Correlations between FEV1 and patient-reported outcomes: A pooled analysis of 23 clinical trials in patients with chronic obstructive pulmonary disease.

BACKGROUND: In clinical trials of inhaled bronchodilators, chronic obstructive pulmonary disease (COPD) guidelines recommend that patient-reported outcomes (PROs) are assessed alongside lung function. How these endpoints are related is unclear. METHODS: Pooled longitudinal data from 23 randomised controlled COPD studies were analyzed (N = 23,213). Treatments included long-acting β2 agonists, long-acting muscarinic antagonists (LABAs or LAMAs) and the LABA/LAMA combination QVA149. Outcome measures were Transition Dyspnoea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ) scores, COPD exacerbation frequency and rescue medication use. Relationships between changes in trough forced expiratory volume in one second (ΔFEV1) and outcomes following treatment were assessed using correlations of data summaries and model-based analysis: generalized linear mixed-effect regression modeling to determine if ΔFEV1 could predict patient outcomes with different treatments. RESULTS: Mean age was 64 years, 73% were male, and most had moderate (45%) or severe (52%) disease. Statistically significant correlations were observed between ΔFEV1 and each outcome measure (exacerbations Rs = 0.05; rescue medication, SGRQ, TDI, r = 0.11-0.16; all p < .001). Patients with greater improvements in trough FEV1 had on average better SGRQ and TDI scores, fewer exacerbations, and used less rescue medication. For SGRQ and TDI scores, minimal clinically important differences were observed over the range of pooled ΔFEV1 values. Model-based predictions confirmed the treatment effect was partly explained by changes in FEV1 from baseline with improvements in PROs observed across all treatments when trough FEV1 improved. Across all endpoints active treatments were better than placebo (p < .0001), and LABA/LAMA treatment resulted in numerically better treatment outcomes than either monocomponent. CONCLUSIONS: These data suggest that FEV1 improvements post-bronchodilation correlate with PRO improvements. Further improvements in patient outcomes may be expected by maximizing lung function improvements. TRIAL REGISTRATION: Registration details for the 23 randomised controlled studies used in this pooled analysis are supplied in Additional File 4

The vacuum bubbles in de Sitter background and black hole pair creation

We study the possible types of the nucleation of vacuum bubbles. We classify vacuum bubbles in de Sitter background and present some numerical solutions. The thin-wall approximation is employed to obtain the nucleation rate and the radius of vacuum bubbles. With careful analysis we confirm that Parke's formula is also applicable to the large true vacuum bubbles. The nucleation of the false vacuum bubble in de Sitter background is also evaluated. The tunneling process in the potential with degenerate vacua is analyzed as the limiting cases of the large true vacuum bubble and false vacuum bubble. Next, we consider the pair creation of black holes in the background of bubble solutions. We obtain static bubble wall solutions of junction equation with black hole pair. The masses of created black holes are uniquely determined by the cosmological constant and surface tension on the wall. Finally, we obtain the rate of pair creation of black holes.Comment: 3 figures, minor including errors and typos corrected, and refs. adde

Explaining Earths Energy Budget: CERES-Based NASA Resources for K-12 Education and Public Outreach

Among atmospheric scientists, the importance of the Earth radiation budget concept is well understood. Papers have addressed the topic for over 100 years, and the large Clouds and the Earth's Radiant Energy System (CERES) science team (among others), with its multiple on-orbit instruments, is working hard to quantify the details of its various parts. In education, Earth's energy budget is a concept that generally appears in middle school and Earth science curricula, but its treatment in textbooks leaves much to be desired. Students and the public hold many misconceptions, and very few people have an appreciation for the importance of this energy balance to the conditions on Earth. More importantly, few have a correct mental model that allows them to make predictions and understand the effect of changes such as increasing greenhouse gas concentrations. As an outreach element of the core CERES team at NASA Langley, a multi-disciplinary group of scientists, educators, graphic artists, writers, and web developers has been developing and refining graphics and resources to explain the Earth's Energy budget over the last few decades. Resources have developed through an iterative process involving ongoing use in front of a variety of audiences, including students and teachers from 3rd to 12th grade as well as public audiences

Recurrence Plot Based Measures of Complexity and its Application to Heart Rate Variability Data

The knowledge of transitions between regular, laminar or chaotic behavior is essential to understand the underlying mechanisms behind complex systems. While several linear approaches are often insufficient to describe such processes, there are several nonlinear methods which however require rather long time observations. To overcome these difficulties, we propose measures of complexity based on vertical structures in recurrence plots and apply them to the logistic map as well as to heart rate variability data. For the logistic map these measures enable us not only to detect transitions between chaotic and periodic states, but also to identify laminar states, i.e. chaos-chaos transitions. The traditional recurrence quantification analysis fails to detect the latter transitions. Applying our new measures to the heart rate variability data, we are able to detect and quantify the laminar phases before a life-threatening cardiac arrhythmia occurs thereby facilitating a prediction of such an event. Our findings could be of importance for the therapy of malignant cardiac arrhythmias

Mechanisms of Hemolysis-Associated Platelet Activation

Background Intravascular hemolysis occurs after blood transfusion, in hemolytic anemias, and in other conditions, and is associated with hypercoagulable states. Hemolysis has been shown to potently activate platelets in vitro and in vivo, and several mechanisms have been suggested to account for this, including: (i) direct activation by hemoglobin (Hb); (ii) increase in reactive oxygen species (ROS); (iii) scavenging of nitric oxide (NO) by released Hb; and (iv) release of intraerythrocytic ADP. Objective To elucidate the mechanism of hemolysis-mediated platelet activation. Methods We used flow cytometry to detect PAC-1 binding to activated platelets for in vitro experiments, and a Siemens\u27 Advia 120 hematology system to assess platelet aggregation by using platelet counts from in vivo experiments in a rodent model. Results We found that Hb did not directly activate platelets. However, ADP bound to Hb could cause platelet activation. Furthermore, platelet activation caused by shearing of red blood cells (RBCs) was reduced in the presence of apyrase, which metabolizes ADP to AMP. The use of ROS scavengers did not affect platelet activation. We also found that cell-free Hb enhanced platelet activation by abrogating the inhibitory effect of NO on platelet activation. In vivo infusions of ADP and purified (ADP-free) Hb, as well as hemolysate, resulted in platelet aggregation, as shown by decreased platelet counts. Conclusion Two primary mechanisms account for RBC hemolysis-associated platelet activation: ADP release, which activates platelets; and cell-free Hb release, which enhances platelet activation by lowering NO bioavailability

Polarization of coalitions in an agent-based model of political discourse

Political discourse is the verbal interaction between political actors in a policy domain. This article explains the formation of polarized advocacy or discourse coalitions in this complex phenomenon by presenting a dynamic, stochastic, and discrete agent-based model based on graph theory and local optimization. In a series of thought experiments, actors compute their utility of contributing a specific statement to the discourse by following ideological criteria, preferential attachment, agenda-setting strategies, governmental coherence, or other mechanisms. The evolving macro-level discourse is represented as a dynamic network and evaluated against arguments from the literature on the policy process. A simple combination of four theoretical mechanisms is already able to produce artificial policy debates with theoretically plausible properties. Any sufficiently realistic configuration must entail innovative and path-dependent elements as well as a blend of exogenous preferences and endogenous opinion formation mechanisms

CXCR2 deficient mice display macrophage-dependent exaggerated acute inflammatory responses

CXCR2 is an essential regulator of neutrophil recruitment to inflamed and damaged sites and plays prominent roles in inflammatory pathologies and cancer. It has therefore been highlighted as an important therapeutic target. However the success of the therapeutic targeting of CXCR2 is threatened by our relative lack of knowledge of its precise in vivo mode of action. Here we demonstrate that CXCR2-deficient mice display a counterintuitive transient exaggerated inflammatory response to cutaneous and peritoneal inflammatory stimuli. In both situations, this is associated with reduced expression of cytokines associated with the resolution of the inflammatory response and an increase in macrophage accumulation at inflamed sites. Analysis using neutrophil depletion strategies indicates that this is a consequence of impaired recruitment of a non-neutrophilic CXCR2 positive leukocyte population. We suggest that these cells may be myeloid derived suppressor cells. Our data therefore reveal novel and previously unanticipated roles for CXCR2 in the orchestration of the inflammatory response