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Computationally efficient simulation of calcium signaling in cardiomyocytes
No full textThe heart pumps blood by the orchestrated contraction of ∼ 3 billion muscle cells called cardiomyocytes. Calcium ions provide an essential link between electrical stimulation of the cardiomyocyte membrane and their contraction as well as sustaining normal heart rhythm. Release of calcium from intracellular stores can be transient and localised near release sites (observed as Calcium sparks by fluorescent microscopy) or can occur as a propagating wave supported by ∼ 20000 release sites throughout the cell. The latter in single cells are recognised as a hallmark of arrhythmia susceptible whole hearts. Development of Ca2+ wave models that incorporated the known properties of calcium release sites has proved challenging and no model has yet achieved this. Moreover, these models are extremely computationally intensive because accurate simulations are usually required at spatial and temporal scales covering several orders of magnitude. The model developed here is composed of more than two million stiff and nonlinear systems with discrete stochastic state transitions. Each system is composed of 62 state equations. The methods used to simulate this model include diagonally iterated fully implicit Runge-Kutta integration with both L-stability and step-size control, constrained Newton’s root finding method with automatic preconditioner generation, and preconditioned Conjugate Residual Squared. These methods are implemented in a parallelised form with load balancing to distribute computation across multiple GPU and CPU computing systems. The simulated Ca2+ activity is similar to that observed in an isolated cardiomyocyte. Ca2+ spark rising time is 10 − 20 ms and falls to baseline within 50 − 100 ms. Waves occur with an approximate period of ∼ 3 seconds, amplitudes rising to 2−10 μm, and propagate with speeds around ∼ 100 μms−1. This model presents a new hypothesis for wave initiation, where calcium embers remain open for orders of magnitude longer than sparks, to supply the increased Ca2+ observed in waves. Sensitivity analysis was performed on the model, using a one-factor-at-a-time method to determine a partial derivative of each model output with respect to each model input. The key wave properties used as output variables were the peak cytoplasmic [Ca2+] during a wave, the minimum cytoplasmic [Ca2+] between waves and the time between wave peaks. The model indicated that wave period was strongly influenced by 1) RyR2 activity, 2) the degree of Ca2+ buffering by CSQ and SERCa rate, 3) rate of entry of Ca2+ into permeabilised cells and 4) rate of diffusion between the LSR and TSR. The last two factors have not been considered in experimental studies and may account for cell-to-cell variations in wave period
Social capital and adolescents who are deaf or hard of hearing
No full textAdolescents who are deaf or hard of hearing (DHH) in countries such as Australia and other developed countries experience superior outcomes in areas such as language, literacy, and access to education in comparison to previous decades. These improved outcomes can be linked to access to universal newborn hearing screening (UNHS) programs widely available in developed nations, in addition to effective early intervention and access to superior assistive hearing technology. Nonetheless, outcomes for adolescents who are DHH are not always commensurate with their typically hearing peers in areas such as pragmatic language development and postschool outcomes. This research project presents a sequential explanatory mixed methodology design with the Stage One quantitative investigation utilising 17 adolescent survey respondents followed by a Stage Two qualitative investigation in which interviews were conducted with 10 adolescents and one of their parents. The Stage One survey ascertained the social capital reserves of the young participants and explored the associations with other variables such as pragmatic language, identity, wellbeing, and school connectedness. The second stage explored the experiences of 10 of the 17 adolescents who completed the Stage One survey. An additional parent of each of the 10 adolescents completed a separate interview, with the adolescent and parent dyads largely treated as single cases. Results of the survey revealed strong associations between social capital and a range of measures including pragmatic language, wellbeing, and school connectedness. Institutional social capital, which encompassed school-based social capital, was seen as particularly important in developing bridging social capital. Self-selected identity was seen as a statistically significant factor in the formation of social capital; however, the results are derived from a small sample and must be treated with caution. The findings of the Stage Two interviews supported the Stage One survey results with the adolescents and their parents generally discussing high reserves of bonding social capital. School connectedness, involvement in third space environments outside of school and the home, and possessing skills related to pragmatic language and discernment were identified as facilitators of social capital. Conversely, negative experiences such as school-related diminished social connections and negative perceptions were identified as barriers to social capital formation. Identity was also a major theme in Stage Two with the establishment of a d/Deaf identity and feeling ‘normal’ discussed by the adolescent participants and their parents. The results and findings support the conclusion that adolescents who are DHH in this sample generally held high bonding social capital which they received from family and close friends, however their bridging social capital may be diminished as they began school and developed social capital with peers and teachers at school. In part, this may be attributable to the unavailability of positive models of deafness to Australian adolescents. A successful school experience is pivotal in facilitating bridging social capital for adolescents, and this involves the adolescents themselves, parents, teachers, and school administrators
Stroke Aetiology and Collateral Status in Acute Ischemic Stroke Patients Receiving Reperfusion Therapy—A Meta-Analysis
No full textBackground: The interplay between collateral status and stroke aetiology may be crucial in the evaluation and management of acute ischemic stroke (AIS). Our understanding of this relationship and its level of association remains sub-optimal. This study sought to examine the association of pre-intervention collateral status with stroke aetiology, specifically large artery atherosclerosis (LAA) and cardio-embolism (CE), in AIS patients receiving reperfusion therapy, by performing a meta-analysis. Methods: Relevant search terms were explored on Medline/PubMed, Embase and Cochrane databases. Studies were included using the following inclusion criteria: (a) patients aged 18 or above; (b) AIS patients; (c) patients receiving reperfusion therapy; (d) total cohort size of >20, and (e) qualitative or quantitative assessment of pre-intervention collateral status on imaging using a grading scale. Random-effects meta-analysis was performed to investigate the association of aetiology with pre-intervention collateral status, and forest plots of risk ratio (RR) were generated. Results: A meta-analysis was conducted on seven studies, with a cumulative cohort of 1235 patients, to assess the association of pre-intervention collateral status with stroke aetiology. Patients with LAA were associated significantly with an increased rate of good collaterals (RR 1.24; 95% CI 1.04–1.50; p = 0.020, z = 2.33). Contrarily, CE aetiology was associated significantly with a decreased rate of good collaterals (RR 0.83; 95% CI 0.71–0.98; p = 0.027, z = −2.213). Conclusions: This study demonstrates that, in AIS patients receiving reperfusion therapy, LAA and CE aetiologies are associated significantly with collateral status
Use of Traditional Chinese Medicine and Its Impact on Medical Cost among Urban Ischemic Stroke Inpatients in China: A National Cross-Sectional Study
No full textBackground: Traditional Chinese medicine (TCM) has long been widely adopted by the Chinese people and has been covered by China’s basic medical insurance schemes to treat ischemic stroke. Previous research has mainly highlighted the therapy effect of TCM on ischemic stroke patients. Some studies have demonstrated that employing TCM can reduce the medical burden on other diseases. But no research has explored whether using TCM could reduce inpatient medical cost for ischemic stroke in mainland China. The purpose of this study is to investigate the impact of the use of TCM on the total inpatient cost of ischemic stroke and to explore whether TCM has played the role of being complementary to, or an alternative for, conventional medicine to treat ischemic stroke. Methods: We conducted a national cross-sectional analysis based on a 5% random sample from claims data of China Urban Employee Basic Medical Insurance (UEBMI) and Urban Resident Basic Medical Insurance (URBMI) schemes in 2015. Mann–Whitney test was used to compare unadjusted total inpatient cost, conventional medication cost, and nonpharmacy cost estimates. Ordinary least square regression analysis was performed to compare demographics-adjusted total inpatient cost and to examine the association between TCM cost and conventional medication cost. Results: A total of 47321 urban inpatients diagnosed with ischemic stroke were identified in our study, with 92.6% (43843) of the patients using TCM in their inpatient treatment. Total inpatient cost for TCM users was significantly higher than TCM nonusers (USD 1217 versus USD 1036, ). Conventional medication cost was significantly lower for TCM users (USD 335 versus USD 436, ). The average cost of TCM per patient among TCM users was USD 289. Among TCM users, conventional medication costs were found to be positively associated with TCM cost after adjusting for confounding factors (Coef. = 0.144, ). Conclusion: Although the use of TCM reduced the cost of conventional medicine compared with TCM nonusers, TCM imposed an extra financial component on the total inpatient cost on TCM users. Our study suggests that TCM mainly played a complementary role to conventional medicine in ischemic stroke treatment in mainland China
An evolutionary perspective on live and mediated popular performance
No full textDeploying philosopher Mark Johnson's idea that all cognitive operations in Homo Sapiens must be continuous with those of other higher mammals, this article takes issue with those theorists who posit an ontological difference between live and mediated performance. Rather, just as all human performances emerged out of animal play, so did mediated performances emerge from live ones (including live popular entertainments). Filmic and electronic media, however, do require actors and spectators to make a few cognitive adjustments, the most notable of which is the unconscious application of our Hypersensitive Agency Detective Device (HADD) to translate the images and sounds on film and radio, for example, into a fully embodied live performer with agency. Given the ontological similarities and the historical distinctions among the many kinds of live and mediated performances in human history, the article suggests that the theories of McLuhan and Ong, updated to take account of the new cognitive sciences, may help us to write empirically responsible performance history. It concludes with three implications of this evolutionary perspective for the study of popular entertainment. Bruce McConachie is Professor of heatre Arts, University of Pittsburgh, USA. His latest book is Engaging Audiences: a cognitive approach to spectating in the theatre (2008)
Extracellular matrix protein 1 as a mediator of inflammation-to-fibrosis progression after myocardial infarction
No full textBackground: Fibrosis is a hallmark of heart disease, particularly following myocardial infarction (MI) and in heart failure. We previously identified a key role for ECM1 in wound healing post-MI but the precise cellular origin and mechanism of ECM1 remained elusive. Here, we aimed to investigate the spatiotemporal cellular origin of ECM1 in healthy and diseased human and mouse hearts, and ECM1 dependent human cardiac fibroblast (HuCFb) signalling mechanisms. Methods: Immunoblotting, immunohistochemistry and mRNA in-situ hybridisation were conducted on non-failing, ischemic (ICM) and dilated (DCM) failing human heart tissue. In-situ hybridisation, flow cytometry and immunoblotting were conducted on mouse heart and bone marrow samples. ECM1 specific analysis of existing single-cell/-nuclei RNA sequencing (sc/snRNAseq) data was conducted. HuCFbs were treated with recombinant ECM1 and phosphoproteomics mass spectrometry (MS), MS of ECM1-HuCFb cell binding partners, wound healing assay, MTT assay, qPCR, and immunoblotting was conducted. Results: ECM1 expression was upregulated in human ICM and DCM, localised interstitially to fibrotic, inflammatory, and peri-vascular areas. ECM1 originates from fibroblasts, macrophages, and pericytes/vascular cells in uninjured human and mouse hearts. In mouse hearts post-MI, ECM1 predominantly originates from M1 macrophages/monocytes (MΦ/Mo) at day-3, and myofibroblasts and M2MΦ’s at day-7. Further, ECM1 expression was correlated with cell-cell communication, collagen organisation, inflammation, cell adhesion and migration. In vitro, ECM1 inhibited HuCFb migration and CCL2 mRNA expression, and stimulated mRNA expression of inflammatory (IL-6, IL-1β), fibrotic (TGF-β1, Col1a2), and non-canonical Wnt gene Wnt5a. MS experiments showed ECM1 stimulates HuCFb Rho protein, cell-cell adhesion, and chemotactic signalling pathways, potentially initiated by ECM1-CTNND1 protein binding. Finally, we created an ECM1 genetic knockout animal (ECM1Δ2). Homozygous ECM1Δ2 knockout resulted in lower body weight, smaller body size, and a significantly lower rate of survival over the first 16 weeks of life, relative to WT. Conclusions: ECM1 represents a novel mechanism in facilitating inflammation-fibrosis crosstalk post-MI and thus a potential therapeutic target
Potential severe asthma hidden in UK primary care
No full textBackground: Severe asthma may be underrecognized in primary care. Objective: Identify and quantify patients with potential severe asthma (PSA) in UK primary care, the proportion not referred, and compare primary care patients with PSA with patients with confirmed severe asthma from UK tertiary care. Methods: This was a historical cohort study including patients from the Optimum Patient Care Research Database (aged ≥16 years, active asthma diagnosis pre-2014) and UK patients in the International Severe Asthma Registry (UK-ISAR aged ≥18 years, confirmed severe asthma in tertiary care). In the OPCRD, PSA was defined as Global INitiative for Asthma 2018 step 4 treatment and 2 or more exacerbations/y or at Global INitiative for Asthma step 5. The proportion of these patients and their referral status in the last year were quantified. Demographic and clinical characteristics of groups were compared. Results: Of 207,557 Optimum Patient Care Research Database patients with asthma, 16,409 (8%) had PSA. Of these, 72% had no referral/specialist review in the past year. Referred patients with PSA tended to have greater prevalence of inhaled corticosteroid/long-acting β2-agonist add-ons (54.1 vs 39.8%), and experienced significantly (P P P 2-agonist add-ons (67.7% vs 54.1%), and have nasal polyposis (24.2% vs 6.8) than referred patients with PSA. Conclusions: Large numbers of patients with PSA in the United Kingdom are underrecognized in primary care. These patients would benefit from a more systematic assessment in primary care and possible specialist referral
Economics: manufacture renewables to build energy security
No full textChina's rise to become the world's largest power producer and source of carbon emissions through burning coal is well recognized. But the nation's renewable-energy systems are expanding even faster than its fossil-fuel and nuclear power. China leads the world in the production and use of wind turbines, solar-photovoltaic cells and smart-grid technologies, generating almost as much water, wind and solar energy as all of France and Germany's power plants combined1. Production of solar cells in China has expanded 100-fold since 2005
An evidence accumulation model driven exploration of endogenously and exogenously triggered errors and their consequences
No full textEvidence accumulation models (EAMs) are based upon cognitive-theories of speeded decision-making. These models propose that evidence accumulates for decision alternatives until the evidence for one alternative reaches some threshold, and a decision is triggered. EAMs have provided an accurate account of entire response time distributions and the differential probabilities of correct and error responses, across a range of speeded decision- making tasks. Consequently, errors and error-related phenomena have been central benchmarks for EAMs. In what has been a somewhat symbiotic process, errors have influenced EAM development. This thesis uses EAMs to investigate what we refer to as exogenous and endogenous errors and their post-error consequences. We use these terms in a novel way to make reference to the events that caused the errors; exogenous errors refer to errors that have been caused by factors external to the organism (e.g., an unexpected change in an environmental regularity), while endogenous errors refer to those errors that have been caused by the organism (e.g., an error of choice on the previous trial). Section One of this thesis focuses on exogenous errors caused by task irrelevant oddballs as they occur in the distraction paradigm (Schröger & Wolff, 1998). Our use of EAMs in this paradigm is novel. We are successful in our attempts to use EAMs with distraction paradigm data. We also extend EAM techniques to include another source of data, omissions, in an effort to gain further insight in to exogenous errors and the impact they have on behaviour. Section Two of this thesis focuses on endogenous errors and their post-error consequences as they occur in recognition memory paradigm experiments. While EAMs have acknowledged differences in the cause and relative speed of errors, post-error research has largely neglected these factors. We conduct an EAM inspired exploration of post-error consequences. We find evidence of different types of post-error consequences and conduct EAM analysis of this data. Our efforts serve to elucidate theoretical understandings and reconcile debate within the literature
Let’s go on a journey
No full textIn 2007, students from the University of Newcastle and Macquarie University organised the inaugural NewMac Humanities Postgraduate Symposium (and its online journal Humanity). For students enrolled in masters and doctoral research programs, it offered the potential to be a significant first step; the start of something big. Designed to give voice to postgraduate researchers in the humanities, NewMac presented an invaluable opportunity to gain experience in formulating and presenting a research paper and to network with peers from related disciplines. It provided a practical and public platform for further developing the research skills currently being acquired within the context of a postgraduate degree: understanding your topic; applying common themes in related disciplines, and; focusing your message to a captive audience