An expert judgment model to predict early stages of the COVID-19 pandemic in the United States.

From February to May 2020, experts in the modeling of infectious disease provided quantitative predictions and estimates of trends in the emerging COVID-19 pandemic in a series of 13 surveys. Data on existing transmission patterns were sparse when the pandemic began, but experts synthesized information available to them to provide quantitative, judgment-based assessments of the current and future state of the pandemic. We aggregated expert predictions into a single "linear pool" by taking an equally weighted average of their probabilistic statements. At a time when few computational models made public estimates or predictions about the pandemic, expert judgment provided (a) falsifiable predictions of short- and long-term pandemic outcomes related to reported COVID-19 cases, hospitalizations, and deaths, (b) estimates of latent viral transmission, and (c) counterfactual assessments of pandemic trajectories under different scenarios. The linear pool approach of aggregating expert predictions provided more consistently accurate predictions than any individual expert, although the predictive accuracy of a linear pool rarely provided the most accurate prediction. This work highlights the importance that an expert linear pool could play in flexibly assessing a wide array of risks early in future emerging outbreaks, especially in settings where available data cannot yet support data-driven computational modeling.

Comparison of combination methods to create calibrated ensemble forecasts for seasonal influenza in the U.S.

The characteristics of influenza seasons vary substantially from year to year, posing challenges for public health preparation and response. Influenza forecasting is used to inform seasonal outbreak response, which can in turn potentially reduce the impact of an epidemic. The United States Centers for Disease Control and Prevention, in collaboration with external researchers, has run an annual prospective influenza forecasting exercise, known as the FluSight challenge. Uniting theoretical results from the forecasting literature with domain-specific forecasts from influenza outbreaks, we applied parametric forecast combination methods that simultaneously optimize model weights and calibrate the ensemble via a beta transformation and made adjustments to the methods to reduce their complexity. We used the beta-transformed linear pool, the finite beta mixture model, and their equal weight adaptations to produce ensemble forecasts retrospectively for the 2016/2017, 2017/2018, and 2018/2019 influenza seasons in the U.S. We compared their performance to methods that were used in the FluSight challenge to produce the FluSight Network ensemble, namely the equally weighted linear pool and the linear pool. Ensemble forecasts produced from methods with a beta transformation were shown to outperform those from the equally weighted linear pool and the linear pool for all week-ahead targets across in the test seasons based on average log scores. We observed improvements in overall accuracy despite the beta-transformed linear pool or beta mixture methods' modest under-prediction across all targets and seasons. Combination techniques that explicitly adjust for known calibration issues in linear pooling should be considered to improve probabilistic scores in outbreak settings.

Chimeric forecasting: combining probabilistic predictions from computational models and human judgment.

Forecasts of the trajectory of an infectious agent can help guide public health decision making. A traditional approach to forecasting fits a computational model to structured data and generates a predictive distribution. However, human judgment has access to the same data as computational models plus experience, intuition, and subjective data. We propose a chimeric ensemble-a combination of computational and human judgment forecasts-as a novel approach to predicting the trajectory of an infectious agent. Each month from January, 2021 to June, 2021 we asked two generalist crowds, using the same criteria as the COVID-19 Forecast Hub, to submit a predictive distribution over incident cases and deaths at the US national level either two or three weeks into the future and combined these human judgment forecasts with forecasts from computational models submitted to the COVID-19 Forecasthub into a chimeric ensemble. We find a chimeric ensemble compared to an ensemble including only computational models improves predictions of incident cases and shows similar performance for predictions of incident deaths. A chimeric ensemble is a flexible, supportive public health tool and shows promising results for predictions of the spread of an infectious agent.

Relationship between insulin resistance, coronary plaque, and clinical outcomes in patients with acute coronary syndromes: an analysis from the PROSPECT study.

BACKGROUND: We investigated the association of insulin resistance (IR) with coronary plaque morphology and the risk of cardiovascular events in patients enrolled in the Providing Regional Observations to Study Predictors of Events in Coronary Tree (PROSPECT) study. METHODS: Patients with acute coronary syndromes (ACS) were divided based on DM status. Non-DM patients were further stratified according to homeostasis-model-assessment IR (HOMA-IR) index as insulin sensitive (IS; HOMA-IR ≤ 2), likely-IR (LIR; 2 < HOMA-IR < 5), or diabetic-IR (DIR; HOMA-IR ≥ 5). Coronary plaque characteristics were investigated by intravascular ultrasound. The primary endpoint was major adverse cardiac events (MACE); a composite of cardiac death, cardiac arrest, myocardial infarction, and rehospitalization for unstable/progressive angina. RESULTS: Among non-diabetic patients, 109 patients (21.5%) were categorized as LIR, and 65 patients (12.8%) as DIR. Patients with DIR or DM had significantly higher rates of echolucent plaque compared with LIR and IS. In addition, DIR and DM were independently associated with increased risk of MACE compared with IS (adjusted hazard ratio [aHR] 2.29, 95% confidence interval [CI] 1.22-4.29, p = 0.01 and aHR 2.12, 95% CI 1.19-3.75, p = 0.009, respectively). CONCLUSIONS: IR is common among patients with ACS. DM and advanced but not early stages of IR are independently associated with increased risk of adverse cardiovascular events. Trial Registration ClinicalTrials.gov Identifier: NCT00180466.

Impact of lesion preparation strategies on outcomes of left main PCI: The EXCEL trial.

OBJECTIVES: We examined outcomes according to lesion preparation strategy (LPS) in patients with left main coronary artery (LMCA) percutaneous coronary intervention (PCI) in the EXCEL trial. BACKGROUND: The optimal LPS for LMCA PCI is unclear. METHODS: We categorized LPS hierarchically (high to low) as: (a) rotational atherectomy (RA); (b) cutting or scoring balloon (CSB); (c) balloon angioplasty (BAL); and d) direct stenting (DIR). The primary endpoint was 3-year MACE; all-cause death, stroke, or myocardial infarction. RESULTS: Among 938 patients undergoing LMCA PCI, RA was performed in 6.0%, CSB 9.5%, BAL 71.3%, and DIR 13.2%. In patients treated with DIR, BAL, CSB, and RA, respectively, there was a progressive increase in SYNTAX score, LMCA complex bifurcation, trifurcation or calcification, number of stents, and total stent length. Any procedural complication occurred in 10.4% of cases overall, with the lowest rate in the DIR (7.4%) and highest in the RA group (16.1%) (ptrend  = .22). There were no significant differences in the 3-year rates of MACE (from RA to DIR: 17.9%, 20.2%, 14.5%, 14.7%; p = .50) or ischemia-driven revascularization (from RA to DIR: 16.8%, 10.8%, 12.3%, 14.2%; p = .65). The adjusted 3-year rates of MACE did not differ according to LPS. CONCLUSIONS: The comparable 3-year outcomes suggest that appropriate lesion preparation may be able to overcome the increased risks of complex LMCA lesion morphology.

Adaptively stacking ensembles for influenza forecasting.

Seasonal influenza infects between 10 and 50 million people in the United States every year. Accurate forecasts of influenza and influenza-like illness (ILI) have been named by the CDC as an important tool to fight the damaging effects of these epidemics. Multi-model ensembles make accurate forecasts of seasonal influenza, but current operational ensemble forecasts are static: they require an abundance of past ILI data and assign fixed weights to component models at the beginning of a season, but do not update weights as new data on component model performance is collected. We propose an adaptive ensemble that (i) does not initially need data to combine forecasts and (ii) finds optimal weights which are updated week-by-week throughout the influenza season. We take a regularized likelihood approach and investigate this regularizer's ability to impact adaptive ensemble performance. After finding an optimal regularization value, we compare our adaptive ensemble to an equal-weighted and static ensemble. Applied to forecasts of short-term ILI incidence at the regional and national level, our adaptive model outperforms an equal-weighted ensemble and has similar performance to the static ensemble using only a fraction of the data available to the static ensemble. Needing no data at the beginning of an epidemic, an adaptive ensemble can quickly train and forecast an outbreak, providing a practical tool to public health officials looking for a forecast to conform to unique features of a specific season.

The win ratio approach for composite endpoints: practical guidance based on previous experience.

The win ratio was introduced in 2012 as a new method for examining composite endpoints and has since been widely adopted in cardiovascular (CV) trials. Improving upon conventional methods for analysing composite endpoints, the win ratio accounts for relative priorities of the components and allows the components to be different types of outcomes. For example, the win ratio can combine the time to death with the number of occurrences of a non-fatal outcome such as CV-related hospitalizations (CVHs) in a single hierarchical composite endpoint. The win ratio can provide greater statistical power to detect and quantify a treatment difference by using all available information contained in the component outcomes. The win ratio can also incorporate quantitative outcomes such as exercise tests or quality-of-life scores. There is a need for more practical guidance on how best to design trials using the win ratio approach. This manuscript provides an overview of the principles behind the win ratio and provides insights into how to implement the win ratio in CV trial design and reporting, including how to determine trial size.

Accuracy of Fractional Flow Reserve Derived From Coronary Angiography.

BACKGROUND: Measuring fractional flow reserve (FFR) with a pressure wire remains underutilized because of the invasiveness of guide wire placement or the need for a hyperemic stimulus. FFR derived from routine coronary angiography (FFRangio) eliminates both of these requirements and displays FFR values of the entire coronary tree. The FFRangio Accuracy versus Standard FFR (FAST-FFR) study is a prospective, multicenter, international trial with the primary goal of determining the accuracy of FFRangio. METHODS: Coronary angiography was performed in a routine fashion in patients with suspected coronary artery disease. FFR was measured in vessels with coronary lesions of varying severity using a coronary pressure wire and hyperemic stimulus. Based on angiograms of the respective arteries acquired in ≥2 different projections, on-site operators blinded to FFR then calculated FFRangio using proprietary software. Coprimary end points were the sensitivity and specificity of the dichotomously scored FFRangio for predicting pressure wire-derived FFR using a cutoff value of 0.80. The study was powered to meet prespecified performance goals for sensitivity and specificity. RESULTS: Ten centers in the United States, Europe, and Israel enrolled a total of 301 subjects and 319 vessels meeting inclusion/exclusion criteria which were included in the final analysis. The mean FFR was 0.81 and 43% of vessels had an FFR≤0.80. The per-vessel sensitivity and specificity were 94% (95% CI, 88% to 97%) and 91% (86% to 95%), respectively, both of which exceeded the prespecified performance goals. The diagnostic accuracy of FFRangio was 92% overall and remained high when only considering FFR values between 0.75 to 0.85 (87%). FFRangio values correlated well with FFR measurements ( r=0.80, P<0.001) and the Bland-Altman 95% confidence limits were between -0.14 and 0.12. The device success rate for FFRangio was 99%. CONCLUSIONS: FFRangio measured from the coronary angiogram alone has a high sensitivity, specificity, and accuracy compared with pressure wire-derived FFR. FFRangio has the promise to substantially increase physiological coronary lesion assessment in the catheterization laboratory, thereby potentially leading to improved patient outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique Identifier: NCT03226262.

Impact of large periprocedural myocardial infarction on mortality after percutaneous coronary intervention and coronary artery bypass grafting for left main disease: an analysis from the EXCEL trial.

AIMS: The prognostic implications of periprocedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) remain controversial. We examined the 3-year rates of mortality among patients with and without PMI undergoing left main coronary artery intervention randomized to PCI with everolimus-eluting stents vs. CABG in the large-scale, multicentre, prospective, randomized EXCEL trial. METHODS AND RESULTS: By protocol, PMI was defined using an identical threshold for PCI and CABG [creatinine kinase-MB (CK-MB) elevation >10× the upper reference limit (URL) within 72 h post-procedure, or >5× URL with new Q-waves, angiographic vessel occlusion, or loss of myocardium on imaging]. Cox proportional hazards modelling was performed controlling for age, sex, hypertension, diabetes mellitus, left ventricular ejection fraction, SYNTAX score, and chronic obstructive pulmonary disease (COPD). A total of 1858 patients were treated as assigned by randomization. Periprocedural MI occurred in 34/935 (3.6%) of patients in the PCI group and 56/923 (6.1%) of patients in the CABG group [odds ratio 0.61, 95% confidence interval (CI) 0.40-0.93; P = 0.02]. Periprocedural MI was associated with SYNTAX score, COPD, cross-clamp duration and total procedure duration, and not using antegrade cardioplegia. By multivariable analysis, PMI was associated with cardiovascular death and all-cause death at 3 years [adjusted hazard ratio (HR) 2.63, 95% CI 1.19-5.81; P = 0.02 and adjusted HR 2.28, 95% CI 1.22-4.29; P = 0.01, respectively]. The effect of PMI was consistent for PCI and CABG for cardiovascular death (Pinteraction = 0.56) and all-cause death (Pinteraction = 0.59). Peak post-procedure CK-MB ≥10× URL strongly predicted mortality, whereas lesser degrees of myonecrosis were not associated with prognosis. CONCLUSION: In the EXCEL trial, PMI was more common after CABG than PCI, and was strongly associated with increased 3-year mortality after controlling for potential confounders. Only extensive myonecrosis (CK-MB ≥10× URL) was prognostically important.

Outcomes of left main revascularization in patients with acute coronary syndromes and stable ischemic heart disease: Analysis from the EXCEL trial.

BACKGROUND: Prompt revascularization is often required in acute coronary syndromes (ACS), whereas stable ischemic heart disease (SIHD) may allow for more measured procedural planning. Whether the acuity of presentation preferentially affects outcomes after coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in patients with left main coronary artery disease (LMCAD) is unknown. We investigated whether the acuity of presentation discriminated patients who derived a differential benefit from PCI versus CABG in the randomized Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial. METHODS: We used multivariable Cox models to assess the interaction between the acuity of presentation, type of revascularization and outcomes in patients with low or intermediate SYNTAX scores enrolled in EXCEL. RESULTS: At baseline, 1151 patients (60.7%) presented with SIHD and 746 patients (39.3%) presented with an ACS. The acuity of presentation was not associated with the primary endpoint of all-cause death, MI, or stroke at 3 years (multivariable adjusted hazard ratio [HR] 0.94; 95% CI 0.70-1.26, P = .64). The primary endpoint rate was similar in patients assigned to PCI versus CABG whether they presented with SIHD (adjusted HR 1.04; 95% CI 0.73-1.48]) or with ACS (HR 0.82; 95% CI 0.54-1.26) (Pinteraction = .34). CONCLUSIONS: The acuity of presentation did not predict outcomes in patients with LMCAD undergoing revascularization, nor did it discriminate patients who derive greater event-free survival from PCI versus CABG.

Incidence and predictors of target lesion failure in patients undergoing contemporary DES implantation-Individual patient data pooled analysis from 6 randomized controlled trials.

BACKGROUND: Drug-eluting stents (DESs) have improved clinical outcomes of patients undergoing percutaneous coronary intervention (PCI). Nevertheless, adverse events related to previously treated lesion still occur. We sought to evaluate the incidence and predictors of target lesion failure (TLF) in patients undergoing contemporary DES implantation. METHODS: Patient-level data from 6 prospective, randomized trials were pooled, and DES treatment outcomes were analyzed at up to 5 years. Primary outcome was TLF (cardiac death, target lesion revascularization, or target vessel myocardial infarction). Cox proportional-hazards model was used to identify predictors of TLF. RESULTS: Overall, 10,072 patients were included in the analysis. TLF rate was 1.7%, 4.3%, and 11.9% at 30 days, 1 year, and 5 years, respectively. The only independent predictor of TLF at 30 days was stent length (hazard ratio [HR] 1.017, 95% CI 1.011-1.024, P < .0001). Moderate/severe calcification, stent length and post procedural diameter sthenosis were predictors between 30 days to 1 year but not at 1 to 5 years. Reference vessel diameter was the only lesion-related predictor at 5 years (P = .003). Clinical predictors of TLF between 30 days and 1 year were diabetes and hypertension (P < .01 for both), and between 1 and 5 years, diabetes (HR 1.40, 95% CI 1.13-1.73, P = .002), prior coronary artery bypass grafting (HR 2.52, 95% CI 1.92-3.30, P < .0001), and prior PCI (HR 1.29, 95% CI 1.02-1.64, P = .04) predicted TLF. CONCLUSIONS: Predictors of TLF vary in the early, late, and very late postprocedural periods. Reference vessel diameter was the only lesion-related predictor of long-term TLF; clinical predictors were diabetes, prior coronary artery bypass grafting, and prior PCI.

Adverse events in patients with high platelet reactivity following successful chronic total occlusion PCI: The Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents (ADAPT-DES) study.

BACKGROUND: Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) typically requires a greater number of stents and longer stent length than non-CTO PCI, placing these patients at greater risk for adverse ischemic events. We sought to determine whether the association between high platelet reactivity (HPR) and the risk of ischemic events is stronger after CTO than non-CTO PCI. METHODS: Patients undergoing successful PCI in the multicenter ADAPT-DES study were stratified according to whether they underwent PCI of a CTO. HPR was defined as VerifyNow platelet reaction units >208. The study primary endpoint was the 2-year risk target vessel failure ([TVF] defined as cardiac death, myocardial infarction, or target lesion revascularization). RESULTS: CTO PCI was performed in 400 of 8448 patients. HPR was present in 34.5% of CTO PCI patients and 43.1% of non-CTO PCI patients (P = .0007). Patients undergoing CTO PCI with versus without HPR had significantly higher 2-year rates of TVF (15.0% versus 8.3%, P = .04) without significant differences in bleeding. HPR was an independent predictor of 2-year TVF (adjusted HR 1.16, 95% CI 1.02-1.34, P = .03) whereas CTO PCI was not (adjusted HR 0.89, 95% CI 0.65-1.22, P = .48). There was a significant interaction between CTO versus non-CTO PCI and PRU as a continuous variable for 2-year TVF (Pinteraction = 0.02). CONCLUSIONS: In ADAPT-DES, HPR was associated with an increased 2-year risk of TVF after PCI, an association that was at least as strong after CTO PCI compared with non-CTO PCI.

Predictors of mortality in patients with non-anterior ST-segment elevation myocardial infarction: Analysis from the HORIZONS-AMI trial.

OBJECTIVES: We sought to identify clinical, electrocardiographic (ECG), and angiographic characteristics that are predictive of 3-year mortality after primary percutaneous coronary intervention (PCI) in patients with non-anterior ST-elevation myocardial infarction (NA-STEMI) from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. BACKGROUND: Which patients with NA-STEMI undergoing PCI have a poor prognosis is uncertain. METHODS: NA-STEMI was defined as ST-segment elevation in lateral (V5, V6, I, aVL), inferior (II, III, aVF), or inferolateral (I, II, III, aVF, and V5-V6) ECG leads or posterior myocardial infarction with ST-segment depression of ≥1 mm in ≥2 contiguous anterior leads. Cox regression was used to identify independent predictors of 3-year mortality. Missing data were imputed using multiple imputation. RESULTS: In HORIZONS-AMI, 2,578/3,602 patients had no prior coronary artery bypass grafting, underwent single-vessel PCI, and had baseline ECG data assessed in an independent core laboratory. Among them, 1,495 (58.0%) had NA-STEMI. Patients with NA-STEMI had lower 3-year mortality risk than those with anterior STEMI (4.5% versus 7.1%, P = 0.004). The independent predictors of increased 3-year mortality in NA-STEMI were older age (median > 59.0 years), diabetes, reduced LVEF (≤50%), Killip class ≥2, post-procedure TIMI flow 0-2 versus 3, renal insufficiency, and ST-resolution <30% at 60 min post-PCI. Patients with 0, 1, 2, 3, and ≥4 of these risk factors had 3-year mortality rates of 1.8%, 2.3%, 3.1%, 6.1%, and 36.3%, respectively (P < 0.0001). CONCLUSIONS: Although NA-STEMI carries a better prognosis than anterior STEMI, high-risk patient cohorts with NA-STEMI may be identified who have substantial 3-year mortality.

Percutaneous coronary intervention of lesions with in-stent restenosis: A report from the ADAPT-DES study.

BACKGROUND: There is a paucity of data from large contemporary cohorts of patients with in-stent restenosis (ISR) treated with drug-eluting stents (DESs), and no studies have examined the impact of high platelet reactivity (HPR) on the occurrence of ischemic events after ISR percutaneous coronary intervention (PCI) with DESs. We sought to report outcomes after PCI of ISR lesions and its association with HPR. METHODS: Patients in the prospective, multicenter ADAPT-DES study were stratified according to whether they had ISR versus non-ISR PCI. Two-year outcomes were compared between the groups using Cox proportional hazards models. HPR was defined as on-clopidogrel P2Y12 platelet reaction units >208 as measured by the VerifyNow assay; target vessel failure (TVF) was defined as the composite of all-cause death, myocardial infarction, or ischemia-driven target vessel revascularization. RESULTS: Among the 8,582 patients included in the ADAPT-DES study, 840 (9.8%) patients underwent successful ISR PCI. ISR PCI was independently associated with a higher 2-year risk of TVF (adjusted hazard ratio [HR] 1.95; 95% CI 1.68-2.27; P<.001) and stent thrombosis (adjusted HR 1.95; 95% CI 1.08-3.51; P=.027) but not bleeding (adjusted HR 0.94; 95% CI 0.73-1.21; P=.64). There was no statistical interaction between HPR and ISR versus non-ISR PCI in regard to TVF (adjusted Pinteraction=.81). CONCLUSIONS: ISR PCI is associated with a considerably higher risk of 2-year adverse ischemic events, with HPR conferring similar risk in ISR and non-ISR PCI. More effective therapeutic strategies for managing ISR lesions are necessary.

Staging classification of aortic stenosis based on the extent of cardiac damage.

AIMS: In patients with aortic stenosis (AS), risk stratification for aortic valve replacement (AVR) relies mainly on valve-related factors, symptoms and co-morbidities. We sought to evaluate the prognostic impact of a newly-defined staging classification characterizing the extent of extravalvular (extra-aortic valve) cardiac damage among patients with severe AS undergoing AVR. METHODS AND RESULTS: Patients with severe AS from the PARTNER 2 trials were pooled and classified according to the presence or absence of cardiac damage as detected by echocardiography prior to AVR: no extravalvular cardiac damage (Stage 0), left ventricular damage (Stage 1), left atrial or mitral valve damage (Stage 2), pulmonary vasculature or tricuspid valve damage (Stage 3), or right ventricular damage (Stage 4). One-year outcomes were compared using Kaplan-Meier techniques and multivariable Cox proportional hazards models were used to identify 1-year predictors of mortality. In 1661 patients with sufficient echocardiographic data to allow staging, 47 (2.8%) patients were classified as Stage 0, 212 (12.8%) as Stage 1, 844 (50.8%) as Stage 2, 413 (24.9%) as Stage 3, and 145 (8.7%) as Stage 4. One-year mortality was 4.4% in Stage 0, 9.2% in Stage 1, 14.4% in Stage 2, 21.3% in Stage 3, and 24.5% in Stage 4 (Ptrend < 0.0001). The extent of cardiac damage was independently associated with increased mortality after AVR (HR 1.46 per each increment in stage, 95% confidence interval 1.27-1.67, P < 0.0001). CONCLUSION: This newly described staging classification objectively characterizes the extent of cardiac damage associated with AS and has important prognostic implications for clinical outcomes after AVR.

Outcomes in elderly and young patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with bivalirudin versus heparin: Pooled analysis from the EUROMAX and HORIZONS-AMI trials.

BACKGROUND: Since older age is a strong predictor of not only bleeding but also of ischemic events, understanding the risk:benefit profile of bivalirudin in the elderly undergoing primary percutaneous coronary intervention (pPCI) for ST-segment elevation (STEMI) is important. For this, we aim to compare elderly with young patients, who all underwent pPCI for STEMI and randomly received either bivalirudin or heparin. METHODS: We performed a patient-level pooled analysis (n=5800) of two large randomized trials. A total of 2149 (37.1%) elderly patients (>65 years of age) with STEMI were enrolled and randomly assigned to either bivalirudin or heparin with or without a GPI (control group) before pPCI. Clinical outcomes at 30 days were analyzed. RESULTS: In elderly patients, bivalirudin significantly reduced non-CABG major bleeding (7.1% vs 10.4%; P<.01), subacute ST (0.4% vs 1.5%; P<.01), and net adverse clinical events (NACE; composite of all-cause mortality, reinfarction, IDR, stroke or protocol-defined non-CABG major bleeding [13.7% vs 17.2%; P=.03]) with comparable rates of stroke, MI, acute ST, or all-cause death, when compared with heparin with or without GPI. CONCLUSIONS: In a large group of elderly patients enrolled in the EUROMAX and HORIZONS-AMI trials, bivalirudin was associated with lower 30-day rates of non-CABG major bleeding, subacute ST and NACE, with similar 30-day rates of acute ST and mortality.

HPV16 methyl-haplotypes determined by a novel next-generation sequencing method are associated with cervical precancer.

We have developed and evaluated a next-generation bisulfite sequencing (NGS) assay to distinguish HPV16 cervical precancer (CIN2-3; N=59) from HPV16-positive transient infections (N=40). Cervical DNA was isolated and treated with bisulfite and HPV16 methylation was quantified by (i) amplification with barcoded primers and massively parallel single molecule sequencing and (ii) site-specific pyrosequencing. Assays were evaluated for agreement using intraclass correlation coefficients (ICC). Odds ratios (OR) for high methylation vs. low methylation were calculated. Single site pyrosequencing and NGS data were correlated (ICC=0.61) and both indicated hypermethylation was associated with precancer (ORs of 2-37). Concordant NGS and pyrosequencing results yieled ORs that were stronger when compared with using either assay separately. Within the L1 region, the ORs for CIN2-3 were 14.3 and 22.4 using pyrosequencing and NGS assays, respectively; when both methods agreed the OR was 153. NGS assays provide methylation haplotypes, termed methyl-haplotypes from single molecule reads: cases had increased methyl-haplotypes with ≥1 methylated CpG site(s) per fragment compared with controls, particularly in L1 (p=3.0×10(-8)). The maximum discrimination of cases from controls for a L1 methyl-haplotype had an AUC of 0.89 corresponding to a sensitivity of 92.5% and a specificity of 73.1%. The strengthening of the OR when the two assays were concordant suggests the true association of CpG methylation with precancer is stronger than with either assay. As cervical cancer prevention moves to DNA testing methods, DNA based biomarkers, such as HPV methylation could serve as a reflex strategy to identify women at high risk for cervix cancer.

Femoral vascular closure device use, bivalirudin anticoagulation, and bleeding after primary angioplasty for STEMI: results from the HORIZONS-AMI trial.

OBJECTIVE: To assess the relationship of femoral vascular closure device (VCD) use to bleeding and ischemic events in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) via different anticoagulation strategies. BACKGROUND: It is unknown whether femoral VCD reduce major bleeding after primary PCI for STEMI using bivalirudin anticoagulation. METHODS: We compared VCD-treated patients with propensity-matched controls in the HORIZONS-AMI trial with respect to net adverse clinical events (NACE), defined as the composite of major bleeding unrelated to coronary artery bypass graft surgery (CABG) and major adverse cardiac events (comprised of death, reinfarction, ischemia-driven target vessel revascularization, and stroke), at 30 days and 1 year. RESULTS: Among 3,602 patients enrolled in HORIZONS-AMI, 2,948 underwent primary PCI via femoral arterial access and 896 (30%) received VCDs, of whom 642 were included in our model along with 642 propensity-matched controls. At 30 days, VCD-treated patients had significantly less NACE (6.7% vs. 10.8%, HR: 0.61, 95% CI: 0.42-0.89, P = 0.009), driven by a lower rate of non-CABG related major bleeding (5.0% vs. 8.1%, HR: 0.61, 95% CI: 0.39-0.94, P = 0.02). Bleeding reduction was maintained at one year and consistent in magnitude regardless of randomization to bivalirudin or unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (P for interaction = 0.84). CONCLUSION: In patients undergoing transfemoral primary PCI for STEMI, VCD use was associated with significantly lower non-CABG major bleeding irrespective of anticoagulation strategy.

HPV16 CpG methyl-haplotypes are associated with cervix precancer and cancer in the Guanacaste natural history study.

OBJECTIVE: To evaluate HPV16 CpG methylation and methyl-haplotypes and their association with cervix precancer and cancer utilizing massively parallel single molecule next-generation sequencing (NGS). METHODS: A nested case-control study of HPV16 positive women was performed in a prospective cohort from Guanacaste, Costa Rica designed to study the natural history of HPV and cervical neoplasia. Controls encompassed 31 women with transient infections; there were 44 cases, including 31 women with CIN3 and 13 with cervical cancer. DNA samples from exfoliated cervical cells were treated with bisulfite and four regions (E6, E2, L2 and L1) were amplified with barcoded primers and tested by NGS. CpG methylation was quantified using a bioinformatics pipeline. RESULTS: Median methylation levels were significantly different between the CIN3+ cases versus controls in the E2, L2, and L1 regions. Methyl-haplotypes, specifically in 5 CpG sites included in the targeted L2 region, with the pattern "--+-+" had the highest Area Under the Curve value (AUC=88.40%) observed for CIN3 vs. CONTROLS: The most significant CpG site, L2 4277, determined by bisulfite NGS had an AUC=78.62%. CONCLUSIONS: This study demonstrates that NGS of bisulfite treated HPV DNA is a useful and efficient technique to survey methylation patterns in HPV16. This procedure provides quantitative information on both individual CpG sites and methyl-haplotypes that identify women with elevated present or subsequent risk for HPV16 CIN3 and cancer.

First-trimester 3D power Doppler of the uteroplacental circulation space and fetal growth restriction.

OBJECTIVE: The objective of the study was to compare the 3-dimensional power Doppler (3DPD) of the uteroplacental circulation space in the first trimester between women who subsequently deliver growth-restricted vs normally grown neonates. STUDY DESIGN: This was a prospective observational study of singleton pregnancies at 11-14 weeks' gestation. The 3DPD indices, vascularization index, flow index, and vascularization flow index were determined on a uteroplacental circulation space sphere biopsy with the virtual organ computer-aided analysis program. Growth restriction was defined as a birthweight less than the 10th percentile for gestational age and was evaluated using both population-based and customized birth curves. RESULTS: Five hundred seventy-seven women were enrolled. Five hundred twenty-six were eligible for analysis using population centiles, and 497 were available for evaluation using customized centiles. There was no difference in the first-trimester 3DPD indices between patients with growth-restricted and normally grown neonates using either curve. CONCLUSION: Three-dimensional power Doppler indices of the uteroplacental circulation space in the first trimester are similar between neonates who develop growth restriction and those who will grow normally.