Are in vitro estimates of cell diffusivity and cell proliferation rate sensitive to assay geometry?

AbstractCells respond to various biochemical and physical cues during wound-healing and tumour progression. in vitro assays used to study these processes are typically conducted in one particular geometry and it is unclear how the assay geometry affects the capacity of cell populations to spread, or whether the relevant mechanisms, such as cell motility and cell proliferation, are somehow sensitive to the geometry of the assay. In this work we use a circular barrier assay to characterise the spreading of cell populations in two different geometries. Assay 1 describes a tumour-like geometry where a cell population spreads outwards into an open space. Assay 2 describes a wound-like geometry where a cell population spreads inwards to close a void. We use a combination of discrete and continuum mathematical models and automated image processing methods to obtain independent estimates of the effective cell diffusivity, D, and the effective cell proliferation rate, λ. Using our parameterised mathematical model we confirm that our estimates of D and λ accurately predict the time-evolution of the location of the leading edge and the cell density profiles for both assay 1 and assay 2. Our work suggests that the effective cell diffusivity is up to 50% lower for assay 2 compared to assay 1, whereas the effective cell proliferation rate is up to 30% lower for assay 2 compared to assay 1

Ergogenic and psychological effects of synchronous music during circuit-type exercise

This is the post print version of the article. The official published version can be obtained from the link below.Objectives: Motivational music when synchronized with movement has been found to improve performance in anaerobic and aerobic endurance tasks, although gender differences pertaining to the potential benefits of such music have seldom been investigated. The present study addresses the psychological and ergogenic effects of synchronous music during circuit-type exercise. Design: A mixed-model design was employed in which there was a within-subjects factor (two experimental conditions and a control) and a between-subjects factor (gender). Methods: Participants (N ¼ 26) performed six circuit-type exercises under each of three synchronous conditions: motivational music, motivationally-neutral (oudeterous) music, and a metronome control. Dependent measures comprised anaerobic endurance, which was assessed using the number of repetitions performed prior to the failure to maintain synchronicity, and post-task affect, which was assessed using Hardy and Rejeski’s (1989) Feeling Scale. Mixed-model 3 (Condition) X 2 (Gender) ANOVAs, ANCOVAs, and MANOVA were used to analyze the data. Results: Synchronous music did not elicit significant (p < .05) ergogenic or psychological effects in isolation; rather, significant (p < .05) Condition X Gender interaction effects emerged for both total repetitions and mean affect scores. Women and men showed differential affective responses to synchronous music and men responded more positively than women to metronomic regulation of their movements. Women derived the greatest overall benefit from both music conditions. Conclusions: Men may place greater emphasis on the metronomic regulation of movement than the remaining, extra-rhythmical, musical qualities. Men and women appear to exhibit differential responses in terms of affective responses to synchronous music

Attachment Styles Within the Coach-Athlete Dyad: Preliminary Investigation and Assessment Development

The present preliminary study aimed to develop and examine the psychometric properties of a new sport-specific self-report instrument designed to assess athletes’ and coaches’ attachment styles. The development and initial validation comprised three main phases. In Phase 1, a pool of items was generated based on pre-existing self-report attachment instruments, modified to reflect a coach and an athlete’s style of attachment. In Phase 2, the content validity of the items was assessed by a panel of experts. A final scale was developed and administered to 405 coaches and 298 athletes (N = 703 participants). In Phase 3, confirmatory factor analysis of the obtained data was conducted to determine the final items of the Coach-Athlete Attachment Scale (CAAS). Confirmatory factor analysis revealed acceptable goodness of fit indexes for a 3-first order factor model as well as a 2-first order factor model for both the athlete and the coach data, respectively. A secure attachment style positively predicted relationship satisfaction, while an insecure attachment style was a negative predictor of relationship satisfaction. The CAAS revealed initial psychometric properties of content, factorial, and predictive validity, as well as reliability

Spacetime as a membrane in higher dimensions

By means of a simple model we investigate the possibility that spacetime is a membrane embedded in higher dimensions. We present cosmological solutions of d-dimensional Einstein-Maxwell theory which compactify to two dimensions. These solutions are analytically continued to obtain dual solutions in which a (d-2)-dimensional Einstein spacetime "membrane" is embedded in d-dimensions. The membrane solutions generalise Melvin's 4-dimensional flux tube solution. The flat membrane is shown to be classically stable. It is shown that there are zero mode solutions of the d-dimensional Dirac equation which are confined to a neighbourhood of the membrane and move within it like massless chiral (d-2)-dimensional fermions. An investigation of the spectrum of scalar perturbations shows that a well-defined mass gap between the zero modes and massive modes can be obtained if there is a positive cosmological term in (d-2) dimensions or a negative cosmological term in d dimensions.Comment: 30 pages, 4 figures in 10 files, epsf. This early brane world paper is being placed on the archive to make it more easily accessible, as its results are used in a new brane world construction in an accompanying submissio

Sarilumab for Previously-Treated Moderate or Severe Rheumatoid Arthritis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Sanofi Genzyme) of sarilumab (SAR; Kevzara®) to submit evidence of its clinical effectiveness and cost-effectiveness for previously treated moderate or severe rheumatoid arthritis (RA). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical effectiveness and cost-effectiveness of the technology, based upon the company's submission to NICE. The clinical effectiveness evidence in the company's submission for SAR was based predominantly on five randomised controlled trials comparing the efficacy of SAR against adalimumab, tocilizumab or placebo. The clinical effectiveness review identified no head-to-head evidence on the efficacy of SAR against all the comparators within the scope. Therefore, the company performed three network meta-analyses (NMAs) in two different populations: two in patients who had had an inadequate response to conventional disease-modifying antirheumatic drugs (cDMARDs) (one for combination therapies and one for monotherapies) and the other one in patients who had had an inadequate response to tumour necrosis factor inhibitors (TNFis). The company's NMAs concluded that SAR in combination with cDMARDs or as monotherapy has a statistically superior efficacy to cDMARDs and a comparable efficacy to most biologic disease-modifying antirheumatic drugs (bDMARDs) in both populations. The company submitted a Markov model that assessed the cost-effectiveness of SAR from the perspective of the National Health Service (NHS) and Personal Social Services in seven different populations: (1) patients with severe RA who have had an inadequate response to cDMARDs (cDMARD-IR); (2) cDMARD-IR patients with severe RA for whom methotrexate (MTX) is contraindicated or not tolerated; (3) patients with severe RA who have had an inadequate response to a TNFi (TNFi-IR); (4) TNFi-IR patients with severe RA for whom rituximab (RTX) is not an option; (5) TNFi-IR patients with severe RA for whom MTX is contraindicated or not tolerated; (6) TNFi-IR patients after RTX; and (7) cDMARD-IR patients with moderate RA whose 28-joint Disease Activity Score (DAS28) is between 4.0 and 5.1. The company's economic evaluation resulted in incremental cost-effectiveness ratios (ICERs) lower than £20,000 per quality-adjusted life year (QALY) gained for SAR in combination with MTX or as monotherapy versus its comparators when the comparators were less effective, and it resulted in cost savings higher than £60,000 per QALY lost when SAR was less effective, except in TNFi-IR patients who are RTX eligible (where the ICER for SAR + MTX compared with RTX + MTX was £130,691 per QALY gained) and in patients with moderate RA and a DAS28 of > 4.0 (where the ICER of SAR + MTX compared with MTX was £38,254 per QALY gained). Following a critique of the model, the ERG undertook exploratory analyses after applying two changes to the company's model: (1) use of a latent class approach to model Health Assessment Questionnaire Disability Index (HAQ-DI) progression for patients on cDMARDs; and (2) amendment of the company's modelling of patient progression from moderate to severe RA. The ICERs estimated by the ERG's exploratory analyses for SAR + MTX increased to £171,466 per QALY gained when compared with RTX + MTX in TNFi-IR patients who are RTX eligible, and to £63,438 per QALY gained when compared with MTX in patients with moderate RA and a DAS28 of > 4.0. The Appraisal Committee concluded that SAR in combination with MTX or as monotherapy is a cost-effective use of NHS resources in the considered populations, except in TNFi-IR patients who are RTX eligible and in patients with moderate RA and a DAS28 of > 4.0

Long‐term trends in the distribution, abundance and impact of native “injurious” weeds

Questions: How can we quantify changes in the distribution and abundance of injurious weed species (Senecio jacobaea, Cirsium vulgare, Cirsium arvense, Rumex obtusifolius, Rumex crispus and Urtica dioica), over long time periods at wide geographical scales? What impact do these species have on plant communities? To what extent are changes driven by anthropogenically induced drivers such as disturbance, eutrophication and management? Location: Great Britain. Methods: Data from national surveys were used to assess changes in the frequency and abundance of selected weed species between 1978 and 2007. This involved novel method development to create indices of change, and to relate changes in distribution and abundance of these species to plant community diversity and inferred changes in resource availability, disturbance and management. Results: Three of the six weed species became more widespread in GB over this period and all of them increased in abundance (in grasslands, arable habitats, roadsides and streamsides). Patterns were complex and varied by landscape context and habitat type. For most of the species, there were negative relationships between abundance, total plant species richness, grassland, wetland and woodland indicators. Each individual species responds to a different combination of anthropogenic drivers but disturbance, fertility and livestock management significantly influenced most species. Conclusions: The increase in frequency and abundance of weeds over decades has implications for landscape‐scale plant diversity, fodder yield and livestock health. This includes reductions in plant species richness, loss of valuable habitat specialists and homogenisation of vegetation communities. Increasing land‐use intensity, excessive nutrient input, overgrazing, sward damage, poaching and bare ground in fields and undermanagement or too frequent cutting on linear features may have led to increases in weeds. These weeds do have conservation value so we are not advocating eradication, rather co‐existence, without dominance. Land management policy needs to adapt to benefit biodiversity and agricultural productivity

Treat-to-target strategies in rheumatoid arthritis: a systematic review and cost-effectiveness analysis

To systematically review clinical and health economic impacts of treat-to-target (TTT) strategies in patients with rheumatoid arthritis (RA) managed in specialist units, compared with routine care. Sixteen and seven electronic databases were searched for clinical RCTs and cost-effectiveness respectively. Study selection, data extraction and quality assessment (Cochrane Collaboration risk of bias criteria) were performed. Evidence was reported by (1) TTT vs. usual care; (2) comparison of different treatment protocols against each other; (3) comparison of different targets against each other. Narrative synthesis was undertaken and conclusions drawn on a trial by trial basis, due to study heterogeneity. Twenty-two RCTs were included. Sixteen were at high risk of bias, five unclear and one low risk. Three trials showed TTT to be more effective than usual care in terms of remissions, in some or all comparisons, whereas one other trial reported no significant difference. Two trials showed TTT to be more effective than usual care in terms of low disease activity (LDA), in some or all comparisons, whereas two trials reported little difference. Some evidence suggests that TTT strategies involving combination therapy can achieve more remissions than those involving monotherapy, but little impact of alternative treatment targets on remission or LDA. Overall, there is evidence that TTT increases remissions in early RA and mixed early and established RA populations, and increases LDA in established RA. Although results varied, typically TTT was estimated to be more cost-effective than usual care. No target appears more effective than others

Quantifying the effect of experimental design choices for in vitro scratch assays

Scratch assays are often used to investigate potential drug treatments for chronic wounds and cancer. Interpreting these experiments with a mathematical model allows us to estimate the cell diffusivity, D, and the cell proliferation rate, λ. However, the influence of the experimental design on the estimates of D and λ is unclear. Here we apply an approximate Bayesian computation (ABC) parameter inference method, which produces a posterior distribution of D and λ, to new sets of synthetic data, generated from an idealised mathematical model, and experimental data for a non-adhesive mesenchymal population of fibroblast cells. The posterior distribution allows us to quantify the amount of information obtained about D and λ. We investigate two types of scratch assay, as well as varying the number and timing of the experimental observations captured. Our results show that a scrape assay, involving one cell front, provides more precise estimates of D and λ, and is more computationally efficient to interpret than a wound assay, with two opposingly directed cell fronts. We find that recording two observations, after making the initial observation, is sufficient to estimate D and λ, and that the final observation time should correspond to the time taken for the cell front to move across the field of view. These results provide guidance for estimating D and λ, while simultaneously minimising the time and cost associated with performing and interpreting the experiment.Stuart T. Johnston, Joshua V. Ross, Benjamin J. Binder, D.L. Sean McElwain, Parvathi Haridas, Matthew J. Simpso

The cost-effectiveness of sequences of biological disease-modifying antirheumatic drug treatment in England for patients with rheumatoid arthritis who can tolerate methotrexate.

Objective: To ascertain whether strategies of treatment with a biological diseasemodifying antirheumatic drug (bDMARD) were cost-effective in an English setting. Results are presented for those patients with moderate-to-severe rheumatoid arthritis (RA) and those with severe RA. Methods: An economic model to assess the cost-effectiveness of seven bDMARDs was developed. A systematic literature review and network meta-analysis was undertaken to establish relative clinical effectiveness. The results together with estimates of: Health Assessment Questionnaire (HAQ) score following European League Against Rheumatism response; annual costs, and utility, per HAQ band; trajectory of HAQ for patients on bDMARDs; and trajectory of HAQ for patients on non-biologic therapy (NBT) were used to populate the model. Results were presented as those associated with the strategy with the median cost-effectiveness. Supplementary analyses were undertaken assessing the change in cost-effectiveness where only patients with the most severe prognoses on NBT were provided with bDMARD treatment. The cost per QALY values were compared with reported thresholds from the National Institute for Health and Care Excellence of £20,000 to £30,000. Results: In the primary analyses, the cost per QALY of a bDMARD strategy was £41,600 for patients with severe RA and £51,100 for those with moderate-to-severe RA. Under the supplementary analyses the cost per QALY fell to £25,300 for those with severe RA and to £28,500 for those with moderate-to-severe RA. Conclusion: The cost-effectiveness of bDMARDs in RA in England is questionable and only meets current accepted levels in subsets of patients with the worst prognoses

Ultra-red Galaxies Signpost Candidate Protoclusters at High Redshift

We present images obtained with LABOCA of a sample of 22 galaxies selected via their red Herschel SPIRE colors. We aim to see if these luminous, rare, and distant galaxies are signposting dense regions in the early universe. Our 870 μm survey covers an area of ≈1 deg2 down to an average rms of $3.9\,\mathrm{mJy}\,{\mathrm{beam}}^{-1}$, with our five deepest maps going ≈2× deeper still. We catalog 86 dusty star-forming galaxies (DSFGs) around our "signposts," detected above a significance of 3.5σ. This implies a ${100}_{-30}^{+30} \%$ overdensity of ${S}_{870}\gt 8.5\,\mathrm{mJy}$ (or {L}_{\mathrm{FIR}}=6.7\times {10}^{12}\mbox{--}2.9\times {10}^{13}\,{L}_{\odot }) DSFGs, excluding our signposts, when comparing our number counts to those in "blank fields." Thus, we are 99.93% confident that our signposts are pinpointing overdense regions in the universe, and ≈95% [50%] confident that these regions are overdense by a factor of at least ≥1.5 × [2×]. Using template spectral energy distributions (SEDs) and SPIRE/LABOCA photometry, we derive a median photometric redshift of z = 3.2 ± 0.2 for our signposts, with an inter-quartile range of z = 2.8–3.6, somewhat higher than expected for ~850 μm selected galaxies. We constrain the DSFGs that are likely responsible for this overdensity to within $| {\rm{\Delta }}z| \leqslant 0.65$ of their respective signposts. These "associated" DSFGs are radially distributed within (physical) distances of 1.6 ± 0.5 Mpc from their signposts, have median star formation rates (SFRs) of $\approx (1.0\pm 0.2)\times {10}^{3}\,{M}_{\odot }\,{\mathrm{yr}}^{-1}$ (for a Salpeter stellar inital mass function) and median gas reservoirs of $\sim 1.7\times {10}^{11}\,{M}_{\odot }$. These candidate protoclusters have average total SFRs of at least $\approx (2.3\pm 0.5)\times {10}^{3}\,{M}_{\odot }\,{\mathrm{yr}}^{-1}$ and space densities of ~9 × 10−7 Mpc−3, consistent with the idea that their constituents may evolve to become massive early-type galaxies in the centers of the rich galaxy clusters we see today