Predicting asthma control and exacerbations: chronic asthma as a complex dynamic model

PURPOSE OF REVIEW: Predicting asthma episodes is notoriously difficult but has potentially significant consequences for the individual, as well as for healthcare services. The purpose of this review is to describe recent insights into the prediction of acute asthma episodes in relation to classical clinical, functional or inflammatory variables, as well as present a new concept for evaluating asthma as a dynamically regulated homeokinetic system. RECENT FINDINGS: Risk prediction for asthma episodes or relapse has been attempted using clinical scoring systems, considerations of environmental factors and lung function, as well as inflammatory and immunological markers in induced sputum or exhaled air, and these are summarized here. We have recently proposed that newer mathematical methods derived from statistical physics may be used to understand the complexity of asthma as a homeokinetic, dynamic system consisting of a network comprising multiple components, and also to assess the risk for future asthma episodes based on fluctuation analysis of long time series of lung function. SUMMARY: Apart from the classical analysis of risk factor and functional parameters, this new approach may be used to assess asthma control and treatment effects in the individual as well as in future research trials.

Variability of lung function predicts loss of asthma control following withdrawal of inhaled corticosteroid treatment

BACKGROUND One aspect of a multidimensional approach to understanding asthma as a complex dynamic disease is to study how lung function varies with time. Variability measures of lung function have been shown to predict response to beta(2)-agonist treatment. An investigation was conducted to determine whether mean, coefficient of variation (CV) or autocorrelation, a measure of short-term memory, of peak expiratory flow (PEF) could predict loss of asthma control following withdrawal of regular inhaled corticosteroid (ICS) treatment, using data from a previous study. METHODS 87 adult patients with mild to moderate asthma who had been taking ICS at a constant dose for at least 6 months were monitored for 2-4 weeks. ICS was then withdrawn and monitoring continued until loss of control occurred as per predefined criteria. Twice-daily PEF was recorded during monitoring. Associations between loss of control and mean, CV and autocorrelation of morning PEF within 2 weeks pre- and post-ICS withdrawal were assessed using Cox regression analysis. Predictive utility was assessed using receiver operator characteristics. RESULTS 53 out of 87 patients had sufficient PEF data over the required analysis period. The mean (389 vs 370 l/min, p<0.0001) and CV (4.5% vs 5.6%, p=0.007) but not autocorrelation of PEF changed significantly from prewithdrawal to postwithdrawal in subjects who subsequently lost control, and were unaltered in those who did not. These changes were related to time to loss of control. CV was the most consistent predictor, with similar sensitivity and sensitivity to exhaled nitric oxide. CONCLUSION A simple, easy to obtain variability measure of daily lung function such as the CV may predict loss of asthma control within the first 2 weeks of ICS withdrawal.

Dynamic of ion channel expression at the plasma membrane of cardiomyocytes

Cardiac myocytes are characterized by distinct structural and functional entities involved in the generation and transmission of the action potential and the excitation-contraction coupling process. Key to their function is the specific organization of ion channels and transporters to and within distinct membrane domains, which supports the anisotropic propagation of the depolarization wave. This review addresses the current knowledge on the molecular actors regulating the distinct trafficking and targeting mechanisms of ion channels in the highly polarized cardiac myocyte. In addition to ubiquitous mechanisms shared by other excitable cells, cardiac myocytes show unique specialization, illustrated by the molecular organization of myocyte-myocyte contacts, e.g., the intercalated disc and the gap junction. Many factors contribute to the specialization of the cardiac sarcolemma and the functional expression of cardiac ion channels, including various anchoring proteins, motors, small GTPases, membrane lipids, and cholesterol. The discovery of genetic defects in some of these actors, leading to complex cardiac disorders, emphasizes the importance of trafficking and targeting of ion channels to cardiac function. A major challenge in the field is to understand how these and other actors work together in intact myocytes to fine-tune ion channel expression and control cardiac excitability.

Simulating the impact of four control strategies on the population dynamics of Neospora caninum infection in Swiss dairy cattle

A dynamic deterministic simulation model was developed to assess the impact of different putative control strategies on the seroprevalence of Neospora caninum in female Swiss dairy cattle. The model structure comprised compartments of "susceptible" and "infected" animals (SI-model) and the cattle population was divided into 12 age classes. A reference model (Model 1) was developed to simulate the current (status quo) situation (present seroprevalence in Switzerland 12%), taking into account available demographic and seroprevalence data of Switzerland. Model 1 was modified to represent four putative control strategies: testing and culling of seropositive animals (Model 2), discontinued breeding with offspring from seropositive cows (Model 3), chemotherapeutic treatment of calves from seropositive cows (Model 4), and vaccination of susceptible and infected animals (Model 5). Models 2-4 considered different sub-scenarios with regard to the frequency of diagnostic testing. Multivariable Monte Carlo sensitivity analysis was used to assess the impact of uncertainty in input parameters. A policy of annual testing and culling of all seropositive cattle in the population reduced the seroprevalence effectively and rapidly from 12% to <1% in the first year of simulation. The control strategies with discontinued breeding with offspring from all seropositive cows, chemotherapy of calves and vaccination of all cattle reduced the prevalence more slowly than culling but were still very effective (reduction of prevalence below 2% within 11, 23 and 3 years of simulation, respectively). However, sensitivity analyses revealed that the effectiveness of these strategies depended strongly on the quality of the input parameters used, such as the horizontal and vertical transmission factors, the sensitivity of the diagnostic test and the efficacy of medication and vaccination. Finally, all models confirmed that it was not possible to completely eradicate N. caninum as long as the horizontal transmission process was not interrupted.

Complexity of chronic asthma and chronic obstructive pulmonary disease: implications for risk assessment, and disease progression and control

Although assessment of asthma control is important to guide treatment, it is difficult since the temporal pattern and risk of exacerbations are often unpredictable. In this Review, we summarise the classic methods to assess control with unidimensional and multidimensional approaches. Next, we show how ideas from the science of complexity can explain the seemingly unpredictable nature of bronchial asthma and emphysema, with implications for chronic obstructive pulmonary disease. We show that fluctuation analysis, a method used in statistical physics, can be used to gain insight into asthma as a dynamic disease of the respiratory system, viewed as a set of interacting subsystems (eg, inflammatory, immunological, and mechanical). The basis of the fluctuation analysis methods is the quantification of the long-term temporal history of lung function parameters. We summarise how this analysis can be used to assess the risk of future asthma episodes, with implications for asthma severity and control both in children and adults.

What do case-control studies estimate? Survey of methods and assumptions in published case-control research

To evaluate strategies used to select cases and controls and how reported odds ratios are interpreted, the authors examined 150 case-control studies published in leading general medicine, epidemiology, and clinical specialist journals from 2001 to 2007. Most of the studies (125/150; 83%) were based on incident cases; among these, the source population was mostly dynamic (102/125; 82%). A minority (23/125; 18%) sampled from a fixed cohort. Among studies with incident cases, 105 (84%) could interpret the odds ratio as a rate ratio. Fifty-seven (46% of 125) required the source population to be stable for such interpretation, while the remaining 48 (38% of 125) did not need any assumptions because of matching on time or concurrent sampling. Another 17 (14% of 125) studies with incident cases could interpret the odds ratio as a risk ratio, with 16 of them requiring the rare disease assumption for this interpretation. The rare disease assumption was discussed in 4 studies but was not relevant to any of them. No investigators mentioned the need for a stable population. The authors conclude that in current case-control research, a stable exposure distribution is much more frequently needed to interpret odds ratios than the rare disease assumption. At present, investigators conducting case-control studies rarely discuss what their odds ratios estimate.

Taking an Object-Centric View on Dynamic Information with Object Flow Analysis

A large body of research analyzes the runtime execution of a system to extract abstract behavioral views. Those approaches primarily analyze control flow by tracing method execution events or they analyze object graphs of heap snapshots. However, they do not capture how objects are passed through the system at runtime. We refer to the exchange of objects as the object flow, and we claim that object flow is necessary to analyze if we are to understand the runtime of an object-oriented application. We propose and detail Object Flow Analysis, a novel dynamic analysis technique that takes this new information into account. To evaluate its usefulness, we present a visual approach that allows a developer to study classes and components in terms of how they exchange objects at runtime. We illustrate our approach on three case studies.

Using Dynamic Analysis for API Migration

When changing the API of a framework, we need to migrate its clients. This is best done automatically. In this paper, we focus on API migration where the mechanism for inversion of control changes. We propose to use dynamic analysis for such API migration since structural refactorings alone are often not sufficient. We consider JExample as a case-study. JExample extends JUnit with first-class dependencies and fixture injection. We investigate how dynamically collected information about test coverage and about instances under test can be used to detect dependency injection candidates.

Transactional Memory in a Dynamic Language

Concurrency control is mostly based on locks and is therefore notoriously difficult to use. Even though some programming languages provide high-level constructs, these add complexity and potentially hard-to-detect bugs to the application. Transactional memory is an attractive mechanism that does not have the drawbacks of locks, however the underlying implementation is often difficult to integrate into an existing language. In this paper we show how we have introduced transactional semantics into Smalltalk by using the reflective facilities of the language. Our approach is based on method annotations, incremental parse tree transformations and an optimistic commit protocol. The implementation does not depend on modifications to the virtual machine and therefore can be changed at the language level. We report on a practical case study, benchmarks and further and on-going work.

Dynamic Synchronization: A Synchronization Model through Behavioral Reflection

In conventional software applications, synchronization code is typically interspersed with functional code, thereby impacting understandability and maintainability of the code base. At the same time, the synchronization defined statically in the code is not capable of adapting to different runtime situations. We propose a new approach to concurrency control which strictly separates the functional code from the synchronization requirements to be used and which adapts objects to be synchronized dynamically to their environment. First-class synchronization specifications express safety requirements, and a dynamic synchronization system dynamically adapts objects to different runtime situations. We present an overview of a prototype of our approach together with several classical concurrency problems, and we discuss open issues for further research.

Governing individual learning in the transition phase of software maintenance offshoring: a dynamic perspective

Prior studies suggest that clients need to actively govern knowledge transfer to vendor staff in offshore outsourcing. In this paper, we analyze longitudinal data from four software maintenance offshore out-sourcing projects to explore why governance may be needed for knowledge transfer and how governance and the individual learning of vendor engineers inter-act over time. Our results suggest that self-control is central to learning, but may be hampered by low levels of trust and expertise at the outset of projects. For these foundations to develop, clients initially need to exert high amounts of formal and clan controls to enforce learning activities against barriers to knowledge sharing. Once learning activities occur, trust and expertise increase and control portfolios may show greater emphases on self-control.

Flow disturbances in stent-related coronary evaginations: a computational fluid-dynamic simulation study

Aims: Angiographic ectasias and aneurysms in stented segments have been associated with late stent thrombosis. Using optical coherence tomography (OCT), some stented segments show coronary evaginations reminiscent of ectasias. The purpose of this study was to explore, using computational fluid-dynamic (CFD) simulations, whether OCT-detected coronary evaginations can induce local changes in blood flow. Methods and results: OCT-detected evaginations are defined as outward bulges in the luminal vessel contour between struts, with the depth of the bulge exceeding the actual strut thickness. Evaginations can be characterised cross ectionally by depth and along the stented segment by total length. Assuming an ellipsoid shape, we modelled 3-D evaginations with different sizes by varying the depth from 0.2-1.0 mm, and the length from 1-9 mm. For the flow simulation we used average flow velocity data from non-diseased coronary arteries. The change in flow with varying evagination sizes was assessed using a particle tracing test where the particle transit time within the segment with evagination was compared with that of a control vessel. The presence of the evagination caused a delayed particle transit time which increased with the evagination size. The change in flow consisted locally of recirculation within the evagination, as well as flow deceleration due to a larger lumen - seen as a deflection of flow towards the evagination. Conclusions: CFD simulation of 3-D evaginations and blood flow suggests that evaginations affect flow locally, with a flow disturbance that increases with increasing evagination size.

Region Specific Response of Intervertebral Disc Cells to Complex Dynamic Loading: An Organ Culture Study Using a Dynamic Torsion-Compression Bioreactor

The spine is routinely subjected to repetitive complex loading consisting of axial compression, torsion, flexion and extension. Mechanical loading is one of the important causes of spinal diseases, including disc herniation and disc degeneration. It is known that static and dynamic compression can lead to progressive disc degeneration, but little is known about the mechanobiology of the disc subjected to combined dynamic compression and torsion. Therefore, the purpose of this study was to compare the mechanobiology of the intervertebral disc when subjected to combined dynamic compression and axial torsion or pure dynamic compression or axial torsion using organ culture. We applied four different loading modalities 1. control: no loading (NL), 2. cyclic compression (CC), 3. cyclic torsion (CT), and 4. combined cyclic compression and torsion (CCT) on bovine caudal disc explants using our custom made dynamic loading bioreactor for disc organ culture. Loads were applied for 8 h/day and continued for 14 days, all at a physiological magnitude and frequency. Our results provided strong evidence that complex loading induced a stronger degree of disc degeneration compared to one degree of freedom loading. In the CCT group, less than 10\% nucleus pulposus (NP) cells survived the 14 days of loading, while cell viabilities were maintained above 70\% in the NP of all the other three groups and in the annulus fibrosus (AF) of all the groups. Gene expression analysis revealed a strong up-regulation in matrix genes and matrix remodeling genes in the AF of the CCT group. Cell apoptotic activity and glycosaminoglycan content were also quantified but there were no statistically significant differences found. Cell morphology in the NP of the CCT was changed, as shown by histological evaluation. Our results stress the importance of complex loading on the initiation and progression of disc degeneration.

Effects of anxiety on decision making and visual search Behaviour in dynamic, time-constrained situations

Einleitung Aktuelle empirische Befunde deuten darauf hin, dass Sportler/innen durch Stress und erhöhte Angst eine reduzierte Effizienz bei der Entscheidungsfindung aufweisen (Wilson, 2008). Erklärt werden kann dieser Befund durch die Attentional-Control-Theory (ACT, Eysenck et al., 2007), die postuliert, dass aufmerksamkeitslenkende Prozesse unter Angst gestört werden. Um diese Annahme für komplexe Situationen im Sport zu prüfen, wurden Fußballspieler unter erhöhten und regulären Druckbedingungen verglichen. Methode Je 11 Experten und Nicht-Experten hatten aus der Perspektive des Abwehrspielers die Aufgabe, in zwei mal 24 Spielsituationen so schnell und korrekt wie möglich verbal anzugeben, welche Aktion der ballführende Spieler (in naher vs. ferner Spielsituation) nach Ausblendung der Szene ausführen wird. Während im ersten Block der Druck nicht erhöht wurde, wurden Druckbedingungen im zweiten Block u.a. durch eine Wettkampfsituation und „falscher“ Ergebnisrückmeldung gesteigert. Entscheidungs- und Blickverhalten (u.a. Anzahl Fixationen), Pupillengröße, Zustandsangst und „Mental Effort“ (Wilson, 2008) wurden erfasst. Neben Expertiseunterschieden wurde erwartet, dass erhöhte Angst die Entscheidungseffizienz sowie das Blickverhalten stört (ACT-Annahme), was mit 2 (Experten/Nicht-Experten) x 2 (nahe/ferne Spielsituation) x 2 (hohe/reguläre Druckbedingung) ANOVAs (? = .05) mit Messwiederholungen auf den letzten beiden Faktoren geprüft wurde. Ergebnisse Druckmanipulationen führten zu höherer Zustandsangst und größeren Pupillendurchmessern. Neben Expertiseunterschieden – Experten antworteten schneller, korrekter und zeigten ein situationsangepasstes visuelles Suchverhalten – wiesen beide Gruppen in Drucksituationen längere Antwortzeiten und höheren Mental Effort auf. Erhöhter Druck führte bei Experten zur Reduktion der Fixationsortwechsel für ferne Spielsituationen. Nicht-Experten differenzierten ihr Suchverhalten weder zwischen Bedingungen noch für Spielsituationen. Diskussion Die Resultate bestätigen die ACT-Annahme, dass Angst und Stress die sportliche Leistung durch längere Reaktionszeiten, höhere kognitive Anstrengung und ein teilweise ineffizientes visuelles Suchverhalten negativ beeinflusst. Eine gestörte Balance zwischen Top-Down und Bottom-Up-Prozessen könnte die Ursache sein (Eysenck et al., 2007). Literatur Eysenck, M. W., Derakshan, N., Santos, R., & Calvo, M. G. (2007). Anxiety and cognitive performance: Attentional control theory. Emotion, 7, 336–353. Wilson, M. (2008). From processing efficiency to attentional control: A mechanistic account of the anxiety-performance relationship. International Review of Sport and Exercise Psychology, 1, 184– 201. 2 Vorträge und Poster