Endoscopic Screening Program for Control of Esophageal Adenocarcinoma in Varied Populations: A Comparative Cost-Effectiveness Analysis.

BACKGROUND & AIMS: Guidelines suggest endoscopic screening for esophageal adenocarcinoma (EAC) among individuals with symptoms of gastroesophageal reflux disease (GERD) and additional risk factors. We aimed to determine at what age to perform screening and whether sex and race should influence the decision. METHODS: We conducted comparative cost-effectiveness analyses using 3 independent simulation models. For each combination of sex and race (White/Black, 100,000 individuals each), we considered 41 screening strategies, including one-time or repeated screening. The optimal strategy was that with the highest effectiveness and an incremental cost-effectiveness ratio <$100,000 per quality-adjusted life-year gained. RESULTS: Among White men, 536 EAC deaths were projected without screening, and screening individuals with GERD twice at ages 45 and 60 years was optimal. Screening the entire White male population once at age 55 years was optimal in 26% of probabilistic sensitivity analysis runs. Black men had fewer EAC deaths without screening (n = 84), and screening those with GERD once at age 55 years was optimal. Although White women had slightly more EAC deaths (n = 103) than Black men, the optimal strategy was no screening, although screening those with GERD once at age 55 years was optimal in 29% of probabilistic sensitivity analysis runs. Black women had a very low burden of EAC deaths (n = 29), and no screening was optimal, as benefits were very small and some strategies caused net harm. CONCLUSIONS: The optimal strategy for screening differs by race and sex. White men with GERD symptoms can potentially be screened more intensely than is recommended currently. Screening women is not cost-effective and may cause net harm for Black women.

Bronchial gene expression alterations associated with radiological bronchiectasis.

OBJECTIVES: Discovering airway gene expression alterations associated with radiological bronchiectasis may improve the understanding of the pathobiology of early-stage bronchiectasis. METHODS: Presence of radiological bronchiectasis in 173 individuals without a clinical diagnosis of bronchiectasis was evaluated. Bronchial brushings from these individuals were transcriptomically profiled and analysed. Single-cell deconvolution was performed to estimate changes in cellular landscape that may be associated with early disease progression. RESULTS: 20 participants have widespread radiological bronchiectasis (three or more lobes). Transcriptomic analysis reflects biological processes associated with bronchiectasis including decreased expression of genes involved in cell adhesion and increased expression of genes involved in inflammatory pathways (655 genes, false discovery rate <0.1, log2 fold-change >0.25). Deconvolution analysis suggests that radiological bronchiectasis is associated with an increased proportion of ciliated and deuterosomal cells, and a decreased proportion of basal cells. Gene expression patterns separated participants into three clusters: normal, intermediate and bronchiectatic. The bronchiectatic cluster was enriched by participants with more lobes of radiological bronchiectasis (p<0.0001), more symptoms (p=0.002), higher SERPINA1 mutation rates (p=0.03) and higher computed tomography derived bronchiectasis scores (p<0.0001). CONCLUSIONS: Genes involved in cell adhesion, Wnt signalling, ciliogenesis and interferon-γ pathways had altered expression in the bronchus of participants with widespread radiological bronchiectasis, possibly associated with decreased basal and increased ciliated cells. This gene expression pattern is not only highly enriched among individuals with radiological bronchiectasis, but also associated with airway-related symptoms in those without discernible radiological bronchiectasis, suggesting that it reflects a bronchiectasis-associated, but non-bronchiectasis-specific lung pathophysiological process.

Bronchial epithelial gene expression and interstitial lung abnormalities.

INTRODUCTION: Interstitial lung abnormalities (ILA) often represent early fibrotic changes that can portend a progressive fibrotic phenotype. In particular, the fibrotic subtype of ILA is associated with increased mortality and rapid decline in lung function. Understanding the differential gene expression that occurs in the lungs of participants with fibrotic ILA may provide insight into development of a useful biomarker for early detection and therapeutic targets for progressive pulmonary fibrosis. METHODS: Measures of ILA and gene expression data were available in 213 participants in the Detection of Early Lung Cancer Among Military Personnel (DECAMP1 and DECAMP2) cohorts. ILA was defined using Fleischner Society guidelines and determined by sequential reading of computed tomography (CT) scans. Primary analysis focused on comparing gene expression in ILA with usual interstitial pneumonia (UIP) pattern with those with no ILA. RESULTS: ILA was present in 51 (24%) participants, of which 16 (7%) were subtyped as ILA with a UIP pattern. One gene, pro platelet basic protein (PPBP) and seventeen pathways (e.g. TNF-α signalling) were significantly differentially expressed between those with a probable or definite UIP pattern of ILA compared to those without ILA. 16 of these 17 pathways, but no individual gene, met significance when comparing those with ILA to those without ILA. CONCLUSION: Our study demonstrates that abnormal inflammatory processes are apparent in the bronchial airway gene expression profiles of smokers with and without lung cancer with ILA. Future studies with larger and more diverse populations will be needed to confirm these findings.

Utility and Cost-Effectiveness of a Nonendoscopic Approach to Barrett's Esophagus Surveillance After Endoscopic Therapy.

BACKGROUND & AIMS: A non-endoscopic approach to Barrett's esophagus (BE) surveillance after radiofrequency ablation (RFA) would offer a less invasive method for monitoring. We assessed the test characteristics and cost-effectiveness of the Cytosponge (Medtronic, Minneapolis, MN) in post-RFA patients. METHODS: We performed a multicenter study of dysplastic BE patients after at least one round of RFA. A positive Cytosponge before endoscopy was defined as intestinal metaplasia (IM) on cytological assessment and/or TFF3 immunohistochemistry. Sensitivity, specificity, and receiver operator characteristic (ROC) curves were calculated. Multivariable regression was used to estimate the odds of a positive Cytosponge in BE. A microsimulation cost-effectiveness model was performed to assess outcomes of various surveillance strategies: endoscopy-only, Cytosponge-only, and alternating endoscopy/Cytosponge. RESULTS: Of 234 patients, Cytosponge adequately sampled the distal esophagus in 175 (75%). Of the 142 with both endoscopic and histologic data, 19 (13%) had residual/recurrent BE. For detecting any residual Barrett's, Cytosponge had a sensitivity of 74%, specificity of 85%, accuracy of 84%, and ROC curve showed an area under the curve of 0.74. The adjusted odds of a positive Cytosponge in BE were 17.1 (95% CI, 5.2-55.9). Cytosponge-only surveillance dominated all the surveillance strategies, being both less costly and more effective. Cytosponge-only surveillance required <1/4th the endoscopies, resulting in only 0.69 additional EAC cases/1000 patients, and no increase in EAC deaths when compared to currently-practiced endoscopy-only surveillance. CONCLUSIONS: A positive Cytosponge test was strongly associated with residual BE after ablation. While the assay needs further refinement in this context, it could serve as a cost-effective surveillance examination.

The Optimal Age to Stop Endoscopic Surveillance of Patients With Barrett's Esophagus Based on Sex and Comorbidity: A Comparative Cost-Effectiveness Analysis.

BACKGROUND AND AIMS: Current guidelines recommend surveillance for patients with nondysplastic Barrett's esophagus (NDBE) but do not include a recommended age for discontinuing surveillance. This study aimed to determine the optimal age for last surveillance of NDBE patients stratified by sex and level of comorbidity. METHODS: We used 3 independently developed models to simulate patients diagnosed with NDBE, varying in age, sex, and comorbidity level (no, mild, moderate, and severe). All patients had received regular surveillance until their current age. We calculated incremental costs and quality-adjusted life-years (QALYs) gained from 1 additional endoscopic surveillance at the current age versus not performing surveillance at that age. We determined the optimal age to end surveillance as the age at which incremental cost-effectiveness ratio of 1 more surveillance was just less than the willingness-to-pay threshold of $100,000/QALY. RESULTS: The benefit of having 1 more surveillance endoscopy strongly depended on age, sex, and comorbidity. For men with NDBE and severe comorbidity, 1 additional surveillance at age 80 years provided 4 more QALYs per 1000 patients with BE at an additional cost of $1.2 million, whereas for women with severe comorbidity the benefit at that age was 7 QALYs at a cost of $1.3 million. For men with no, mild, moderate, and severe comorbidity, the optimal ages of last surveillance were 81, 80, 77, and 73 years, respectively. For women, these ages were younger: 75, 73, 73, and 69 years, respectively. CONCLUSIONS: Our comparative modeling analysis illustrates the importance of considering comorbidity status and sex when deciding on the age to discontinue surveillance in patients with NDBE.

Optimizing Management of Patients With Barrett's Esophagus and Low-Grade or No Dysplasia Based on Comparative Modeling.

BACKGROUND & AIMS: Endoscopic treatment is recommended for patients with Barrett's esophagus (BE) with high-grade dysplasia, yet clinical management recommendations are inconsistent for patients with BE without dysplasia (NDBE) or with low-grade dysplasia (LGD). We used a comparative modeling analysis to identify optimal management strategies for these patients. METHODS: We used 3 independent population-based models to simulate cohorts of 60-year-old individuals with BE in the United States. We followed up each cohort until death without surveillance and treatment (natural disease progression), compared with 78 different strategies of management for patients with NDBE or LGD. We determined the optimal strategy using cost-effectiveness analyses, at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). RESULTS: In the 3 models, the average cumulative incidence of esophageal adenocarcinoma was 111 cases, with costs totaling $5.7 million per 1000 men with BE. Surveillance and treatment of men with BE prevented 23% to 75% of cases of esophageal adenocarcinoma, but increased costs to $6.2 to $17.3 million per 1000 men with BE. The optimal strategy was surveillance every 3 years for men with NDBE and treatment of LGD after confirmation by repeat endoscopy (incremental cost-effectiveness ratio, $53,044/QALY). The average results for women were consistent with the results for men for LGD management, but the optimal surveillance interval for women with NDBE was 5 years (incremental cost-effectiveness ratio, $36,045/QALY). CONCLUSIONS: Based on analyses from 3 population-based models, the optimal management strategy for patient with BE and LGD is endoscopic eradication, but only after LGD is confirmed by a repeat endoscopy. The optimal strategy for patients with NDBE is endoscopic surveillance, using a 3-year interval for men and a 5-year interval for women.

Model to Determine the Optimal Dietary Elimination Strategy for Treatment of Eosinophilic Esophagitis.

BACKGROUND & AIMS: Elimination diets are effective treatments for eosinophilic esophagitis (EoE), but foods that activate esophagitis are identified empirically, via a process that involves multiple esophagogastroduodenoscopies (EGDs). No optimized approach has been developed to identify foods that activate EoE. We aimed to compare clinical strategies to provide data to guide treatment. METHODS: We developed a computer-based simulation model to determine promising empiric elimination strategies based on reported prevalence values for foods that activate EoE. We conducted a review, searching PubMed through October 1, 2017, for prospective and retrospective studies of EoE and diet. Each patient in our simulated cohort was assigned a profile comprising as many as 12 foods known to induce EoE, including dairy, wheat, eggs, soy, nuts, seafood, beef, corn, chicken, potato, pork, and/or rice. To balance the strategy success rate with the number of EGDs required for food identification, we applied an efficiency frontier approach. Strategies on the frontier were the most efficient, requiring fewer EGDs for higher or equivalent success rates relative to their comparable, neighboring strategies. RESULTS: In all simulations, we found the 1,4,8-food and 1,3-food strategies to be the most efficient in identifying foods that induce EoE, resulting in the highest rate of the correct identification of food triggers balanced by the number of EGDs required to complete the food elimination strategy. Both strategies begin with elimination of dairy; if EoE remission is not achieved, the 1,3 diet proceeds to eliminate wheat and eggs in addition to dairy, and the 1,4,8 strategy removes wheat, eggs, dairy, and soy. In the case of persistent EoE after the second round of food elimination, the 1,3-food strategy terminates, whereas the 1,4,8-food diet eliminates corn, chicken, beef, and pork. The 1,4,8-food diet resulted in correct identification of foods that activated esophagitis in 76.68% of patients, with a mean of 4.13 EGDs and a median of 6 EGDs. The 1,3-food strategy identified foods that activated esophagitis in 42.76% of patients, with a mean of 3.36 EGDs and a median of 2 EGDs required. CONCLUSIONS: In this modeling analysis, we found the 1,4,8-food and 1,3-food elimination strategies to be the most efficient in detection of foods that induce EoE in patients. However, the ideal elimination strategy will vary based on clinical priorities. Additional research on specific foods that induce EoE are needed to confirm the predictions of this model.

The race for the prize: T-cell trafficking strategies for optimal surveillance.

The initiation of T-cell responses requires rare precursors to locate a draining lymph node (dLN) and encounter dendritic cells (DCs) presenting peptide-major histocompatibility complexes (pMHCs). To locate this needle in the haystack rapidly, T cells face an optimization problem-what is the most efficient trafficking strategy for surveillance and recirculation through blood? Two extremes are scanning low numbers of DCs per node with frequent recirculation, or meticulous surveillance with infrequent recirculation. Naive T cells also require stimulation by self-pMHCs. To enable efficient location of both foreign and self, has evolution settled on an optimum time for T cells to spend surveying each lymph node? Using a data-driven mathematical model, we show the most efficient strategy for detecting antigen in a dLN depends on its abundance. Detection of low-density antigen is optimized with systemically slow transit. In contrast, at high densities or if dLN egress is restricted, rapid transit through other nodes is optimal. We argue that blood-lymph recirculation dynamics facilitate a trade-off, and are consistent with dominant roles for the very early detection of rare foreign antigens in a dLN, and the efficient accumulation of signals from systemically distributed self-antigens.

Postchallenge responses of nitrotyrosine and TNF-alpha during 75-g oral glucose tolerance test are associated with the presence of coronary artery diseases in patients with prediabetes.

BACKGROUND: Meta-analysis has demonstrated an exponential relationship between 2-hr postchallenge hyperglycemia and coronary artery disease (CAD). Pulsatile hyperglycemia can acutely increase proinflammatory cytokines by oxidative stress. We hypothesized that postchallenge proinflammatory and nitrosative responses after 75 g oral glucose tolerance tests (75 g-OGTT) might be associated with CAD in patients without previously recognized type 2 diabetes mellitus (T2DM). METHODS: Serial changes of plasma glucose (PG), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and nitrotyrosine levels were analyzed during 75 g-OGTT in 120 patients (81 male; age 62 ± 11 years) before coronary angiography. Patients were classified as normal (NGT; 42%), impaired (IGT; 34%) and diabetic (T2DM; 24%) glucose tolerance by 75 g-OGTT. RESULTS: Postchallenge hyperglycemia elicited TNF-α, IL-6 and nitrotyrosine levels time-dependently, and 2-hr median levels of TNF-α (7.1 versus 6.4 pg/ml; P < 0.05) and nitrotyrosine (1.01 versus 0.83 µmol/l; P < 0.05), but not IL-6 or PG, were significantly higher in patients with CAD in either IGT or T2DM groups. After adjusting risk factors and glucose tolerance status, 2-hr nitrotyrosine in highest quartiles (OR: 3.1, P < 0.05) remained an independent predictor of CAD by logistic regression analysis. CONCLUSIONS: These results highlight postchallenge proinflammatory and nitrosative responses by 75 g-OGTT, rather than hyperglycemia per se, are associated with CAD in patients without previous recognized diabetes.

Incident Cancer Risk and Signatures Among Older MUTYH Carriers: Analysis of Population-Based and Genomic Cohorts.

MUTYH carriers have an increased colorectal cancer risk in case-control studies, with loss of heterozygosity (LOH) as the presumed mechanism. We evaluated cancer risk among carriers in a prospective, population-based cohort of older adults. In addition, we assessed if cancers from carriers demonstrated mutational signatures (G:C>T:A transversions) associated with early LOH. We calculated incident risk of cancer and colorectal cancer among 13,131 sequenced study participants of the ASPirin in Reducing Events in the Elderly cohort, stratified by sex and adjusting for age, smoking, alcohol use, BMI, polyp history, history of cancer, and aspirin use. MUTYH carriers were identified among 13,033 participants in The Cancer Genome Atlas and International Cancer Genome Consortium, and somatic signatures of cancers were analyzed. Male MUTYH carriers demonstrated an increased risk for overall cancer incidence [multivariable HR, 1.66; 95% confidence interval (CI), 1.03-2.68; P = 0.038] driven by increased colorectal cancer incidence (multivariable HR, 3.55; 95% CI, 1.42-8.78; P = 0.007), as opposed to extracolonic cancer incidence (multivariable HR, 1.40; 95% CI, 0.81-2.44; P = 0.229). Female carriers did not demonstrate increased risk of cancer, colorectal cancer, or extracolonic cancers. Analysis of mutation signatures from cancers of MUTYH carriers revealed no significant contribution toward early mutagenesis from widespread G:C>T:A transversions among gastrointestinal epithelial cancers. Among cancers from carriers, somatic transversions associated with base-excision repair deficiency are uncommon, suggestive of diverse mechanisms of carcinogenesis in carriers compared with those who inherit biallelic MUTYH mutations. PREVENTION RELEVANCE: Despite absence of loss of heterozygosity in colorectal cancers, elderly male MUTYH carriers appeared to be at increased of colorectal cancer.

Minimal Associations between Short-Term Dietary Intake and Salivary Microbiome Composition.

BACKGROUND: Increasing evidence points to the esophageal microbiome as an important co-factor in esophageal neoplasia. Esophageal microbiome composition is strongly influenced by the oral microbiome. Salivary microbiome assessment has emerged as a potential non-invasive tool to identify patients at risk for esophageal cancer, but key host and environmental factors that may affect the salivary microbiome have not been well-defined. This study aimed to evaluate the impact of short-term dietary intake on salivary microbiome composition. METHODS: Saliva samples were collected from 69 subjects prior to upper endoscopy who completed the Automated Self-Administered 24-Hour (ASA24) Dietary Assessment. Salivary microbiome composition was determined using 16S rRNA amplicon sequencing. RESULTS: There was no significant correlation between alpha diversity and primary measures of short-term dietary intake (total daily calories, fat, fiber, fruit/vegetables, red meat intake, and fasting time). There was no evidence of clustering on beta diversity analyses. Very few taxonomic alterations were found for short-term dietary intake; an increased relative abundance of Neisseria oralis and Lautropia sp. was associated with high fruit and vegetable intake, and an increased relative abundance of a taxon in the family Gemellaceae was associated with increased red meat intake. CONCLUSIONS: Short-term dietary intake was associated with only minimal salivary microbiome alterations and does not appear to have a major impact on the potential use of the salivary microbiome as a biomarker for esophageal neoplasia.

Homologous Recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial Tumors.

INTRODUCTION: Somatic mutations in BRCA1/2 and other homologous recombination repair (HRR) genes have been associated with sensitivity to PARP inhibitors and/or platinum agents in several cancers, whereas hypermutant tumors caused by alterations in POLE or mismatch repair genes have demonstrated robust responses to immunotherapy. We investigated the relationship between somatic truncations in HRR genes and hypermutation in colorectal cancer (CRC) and endometrial cancer (EC). METHODS: We analyzed the mutational spectra associated with somatic BRCA1/2 truncations in multiple genomic cohorts (N = 2,335). From these results, we devised a classifier incorporating HRR genes to predict hypermutator status among microsatellite stable (MSS) tumors. Using additional genomic cohorts (N = 1,439) and functional in vivo assays, we tested the classifier to disambiguate POLE variants of unknown significance and identify MSS hypermutators without somatic POLE exonuclease domain mutations. RESULTS: Hypermutator phenotypes were prevalent among CRCs with somatic BRCA1/2 truncations (50/62, 80.6%) and ECs with such mutations (44/47, 93.6%). The classifier predicted MSS hypermutators with a cumulative true-positive rate of 100% in CRC and 98.0% in EC and a false-positive rate of 0.07% and 0.63%. Validated by signature analyses of tumor exomes and in vivo assays, the classifier accurately reassigned multiple POLE variants of unknown significance as pathogenic and identified MSS hypermutant samples without POLE exonuclease domain mutations. DISCUSSION: Somatic truncations in HRR can accurately fingerprint MSS hypermutators with or without known pathogenic exonuclease domain mutations in POLE and may serve as a low-cost biomarker for immunotherapy decisions in MSS CRC and EC.

Comparing Surgical Experience and Skill Using a High-Fidelity, Total Laparoscopic Hysterectomy Model.

OBJECTIVE: To evaluate differences in standardized scores and surgical confidence in the completion of a standardized total laparoscopic hysterectomy and bilateral salpingo-oophorectomy (TLH-BSO) among obstetrician-gynecologists (ob-gyns) with different levels of training, and to assess a TLH-BSO model for validity. METHODS: We conducted a prospective cohort study of 68 participants within four categories of ob-gyns: 1) graduating or recently graduated residents (n=18), 2) minimally invasive gynecologic surgery graduating or recently graduated fellows (n=16), 3) specialists in general obstetrics and gynecology (n=15), and 4) fellowship-trained minimally invasive gynecologic surgery subspecialists (n=19) who completed a TLH-BSO simulation. Participants completed presimulation questionnaires assessing laparoscopic confidence. Participants performed a video-recorded TLH-BSO and contained specimen removal on a standardized 250-g biological model in a simulated operating room and completed a postsimulation questionnaire. RESULTS: Randomized videos were scored by blinded experts using the validated OSATS (Objective Structured Assessment of Technical Skills). The surgery was divided into five standardized segments: 1) adnexa, 2) dissection and pedicles, 3) colpotomy, 4) cuff closure, and 5) tissue extraction. Minimally invasive gynecologic surgery subspecialists averaging 8.9 years in practice scored highest in all categories (overall median score 91%, P<.001), followed by fellows (64%, P<.001), specialists in obstetrics and gynecology averaging 19.7 years in practice (63%, P<.001), and residents (56%, P<.001). Residents, fellows and specialists in obstetrics and gynecology were comparable overall. Fellows scored higher on cuff closure (63% vs 50%, P<.03) and tissue extraction (77% vs 60%, P<.009) compared with specialists in obstetrics and gynecology. Minimally invasive gynecologic surgery subspecialists were fastest overall and on each individual component. Residents were slowest in almost all categories. CONCLUSION: When performing a TLH-BSO of a standardized 250-g uterus on a simulation model, fellowship-trained minimally invasive gynecologic surgery subspecialists achieved higher OSATS in all areas and completed all components faster. Similar performances were noted between residents, fellows, and specialists in obstetrics and gynecology in practice an average of 19.7 years. FUNDING SOURCE: Support from Applied Medical, Medtronic, CooperSurgical, and Karl Storz in the form of in-kind equipment was obtained through unrestricted educational grants.

The cost-effectiveness of pharmacotherapy and lifestyle intervention in the treatment of obesity.

BACKGROUND: The Food and Drug Administration has approved several pharmacotherapies for the treatment of obesity. This study assesses the cost-effectiveness of six pharmacotherapies and lifestyle intervention for people with mild obesity (body mass indices [BMIs] 30 to 35). METHODS: A microsimulation model was constructed to compare seven weight loss strategies plus no treatment: intensive lifestyle intervention, orlistat, phentermine, phentermine/topiramate, lorcaserin, liraglutide, and semaglutide. Weight loss, quality-of-life scores, and costs were estimated using clinical trials and other published literature. Endpoints included costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay (WTP) threshold of $100 000/QALY. Results were analysed at 1-, 3-, and 5-year time horizons. RESULTS: At each of the three follow-up periods, phentermine was the cost-effective strategy, with ICERs of $46 258/QALY, $20 157/QALY, and $17 880/QALY after 1, 3, and 5 years, respectively. Semaglutide was the most effective strategy in the 3- and 5-year time horizons, with total QALYs of 2.224 and 3.711, respectively. However, the ICERs were prohibitively high at $1 437 340/QALY after 3 years and $576 931/QALY after 5 years. Deterministic and probabilistic sensitivity analyses indicated these results were robust. CONCLUSIONS: Phentermine is the cost-effective pharmacologic weight-loss strategy. Although semaglutide is the most effective, it is not cost-effective because of its high price.

Thirty-Year Risk of Cardiovascular Disease Events in Adolescents with Severe Obesity.

OBJECTIVE: Quantifying risk for cardiovascular disease (CVD) events among adolescents is difficult owing to the long latent period between risk factor development and disease outcomes. This study examined the 30-year CVD event risk among adolescents with severe obesity treated with and without metabolic and bariatric surgery (MBS), compared with youths with moderate obesity, overweight, or normal weight. METHODS: Cross-sectional and longitudinal comparisons of five frequency-matched (age and diabetes status) groups were performed: normal weight (n = 247), overweight (n = 54), obesity (n = 131), severe obesity without MBS (n = 302), and severe obesity undergoing MBS (n = 215). A 30-year CVD event score developed by the Framingham Heart Study was the primary outcome. Data are mean (SD) with differences between time points for MBS examined using linear mixed models. RESULTS: Preoperatively, the likelihood of CVD events was higher among adolescents undergoing MBS (7.9% [6.7%]) compared with adolescents with severe obesity not referred for MBS (5.5% [4.0%]), obesity (3.9% [3.0%]), overweight (3.1% [2.4%]), and normal weight (1.8% [0.8%]; all P < 0.001). At 1 year after MBS, event risk was significantly reduced (7.9% [6.7%] to 4.0% [3.4%], P < 0.0001) and was sustained for up to 5 years after MBS (P < 0.0001, all years vs. baseline). CONCLUSIONS: Adolescents with severe obesity are at elevated risk for future CVD events. Following MBS, the predicted risk of CVD events was substantially and sustainably reduced.

Effects of verapamil and procainamide on acute atrial electrical remodeling induced by short-term rapid atrial pacing in humans.

Atrial electrical remodeling (ER) after spontaneous or pacing-induced atrial fibrillation has been previously described in humans. We investigated atrial ER induced by a 5-minute period of rapid atrial pacing and the pharmacologic effects of verapamil and procainamide on this atrial ER phenomenon. The atrial effective refractory periods (ERPs) at drive cycle lengths of 400 (ERP 400 ) and 600 (ERP 600 ) ms, at five representative atrial sites (high right atrium [HRA]; proximal, middle and distal coronary sinus; interatrial septum), were determined in 20 patients at baseline and immediately after cessation of a 5-minute period of rapid pacing from the HRA at a rate of 150 bpm. The degrees of atrial ERP 400 and ERP 600 shortening after pacing were calculated as acute atrial ER. The same protocol was repeated in another 15 patients after intravenous administration of verapamil (0.15 mg/kg) and in another 15 patients after intravenous administration of procainamide (15 mg/kg). The results demonstrated that, in the control state acute atrial ER can be significantly demonstrated at each atrial representative site ( p < 0.001). The mean ERP 400 and ERP 600 shortenings were 9 +/- 4% and 8 +/- 4%, respectively. After procainamide infusion, but not after verapamil, baseline ERP 400 and ERP 600 values were significantly prolonged at the five representative atrial sites ( p < 0.01). Acute atrial ER could still be demonstrated at each atrial site after procainamide or verapamil infusion ( p < 0.001). In conclusion, acute atrial ER can be demonstrated after only a 5-minute period of rapid atrial pacing in humans. Intravenous verapamil or procainamide does not abolish this ER process.

Validation of a new index for estimating arterial stiffness: measurement of the QPV interval by Doppler ultrasound.

BACKGROUND: Pulse wave velocity (PWV), a relevant indicator of arterial stiffness, can be measured noninvasively with a variety of automatic devices, but most are complexly equipped. We developed a novel index for estimating arterial stiffness as "QPV interval," which was determined by means of surface electrocardiogram and Doppler ultrasound of the brachial artery simultaneously. HYPOTHESIS: This study aimed to validate the QPV interval as an exact and convenient index for estimation of arterial stiffness. METHODS: Forty-seven patients with untreated essential hypertension and 19 normotensive subjects were enrolled. Brachial-ankle PWV (baPWV) was measured using an automatic volume-plethysmographic apparatus, and Doppler ultrasound was implemented sequentially to measure the QPV interval in each subject. Clinical biochemistry and echocardiography were performed on the same day. RESULTS: Mean baPWV was significantly higher in hypertensive patients than in normotensive subjects (p = 0.002), whereas mean QPV interval was significantly shorter in hypertensive patients than in the normotensive group (p = 0.019). A simple regression analysis demonstrated an inverse correlation between the QPV interval and baPWV (r = -0.671, p < 0.001) in all enrolled subjects. In a stepwise regression model that adjusted for age, systolic blood pressure, and other determinants of baPWV, the negative association remained between the QPV interval and baPWV (p < 0.001). CONCLUSION: The QPV interval correlates inversely with baPWV, independent of age and other determinants of baPWV; hence, the QPV interval can serve as a simple and convenient index for assessing arterial stiffness in clinical practice.

Plasma renin level and aldosterone to renin ratio are associated with presence of carotid plaques in patients with stable coronary artery disease.

INTRODUCTION: We aimed to determine the association between plasma aldosterone and renin levels as well as their ratios with carotid plaques in patients with coronary artery disease (CAD). MATERIALS AND METHODS: Carotid intima-media thickness (IMT) and plaque score were evaluated in 111 patients with stable CAD. Plasma renin and aldosterone levels were measured in all patients. Aldosterone to renin ratio (ARR) was calculated. All patients were categorized into: Group 1 (normal coronary angiography), Group 2 (patients had CAD but without carotid plaque) and Group 3 (patients had CAD and at least one carotid plaque). RESULTS: Renin levels are significantly higher in Group 3 than in Group 1 and 2. ARR was significantly lower in Group 3 than in Group 1 and 2. Renin levels were found to be positively correlated with carotid IMT and plaque score but ARR was inversely associated with carotid IMT and plaque score. Renin levels and ARR are independently associated with presence of carotid plaque in CAD patients (OR 1.124, CI 1.021-1.237, p = 0.017 and OR 0.906, CI 0.839-0.978, p = 0.011, adjusted for age, respectively). CONCLUSIONS: Plasma renin and ARR but not aldosterone are independently associated with presence of carotid plaques in CAD patients. Hence, the linkage between aldosterone and renin plays a more important role than aldosterone alone in carotid atherosclerosis.

Clinical proteomics identifies urinary CD14 as a potential biomarker for diagnosis of stable coronary artery disease.

Inflammation plays a key role in coronary artery disease (CAD) and other manifestations of atherosclerosis. Recently, urinary proteins were found to be useful markers for reflecting inflammation status of different organs. To identify potential biomarker for diagnosis of CAD, we performed one-dimensional SDS-gel electrophoresis followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Among the proteins differentially expressed in urine samples, monocyte antigen CD14 was found to be consistently expressed in higher amounts in the CAD patients as compared to normal controls. Using enzyme-linked immunosorbent assays to analyze the concentrations of CD14 in urine and serum, we confirmed that urinary CD14 levels were significantly higher in patients (n = 73) with multi-vessel and single vessel CAD than in normal control (n = 35) (P < 0.001). Logistic regression analysis further showed that urinary CD14 concentration level is associated with severity or number of diseased vessels and SYNTAX score after adjustment for potential confounders. Concomitantly, the proportion of CD14+ monocytes was significantly increased in CAD patients (59.7 ± 3.6%) as compared with healthy controls (14.9 ± 2.1%) (P < 0.001), implicating that a high level of urinary CD14 may be potentially involved in mechanism(s) leading to CAD pathogenesis. By performing shotgun proteomics, we further revealed that CD14-associated inflammatory response networks may play an essential role in CAD. In conclusion, the current study has demonstrated that release of CD14 in urine coupled with more CD14+ monocytes in CAD patients is significantly correlated with severity of CAD, pointing to the potential application of urinary CD14 as a novel noninvasive biomarker for large-scale diagnostic screening of susceptible CAD patients.