Search

Aims The prognosis of patients with atrial fibrillation (AF) and ischemic stroke while taking oral anticoagulation is poorly understood. This study aimed to characterize the outcomes of patients following a stroke event while on oral anticoagulation. Methods and results Individual participant data from five pivotal randomized trials of antithrombotic therapy in AF were used to assess the outcomes of patients with a post-randomization ischemic stroke while on study medication (warfarin, standard-, or lower-dose direct oral anticoagulant regimen) during trial follow-up. The primary outcome was recurrent ischemic stroke after the first post-randomization ischemic stroke. The primary analysis included 1163 patients with a first post-randomization ischemic stroke while on study medication (median age 73 years, 39.3% female, 35.4% history of stroke before trial enrollment). During a median continued follow-up of 337 days, 74 patients had a recurrent ischemic stroke [cumulative incidence at 1 year: 7.0%, 95% confidence interval (CI) 5.2%–8.7%]. The cumulative incidence of mortality at 3 months after stroke was 12.4% (95% CI 10.5%–14.4%). Consistent results for the incidence of recurrent ischemic stroke at 1 year were obtained in an analysis accounting for the competing risk of death (6.2%, 95% CI 4.8%–7.9%) and in a landmark analysis excluding the first 2 weeks after the index stroke and only including patients without permanent study drug discontinuation since then (6.8%, 95% CI 4.6%–8.9%). Conclusion Patients with AF and ischemic stroke while on oral anticoagulation are at increased risk of recurrent ischemic stroke and death. These patients currently have an unmet medical need.

Background: Iron deficiency is common in heart failure and associated with worse outcomes. We examined the prevalence and consequences of iron deficiency in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) and the effect of dapagliflozin on markers of iron metabolism. We also analyzed the effect of dapagliflozin on outcomes, according to iron status at baseline. Methods: Iron deficiency was defined as a ferritin level Results: Of the 4744 patients randomized in DAPA-HF, 3009 had ferritin and transferrin saturation measurements available at baseline, and 1314 of these participants (43.7%) were iron deficient. The rate of the primary outcome was higher in patients with iron deficiency (16.6 per 100 person-years) compared with those without (10.4 per 100 person-years; P P -interaction=0.59). Similar findings were observed for cardiovascular death, heart failure hospitalization, and all-cause mortality. Transferrin saturation, ferritin, and hepcidin were reduced and total iron-binding capacity and soluble transferrin receptor increased with dapagliflozin compared with placebo. Conclusions: Iron deficiency was common in DAPA-HF and associated with worse outcomes. Dapagliflozin appeared to increase iron use but improved outcomes, irrespective of iron status at baseline. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03036124.

Background: Insulin-like growth factor–binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown. Objectives: The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Methods: The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means. Results: A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34). Conclusions: Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level.

Background: Direct oral anticoagulants (DOACs) are preferred over warfarin for stroke prevention in atrial fibrillation. Meta-analyses using individual patient data offer substantial advantages over study-level data. Methods: We used individual patient data from the COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) database, which includes all patients randomized in the 4 pivotal trials of DOACs versus warfarin in atrial fibrillation (RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy], ROCKET AF [Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], and ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48]), to perform network meta-analyses using a stratified Cox model with random effects comparing standard-dose DOAC, lower-dose DOAC, and warfarin. Hazard ratios (HRs [95% CIs]) were calculated for efficacy and safety outcomes. Covariate-by-treatment interaction was estimated for categorical covariates and for age as a continuous covariate, stratified by sex. Results: A total of 71 683 patients were included (29 362 on standard-dose DOAC, 13 049 on lower-dose DOAC, and 29 272 on warfarin). Compared with warfarin, standard-dose DOACs were associated with a significantly lower hazard of stroke or systemic embolism (883/29 312 [3.01%] versus 1080/29 229 [3.69%]; HR, 0.81 [95% CI, 0.74–0.89]), death (2276/29 312 [7.76%] versus 2460/29 229 [8.42%]; HR, 0.92 [95% CI, 0.87–0.97]), and intracranial bleeding (184/29 270 [0.63%] versus 409/29 187 [1.40%]; HR, 0.45 [95% CI, 0.37–0.56]), but no statistically different hazard of major bleeding (1479/29 270 [5.05%] versus 1733/29 187 [5.94%]; HR, 0.86 [95% CI, 0.74–1.01]), whereas lower-dose DOACs were associated with no statistically different hazard of stroke or systemic embolism (531/13 049 [3.96%] versus 1080/29 229 [3.69%]; HR, 1.06 [95% CI, 0.95–1.19]) but a lower hazard of intracranial bleeding (55/12 985 [0.42%] versus 409/29 187 [1.40%]; HR, 0.28 [95% CI, 0.21–0.37]), death (1082/13 049 [8.29%] versus 2460/29 229 [8.42%]; HR, 0.90 [95% CI, 0.83–0.97]), and major bleeding (564/12 985 [4.34%] versus 1733/29 187 [5.94%]; HR, 0.63 [95% CI, 0.45–0.88]). Treatment effects for standard- and lower-dose DOACs versus warfarin were consistent across age and sex for stroke or systemic embolism and death, whereas standard-dose DOACs were favored in patients with no history of vitamin K antagonist use ( P =0.01) and lower creatinine clearance ( P =0.09). For major bleeding, standard-dose DOACs were favored in patients with lower body weight ( P =0.02). In the continuous covariate analysis, younger patients derived greater benefits from standard-dose (interaction P =0.02) and lower-dose DOACs (interaction P =0.01) versus warfarin. Conclusions: Compared with warfarin, DOACs have more favorable efficacy and safety profiles among patients with atrial fibrillation.

ImportanceDapagliflozin reduces the risk of hospitalizations for heart failure and the progression of chronic kidney disease in patients with and without type 2 diabetes (T2D), whereas the effects on reducing atherosclerotic events appear less clear.ObjectiveTo explore whether N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) levels can identify a subset of patients with T2D at higher risk and who might benefit more from dapagliflozin with regard to atherosclerotic events.Design, Setting, and ParticipantsThis was a secondary analysis of the DECLARE-TIMI 58 trial, a randomized clinical trial of dapagliflozin in patients with T2D and either multiple risk factors for atherosclerotic cardiovascular disease (ASCVD; approximately 60%) or established ASCVD (approximately 40%). All patients with available blood samples at randomization were included in these analyses. Data were collected from May 2013 to September 2018, and data were analyzed from May 2019 to June 2022.InterventionsDapagliflozin vs placebo.Main Outcomes and MeasuresMajor adverse cardiovascular events (MACE), the composite of myocardial infarction, ischemic stroke, or cardiovascular death, which was one of dual primary outcomes of the main trial.ResultsOf 14 565 included patients, 9143 (62.8%) were male, and the mean (SD) age was 63.9 (6.8) years. When tested individually in a multivariable model for MACE risk, NT-proBNP and hsTnT were each significantly associated with the risk of MACE (adjusted hazard ratio [aHR] per 1 SD in log-transformed biomarker: NT-proBNP, 1.62; 95% CI, 1.49-1.76; hsTnT: 1.59; 95% CI, 1.46-1.74). The magnitude of the association was similar in patients with ASCVD (NT-proBNP: aHR, 1.60; 95% CI, 1.45-1.77; hsTnT: aHR, 1.62; 95% CI, 1.45-1.81) and multiple risk factors for ASCVD (NT-proBNP: aHR, 1.62; 95% CI, 1.40-1.88; hsTnT: aHR, 1.51; 95% CI, 1.29-1.77). Moreover, both biomarkers remained independently associated with MACE when both were included in the multivariable model (NT-proBNP: aHR, 1.46; 95% CI, 1.34-1.60; hsTnT: aHR, 1.39; 95% CI, 1.26-1.53). Modeled as a continuous variable, baseline biomarker levels did not modify the relative treatment effect of dapagliflozin vs placebo with MACE. However, the relative risk reduction numerically grew with higher biomarker levels, as did the baseline risk. Thus, MACE event rates were nominally lower in dapagliflozin-treated vs placebo-treated patients with biomarker concentrations in the top quartile (NT-proBNP: HR, 0.83; 95% CI, 0.71-0.97; absolute risk reduction [ARR], 2.4%; hsTnT: HR, 0.85; 95% CI, 0.72-0.99; ARR, 2.7%), whereas there was no significant treatment effect in patients with biomarkers levels in quartiles 1 to 3 (NT-proBNP: HR, 1.02; 95% CI, 0.88-1.18; ARR, 0%; hsTnT: HR, 0.97; 95% CI, 0.84-1.13; ARR, 0.2%).Conclusions and RelevanceIn this study, NT-proBNP and hsTnT levels were associated with the risk for future cardiovascular events in both primary and secondary prevention patients with T2D. Both cardiac biomarkers were helpful to identify patients at very high risk for atherosclerotic events that may derive reduction in risk of MACE with dapagliflozin.Trial RegistrationClinicalTrials.gov Identifier: NCT01730534

Aims: Blood uric acid (UA) levels are frequently elevated in patients with heart failure and reduced ejection fraction (HFrEF), may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium–glucose cotransporter 2 inhibitors may have this effect. We aimed to examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA-HF trial. Methods and results: The association between UA and the primary composite outcome of cardiovascular death or worsening heart failure, its components, and all-cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA ≥6.8 mg/dl) versus tertile 1 (2), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted hazard ratio tertile 3 vs. tertile 1: 1.32, 95% confidence interval [CI] 1.06–1.66; p = 0.01). The risk of heart failure hospitalization and cardiovascular death increased by 7% and 6%, respectively per 1 mg/dl unit increase of UA (p = 0.04 and p = 0.07). Spline analysis revealed a linear increase in risk above a cut-off UA value of 7.09 mg/dl. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dl (95% CI −0.93 to −0.74) over 12 months (p < 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration. Conclusion: Uric acid remains an independent predictor of worse outcomes in a well-treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration.

Supplemental Digital Content is available in the text., Background: The coronavirus disease 2019 (COVID-19) pandemic has exposed longstanding racial and ethnic inequities in health risks and outcomes in the United States. We aimed to identify racial and ethnic differences in presentation and outcomes for patients hospitalized with COVID-19. Methods: The American Heart Association COVID-19 Cardiovascular Disease Registry is a retrospective observational registry capturing consecutive patients hospitalized with COVID-19. We present data on the first 7868 patients by race/ethnicity treated at 88 hospitals across the United States between January 17, 2020, and July 22, 2020. The primary outcome was in-hospital mortality. Secondary outcomes included major adverse cardiovascular events (death, myocardial infarction, stroke, heart failure) and COVID-19 cardiorespiratory ordinal severity score (worst to best: death, cardiac arrest, mechanical ventilation with mechanical circulatory support, mechanical ventilation with vasopressors/inotrope support, mechanical ventilation without hemodynamic support, and hospitalization alone. Multivariable logistic regression analyses were performed to assess the relationship between race/ethnicity and each outcome adjusting for differences in sociodemographic, clinical, and presentation features, and accounting for clustering by hospital. Results: Among 7868 patients hospitalized with COVID-19, 33.0% were Hispanic, 25.5% were non-Hispanic Black, 6.3% were Asian, and 35.2% were non-Hispanic White. Hispanic and Black patients were younger than non-Hispanic White and Asian patients and were more likely to be uninsured. Black patients had the highest prevalence of obesity, hypertension, and diabetes. Black patients also had the highest rates of mechanical ventilation (23.2%) and renal replacement therapy (6.6%) but the lowest rates of remdesivir use (6.1%). Overall mortality was 18.4% with 53% of all deaths occurring in Black and Hispanic patients. The adjusted odds ratios for mortality were 0.93 (95% CI, 0.76–1.14) for Black patients, 0.90 (95% CI, 0.73–1.11) for Hispanic patients, and 1.31 (95% CI, 0.96–1.80) for Asian patients compared with non-Hispanic White patients. The median odds ratio across hospitals was 1.99 (95% CI, 1.74–2.48). Results were similar for major adverse cardiovascular events. Asian patients had the highest COVID-19 cardiorespiratory severity at presentation (adjusted odds ratio, 1.48 [95% CI, 1.16–1.90]). Conclusions: Although in-hospital mortality and major adverse cardiovascular events did not differ by race/ethnicity after adjustment, Black and Hispanic patients bore a greater burden of mortality and morbidity because of their disproportionate representation among COVID-19 hospitalizations.

CD8+ T cells are key mediators of antiviral and antitumor immunity. The isolation and study of Ag-specific CD8+ T cells, as well as mapping of their MHC restriction, has practical importance to the study of disease and the development of therapeutics. Unfortunately, most experimental approaches are cumbersome, owing to the highly variable and donor-specific nature of MHC-bound peptide/TCR interactions. Here we present a novel system for rapid identification and characterization of Ag-specific CD8+ T cells, particularly well suited for samples with limited primary cells. Cells are stimulated ex vivo with Ag of interest, followed by live cell sorting based on surface-trapped TNF-α. We take advantage of major advances in single-cell sequencing to generate full-length sequence data from the paired TCR α- and β-chains from these Ag-specific cells. The paired TCR chains are cloned into retroviral vectors and used to transduce donor CD8+ T cells. These TCR transductants provide a virtually unlimited experimental reagent, which can be used for further characterization, such as minimal epitope mapping or identification of MHC restriction, without depleting primary cells. We validated this system using CMV-specific CD8+ T cells from rhesus macaques, characterizing an immunodominant Mamu-A1*002:01-restricted epitope. We further demonstrated the utility of this system by mapping a novel HLA-A*68:02-restricted HIV Gag epitope from an HIV-infected donor. Collectively, these data validate a new strategy to rapidly identify novel Ags and characterize Ag-specific CD8+ T cells, with applications ranging from the study of infectious disease to immunotherapeutics and precision medicine.

Background Currently, there is limited research on the prognostic value of NT-proBNP (N-terminal pro-B-type natriuretic peptide) as a biomarker in COVID-19. We proposed the a priori hypothesis that an elevated NT-proBNP concentration at admission is associated with increased in-hospital mortality. Methods and Results In this prospective, observational cohort study of the American Heart Association's COVID-19 Cardiovascular Disease Registry, 4675 patients hospitalized with COVID-19 were divided into normal and elevated NT-proBNP cohorts by standard age-adjusted heart failure thresholds, as well as separated by quintiles. Patients with elevated NT-proBNP (n=1344; 28.7%) were older, with more cardiovascular risk factors, and had a significantly higher rate of in-hospital mortality (37% versus 16%; P

Understanding possible climate futures that include carbon dioxide removal (CDR) and solar radiation modification (SRM) requires thinking not just about staying within the remaining carbon budget, but also about politics and people. However, despite growing interest in CDR and SRM, scenarios focused on these potential responses to climate change tend to exclude feedbacks between social and climate systems (a criticism applicable to climate change scenarios more generally). We adapted the Manoa Mash- Up method to generate scenarios for CDR and SRM that were more integrative, creative, and dynamic. The method was modified to identify important branching points in which different choices in how to respond to climate change (feedbacks between climate and social dynamics) lead to a plurality of climate futures. An interdisciplinary group of participants imagined distant futures in which SRM or CDR develop into a major social-environmental force. Groups received other "seeds" of change, such as Universal Basic Income or China's Belt and Road Initiative, and surprises, such as permafrost collapse that grew to influence the course of events to 2100. Groups developed narratives describing pathways to the future and identified bifurcation points to generate families of branching scenarios. Four climate-social dynamics were identified: motivation to mitigate, moral hazard, social unrest, and trust in institutions. These dynamics could orient toward better or worse outcomes with SRM and CDR deployment (and mitigation and adaptation responses more generally) but are typically excluded from existing climate change scenarios. The importance of these dynamics could be tested through the inclusion of social-environmental feedbacks into integrated assessment models (IAM) exploring climate futures. We offer a step-by-step guide to the modified Manoa Mash-up method to generate more integrative, creative, and dynamic scenarios; reflect on broader implications of using this method for generating more dynamic scenarios for climate change research and policy; and provide examples of using the scenarios in climate policy communication, including a choose-your-own adventure game called Survive the Century (https://survivethecentury.net/), which was played by over 15,000 people in the first 2 weeks of launching.

Supplemental Material, sj-docx-1-jic-10.1177_08850666211003489 for Trends in Therapy and Outcomes Associated With Respiratory Failure in Patients Admitted to the Cardiac Intensive Care Unit by Jacob C. Jentzer, Carlos L. Alviar, P. Elliott Miller, Thomas Metkus, Courtney E. Bennett, David A. Morrow, Gregory W. Barsness, Kianoush B. Kashani and Ognjen Gajic in Journal of Intensive Care Medicine

Supplemental Material, sj-docx-2-jic-10.1177_08850666211003489 for Trends in Therapy and Outcomes Associated With Respiratory Failure in Patients Admitted to the Cardiac Intensive Care Unit by Jacob C. Jentzer, Carlos L. Alviar, P. Elliott Miller, Thomas Metkus, Courtney E. Bennett, David A. Morrow, Gregory W. Barsness, Kianoush B. Kashani and Ognjen Gajic in Journal of Intensive Care Medicine

International audience; Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO was associated with lower mortality. Methods: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading using an Impella at 16 tertiary care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity score–matched cohort. Results: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio, 0.79 [95% CI, 0.63–0.98]; P =0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site–related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%). Conclusions: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.

Kristian Thygesen∗ (Denmark) Joseph S. Alpert∗ (USA) Allan S. Jaffe (USA) Bernard R. Chaitman (USA) Jeroen J. Bax (The Netherlands) David A. Morrow (USA) Harvey D. White∗ (New Zealand) Hans Mickley (Denmark) Filippo Crea (Italy) Frans Van de Werf (Belgium) Chiara Bucciarelli-Ducci (

Highlights • We identify diverse rationales to call for anticipatory governance of solar geoengineering, in light of a climate crisis. • These rationales range from governing to enable versus governing to restrict the possible future use of solar geoengineering. • Such diverse rationales highlight the importance of focusing on why govern solar geoengineering in the first place. • These rationales are linked to contrasting underlying visions of the possible role for solar geoengineering in a future impacted by climate change • The analysis shows how governance proposals in the literature are related to these divergent rationales and future visions., This article identifies diverse rationales to call for anticipatory governance of solar geoengineering, in light of a climate crisis. In focusing on governance rationales, we step back from proliferating debates in the literature on ‘how, when, whom, and where’ to govern, to address the important prior question of why govern solar geoengineering in the first place: to restrict or enable its further consideration? We link these opposing rationales to contrasting underlying visions of a future impacted by climate change. These visions see the future as either more or less threatening, depending upon whether it includes the possible future use of solar geoengineering. Our analysis links these contrasting visions and governance rationales to existing governance proposals in the literature. In doing so, we illustrate why some proposals differ so significantly, while also showing that similar-sounding proposals may emanate from quite distinct rationales and thus advance different ends, depending upon how they are designed in practice.

Carbon dioxide removal (CDR) is rising up the climate-policy agenda. Four principles for thinking about its role in climate policy can help ensure that CDR supports the kind of robust, abatement-focused long-term climate strategy that is essential to fair and effective implementation.

Supplemental material, 10.1177_1358863X19892690_Supplementary_tables_and_figures for Effect of vorapaxar on cardiovascular and limb outcomes in patients with peripheral artery disease with and without coronary artery disease: Analysis from the TRA 2°P-TIMI 50 trial by Arman Qamar, David A Morrow, Mark A Creager, Benjamin M Scirica, Jeffrey W Olin, Joshua A Beckman, Sabina A Murphy and Marc P Bonaca in Vascular Medicine

The coronavirus disease-2019 (COVID-19), a contagious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2), has reached pandemic status. As it spreads across the world, it has overwhelmed healthcare systems, strangled the global economy and led to a devastating loss of life. Widespread efforts from regulators, clinicians and scientists are driving a rapid expansion of knowledge of the SARS-CoV2 virus and the COVID-19 disease. We review the most current data with a focus on our basic understanding of the mechanism(s) of disease and translation to the clinical syndrome and potential therapeutics. We discuss the basic virology, epidemiology, clinical manifestation, multi-organ consequences, and outcomes. With a focus on cardiovascular complications, we propose several mechanisms of injury. The virology and potential mechanism of injury form the basis for a discussion of potential disease-modifying therapies.

Carbon dioxide removal (CDR) is often characterized as separate from climate change mitigation. Discussion of CDR governance – despite enjoying growing interest – tends to overlook how key provisions on mitigation apply. Similarly, many climate policy processes have ignored CDR. CDR may have been discursively held separate from ‘mitigation’ due to a partial conceptual overlap with ‘geoengineering’. We unpack how the ‘mitigation of climate change’ – as defined in the United Nations Framework Convention on Climate Change and its Paris Agreement – includes CDR as defined by the Intergovernmental Panel on Climate Change. We point to important implications and opportunities for strengthening governance by enhanced clarity regarding parties’ obligations, principled equitable distribution of removal efforts, prioritization of rapid emissions reductions and careful paths to long-term removals, and a need for considering sustainability and human rights issues in the pursuit of CDR.

High-sensitivity cardiac troponin (hs-cTn) I or T methods have been in use in certain regions for years but are now increasingly globally adopted, including in the United States. Accordingly, inevitable challenges are created for institutions transitioning from conventional cardiac troponin (cTn) assays. hs-cTn assays have higher analytic precision at lower concentrations, yielding greater clinical sensitivity for myocardial injury and allowing accurate recognition of small changes in troponin concentration (rise or fall) within a short time frame. Although much of the knowledge regarding troponin biology that was applicable with older troponin assays still holds true, considerable education regarding the differences between conventional cTn and hs-cTn is needed before medical systems convert to the newer methods. This includes a basic understanding of how hs-cTn testing differs from conventional cTn testing and how it is best deployed in different settings, such as the emergency department and inpatient services. This Expert Panel will review important concepts for institutional transition to hs-cTn methodology, providing recommendations useful for education before implementation.

Heart failure is a chronic disease in which a weakened heart is no longer able to deliver adequate blood flow to supply the body with needed oxygen and nutrients. Heart failure is the most common reason for hospitalization in the United States for patients age 65 and over, accounting for over 1,000,000 hospital admissions annually. Due to the chronic nature of this debilitating condition and associated symptoms, patients discharged from the hospital with a diagnosis of heart failure are at high risk for readmission. Effective self-care behaviors have been shown to reduce readmissions and improve quality of life for these patients. Unfortunately, evidence shows that nurses are often unprepared to deliver effective self-care education to their patients with heart failure. The primary goal of this project was to implement an educational intervention within a multi-hospital system to improve nurses' knowledge and comfort level in delivering heart failure self-care education to their patients. Two conceptual models were used to guide the project, andragogy and Carper's Fundamental Patterns of Knowing in Nursing. The Nurses' Knowledge of Heart Failure Education Principles Survey (NKHFEP) measured nurses' knowledge of heart failure self-care principles before and after the intervention. A Likert-scale survey was used to assess nurses' self-perception of heart failure knowledge and comfort in delivering such education. Post-intervention scores on the NKHFEP survey indicated a significant improvement in heart failure knowledge, and participant self-assessment of knowledge and comfort levels also increased post-intervention. The class is now a permanent offering in the hospital system's central education department. By empowering nurses to deliver effective heart failure education to their patients, this project has a high likelihood of improving patient outcomes as part of a multimodal approach to reducing heart failure readmissions.

Background Ticagrelor reduced cardiovascular death, myocardial infarction (MI), or stroke in patients with prior MI in PEGASUS-TIMI 54 (Prevention of Cardiovascular Events [eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin). MI can occur in diverse settings and with varying severity; therefore, understanding the types and sizes of MI events prevented is of clinical importance. Methods and Results MIs were adjudicated by a blinded clinical events committee and categorized by subtype and fold elevation of peak cardiac troponin over the upper limit of normal. A total of 1042 MIs occurred in 898 of the 21 162 randomized patients over a median follow-up of 33 months. The majority of the MIs (76%) were spontaneous (Type 1), with demand MI (Type 2) and stent thrombosis (Type 4b) accounting for 13% and 9%, respectively; sudden death (Type 3), percutaneous coronary intervention-related (Type 4a) and coronary artery bypass graft-related (Type 5) each accounted for

The hospitality industry constantly faces the challenge of identifying, recruiting, and retaining qualified and committed employees. The US government has recently proposed gainful employment legislation that would give the Department of Education (DOE) the authority to regulate for-profit colleges and certificate programs at not-for-profit institutions of higher learning, requiring them to meet minimum student debt ratios. These demands add to the pressure on hospitality college administrators to design courses and academic programming that not only prepare workers for their careers, but also reinforce student commitment towards working in a specific industry. This explanatory sequential research study was undertaken to investigate the influence a study tour course has on student commitment to the hospitality industry. Primary data collection methods included pre- and post-tour surveys of the 67 purposively selected study tour course participants and subsequent focus group interviews with participants recruited from that group. An analysis of the resultant data ensued to determine how completion of a study tour course influenced participants' levels of commitment to their chosen career path.

The commercial development of advanced therapy medicinal products (ATMPs) represents great opportunity for therapeutic innovation but is beset by many challenges for its developers. Although the ATMP field continues to progress at a rapid pace, evidenced by the increasing number of clinical trials conducted over the past few years, several factors continue to complicate the introduction of ATMPs as a curative treatment for multiple disease types, by blocking their translational pathway from research to the patient. While several recent publications (Trounson and McDonald, 2015; Abou-El-Enein et al., 2016a,b) as well as an Innovative Medicines Initiative consultation (IMI, 2016) this year have highlighted the major gaps in ATMP development, with manufacturing, regulatory, and reimbursement issues at the forefront, there remains to be formulated a coherent strategy to address these by bringing the relevant stakeholders to a single forum, whose task it would be to design and execute a delta plan to alleviate the most pressing bottlenecks. This article focuses on two of the most urgent areas in need of attention in ATMP development, namely manufacturing and reimbursement, and promotes the concept of innovation-dedicated research infrastructures to support a multi-sector approach for ensuring the successful development, entry, and ensuing survival of ATMPs in the healthcare market.

This paper presents a data acquisition unit which synchronously samples multiple channels in a manner such that the time of day at which each sample is taken is known. This allows measurements taken at multiple locations to be compared with confidence. The intended application is wide area electrical power system measurements, in particular Phasor Measurement Units (PMU).The novelty of the authors’ design is the application of an open hardware development platform to discipline a commodity ADC to a broadcast time signal, usually but not exclusively GPS. The methodology used creates a driver layer for the ADC to achieve real-time sampling in a non-preemptive Linux environment. The use of open hardware and software addresses the need for a transparent instrument for use in research and development of PMU technology.Through a choice of either a software or hardware phase locked loop (PLL), the ADC is controlled to acquire exactly 256 samples per nominal power system cycle (i.e. 50 Hz / 60 Hz), precisely time synchronized to GPS, at 16-bit resolution and 94.2 dB SNR. The design of a PCB expansion board featuring all necessary components is provided. The performance of the system is evaluated. Interoperability and data exchange with other systems is achieved by use of open schemas and communication protocols. This allows rapid integration with popular numerical simulation environments.

In acute coronary syndrome (ACS), potassium levels 4.0 mEq/L in ACS. Our study evaluated the association between potassium levels, cardiac arrhythmias, and cardiovascular death in patients with non-ST-segment elevation myocardial infarction or unstable angina.

Discussions of climate engineering (CE) governance stand now at a crucial juncture. While the CE research community’s ideas about governance have become increasingly sophisticated and specific over the last half decade, they have by and large not been translated into actual governance mechanisms. This working paper summarizes the main points of agreement among major reports on CE governance and lays out some major open questions. This paper also surveys those reports with a view to helping readers understand each report’s distinctive features and major recommendations regarding CE governance.

The Hedgehog pathway is a pivotal morphogenic driver during embryonic development and a key regulator of adult stem cell self-renewal. The discovery of resident multipotent vascular stem cells and adventitial progenitors within the vessel wall has transformed our understanding of the origin of medial and neointimal vascular smooth muscle cells (SMCs) during vessel repair in response to injury, lesion formation, and overall disease progression. This review highlights the importance of components of the Hh and Notch signalling pathways within the medial and adventitial regions of adult vessels, their recapitulation following vascular injury and disease progression, and their putative role in the maintenance and differentiation of resident vascular stem cells to vascular lineages from discrete niches within the vessel wall.

Background Unfractionated heparin is often used as adjunctive therapy with fibrinolysis in patients with ST-elevation myocardial infarction. We compared a low-molecular-weight heparin, enoxaparin, with unfractionated heparin for this purpose. Methods We randomly assigned 20,506 patients with ST-elevation myocardial infarction who were scheduled to undergo fibrinolysis to receive enoxaparin throughout the index hospitalization or weight-based unfractionated heparin for at least 48 hours. The primary efficacy end point was death or nonfatal recurrent myocardial infarction through 30 days. Results The primary end point occurred in 12.0 percent of patients in the unfractionated heparin group and 9.9 percent of those in the enoxaparin group (17 percent reduction in relative risk, P

International audience; Vorapaxar, a novel antiplatelet therapy, reduces thrombotic events in patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD); however, because of an increased risk of intracranial hemorrhage, it is contraindicated in patients with a history of stroke. The aim of this study was to investigate the incidence of new ischemic stroke and subsequent death or intracerebral hemorrhage in patients with MI or PAD and no cerebrovascular disease (CVD) treated with vorapaxar. The TRA 2 °P-TIMI 50 (Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis In Myocardial Infarction 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar 2.5 mg daily in 26,449 patients with atherosclerosis, stratified by qualifying disease (MI, PAD, or CVD). A total of 20,170 patients with MI/PAD, but no CVD, were enrolled. In patients with MI/PAD and no prior stroke or transient ischemic attack, vorapaxar reduced first ischemic stroke (hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.43 to 0.75; p < 0.001). The risk of hemorrhagic conversion after stroke (HR: 1.19, 95% CI: 0.49 to 2.91; p = 0.70) or death (HR: 1.09, 95% CI: 0.57 to 2.07; p = 0.79) during follow-up was not significantly increased with vorapaxar in patients who had a new ischemic stroke (n = 204). Although hemorrhagic stroke was increased (HR: 2.79, 95% CI: 1.00 to 7.73; p = 0.049), overall stroke was significantly reduced (HR: 0.67, 95% CI: 0.52 to 0.87; p = 0.002). Vorapaxar reduces ischemic stroke in patients with MI or PAD and no known CVD. There does not appear to be a significant increase in the risk of hemorrhagic conversion or death in patients who experienced a first ischemic stroke on vorapaxar. Although primary hemorrhagic stroke is increased, vorapaxar reduces the total incidence of stroke. (Trial to Assess the Effects of Vorapaxar (SCH 530348; MK-5348) in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2 °P-TIMI 50]; NCT00526474).

In 1962, the United States conducted its final atmospheric nuclear test. Since 1962, the American national laboratories have attempted to simulate the results observed in exo-atmospheric testing in order to understand and explain how high-energy electrons became trapped further across the Earth’s magnetic field than expected. In this thesis, my research will use a computer modeling program designed by the late Dr. Dennis Hewett for LLNL in 1972 to simulate the debris from a High Altitude Nuclear Explosion (HANE). The objective of this research is to examine two physical phenomena, collisionless shocks driven by multiple ion species and charge exchange, to determine their independent relevance to the final spatial disposition of fission fragments from a HANE. This research used the ZMR code, a one-dimensional, particle-in-cell plasma code to simulate the movement of the debris ions produced by the HANE. The debris ions are assumed to be the source of the measured high-energy electrons due to subsequent beta-decay. These high-energy electrons can damage the satellite network vital to the Department of Defense and security of the nation. http://archive.org/details/motionofdebrisfr1094542691 Lieutenant Colonel, United States Army Approved for public release; distribution is unlimited.

OBJECTIVES: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.BACKGROUND: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.METHODS: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.RESULTS: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.CONCLUSIONS: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

Naval Postgraduate School Acquisition Research Program

Naval Postgraduate School Acquisition Research Program

Naval Postgraduate School Acquisition Research Program

Proceedings Paper (for Acquisition Research Program) Cost and time overruns in Major Defense Acquisition Programs (MDAPs) have become a high-profile problem attracting the interest of Congress, government, and watchdog groups. According to the GAO, the 98 MDAPs from FY2010 collectively ran $402 billion over budget and were an average of 22 months behind schedule since their first full estimate. President Obama''s memorandum on government contracting of 4 March 2009 also highlighted this issue. This paper presents findings of research on the root causes of cost and schedule delays for 92 MDAPs active in 2010 and 12 cancelled programs. The results do not establish causality but they do indicate multiple notable correlations. Inaccurate cost estimates are responsible for the strongest correlation with net cost growth changes and are associated with 40% of the accumulated cost overruns. In addition, the start year has little impact on the compound annual growth rate of cost overruns. This suggests that relatively better performance of newer programs may prove illusionary as programs age. Finally, fixed price contracts appear to have relatively smaller overruns, although this may tell us more about which programs are likely to receive fixed price contracts rather than what effect fixed price contracts may have on program performance. Naval Postgraduate School Acquisition Research Program Approved for public release; distribution is unlimited.

Troponin is the preferred biomarker for risk stratification in non-ST elevation ACS. The incremental prognostic use of the initial magnitude of troponin elevation and its value in conjunction with ST-segment resolution (STRes) in ST elevation myocardial infarction (STEMI) is less well defined.Troponin T (TnT) was measured in 1,250 patients at presentation undergoing fibrinolysis for STEMI in CLARITY-TIMI 28. ST-segment resolution was measured at 90 minutes. Multivariable logistic regression was used to examine the independent association between TnT levels, STRes, and 30-day cardiovascular (CV) mortality.Patients were classified into undetectable TnT at baseline (n = 594), detectable but below the median of 0.12 ng/mL (n = 330), and above the median (n = 326). Rates of 30-day CV death were 1.5%, 4.5%, and 9.5%, respectively (P.0001). Compared with those with undetectable levels and adjusting for baseline factors, the odds ratios for 30-day CV death were 4.56 (1.72-12.08, P = .002) and 5.81 (2.29-14.73, P = .0002) for those below and above the median, respectively. When combined with STRes, there was a significant gradient of risk, and in a multivariable model both baseline TnT (P = .004) and STRes (P = .003) were significant predictors of 30-day CV death. The addition of TnT and STRes to clinical risk factors significantly improved the C-statistic (from 0.86 to 0.90, P = .02) and the integrated discriminative improvement (7.1% increase) (P = .0009).Baseline TnT and 90-minute STRes are independent predictors of 30-day CV death in patients with STEMI. Use of these 2 simple, readily available tools can aid clinicians in early risk stratification.

Background Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances. Methods With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease. Findings Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure. Interpretation Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids. Funding UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.

Vascular Smooth Muscle Cell (SMC) fate decisions are fundamental features in the pathogenesis of vascular disease. We investigated the role of Notch 1 and 3 receptor signalling in controlling adult rat SMC growth in vitro. Constitutive expression of active Notch receptors, Notch 1 IC. and Notch 3 IC, resulted in significant upregulation of CBF-l/RBP-Jk-dependent promoter activity and Notch target gene expression concomitant with significant increases in SMC growth. Moreover, inhibition of endogenous Notch mediated CBF-l/RBP-Jk regulated gene expression resulted in a significant decrease in cell growth. Furthermore we examined the specific role of a Hedgehog (Hh)/vascular endothelial growth factor (VEGF) pathway in controlling vascular SMC growth through regulation of Notch signalling. We determined that Hh signalling pathway components are constitutively expressed VSMC in culture. Moreover activation of Hh signalling with recombinant Shh resulted in a significant increase in Hh signalling concomitant with an increase in VEGF expression, cell growth and activation of Notch target gene expression in SMC. Inhibition of Hh signalling with cyclopamine resulted in a decrease in Hh signalling concomitant with a decrease in SMC growth while concurrently decreasing Notch target gene expression. Moreover, Shh-mediated stimulation of SMC growth was significantly attenuated following inhibition of Notch target gene expression. In addition, we investigated the role of cyclic strain in modulating Notch/Hh mediated growth of SMC in vitro. Rat SMC cultured under the condition of cyclic strain exhibited a temporal and force dependent reduction in Notch and Hh signalling concomitant with a decrease in SMC growth. Furthermore we could reverse this downregulation of Notch/Hh signalling and subsequent decrease in SMC growth by over-expression of Notch 3 IC .To validate these finding we utilized two in vivo models of increased biomechanical forces and vascular remodelling where we determined that altered mechanical forces significantly downregulate Notch/Hh signalling concomitant with decreased growth in vivo. Collectively, these data suggest that Hh control of SMC fate via VEGF activation of Notch may represent a novel therapeutic target for disease states in which changes in vascular cell fate occur.