The Adaptive Poisson–Boltzmann Solver (APBS) software was developed to solve the equations of continuum electrostatics for large biomolecular assemblages that have provided impact in the study of a ...broad range of chemical, biological, and biomedical applications. APBS addresses the three key technology challenges for understanding solvation and electrostatics in biomedical applications: accurate and efficient models for biomolecular solvation and electrostatics, robust and scalable software for applying those theories to biomolecular systems, and mechanisms for sharing and analyzing biomolecular electrostatics data in the scientific community. To address new research applications and advancing computational capabilities, we have continually updated APBS and its suite of accompanying software since its release in 2001. In this article, we discuss the models and capabilities that have recently been implemented within the APBS software package including a Poisson–Boltzmann analytical and a semi‐analytical solver, an optimized boundary element solver, a geometry‐based geometric flow solvation model, a graph theory‐based algorithm for determining pKa values, and an improved web‐based visualization tool for viewing electrostatics.
Coronary artery bypass grafting (CABG) has been considered the standard of care for patients with three-vessel disease (3VD), but long-term comparative results from randomized trials of CABG vs. ...percutaneous coronary intervention (PCI) using drug-eluting stents (DES) remain limited.
Patients with de novo 3VD or left main disease were randomly assigned to PCI with the paclitaxel-eluting first-generation stent or CABG in the SYNTAX trial. This pre-specified analysis presents the 5-year outcomes of patients with 3VD (n = 1095). The rate of major adverse cardiac and cerebrovascular events (MACCE) was significantly higher in patients with PCI compared with CABG (37.5 vs. 24.2%, respectively; P < 0.001). Percutaneous coronary intervention as opposed to CABG resulted in significantly higher rates of the composite of death/stroke/myocardial infarction (MI) (22.0 vs. 14.0%, respectively; P < 0.001), all-cause death (14.6 vs. 9.2%, respectively; P = 0.006), MI (9.2 vs. 4.0%, respectively; P = 0.001), and repeat revascularization (25.4 vs. 12.6%, respectively; P < 0.001); however, stroke was similar between groups at 5 years (3.0 vs. 3.5%, respectively; P = 0.66). Results were dependent on lesion complexity (P for interaction = 0.12); in patients with a low (0-22) SYNTAX score, PCI vs. CABG resulted in similar rates of MACCE (33.3% vs. 26.8%, respectively; P = 0.21) but significantly more repeat revascularization (25.4% vs. 12.6%, respectively; P = 0.038), while in intermediate (23-32) or high (≥ 33) SYNTAX score terciles, CABG demonstrated clear superiority in terms of MACCE, death, MI, and repeat revascularization. Differences in MACCE between PCI and CABG were larger in diabetics hazard ratio (HR) = 2.30 than non-diabetics (HR = 1.51), although the P for interaction failed to reach significance for MACCE (P for interaction = 0.095) or any of the other endpoints.
Five-year results of patients with 3VD treated with CABG or PCI using the first-generation paclitaxel-eluting DES suggest that CABG should remain the standard of care as it resulted in significantly lower rates of death, MI, and repeat revascularization, while stroke rates were similar. For patients with low SYNTAX scores, PCI is an acceptable revascularization strategy, although at a price of significantly higher rates of repeat revascularization.
NCT00114972.
There are no data available on specific causes of death from randomized trials that have compared coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI).
The purpose of ...this study was to investigate specific causes of death, and its predictors, after revascularization for complex coronary disease in patients.
An independent Clinical Events Committee consisting of expert physicians who were blinded to the study treatment subclassified causes of death as cardiovascular (cardiac and vascular), noncardiovascular, or undetermined according to the trial protocol. Cardiac deaths were classified as sudden cardiac, related to myocardial infarction (MI), and other cardiac deaths.
In the randomized cohort, there were 97 deaths after CABG and 123 deaths after PCI during a 5-year follow-up. After CABG, 49.4% of deaths were cardiovascular, with the greatest cause being heart failure, arrhythmia, or other causes (24.6%), whereas after PCI, the majority of deaths were cardiovascular (67.5%) and as a result of MI (29.3%). The cumulative incidence rates of all-cause death were not significantly different between CABG and PCI (11.4% vs. 13.9%, respectively; p = 0.10), whereas there were significant differences in terms of cardiovascular (5.8% vs. 9.6%, respectively; p = 0.008) and cardiac death (5.3% vs. 9.0%, respectively; p = 0.003), which were caused primarily by a reduction in MI-related death with CABG compared with PCI (0.4% vs. 4.1%, respectively; p <0.0001). Treatment with PCI versus CABG was an independent predictor of cardiac death (hazard ratio: 1.55; 95% confidence interval: 1.09 to 2.33; p = 0.045). The difference in MI-related death was seen largely in patients with diabetes, 3-vessel disease, or high SYNTAX (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries) trial scores.
During a 5-year follow-up, CABG in comparison with PCI was associated with a significantly reduced rate of MI-related death, which was the leading cause of death after PCI. Treatments following PCI should target reducing post-revascularization spontaneous MI. Furthermore, secondary preventive medication remains essential in reducing events post-revascularization. (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries SYNTAX; NCT00114972).
Numerous definitions for peri-procedural myocardial infarction (PMI) following percutaneous coronary intervention (PCI) and coronary bypass grafting (CABG) surgery exist.
The purpose of this study ...was to investigate the PMI rates according to various definitions, their clinically relevant association with all-cause mortality at 10 years, and their impact on composite endpoints at 5 years in the SYNTAXES (Synergy between PCI with Taxus and Cardiac Surgery Extended Survival) trial.
PMI was classified as a myocardial infarction occurring within 48 h of the procedure according to definitions of the SYNTAX (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries), ISCHEMIA (International Study Of Comparative Health Effectiveness With Medical And Invasive Approaches), and EXCEL (Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trials; the Fourth Universal Definition of MI; and the Society for Cardiovascular Angiography and Interventions (SCAI). Of the 1,800 patients enrolled, 1,652 with creatine kinase and/or creatine kinase-myocardial band (CK-MB) post-procedure were included. The association between PMI and mortality was analyzed by Cox regression.
PMI rates according to the SYNTAX and Fourth Universal Definition of MI, both of which required CK-MB elevation and electrocardiographic evidence of permanent myocardial damage, were 2.7% and 3.0%, respectively, in the PCI arm versus 2.4% and 2.1%, respectively, in the CABG arm. PMI rates according to the SCAI or EXCEL definition were higher in the PCI (5.7%) and CABG (16.5%) arms. PMIs according to the SYNTAX and Fourth Universal Definition of MI were more strongly associated with mortality than EXCEL and SCAI PMIs defined by isolated enzyme elevation when CK-MB was more than 10 times ULN. The impact of these “enzyme-driven events” on time-to-event curves and the composite endpoints was greater in the surgical cohort. PMIs after PCI were associated with 10-year mortality regardless of definition, whereas their impact on mortality after CABG was limited to 1 year.
The rates of PMI are highly dependent on their definition, which affects time-to-event curves, composite endpoints, and their lethal prognostic relevance. (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival SYNTAXES; NCT03417050; SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries SYNTAX; NCT00114972)
Display omitted
The Antarctic Dry Valleys (ADV) are generally classified as a hyper-arid, cold-polar desert. The region has long been considered an important terrestrial analog for Mars because of its generally cold ...and dry climate and because it contains a suite of landforms at macro-, meso-, and microscales that closely resemble those occurring on the martian surface. The extreme hyperaridity of both Mars and the ADV has focused attention on the importance of salts and brines on soil development, phase transitions from liquid water to water ice, and ultimately, on process geomorphology and landscape evolution at a range of scales on both planets. The ADV can be subdivided into three microclimate zones: a coastal thaw zone, an inland mixed zone, and a stable upland zone; zones are defined on the basis of summertime measurements of atmospheric temperature, soil moisture, and relative humidity. Subtle variations in these climate parameters result in considerable differences in the distribution and morphology of: (1) macroscale features (e.g., slopes and gullies); (2) mesoscale features (e.g., polygons, including ice-wedge, sand-wedge, and sublimation-type polygons, as well as viscous-flow features, including solifluction lobes, gelifluction lobes, and debris-covered glaciers); and (3) microscale features (e.g., rock-weathering processes/features, including salt weathering, wind erosion, and surface pitting). Equilibrium landforms are those features that formed in balance with environmental conditions within fixed microclimate zones. Some equilibrium landforms, such as sublimation polygons, indicate the presence of extensive near-surface ice; identification of similar landforms on Mars may also provide a basis for detecting the location of shallow ice. Landforms that today appear in disequilibrium with local microclimate conditions in the ADV signify past and/or ongoing shifts in climate zonation; understanding these shifts is assisting in the documentation of the climate record for the ADV. A similar type of landform analysis can be applied to the surface of Mars where analogous microclimates and equilibrium landforms occur (1) in a variety of local environments, (2) in different latitudinal bands, and (3) in units of different ages. Documenting the nature and evolution of the ADV microclimate zones and their associated geomorphic processes is helping to provide a quantitative framework for assessing the evolution of climate on Mars.
The early climate of Mars (Noachian Period, the first ~20% of its history) is thought to differ significantly from that of its more recent history (Amazonian Period, the last ~66%) which is ...characterized by hyperarid, hypothermal conditions that result in mean annual air temperatures (MAAT) well below 0°C, a global cryosphere, minimal melting on the ground surface, and a horizontally stratified hydrologic system. We explore the nature of the fluvial and lacustrine environments in the Mars-like hyperarid, hypothermal McMurdo Dry Valleys (MDV), where the MAAT is well below 0°C (~ -14 to -30°C) in order to assess whether the Late Noachian geologic record can be explained by a climate characterized by “cold and icy” conditions. We find that the MDV hydrological system and cycle provide important insights into the potential configuration of a “cold and icy” early Mars climate in which MDV-like ephemeral streams and rivers, and both closed-basin and open-basin lakes could form. We review a series of MDV fluvial and lacustrine features to guide investigators in the analysis of the geomorphology of early Mars and we outline a new model for the nature and evolution of a “cold and icy” Late Noachian climate based on these observations. We conclude that a cold and icy Late Noachian Mars with MAAT below freezing, but peak seasonal and peak daily temperatures above 0°C, could plausibly account for the array of Noachian-aged fluvial and lacustrine features observed on Mars. Our assessment also provides insight into the potential effects of punctuated warming on a cold and icy early Mars, in which impact crater formation or massive volcanic eruptions cause temperatures in the melting range for decadal to centennial timescales. We outline a set of outstanding questions and tests concerning the nature and evolution of these features on Mars.
Stable complex coronary artery disease can be treated with coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or medical therapy. Multidisciplinary decision-making has ...gained more emphasis over the recent years to select the most optimal treatment strategy for individual patients with stable complex coronary artery disease. However, the so-called 'Heart Team' concept has not been widely implemented. Yet, decision-making has shown to remain suboptimal; there is large variability in PCI-to-CABG ratios, which may predominantly be the consequence of physician-related factors that have raised concerns regarding overuse, underuse, and inappropriate selection of revascularization. In this review, we summarize these and additional data to support the statement that a multidisciplinary Heart Team consisting of at least a clinical/non-invasive cardiologist, interventional cardiologist, and cardiac surgeon, can together better analyse and interpret the available diagnostic evidence, put into context the clinical condition of the patient as well as consider individual preference and local expertise, and through shared decision-making with the patient can arrive at a most optimal joint treatment strategy recommendation for patients with stable complex coronary artery disease. In addition, other aspects of Heart Team decision-making are discussed: the organization and logistics, involvement of physicians, patients, and assisting personnel, the need for validation, and its limitations.
Age and acute myeloid leukemia Appelbaum, Frederick R.; Gundacker, Holly; Head, David R. ...
Blood,
05/2006, Volume:
107, Issue:
9
Journal Article
Peer reviewed
Open access
We conducted a retrospective analysis of 968 adults with acute myeloid leukemia (AML) on 5 recent Southwest Oncology Group trials to understand how the nature of AML changes with age. Older study ...patients with AML presented with poorer performance status, lower white blood cell counts, and a lower percentage of marrow blasts. Multidrug resistance was found in 33% of AMLs in patients younger than age 56 compared with 57% in patients older than 75. The percentage of patients with favorable cytogenetics dropped from 17% in those younger than age 56 to 4% in those older than 75. In contrast, the proportion of patients with unfavorable cytogenetics increased from 35% in those younger than age 56 to 51% in patients older than 75. Particularly striking were the increases in abnormalities of chromosomes 5, 7, and 17 among the elderly. The increased incidence of unfavorable cytogenetics contributed to their poorer outcome, and, within each cytogenetic risk group, treatment outcome deteriorated markedly with age. Finally, the combination of a poor performance status and advanced age identified a group of patients with a very high likelihood of dying within 30 days of initiating induction therapy. The distinct biology and clinical responses seen argue for age-specific assessments when evaluating therapies for AML.
The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial was a non-inferiority trial that compared percutaneous coronary intervention (PCI) using first-generation paclitaxel-eluting ...stents with coronary artery bypass grafting (CABG) in patients with de-novo three-vessel and left main coronary artery disease, and reported results up to 5 years. We now report 10-year all-cause death results.
The SYNTAX Extended Survival (SYNTAXES) study is an investigator-driven extension of follow-up of a multicentre, randomised controlled trial done in 85 hospitals across 18 North American and European countries. Patients with de-novo three-vessel and left main coronary artery disease were randomly assigned (1:1) to the PCI group or CABG group. Patients with a history of PCI or CABG, acute myocardial infarction, or an indication for concomitant cardiac surgery were excluded. The primary endpoint of the SYNTAXES study was 10-year all-cause death, which was assessed according to the intention-to-treat principle. Prespecified subgroup analyses were performed according to the presence or absence of left main coronary artery disease and diabetes, and according to coronary complexity defined by core laboratory SYNTAX score tertiles. This study is registered with ClinicalTrials.gov, NCT03417050.
From March, 2005, to April, 2007, 1800 patients were randomly assigned to the PCI (n=903) or CABG (n=897) group. Vital status information at 10 years was complete for 841 (93%) patients in the PCI group and 848 (95%) patients in the CABG group. At 10 years, 248 (28%) patients had died after PCI and 212 (24%) after CABG (hazard ratio 1·19 95% CI 0·99–1·43, p=0·066). Among patients with three-vessel disease, 153 (28%) of 546 had died after PCI versus 114 (21%) of 549 after CABG (hazard ratio 1·42 95% CI 1·11–1·81), and among patients with left main coronary artery disease, 95 (27%) of 357 had died after PCI versus 98 (28%) of 348 after CABG (0·92 0·69–1·22, pinteraction=0·023). There was no treatment-by-subgroup interaction with diabetes (pinteraction=0·60) and no linear trend across SYNTAX score tertiles (ptrend=0·20).
At 10 years, no significant difference existed in all-cause death between PCI using first-generation paclitaxel-eluting stents and CABG. However, CABG provided a significant survival benefit in patients with three-vessel disease, but not in patients with left main coronary artery disease.
German Foundation of Heart Research (SYNTAXES study, 5–10-year follow-up) and Boston Scientific Corporation (SYNTAX study, 0–5-year follow-up).
The benefit of optimal medical therapy (OMT) on 5-year outcomes in patients with 3-vessel disease and/or left main disease after percutaneous coronary intervention or coronary artery bypass grafting ...(CABG) was demonstrated in the randomized SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) trial.
The objective of this analysis is to assess the impact of the status of OMT at 5 years on 10-year mortality after percutaneous coronary intervention or CABG.
This is a subanalysis of the SYNTAXES (Synergy Between PCI With Taxus and Cardiac Surgery Extended Survival) study, which evaluated for up to 10 years the vital status of patients who were originally enrolled in the SYNTAX trial. OMT was defined as the combination of 4 types of medications: at least 1 antiplatelet drug, statin, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and beta-blocker. After stratifying participants by the number of individual OMT agents at 5 years and randomized treatment, a landmark analysis was conducted to assess the association between treatment response and 10-year mortality.
In 1,472 patients, patients on OMT at 5 years had a significantly lower mortality at 10 years compared with those on ≤2 types of medications (13.1% vs 19.9%; adjusted HR: 0.470; 95% CI: 0.292-0.757; P = 0.002) but had a mortality similar to those on 3 types of medications. Furthermore, patients undergoing CABG with the individual OMT agents, antiplatelet drug and statin, at 5 years had lower 10-year mortality than those without.
In patients with 3-vessel and/or left main disease undergoing percutaneous coronary intervention or CABG, medication status at 5 years had a significant impact on 10-year mortality. Patients on OMT with guideline-recommended pharmacologic therapy at 5 years had a survival benefit. (Synergy Between PCI With Taxus and Cardiac Surgery: SYNTAX Extended Survival SYNTAXES; NCT03417050; Taxus Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries SYNTAX; NCT00114972)
Display omitted
PDF
