Neutrophil extracellular traps in chronic lung disease:implications for pathogenesis and therapy

Neutrophilic inflammation has a key role in the pathophysiology of multiple chronic lung diseases. The formation of neutrophil extracellular traps (NETs) has emerged as a key mechanism of disease in neutrophilic lung diseases including asthma, COPD, cystic fibrosis and, most recently, bronchiectasis. NETs are large, web-like structures composed of DNA and anti-microbial proteins that are able to bind pathogens, prevent microbial dissemination and degrade bacterial virulence factors. The release of excess concentrations of proteases, antimicrobial proteins, DNA and histones, however, also leads to tissue damage, impaired mucociliary clearance, impaired bacterial killing and increased inflammation. A number of studies have linked airway NET formation with greater disease severity, increased exacerbations and overall worse disease outcomes across the spectrum of airway diseases. Treating neutrophilic inflammation has been challenging in chronic lung disease because of the delicate balance between reducing inflammation and increasing the risk of infections through immunosuppression. Novel approaches to suppressing NET formation or the associated inflammation are in development and represent an important therapeutic target. This review will discuss the relationship between NETs and the pathophysiology of cystic fibrosis, asthma, COPD and bronchiectasis, and explore the current and future development of NET-targeting therapies

Is the Scottish population living dangerously? Prevalence of multiple risk factors: the Scottish Health Survey 2003

<b>Background:</b> Risk factors are often considered individually, we aimed to investigate the prevalence of combinations of multiple behavioural risk factors and their association with socioeconomic determinants.<p></p> <b>Methods:</b> Multinomial logistic regression was used to model the associations between socioeconomic factors and multiple risk factors from data in the Scottish Health Survey 2003. Prevalence of five main behavioural risk factors - smoking alcohol, diet, overweight/obesity, and physical inactivity, and the odds in relation to demographic, individual and area socioeconomic factors.<p></p> <b>Results:</b> Full data were available on 6,574 subjects (80.7% of the survey sample). Nearly the whole adult population (97.5%) reported to have at least one behavioural risk factor; while 55% have three or more risk factors; and nearly 20% have four or all five risk factors. The most important determinants for having four or five multiple risk factors were low educational attainment which conferred around a 3-fold increased odds compared to high education; and residence in the most deprived communities (relative to least deprived) which had greater than 3-fold increased odds.<p></p> <b>Conclusions:</b> The prevalence of multiple behavioural risk factors was high and the prevalence of absence of all risk factors very low. These behavioural patterns were socioeconomically determined. Policy to address factors needs to be joined up and better consider underlying socioeconomic circumstances.<p></p&gt

Two-dimensional colloidal fluids exhibiting pattern formation

Fluids with competing short range attraction and long range repulsive interactions between the particles can exhibit a variety of microphase separated structures. We develop a lattice-gas (generalised Ising) model and analyse the phase diagram using Monte Carlo computer simulations and also with density functional theory (DFT). The DFT predictions for the structures formed are in good agreement with the results from the simulations, which occur in the portion of the phase diagram where the theory predicts the uniform fluid to be linearly unstable. However, the mean-field DFT does not correctly describe the transitions between the different morphologies, which the simulations show to be analogous to micelle formation. We determine how the heat capacity varies as the model parameters are changed. There are peaks in the heat capacity at state points where the morphology changes occur. We also map the lattice model onto a continuum DFT that facilitates a simplification of the stability analysis of the uniform fluid.Comment: 13 pages, 15 figure

Aspirated capacitor measurements of air conductivity and ion mobility spectra

Measurements of ions in atmospheric air are used to investigate atmospheric electricity and particulate pollution. Commonly studied ion parameters are (1) air conductivity, related to the total ion number concentration, and (2) the ion mobility spectrum, which varies with atmospheric composition. The physical principles of air ion instrumentation are long-established. A recent development is the computerised aspirated capacitor, which measures ions from (a) the current of charged particles at a sensing electrode, and (b) the rate of charge exchange with an electrode at a known initial potential, relaxing to a lower potential. As the voltage decays, only ions of higher and higher mobility are collected by the central electrode and contribute to the further decay of the voltage. This enables extension of the classical theory to calculate ion mobility spectra by inverting voltage decay time series. In indoor air, ion mobility spectra determined from both the novel voltage decay inversion, and an established voltage switching technique, were compared and shown to be of similar shape. Air conductivities calculated by integration were: 5.3 +- 2.5 fS/m and 2.7 +- 1.1 fS/m respectively, with conductivity determined to be 3 fS/m by direct measurement at a constant voltage. Applications of the new Relaxation Potential Inversion Method (RPIM) include air ion mobility spectrum retrieval from historical data, and computation of ion mobility spectra in planetary atmospheres.Comment: To be published in Review of Scientific Instrument

Inhaled corticosteroids and the lung microbiome in copd

The Global Initiative for Chronic Obstructive Lung Disease 2021 Report recommends inhaled corticosteroid (ICS)-containing regimens as part of pharmacological treatment in patients with chronic obstructive lung disease (COPD) and frequent exacerbations, particularly with eosinophilic inflammation. However, real-world studies reveal overprescription of ICS in COPD, irrespective of disease presentation and inflammatory endotype, leading to increased risk of side effects, mainly respiratory infections. The optimal use of ICS in COPD therefore remains an area of intensive research, and additional biomarkers of benefit and risk are needed. Although the interplay between inflammation and infection in COPD is widely acknowledged, the role of the microbiome in shaping lower airway inflammation has only recently been explored. Next-generation sequencing has revealed that COPD disease progression and exacerbation frequency are associated with changes in the composition of the lung microbiome, and that the immunosuppressive effects of ICS can contribute to potentially deleterious airway microbiota changes by increasing bacterial load and the abundance of potentially pathogenic taxa such as Streptococcus and Haemophilus. Here, we explore the relationship between microbiome, inflammation, ICS use and disease phenotype. This relationship may inform the benefit:risk assessment of ICS use in patients with COPD and lead to more personalised pharmacological management

Simplifying Algebra in Feynman Graphs, Part III: Massive Vectors

A T-dualized selfdual inspired formulation of massive vector fields coupled to arbitrary matter is generated; subsequently its perturbative series modeling a spontaneously broken gauge theory is analyzed. The new Feynman rules and external line factors are chirally minimized in the sense that only one type of spin index occurs in the rules. Several processes are examined in detail and the cross-sections formulated in this approach. A double line formulation of the Lorentz algebra for Feynman diagrams is produced in this formalism, similar to color ordering, which follows from a spin ordering of the Feynman rules. The new double line formalism leads to further minimization of gauge invariant scattering in perturbation theory. The dualized electroweak model is also generated.Comment: 39 pages, LaTeX, 8 figure

Can Modal Skepticism Defeat Humean Skepticism?

My topic is moderate modal skepticism in the spirit of Peter van Inwagen. Here understood, this is a conservative version of modal empiricism that severely limits the extent to which an ordinary agent can reasonably believe “exotic” possibility claims. I offer a novel argument in support of this brand of skepticism: modal skepticism grounds an attractive (and novel) reply to Humean skepticism. Thus, I propose that modal skepticism be accepted on the basis of its theoretical utility as a tool for dissolving philosophical paradox

Artificial Brains and Hybrid Minds

The paper develops two related thought experiments exploring variations on an ‘animat’ theme. Animats are hybrid devices with both artificial and biological components. Traditionally, ‘components’ have been construed in concrete terms, as physical parts or constituent material structures. Many fascinating issues arise within this context of hybrid physical organization. However, within the context of functional/computational theories of mentality, demarcations based purely on material structure are unduly narrow. It is abstract functional structure which does the key work in characterizing the respective ‘components’ of thinking systems, while the ‘stuff’ of material implementation is of secondary importance. Thus the paper extends the received animat paradigm, and investigates some intriguing consequences of expanding the conception of bio-machine hybrids to include abstract functional and semantic structure. In particular, the thought experiments consider cases of mind-machine merger where there is no physical Brain-Machine Interface: indeed, the material human body and brain have been removed from the picture altogether. The first experiment illustrates some intrinsic theoretical difficulties in attempting to replicate the human mind in an alternative material medium, while the second reveals some deep conceptual problems in attempting to create a form of truly Artificial General Intelligence

Illusions of gunk

The possibility of gunk has been used to argue against mereological nihilism. This paper explores two responses on the part of the microphysical mereological nihilist: (1) the contingency defence, which maintains that nihilism is true of the actual world; but that at other worlds, composition occurs; (2) the impossibility defence, which maintains that nihilism is necessary true, and so gunk worlds are impossible. The former is argued to be ultimately unstable; the latter faces the explanatorily burden of explaining the illusion that gunk is possible. It is argued that we can discharge this burden by focussing on the contingency of the microphysicalist aspect of microphysical mereological nihilism. The upshot is that gunk-based arguments against microphysical mereological nihilism can be resisted