Presence of a prothrombotic state in people with idiopathic pulmonary fibrosis: a population-based case-control study

BACKGROUND: Laboratory studies suggest that the clotting cascade is activated in fibrotic lungs. Since humans vary in their tendency to clot due to a variety of inherited or acquired defects, we investigated whether a prothrombotic state increases the chance of developing idiopathic pulmonary fibrosis (IPF) and/or worsens the prognosis of IPF. METHODS: We recruited 211 incident cases of IPF and 256 age-and sex-matched general population controls and collected data on medical history, medication, smoking habit, blood samples as well as lung function and high-resolution CT scans done as part of routine clinical care. A prothrombotic state was defined as the presence of at least one inherited or acquired clotting defect or marker of fibrinolytic dysfunction. We used logistic regression to quantify the association between a prothrombotic state and IPF adjusted for age, sex, smoking habit and highly sensitive C reactive protein. Cox regression was used to determine the influence of a prothrombotic state on survival. RESULTS: Cases were more than four times more likely than controls to have a prothrombotic state (OR 4.78, 95% CI 2.93 to 7.80; p<0.0001). Cases with a prothrombotic state were also likely to have more severe disease (forced vital capacity <70% predicted) at presentation (OR 10.79, 95% CI 2.43 to 47.91) and had a threefold increased risk of death (HR 3.26, 95% CI 1.09 to 9.75). CONCLUSIONS: People with IPF are more likely to have a prothrombotic state than general population controls and the presence of a prothrombotic state has an adverse impact on survival

Mass spectrometry-based characterisation of the cardiac microtissue metabolome and lipidome

Introduction: The use of large, non-sample specific metabolite reference libraries often results in high proportions of false positive annotations in untargeted metabolomics. Objective: This study aimed to measure and curate a library of polar metabolites and lipids present in cardiac microtissues. Results: Untargeted ultra-high performance liquid chromatography-coupled mass spectrometry measurements of cardiac microtissue intracellular extracts were annotated by comparison against four spectral databases and a retention time library. The annotations were combined to create a library of 313 polar metabolites and 1004 lipids. Conclusions: The curated library will facilitate higher confidence metabolite annotation in mass spectrometry-based untargeted metabolomics of cardiac microtissues.</p

Investigation of Salmonella Contamination of Pigs in Australia

Microbiological surveys of pigs before, during and after slaughter and processing have been conducted at abattoirs in Australia, to estimate the incidence and risk factors for Salmonella contamination on carcasses. In one such survey, approximately 10% of carcasses were positive for Salmonella contamination at the end of the slaughter line, although there was considerable variation between abattoirs and between herds in the incidence of contamination. A range of Salmonella serotypes was recovered from carcasses, with the most common being S. derby, S. give, S. anatum, and S. ohio. The incidence of Salmonella contamination on carcasses varied along the slaughter line: some contamination on the skin surface of carcasses survived scalding and dehairing, despite the temperatures achieved during these processes

Information discernment and the psychophysiological effects of misinformation

Purpose The purpose of this paper is to determine to what extent a person’s psychophysiological well-being is affected by misinformation and whether their level of information discernment has any positive or negative effect on the outcome. Design/methodology/approach Participants (n = 48) were randomly and blindly allocated to one of two groups: control group participants were told a person they were working with was a student; experimental group participants were additionally led to believe that this other participant had extreme religious views. This was both stigmatising and misinforming, as this other person was an actor. Participants completed a pre-screening booklet and a series of tasks. Participants’ cardiovascular responses were measured during the procedure. Findings Participants with high levels of information discernment, i.e. those who are curious, use multiple sources to verify information, are sceptical about search engine information, are cognisant of the importance of authority and are aware that knowledge changes and is contradictory at times exhibited an adaptive stress response, i.e. healthy psychophysiological outcomes and responded with positive emotions before and after a stressful task. Social implications The findings indicate the potential harmful effects of misinformation and discuss how information literacy or Metaliteracy interventions may address this issue. Originality/value The first study to combine the hitherto unrelated theoretical areas of information discernment (a sub-set of information literacy), affective states (positive affect negative affect survey) and stress (challenge and threat cardiovascular measures)

Governing Digital Health Data: A Public Values Perspective

Governments are adopting digital health (DH) to capture patient data and applying advanced analytics to ‘learn’ from that data. This has rendered DH data governance approaches insufficient and led to public sector decision-makers using health data without considering the public, resulting in harm and eroding trust. Yet, public sector organizations are responsible for upholding public values. How then can governments govern DH data in line with public values? To provide insights, we propose a multi-phase, mixed-methods design embedded in a public health system to identify the public’s values implicated in DH data governance and their (mis)alignment with other stakeholders’ values. Ultimately, our research will contribute to literature and practice by explaining the complexity of appropriately governing DH data and by providing the foundations for research to create a public values-oriented approach to governing DH data

Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics

Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated. Here we assemble a workflow to discover and analyse pharmaceutical-related measurements from routine untargeted UHPLC-MS metabolomics datasets, derived from in vivo (rat plasma and cardiac tissue, and human plasma) and in vitro (human cardiomyocytes) studies that were principally designed to investigate endogenous metabolic responses to drug exposure. Our findings clearly demonstrate how untargeted metabolomics can discover extensive biotransformation maps, temporally-changing relative systemic exposure, and direct associations of endogenous biochemical responses to the internal dose

Discovering a predictive metabolic signature of drug-induced structural cardiotoxicity in cardiac microtissues

Improved prediction of drug-induced structural cardiotoxicity is required to reduce attrition driven by cardiac safety concerns in drug discovery. Omics measurements are well suited to this need, offering the potential to discover molecular signatures associated with toxicological endpoints. In addition, untargeted metabolomics can simultaneously measure xenobiotic fate within the test system. We present an extensive metabolomics study to discover a predictive metabolic signature of drug-induced structural cardiotoxicity. A human-relevant in vitro cardiac model, cardiac microtissues, were exposed to twelve xenobiotics (eight clinically labelled structural cardiotoxins and four non-cardiotoxic pharmaceuticals), each at two concentrations, for 6, 24, and 48 h. The measurements were made by direct-infusion and liquid-chromatography mass spectrometry from intracellular polar and lipid extracts, and spent culture medium, respectively. Data were used to quantify levels, and reveal the metabolic fate of the xenobiotics, and to simultaneously explore their effects on the cardiac microtissues. Xenobiotic quantification revealed free concentrations to be typically lower than nominal values, whilst discovery of xenobiotic-related features evidenced the biotransformation capacity of the microtissues. Both common and condition-specific effects of the xenobiotics on the intracellular metabolome, lipidome, and metabolic footprint were discovered. Moreover, metabolic signatures with capacity to predict structural cardiotoxicity were revealed. These included features representing several ceramides, energy metabolism intermediates, e.g. creatine, purine-related metabolites, and markers of oxidative stress, e.g. glutathione.</p

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Computational approaches identify a transcriptomic fingerprint of drug-induced structural cardiotoxicity

Structural cardiotoxicity (SCT) presents a high-impact risk that is poorly tolerated in drug discovery unless significant benefit is anticipated. Therefore, we aimed to improve the mechanistic understanding of SCT. First, we combined machine learning methods with a modified calcium transient assay in human-induced pluripotent stem cell-derived cardiomyocytes to identify nine parameters that could predict SCT. Next, we applied transcriptomic profiling to human cardiac microtissues exposed to structural and non-structural cardiotoxins. Fifty-two genes expressed across the three main cell types in the heart (cardiomyocytes, endothelial cells, and fibroblasts) were prioritised in differential expression and network clustering analyses and could be linked to known mechanisms of SCT. This transcriptomic fingerprint may prove useful for generating strategies to mitigate SCT risk in early drug discovery