Elastic-Plastic Wave Propagation in Uniform and Periodic Granular Chains

We investigate the properties of high-amplitude stress waves propagating through chains of elastic–plastic particles using experiments and simulations. We model the system after impact using discrete element method (DEM) with strain-rate dependent contact interactions. Experiments are performed on a Hopkinson bar coupled with a laser vibrometer. The bar excites chains of 50 identical particles and dimer chains of two alternating materials. After investigating how the speed of the initial stress wave varies with particle properties and loading amplitude, we provide an upper bound for the leading pulse velocity that can be used to design materials with tailored wave propagation

Strain-rate-dependent model for the dynamic compression of elastoplastic spheres

We present a force-displacement contact model for the compressive loading of elastoplastic spheres. This model builds from the well known Hertz contact law for elastic, quasistatic compression to incorporate a material's strain-rate-dependent plasticity in order to describe collisions between particles. In the quasistatic regime, finite-element analysis is used to derive an empirical function of the material properties. A Johnson-Cook strain rate dependence is then included into the model to study dynamic effects. We validate the model using split Hopkinson bar experiments and show that the model can accurately simulate the force-displacement response of strain-rate-dependent elastoplastic spheres during dynamic compression and unloading

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Guided Impact Mitigation in 2D and 3D Granular Crystals

We simulate the dynamics of impacts on 1D, 2D and 3D arrays of metallic spheres in order to design novel granular protection systems. The dynamics of these highly organized systems of spheres, commonly called granular crystals, are governed by the contact law that describes how each particle interacts with the others. We use our recently developed force-displacement model of the dynamic compression of elastic-plastic spheres as the building block to investigate the response of systems comprised of metallic spheres to an impact. We first provide preliminary experimental results using a drop tower as validation of our numerical approach for 2D and 3D systems. We then use simulations of large periodic granular crystals in order to determine which particle properties govern the velocity of stress waves in these materials. We show that the properties of 1D systems can be scaled to predict the behavior of more complex 2D and 3D granular crystals. Because we can choose the material properties of each of the constituent particles and design how the particles are geometrically packed, we can leverage the heterogeneity of the system to create materials with unique properties such as anisotropic local stiffnesses and wave propagation velocities. We show that these materials allow us to design the dispersion and dissipation properties within the material in order to influence the propagation of a stress wave. Using these materials, we can therefore design protection systems or armor that directs damage away from sensitive parts or localizes damage to an unimportant area after impact from a projectile or a blast

From Mechanosensitivity to Inflammatory Responses: New Players in the Pathology of Glaucoma

PURPOSE OF THE STUDY: Many blinding diseases of the inner retina are associated with degeneration and loss of retinal ganglion cells (RGCs). Recent evidence implicates several new signaling mechanisms as causal agents associated with RGC injury and remodeling of the optic nerve head. Ion channels such as Transient receptor potential vanilloid isoform 4 (TRPV4), pannexin-1 (Panx1) and P2X7 receptor are localized to RGCs and act as potential sensors and effectors of mechanical strain, ischemia and inflammatory responses. Under normal conditions, TRPV4 may function as an osmosensor and a polymodal molecular integrator of diverse mechanical and chemical stimuli, whereas P2X7R and Panx1 respond to stretch- and/or swelling-induced adenosine triphosphate release from neurons and glia. Ca(2+) influx, induced by stimulation of mechanosensitive ion channels in glaucoma, is proposed to influence dendritic and axonal remodeling that may lead to RGC death while (at least initially) sparing other classes of retinal neuron. The secondary phase of the retinal glaucoma response is associated with microglial activation and an inflammatory response involving Toll-like receptors (TLRs), cluster of differentiation 3 (CD3) immune recognition molecules associated with the T-cell antigen receptor, complement molecules and cell type-specific release of neuroactive cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The retinal response to mechanical stress thus involves a diversity of signaling pathways that sense and transduce mechanical strain and orchestrate both protective and destructive secondary responses. CONCLUSIONS: Mechanistic understanding of the interaction between pressure-dependent and independent pathways is only beginning to emerge. This review focuses on the molecular basis of mechanical strain transduction as a primary mechanism that can damage RGCs. The damage occurs through Ca(2+)-dependent cellular remodeling and is associated with parallel activation of secondary ischemic and inflammatory signaling pathways. Molecules that mediate these mechanosensory and immune responses represent plausible targets for protecting ganglion cells in glaucoma, optic neuritis and retinal ischemia

Feasibility of reporting results of large randomised controlled trials to participants:experience from the Fluoxetine or Control under supervision (FOCUS) trial

Objectives Informing research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.Design In the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.Setting UK stroke services.Participants 3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.Results Of those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.Conclusion It is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration number ISRCTN83290762; Post-results