Design and validation of an unmanned surface vehicle simulation mode

In this paper we present a multiphysics simulation model of Halcyon, an autonomous unmanned surface vehicle (USV). The simulation model presented in this paper has been developed to rapidly progress the design, development and validation of Halcyon's autonomy management system, particularly in challenging sea conditions. Using simulation for this purpose enables extensive testing across the full environmental operating envelope of the vessel, hence greatly reducing the need for real-world sea-trials. The simulator is comprised of a novel and comprehensive sea-surface wave environment model, a six degree of freedom nonlinear unified seakeeping and manoeuvring boat dynamics model, an actuation dynamics model, an autopilot and an interface with an autonomy management system. Results are presented that show good agreement between real-world and simulated sea-trials data

Static and Dynamic Lung Volumes in Swimmers and Their Ventilatory Response to Maximal Exercise

Purpose While the static and dynamic lung volumes of active swimmers is often greater than the predicted volume of similarly active non-swimmers, little is known if their ventilatory response to exercise is also different. Methods Three groups of anthropometrically matched male adults were recruited, daily active swimmers (n = 15), daily active in fields sport (Rugby and Football) (n = 15), and recreationally active (n = 15). Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and maximal voluntary ventilation (MVV) was measured before and after exercise to volitional exhaustion. Results Swimmers had significantly larger FVC (6.2 ± 0.6 l, 109 ± 9% pred) than the other groups (5.6 ± 0.5 l, 106 ± 13% pred, 5.5 ± 0.8, 99% pred, the sportsmen and recreational groups, respectively). FEV1 and MVV were not different. While at peak exercise, all groups reached their ventilatory reserve (around 20%), the swimmers had a greater minute ventilation rate than the recreational group (146 ± 19 vs 120 ± 87 l/min), delivering this volume by breathing deeper and slower. Conclusions The swimmers utilised their larger static volumes (FVC) differently during exercise by meeting their ventilation volume through long and deep breaths

Maggot secretions suppress pro-inflammatory responses of human monocytes through elevation of cyclic AMP

AIMS/HYPOTHESIS: Maggots of the blowfly Lucilia sericata are used for the treatment of chronic wounds. As monocytes may contribute to the excessive inflammatory responses in such wounds, this study focussed on the effects of maggot secretions on the pro-inflammatory activities of these cells. METHODS: Freshly isolated monocytes were incubated with a range of secretions for 1 h and then stimulated with lipopolysaccharides (range 0-100 ng/ml) or lipoteichoic acid (range 0-5 microg/ml) for 18 h. The expression of cell surface molecules, cytokine and chemokine levels in culture supernatants, cell viability, chemotaxis, and phagocytosis and killing of Staphylococcus aureus were measured. RESULTS: Maggot secretions dose-dependently inhibited production of the pro-inflammatory cytokines TNF-alpha, IL-12p40 and macrophage migration inhibitory factor by lipopolysaccharides- and lipoteichoic acid-stimulated monocytes, while enhancing production of the anti-inflammatory cytokine IL-10. Expression of cell surface receptors involved in pathogen recognition remained unaffected by secretions. In addition, maggot secretions altered the chemokine profile of monocytes by downregulating macrophage inflammatory protein-1beta and upregulating monocyte chemoattractant protein-1 and IL-8. Nevertheless, chemotactic responses of monocytes were inhibited by secretions. Furthermore, maggot secretions did not affect phagocytosis and intracellular killing of S. aureus by human monocytes. Finally, secretions induced a transient rise in the intracellular cyclic AMP concentration in monocytes and Rp-cyclic AMPS inhibited the effects of secretions. CONCLUSIONS/INTERPRETATION: Maggot secretions inhibit the pro-inflammatory responses of human monocytes through a cyclic AMP-dependent mechanism. Regulation of the inflammatory processes by maggots contributes to their beneficial effects on chronic wound

Computational Analysis of Phosphopeptide Binding to the Polo-Box Domain of the Mitotic Kinase PLK1 Using Molecular Dynamics Simulation

The Polo-Like Kinase 1 (PLK1) acts as a central regulator of mitosis and is over-expressed in a wide range of human tumours where high levels of expression correlate with a poor prognosis. PLK1 comprises two structural elements, a kinase domain and a polo-box domain (PBD). The PBD binds phosphorylated substrates to control substrate phosphorylation by the kinase domain. Although the PBD preferentially binds to phosphopeptides, it has a relatively broad sequence specificity in comparison with other phosphopeptide binding domains. We analysed the molecular determinants of recognition by performing molecular dynamics simulations of the PBD with one of its natural substrates, CDC25c. Predicted binding free energies were calculated using a molecular mechanics, Poisson-Boltzmann surface area approach. We calculated the per-residue contributions to the binding free energy change, showing that the phosphothreonine residue and the mainchain account for the vast majority of the interaction energy. This explains the very broad sequence specificity with respect to other sidechain residues. Finally, we considered the key role of bridging water molecules at the binding interface. We employed inhomogeneous fluid solvation theory to consider the free energy of water molecules on the protein surface with respect to bulk water molecules. Such an analysis highlights binding hotspots created by elimination of water molecules from hydrophobic surfaces. It also predicts that a number of water molecules are stabilized by the presence of the charged phosphate group, and that this will have a significant effect on the binding affinity. Our findings suggest a molecular rationale for the promiscuous binding of the PBD and highlight a role for bridging water molecules at the interface. We expect that this method of analysis will be very useful for probing other protein surfaces to identify binding hotspots for natural binding partners and small molecule inhibitors

T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations

Identifying Work System Components and Constraints of Cancer Multidisciplinary Team Meetings

Multidisciplinary teams have been introduced into cancer care to improve quality of care and are now considered the gold standard for the management of cancer patients in the UK. Meetings of these teams provide an opportunity for experts to discuss the best possible treatment options for the patient. Trends show that referral numbers to these meetings are increasing, placing strain on the capacity of meetings to function optimally. This in turn has cognitive and workload implications for staff involved. Promoting MDT Excellence is a project that aims to examine the variation in practice of these meetings across one NHS Trust and to understand the challenges they are currently facing. In the first phase of this project, a systems analysis of cancer multidisciplinary teams was conducted for the purpose of identifying system constraints and resource issues. A total of twelve meetings were observed, and 42 staff from four specialties were interviewed. Using the SEIPS 2.0 model, key work system components and constraints for multidisciplinary team meetings were identified for the people involved, the tasks, tools and technology, organisation of work, internal environment and external environment. Furthermore, aspects that promoted efficient ways of working and positive outcomes were captured. Examples identified included adopting a more structured agenda, real time digital notetaking and different work organisation techniques, such as distribution of responsibilities and the scheduling of patient groups to be discussed during the meeting. These results provide the basis for a multifaceted approach for system improvement for this work process

Identifying Work System Components and Constraints of Cancer Multidisciplinary Team Meetings

Multidisciplinary teams have been introduced into cancer care to improve quality of care and are now considered the gold standard for the management of cancer patients in the UK. Meetings of these teams provide an opportunity for experts to discuss the best possible treatment options for the patient. Trends show that referral numbers to these meetings are increasing, placing strain on the capacity of meetings to function optimally. This in turn has cognitive and workload implications for staff involved. Promoting MDT Excellence is a project that aims to examine the variation in practice of these meetings across one NHS Trust and to understand the challenges they are currently facing. In the first phase of this project, a systems analysis of cancer multidisciplinary teams was conducted for the purpose of identifying system constraints and resource issues. A total of twelve meetings were observed, and 42 staff from four specialties were interviewed. Using the SEIPS 2.0 model, key work system components and constraints for multidisciplinary team meetings were identified for the people involved, the tasks, tools and technology, organisation of work, internal environment and external environment. Furthermore, aspects that promoted efficient ways of working and positive outcomes were captured. Examples identified included adopting a more structured agenda, real time digital notetaking and different work organisation techniques, such as distribution of responsibilities and the scheduling of patient groups to be discussed during the meeting. These results provide the basis for a multifaceted approach for system improvement for this work process