Abstract From a critical review of the evidence on the cholinergic anti-inflammatory pathway and its mode of action, the following conclusions were reached. (1) Both local and systemic inflammation ...may be suppressed by electrical stimulation of the peripheral cut end of either vagus. (2) The spleen mediates most of the systemic inflammatory response (measured by TNF-α production) to systemic endotoxin and is also the site where that response is suppressed by vagal stimulation. (3) The anti-inflammatory effect of vagal stimulation depends on the presence of noradrenaline-containing nerve terminals in the spleen. (4) There is no disynaptic connection from the vagus to the spleen via the splenic sympathetic nerve: vagal stimulation does not drive action potentials in the splenic nerve. (5) Acetylcholine-synthesizing T lymphocytes provide an essential non-neural link in the anti-inflammatory pathway from vagus to spleen. (6) Alpha-7 subunit-containing nicotinic receptors are essential for the vagal anti-inflammatory action: their critical location is uncertain, but is suggested here to be on splenic sympathetic nerve terminals. (7) The vagal anti-inflammatory pathway can be activated electrically or pharmacologically, but it is not the efferent arm of the inflammatory reflex response to endotoxemia.
The handling of missing data is a challenge for inference and regression modelling. A particular challenge is dealing with missing predictor information, particularly when trying to build and make ...predictions from models for use in clinical practice.
We utilise a flexible Bayesian approach for handling missing predictor information in regression models. This provides practitioners with full posterior predictive distributions for both the missing predictor information (conditional on the observed predictors) and the outcome-of-interest. We apply this approach to a previously proposed counterfactual treatment selection model for type 2 diabetes second-line therapies. Our approach combines a regression model and a Dirichlet process mixture model (DPMM), where the former defines the treatment selection model, and the latter provides a flexible way to model the joint distribution of the predictors.
We show that DPMMs can model complex relationships between predictor variables and can provide powerful means of fitting models to incomplete data (under missing-completely-at-random and missing-at-random assumptions). This framework ensures that the posterior distribution for the parameters and the conditional average treatment effect estimates automatically reflect the additional uncertainties associated with missing data due to the hierarchical model structure. We also demonstrate that in the presence of multiple missing predictors, the DPMM model can be used to explore which variable(s), if collected, could provide the most additional information about the likely outcome.
When developing clinical prediction models, DPMMs offer a flexible way to model complex covariate structures and handle missing predictor information. DPMM-based counterfactual prediction models can also provide additional information to support clinical decision-making, including allowing predictions with appropriate uncertainty to be made for individuals with incomplete predictor data.
Advances in scientific computing have allowed the development of complex models that are being routinely applied to problems in disease epidemiology, public health and decision making. The utility of ...these models depends in part on how well they can reproduce empirical data. However, fitting such models to real world data is greatly hindered both by large numbers of input and output parameters, and by long run times, such that many modelling studies lack a formal calibration methodology. We present a novel method that has the potential to improve the calibration of complex infectious disease models (hereafter called simulators). We present this in the form of a tutorial and a case study where we history match a dynamic, event-driven, individual-based stochastic HIV simulator, using extensive demographic, behavioural and epidemiological data available from Uganda. The tutorial describes history matching and emulation. History matching is an iterative procedure that reduces the simulator's input space by identifying and discarding areas that are unlikely to provide a good match to the empirical data. History matching relies on the computational efficiency of a Bayesian representation of the simulator, known as an emulator. Emulators mimic the simulator's behaviour, but are often several orders of magnitude faster to evaluate. In the case study, we use a 22 input simulator, fitting its 18 outputs simultaneously. After 9 iterations of history matching, a non-implausible region of the simulator input space was identified that was 10(11) times smaller than the original input space. Simulator evaluations made within this region were found to have a 65% probability of fitting all 18 outputs. History matching and emulation are useful additions to the toolbox of infectious disease modellers. Further research is required to explicitly address the stochastic nature of the simulator as well as to account for correlations between outputs.
Much progress has been made during the past 30 years with respect to elucidating the neural and endocrine pathways by which bodily needs for water and energy are brought to conscious awareness ...through the generation of thirst and hunger. One way that circulating hormones influence thirst and hunger is by acting on neurones within sensory circumventricular organs (CVOs). This is possible because the subfornical organ and organum vasculosum of the lamina terminalis (OVLT), the sensory CVOs in the forebrain, and the area postrema in the hindbrain lack a normal blood‐brain barrier such that neurones within them are exposed to blood‐borne agents. The neural signals generated by hormonal action in these sensory CVOs are relayed to several sites in the cerebral cortex to stimulate or inhibit thirst or hunger. The subfornical organ and OVLT respond to circulating angiotensin II, relaxin and hypertonicity to drive thirst‐related neural pathways, whereas circulating amylin, leptin and possibly glucagon‐like peptide‐1 act at the area postrema to influence neural pathways inhibiting food intake. As a result of investigations using functional brain imaging techniques, the insula and anterior cingulate cortex, as well as several other cortical sites, have been implicated in the conscious perception of thirst and hunger in humans. Viral tracing techniques show that the anterior cingulate cortex and insula receive neural inputs from thirst‐related neurones in the subfornical organ and OVLT, with hunger‐related neurones in the area postrema having polysynaptic efferent connections to these cortical regions. For thirst, initially, the median preoptic nucleus and, subsequently, the thalamic paraventricular nucleus and lateral hypothalamus have been identified as likely sites of synaptic links in pathways from the subfornical organ and OVLT to the cortex. The challenge remains to identify the links in the neural pathways that relay signals originating in sensory CVOs to cortical sites subserving either thirst or hunger.
Key points
It is believed that the CNS controls inflammation via the autonomic nervous system, but the strength of this action and the neural pathways responsible are unclear.
In anaesthetized rats ...we measured the inflammatory response to lipopolysaccharide (LPS, 60 μg kg−1, i.v.) by plasma tumour necrosis factor α (TNFα) levels 90 min later.
Bilateral section of the splanchnic sympathetic nerves before LPS treatment resulted in a 5‐fold increase in the plasma TNFα response, but bilateral vagotomy had no effect.
LPS treatment strongly increased efferent activity in the splanchnic sympathetic nerve and its splenic branch; vagotomy did not affect this.
These results show that, besides directly stimulating inflammation, LPS engages a powerful anti‐inflammatory reflex that can inhibit the plasma TNFα response by 80%.
The reflex efferent arm is in the splanchnic sympathetic nerves; the vagi play no part.
We investigated a neural reflex that controls the strength of inflammatory responses to immune challenge – the inflammatory reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 μg kg−1), we found strong increases in plasma levels of the key inflammatory mediator tumour necrosis factor α (TNFα) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5‐fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural reflex that is powerful enough to cause an 80% suppression of the acute systemic inflammatory response. The efferent arm of this reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this reflex could play an important role in immune function as well as inflammatory diseases.
Geoscience methods are increasingly being utilised in criminal, environmental and humanitarian forensic investigations, and the use of such methods is supported by a growing body of experimental and ...theoretical research. Geoscience search techniques can complement traditional methodologies in the search for buried objects, including clandestine graves, weapons, explosives, drugs, illegal weapons, hazardous waste and vehicles. This paper details recent advances in search and detection methods, with case studies and reviews. Relevant examples are given, together with a generalised workflow for search and suggested detection technique(s) table. Forensic geoscience techniques are continuing to rapidly evolve to assist search investigators to detect hitherto difficult to locate forensic targets.
The ‘inflammatory reflex’ acts through efferent neural connections from the central nervous system to lymphoid organs, particularly the spleen, that suppress the production of inflammatory cytokines. ...Stimulation of the efferent vagus has been shown to suppress inflammation in a manner dependent on the spleen and splenic nerves. The vagus does not innervate the spleen, so a synaptic connection from vagal preganglionic neurons to splenic sympathetic postganglionic neurons was suggested. We tested this idea in rats. In a preparatory operation, the anterograde tracer DiI was injected bilaterally into the dorsal motor nucleus of vagus and the retrograde tracer Fast Blue was injected into the spleen. On histological analysis 7–9 weeks later, 883 neurons were retrogradely labelled from the spleen with Fast Blue as follows: 89% in the suprarenal ganglia (65% left, 24% right); 11% in the left coeliac ganglion; but none in the right coeliac or either of the superior mesenteric ganglia. Vagal terminals anterogradely labelled with DiI were common in the coeliac but sparse in the suprarenal ganglia, and confocal analysis revealed no putative synaptic connection with any Fast Blue‐labelled cell in either ganglion. Electrophysiological experiments in anaesthetized rats revealed no effect of vagal efferent stimulation on splenic nerve activity or on that of 15 single splenic‐projecting neurons recorded in the suprarenal ganglion. Together, these findings indicate that vagal efferent neurons in the rat neither synapse with splenic sympathetic neurons nor drive their ongoing activity.
Potentially Toxic Elements (PTEs) otherwise known as heavy metals are ubiquitous in soils and can have a range of negative health and environmental impacts. In terrestrial systems understanding how ...PTEs move in the environment is made challenging by the complex interactions within soil and the wider environment and the compositional nature of PTEs. PTEs are compositional because data of individual PTEs within in a sample are ratios which may be under a sum constraint, where individual components sum up to a whole. In this study three different scenarios were considered, one using the centred log ratio transformation (clr) a compositional transformation, the more “traditional” log10 transformation (log10) and untransformed data acting as a comparison (unt) were applied to four different datasets. Three were the Liver, Muscle and Kidney tissue of Eurasian Badgers (Meles meles) and the fourth was soil and data were extracted from a regional geospatial survey. Cluster analysis demonstrated that the clr and log10 transformation were able to resolve compositional trends at the point of the individual sample, whilst unt could not and did not meet the preconditions for the next phase of analysis. At the level of compositional trends between PTEs complex heatmaps demonstrated that clr was able to isolate PTE relationships and highlight commonalities between different datasets, whilst log10 could not. In the final phase, principal component analysis (PCA) of the clr transformation showed similarities between the signals in the soft tissues and the disparities they had with soil, whilst the log10 transformation was unable to achieve this. Overall, the clr transformation was shown to perform more consistently under a variety of analytical scenarios and the compositional approach will provide more realistic interpretations about PTEs in both soil and animal soft tissue than the log10 or unt conditions.
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•First ecotoxicological study to compare compositional and “traditional” approaches•Both log10 and clr resolve compositional trends at the point of the individual.•The clr transformation is best able to resolve trends between PTEs.•A compositional approach should be adopted for terrestrial ecotoxicology.
In recent decades, Saiga antelope (
Saiga t. tatarica
) mass die-offs have become more common. The mass die-off of 2015 in central Kazakhstan, recorded 140,000 individual deaths across multiple ...herds. Previously, research has shown atmospheric humidity, the bacterium
Pasteurella multocida
serotype B, and resultant haemorrhagic septicaemia, were the primary cause. However, other synergistic factors may have impacted this process. Here we use a multivariate compositional data analysis (CoDA) approach to assess what other factors may have been involved. We show a pollutant linkage mechanism where relative humidity and dewpoint temperature combine with environmental pollutants, potentially toxic elements (e.g., Hg, As), complex carbon compounds (e.g., Acetone, Toluene), and inorganic compounds (e.g., CHx, SO
2
) which affected the Saiga during the calving season (start and peak) and at the onset of the mass die-off. We suggest a mechanism for this process. Upon arrival at their carving grounds, the Saiga experienced a sudden precipitation event, a spike in temperatures, and resultant high humidity occurs. The infectious bacterium
P
.
multocida
serotype B then spreads. Further, environmental pollutants contained within steppe soils are released to the air, forming localised smog events, these synergistically combine, and mass die-off occurs.
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