peptide-liposome induction of polyclonal HIV-1 B cell lineages of mature bnAbs and their precursors, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains with lineage initiation after the second immunization. Neutralization was enhanced by vaccine selection of improbable mutations that increased antibody binding to gp41 and lipids. This study demonstrates proof of concept for rapid vaccine induction of human B cell lineages with heterologous neutralizing activity and selection of antibody improbable mutations and outlines a path for successful HIV-1 vaccine development.

SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition.

A recombinant lineage of the SARS-CoV-2 Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryo-EM structures of XBB.1.5, XBB.1.16, EG.5 and EG.5.1 spike (S) ectodomains to reveal reinforced 3-RBD-down receptor inaccessible closed states mediated by interprotomer receptor binding domain (RBD) interactions previously observed in BA.1 and BA.2. Improved XBB.1.5 and XBB.1.16 RBD stability compensated for stability loss caused by early Omicron mutations, while the F456L substitution reduced EG.5 RBD stability. S1 subunit mutations had long-range impacts on conformation and epitope presentation in the S2 subunit. Our results reveal continued S protein evolution via simultaneous optimization of multiple parameters including stability, receptor binding and immune evasion, and the dramatic effects of relatively few residue substitutions in altering the S protein conformational landscape.

Evolution of the SARS-CoV-2 Omicron spike.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern, first identified in November 2021, rapidly spread worldwide and diversified into several subvariants. The Omicron spike (S) protein accumulated an unprecedented number of sequence changes relative to previous variants. In this review, we discuss how Omicron S protein structural features modulate host cell receptor binding, virus entry, and immune evasion and highlight how these structural features differentiate Omicron from previous variants. We also examine how key structural properties track across the still-evolving Omicron subvariants and the importance of continuing surveillance of the S protein sequence evolution over time.

Conformational flexibility of HIV-1 envelope glycoproteins modulates transmitted / founder sensitivity to broadly neutralizing antibodies.

HIV-1 envelope glycoproteins (Envs) mediate viral entry and are the sole target of neutralizing antibodies. Envs of most primary HIV-1 strains exist in a closed conformation and occasionally sample more open states. Thus, current knowledge guides immunogen design to mimic the closed Env conformation as the preferred target for eliciting broadly neutralizing antibodies (bnAbs) to block HIV-1 entry. Here we show that Env-preferred conformations of 6 out of 13 (46%) transmitted/founder (T/F) strains tested are incompletely closed. As a result, entry of these T/Fs into target cells is sensitive to antibodies that recognize internal epitopes exposed on open Env conformations. A cryo-electron microscopy structure of unliganded, incompletely closed T/F Envs (1059-SOSIP) at 3.6 Å resolution exhibits an asymmetric configuration of Env protomers with increased sampling of states with incompletely closed trimer apex. Double electron-electron resonance spectroscopy provided further evidence for enriched occupancy of more open Env conformations. Consistent with conformational flexibility, 1059 Envs were associated with resistance to most bnAbs that exhibit reduced potency against functional Env intermediates. To follow the fate of incompletely closed Env in patients, we reconstructed de novo the post-transmission evolutionary pathway of a second T/F Env (CH040), which is sensitive to the V3-targeting antibody 19b and highly resistant to most bnAbs. Evolved viruses exhibited increased resistance to cold, soluble CD4 and 19b, all of which correlate with closing of the adapted Env trimer. Lastly, we show a correlation between efficient neutralization of multiple Env conformations and increased antiviral breadth of CD4-binding site (CD4bs) bnAbs. In particular, N6 bnAb, which uniquely recognizes different Env conformations, efficiently neutralizes 50% of the HIV-1 strains that were resistant to VRC01 and transmitted during the first-in-humans antibody-mediated prevention trial (HVTN 704). VRC01-resistant Envs are incompletely closed based on their sensitivity to cold and on partial sensitivity to antibodies targeting internal, typically occluded, epitopes. Most VRC01-resistant Envs retain the VRC01 epitope according to VRC01 binding to their gp120 subunit at concentrations that have no significant effect on virus entry, and they exhibit cross resistance to other CD4bs bnAbs that poorly recognize functional Env intermediates. Our findings refine current knowledge of Env conformational states and provide guidance for developing new strategies for bnAb immunotherapy and Env-based immunogen design.

Independent external validation of the QRISK3 cardiovascular disease risk prediction model using UK Biobank.

OBJECTIVE: To externally evaluate the performance of QRISK3 for predicting 10 year risk of cardiovascular disease (CVD) in the UK Biobank cohort. METHODS: We used data from the UK Biobank, a large-scale prospective cohort study of 403 370 participants aged 40-69 years recruited between 2006 and 2010 in the UK. We included participants with no previous history of CVD or statin treatment and defined the outcome to be the first occurrence of coronary heart disease, ischaemic stroke or transient ischaemic attack, derived from linked hospital inpatient records and death registrations. RESULTS: Our study population included 233 233 women and 170 137 men, with 9295 and 13 028 incident CVD events, respectively. Overall, QRISK3 had moderate discrimination for UK Biobank participants (Harrell's C-statistic 0.722 in women and 0.697 in men) and discrimination declined by age (<0.62 in all participants aged 65 years or older). QRISK3 systematically overpredicted CVD risk in UK Biobank, particularly in older participants, by as much as 20%. CONCLUSIONS: QRISK3 had moderate overall discrimination in UK Biobank, which was best in younger participants. The observed CVD risk for UK Biobank participants was lower than that predicted by QRISK3, particularly for older participants. It may be necessary to recalibrate QRISK3 or use an alternate model in studies that require accurate CVD risk prediction in UK Biobank.

A Standardized Assessment of Processed Red Meat and Processed Poultry Intake in the US Population Aged ≥2 Years Using NHANES.

BACKGROUND: Standardized methods are needed to investigate intake patterns of processed meat subtypes, considering health concerns surrounding processed meat intake. OBJECTIVES: The objectives of this study were to create a standardized method of disaggregating processed meat into processed red meat and processed poultry and describe intake patterns of the US population aged ≥2 y. METHODS: Two researchers independently manually disaggregated processed meat from the Food Patterns Equivalents Database into processed red meat and processed poultry based on available information from the Foods and Nutrient Database for Dietary Studies. We created an SAS program (called Processed Meat Categories) to mimic the manual coding. We used the program to describe intake patterns and trends over time of processed red meat and processed poultry using 24-h recalls from 2007-2008 through 2017-2018 NHANES data with SAS survey-weighted procedures for complex surveys. RESULTS: The SAS program had high agreement with the manual code (Pearson concordance correlation ≥0.95). Of the US population aged ≥2 y, 46.8% (95% CI: 45.3, 48.2%) reported consuming any processed meat, 42.5% (95% CI: 41.0, 43.9%) reported consuming processed red meat, and 11.3% (95% CI: 10.2, 12.4%) reported consuming processed poultry. Most [74.1 ± 0.13% (SEM)] processed meat reported was red meat compared with poultry, and 32.1 ± 0.01% of total red meat and 13.7 ± 0.01% of total poultry reported were processed. Prevalence of processed poultry intake increased from 9.5% (95% CI: 8.9, 10.1%) in 2007-2010 to 11.3% (95% CI: 10.2, 12.4%) in 2015-2018 (P < 0.0001), but mean intake amount did not change. Prevalence of processed red meat intake did not change over time, but mean intake decreased from 0.8 ± 0.03 ounce-equivalents in 2007-2010 to 0.7 ± 0.02 ounce-equivalents (P = 0.0058) in 2015-2018. CONCLUSIONS: The Processed Meat Categories SAS program is a tool available for researchers to standardize estimates of processed meat subtypes for future dietary patterns research. Intake of total processed meat did not change in the United States, but intake amount of processed red meat decreased and the prevalence of processed poultry consumers increased.

Clostridioides difficile exploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota.

Clostridioides difficile is a bacterial pathogen that causes a range of clinical disease from mild to moderate diarrhea, pseudomembranous colitis, and toxic megacolon. Typically, C. difficile infections (CDIs) occur after antibiotic treatment, which alters the gut microbiota, decreasing colonization resistance against C. difficile. Disease is mediated by two large toxins and the expression of their genes is induced upon nutrient depletion via the alternative sigma factor TcdR. Here, we use tcdR mutants in two strains of C. difficile and omics to investigate how toxin-induced inflammation alters C. difficile metabolism, tissue gene expression and the gut microbiota, and to determine how inflammation by the host may be beneficial to C. difficile. We show that C. difficile metabolism is significantly different in the face of inflammation, with changes in many carbohydrate and amino acid uptake and utilization pathways. Host gene expression signatures suggest that degradation of collagen and other components of the extracellular matrix by matrix metalloproteinases is a major source of peptides and amino acids that supports C. difficile growth in vivo. Lastly, the inflammation induced by C. difficile toxin activity alters the gut microbiota, excluding members from the genus Bacteroides that are able to utilize the same essential nutrients released from collagen degradation.

Heterogeneity in Meat Food Groups Can Meaningfully Alter Population-Level Intake Estimates of Red Meat and Poultry.

Heterogeneity in meat food groups hinders interpretation of research regarding meat intake and chronic disease risk. Our objective was to investigate how heterogeneity in red meat (RM) and poultry food groups influences US population intake estimates. Based on a prior systematic review, we created an ontology of methods used to estimate RM [1= unprocessed RM; 2 (reference)= unprocessed RM + processed RM; 3= unprocessed RM + processed RM + processed poultry; and 4=unprocessed RM + processed RM + processed poultry + chicken patties/nuggets/tenders (PNT)] and three for poultry [A=unprocessed poultry; B= unprocessed poultry + PNT; C (reference)= unprocessed poultry + processed poultry + PNT). We applied methods to 2015-18 National Health and Nutrition Examination Survey data to estimate RM and poultry intake prevalence and amount. We estimated and compared intakes within RM and within poultry methods via the NCI Method for individuals ≥2 years old (n = 15,038), adjusted for age, sex, and race/Hispanic origin. We compared the population percentage that exceeded age- and sex-specific RM and poultry allotments from the Dietary Guidelines for Americans recommended eating patterns. The percent that consumed RM ranged from 47 ± 1.2% to 75 ± 0.8% across methods and mean amount ranged from 10.5 ± 0.28 to 18.2 ± 0.35 lean oz-equivalents/week; 38 ± 1.2% to 71 ± 0.7% and 9.8 ± 0.35 to 13.3 ± 0.35 lean oz-equivalents/week across poultry methods. Estimates for higher, but not lower, intake percentiles differed across RM methods. Compared to the reference, Method 1 was ≥3.0 oz-equivalents/week lower from 20th-70th percentiles, ≥6.0 oz-equivalents/week lower from 75th-90th percentiles, and ≥9.0 oz-equivalents/week lower for the 95th percentile. Method 4, but not Method 3, was ≥3.0 oz-equivalents/week higher than the reference from 50 to 95th percentiles. The population percentage that exceeded allotments was 27 ± 1.8% lower for Method 1, 9 ± 0.8% higher for Method 3, and 14 ± 0.9% higher for Method 4 compared to the reference. Differences were less pronounced for poultry. Our analysis quantifies the magnitude of bias introduced by heterogeneous meat food group methodology. Explicit descriptions of meat food groups are important for development of dietary recommendations to ensure that research studies are compared appropriately.

Estimating Usual Dietary In take From National Health and Nut rition Examination Survey Data Using the National Cancer Institute Method.

Dietary recommendations are intended to be met based on dietary intake over long periods, as associations between diet and health result from habitual intake, not a single eating occasion or day of intake. Measuring usual intake directly is impractical for large population-based surveys due to the respondent burden associated with reporting habitual intake over longer periods. Therefore, analytical techniques were developed to estimate usual intake using as few as 2 days of 24-hour dietary recall data. With National Health and Nutrition Examination Survey (NHANES) data, this report demonstrates how to estimate usual intake using the National Cancer Institute (NCI). This report demonstrates how to estimate the usual intake of nutrients consumed daily or episodically using NHANES data. Means, percentiles, and the percentages above or below specified Dietary Reference Intake (DRI) values for given day, within-person mean (WPM), and estimates of usual intake are presented. Consistent with previous analyses, mean intakes were similar across methods. However, the distributions estimated by nonusual intake methods were wider compared with the NCI Method, which can lead to misclassification of the percentage of the population above or below certain DRIs. Use of NHANES data to examine the proportion of the population at risk of insufficiency or excess of certain nutrients, with methods like given day and WPM that do not address within-person variation, may lead to biased estimates.

Pathogenesis and progression of oesophageal adenocarcinoma varies by prior diagnosis of Barrett's oesophagus.

BACKGROUND: The absolute risk of oesophageal adenocarcinoma (EA) among individuals with Barrett's oesophagus (BE) is low and a majority of EA cases are diagnosed among individuals with no prior BE diagnosis. To ensure that insights from EA case-control studies are transferable to clinical management of BE populations, we conducted a case-case study to compare the clinical presentation, medical history and survival of EA cases with and without a prior BE diagnosis in the Surveillance, Epidemiology and End Results Medicare database. METHODS: Eligible EA cases were diagnosed at age ⩾68 years during 1994-2009. There were 5271 EA cases in this study, 87% of which did not have a prior diagnosis of BE (EA-no prior BE). RESULTS: Multivariable case-case comparisons evidenced adverse associations of GERD, ever cigarette smoking, hypertension, dyslipidemia, weight loss, peptic ulcer and irritable bowel disease each in EA-prior BE compared with EA-no prior BE. Obesity, metabolic syndrome, impaired fasting glucose and diabetes did not differ between groups. EA-prior BE cases were diagnosed with less advanced disease, were more likely to undergo surgery and less likely to receive chemotherapy and radiotherapy, and had better overall mean survival (2.5 vs 1.4 years). This survival advantage persisted in the multivariable Cox model (HR=0.69, 95%CI: 0.60, 0.78), despite adjustment for many factors including stage, grade and clinical interventions. CONCLUSIONS: This study provides evidence that EA cases occurring among individuals previously diagnosed with BE are different from the large majority of EA cases that occur without a prior BE diagnosis. Regardless of whether these differences emanate from aetiology, biology and/or selection biases, they underscore the importance of a prudent approach in using knowledge from EAC case-control studies in the management of BE populations.

Comprehensive Evaluation of Medical Conditions Associated with Risk of Non-Hodgkin Lymphoma using Medicare Claims ("MedWAS").

BACKGROUND: Certain medical conditions affect risk of non-Hodgkin lymphoma (NHL), but the full range of associations is unknown. We implemented a novel method ("medical condition-wide association study," MedWAS) to comprehensively evaluate medical risk factors for NHL documented in administrative health claims. METHODS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we conducted a case-control study comparing NHL cases [N = 52,691, age 66+ years, with five subtypes: chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), T-cell lymphoma (TCL)] to controls (N = 200,000). We systematically screened for associations with 5,926 medical conditions documented in Medicare claims more than 1 year before selection. RESULTS: Fifty-five conditions were variously associated with NHL. Examples include well-established associations of human immunodeficiency virus, solid organ transplantation, and hepatitis C virus with increased DLBCL risk (ORs 3.83, 4.27, and 1.74, respectively), and autoimmune conditions with DLBCL and MZL (e.g., ORs of 2.10 and 4.74, respectively, for Sjögren syndrome). Risks for all NHL subtypes were increased after diagnoses of nonmelanoma skin cancer (ORs 1.19-1.55), actinic keratosis (1.12-1.25), or hemolytic anemia (1.64-4.07). Nine additional skin conditions increased only TCL risk (ORs 2.20-4.12). Diabetes mellitus was associated with increased DLBCL risk (OR 1.09). Associations varied significantly across NHL subtypes for 49 conditions (89%). CONCLUSION: Using an exploratory method, we found numerous medical conditions associated with NHL risk, and many associations varied across NHL subtypes. IMPACT: These results point to etiologic heterogeneity among NHL subtypes. MedWAS is a new method for assessing the etiology of cancer and other diseases. Cancer Epidemiol Biomarkers Prev; 25(7); 1105-13. ©2016 AACR.

Cancer Risk After Pernicious Anemia in the US Elderly Population.

BACKGROUND & AIMS: Pernicious anemia, a result of autoimmune gastritis, is the most common cause of vitamin B12 deficiency, affecting 2% to 5% of the elderly population. Treatment with vitamin B12 cures the anemia, but not the gastritis. Findings from small studies have indicated that patients with pernicious anemia could have an increased risk of cancer. METHODS: We performed a population-based, case-control study of individuals in the Surveillance, Epidemiology, and End Results-Medicare database, comparing 1,138,390 cancer cases (age, 66-99 y) with 100,000 matched individuals without cancer (controls). Individuals with pernicious anemia were identified based on their medical claims within the year before selection for the study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, and models were adjusted for sex, age, and calendar year of diagnosis and selection. RESULTS: Compared with controls, we found individuals with pernicious anemia to be at increased risk for noncardia gastric adenocarcinoma (OR, 2.18; 95% CI, 1.94-2.45) and gastric carcinoid tumors (OR, 11.43; 95% CI, 8.90-14.69). In addition, people with pernicious anemia have an increased risk of developing tonsilar cancer (OR, 2.00; 95% CI, 1.40-2.85), hypopharyngeal cancer (OR, 1.92; 95% CI, 1.35-2.73), esophageal squamous cell carcinoma (OR, 2.12; 95% CI, 1.76-2.55), small intestinal cancer (OR, 1.63; 95% CI, 1.32-2.02), liver cancer (OR, 1.49; 95% CI, 1.28- 1.73), myeloma (OR, 1.55; 95% CI, 1.37-1.75), acute myeloid leukemia (OR, 1.68; 95% CI, 1.46-1.93), and myelodysplastic syndrome (OR, 2.87; 95% CI, 2.53-3.26). People with pernicious anemia have a lower risk of rectal cancer than the general population (OR, 0.82; 95% CI, 0.74- 0.92). CONCLUSIONS: In a population-based, case-control study of individuals in the Surveillance, Epidemiology, and End Results-Medicare database, we found individuals with pernicious anemia to have significantly increased risks of gastric carcinoid tumors, adenocarcinomas, and other cancers located throughout the body.

Household Food Insecurity Is a Stronger Marker of Adequacy of Nutrient Intakes among Canadian Compared to American Youth and Adults.

BACKGROUND: The most recent statistics indicate that the prevalence of food insecurity in the United States is double that in Canada, but the extent to which the nutrition implications of this problem differ between the countries is not known. OBJECTIVE: This study was undertaken to compare adequacy of nutrient intakes in relation to household food insecurity among youth and adults in Canada and the United States. METHODS: Data from comparable nationally representative surveys, the 2004 Canadian Community Health Survey and the 2003-2006 NHANES, were used to estimate prevalences of inadequate intakes of vitamins A and C, folate, calcium, magnesium, and zinc among youth and adults in food-secure and food-insecure households. Potential differences in the composition of the populations between the 2 countries were addressed by using standardization, and analyses also accounted for participation in food and nutrition assistance programs in the United States. RESULTS: Larger gaps in the prevalences of inadequate intakes between those in food-secure and food-insecure households were observed in Canada than in the United States for calcium and magnesium. For calcium, the prevalences of inadequate intakes among those in food-secure and food-insecure households in Canada were 50% and 66%, respectively, compared with 50% and 51%, respectively, in the United States. For magnesium, the prevalences of inadequate intakes in Canada were 39% and 60% among those in food-secure and food-insecure households, respectively, compared with 60% and 61%, respectively, in the United States. These findings were largely unchanged after we accounted for participation in food and nutrition assistance programs in the United States. CONCLUSIONS: This study suggests that household food insecurity is a stronger marker of nutritional vulnerability in Canada than in the United States. The results highlight the need for research to elucidate the effects of domestic policies affecting factors such as food prices and fortification on the nutritional manifestations of food insecurity.

Endoscopic ultrasonography in esophageal cancer leads to improved survival rates: results from a population-based study.

BACKGROUND: The advantages of endoscopic ultrasound (EUS) and computed tomography (CT)-positron emission tomography (PET) with respect to survival for esophageal cancer patients are unclear. This study aimed to assess the effects of EUS, CT-PET, and their combination on overall survival with respect to cases not receiving these procedures. METHODS: Patients who were ≥66 years old when diagnosed with esophageal cancer were identified in the Surveillance, Epidemiology, and End Results-Medicare linked database. Cases were split into 4 analytic groups: EUS only (n = 318), CT-PET only (n = 853), EUS+CT-PET (n = 189), and no EUS or CT-PET (n = 2439). Survival times were estimated with the Kaplan-Meier method and were compared with the log-rank test for each group versus the no EUS or CT-PET group. Multivariate Cox proportional hazards models were used to compare 1-, 3-, and 5-year survival rates. RESULTS: Kaplan-Meier analyses showed that EUS, CT-PET, and EUS+CT-PET patients had improved survival for all stages (with the exception of stage 0 disease) in comparison with patients undergoing no EUS or CT-PET. Receipt of EUS increased the likelihood of receiving endoscopic therapies, esophagectomy, and chemoradiation. Multivariate Cox proportional hazards models showed that receipt of EUS was a significant predictor of improved 1- (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.39-0.59; P < .0001), 3- (HR, 0.57; 95% CI, 0.48-0.66; P < .0001), and 5-year survival (HR, 0.59; 95% CI, 0.50-0.68). Similar results were noted when the results were stratified on the basis of histology and for the CT-PET and EUS+CT-PET groups. CONCLUSIONS: Receipt of either EUS or CT-PET alone in esophageal cancer patients was associated with improved 1-, 3-, and 5-year survival. Future studies should identify barriers to the dissemination of these staging modalities.

Metabolic syndrome increases risk of Barrett esophagus in the absence of gastroesophageal reflux: an analysis of SEER-Medicare Data.

GOALS: To evaluate the association between metabolic syndrome (MetS) and risk of Barrett esophagus (BE) using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database compared with 2 control groups--Medicare population controls and endoscopy controls. BACKGROUND: BE principally arises as an adaptation to the proinflammatory state induced by gastroesophageal reflux disease (GERD). The relationship between obesity and BE is presumed to be mediated by GERD. However, evidence suggests central adiposity also increases risk of BE independent of GERD. Central adiposity is one risk factor defining MetS, which confers a systemic proinflammatory state--a potential GERD-independent mechanism by which obesity could increase the risk of BE. STUDY: MetS was defined as diagnosis of at least 3 of the following conditions: obesity, elevated triglycerides, high blood pressure, and elevated fasting glucose. Multivariable logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. RESULTS: In 2198 incident BE cases, prior MetS was significantly associated with BE (odds ratio, 1.20; 95% confidence interval: 1.07, 1.36) compared with population controls. However, GERD status modified the association; among those without prior GERD, MetS increased risk of BE by 34%; however, no association was observed among those with a prior GERD diagnosis (P-value for effect modification <0.001). MetS was not associated with risk of BE compared with endoscopy controls. CONCLUSIONS: MetS increased the risk of BE compared with population controls, an association driven by and confined to the non-GERD stratum. MetS may mediate an association between central adiposity and BE for those without GERD.

Elevated levels of procoagulant plasma microvesicles in dialysis patients.

Cardiovascular (CV) death remains the largest cause of mortality in dialysis patients, unexplained by traditional risk factors. Endothelial microvesicles (EMVs) are elevated in patients with traditional CV risk factors and acute coronary syndromes while platelet MVs (PMVs) are associated with atherosclerotic disease states. This study compared relative concentrations of circulating MVs from endothelial cells and platelets in two groups of dialysis patients and matched controls and investigated their relative thromboembolic risk. MVs were isolated from the blood of 20 haemodialysis (HD), 17 peritoneal dialysis (PD) patients and 20 matched controls. Relative concentrations of EMVs (CD144(+ ve)) and PMVs (CD42b(+ ve)) were measured by Western blotting and total MV concentrations were measured using nanoparticle-tracking analysis. The ability to support thrombin generation was measured by reconstituting the MVs in normal plasma, using the Continuous Automated Thrombogram assay triggered with 1µM tissue factor. The total concentration of MVs as well as the measured sub-types was higher in both patient groups compared to controls (p<0.05). MVs from HD and PD patients were able to generate more thrombin than the controls, with higher peak thrombin, and endogenous thrombin potential levels (p<0.02). However there were no differences in either the relative quantity or activity of MVs between the two patient groups (p>0.3). Dialysis patients have higher levels of circulating procoagulant MVs than healthy controls. This may represent a novel and potentially modifiable mediator or predictor of occlusive cardiovascular events in these patients.