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

Left atrial enlargement on non-gated CT is associated with large vessel occlusion in acute ischaemic stroke

BACKGROUND: Recent reports have suggested that atrial fibrillation (AF) is more prevalent in the large vessel occlusion (LVO) subgroup of acute ischaemic stroke patients. Given the association between left atrial enlargement (LAE) and AF, we sought to evaluate the feasibility of assessing LAE on non-gated CT and its association with LVO in the hyperacute stroke setting. METHODS: We analysed our prospectively collected database that included all stroke patients referred for consideration of endovascular treatment between April 14, 2020, and May 21, 2020. During this period, a CT chest was included in our regional stroke protocol to aid triage of patients suspected for COVID-19 from which cardiac measurements were obtained. Patients were dichotomized into LVO and no-LVO groups, and LA measurements were trichotomized into normal, borderline, and enlarged. Univariate analyses were performed between groups. RESULTS: Of the included 38 patients, 21 were categorized as LVO and 17 as no LVO. There was a statistically significant association between LAE and LVO (p = 0.028). No significant difference was demonstrated between groups for the baseline AF and other clinical characteristics, except for baseline NIHSS (p = 0.0005). There was excellent inter- and intra-rater reliability (ICC = 0.969) for LA measurements. CONCLUSION: Our study provides preliminary data to suggest LAE is more prevalent in the LVO stroke subgroup at presentation and can be reliably assessed on non-gated CT in the hyperacute setting. These findings have potential implications for stratifying secondary management and may prompt a more rigorous pursuit of occult AF or other cardiac causes of stroke. Copyright © 2021 The Author(s) Published by S. Karger AG, Basel.https://doi.org/10.1159/00051912

Doxorubicin In Vivo Rapidly Alters Expression and Translation of Myocardial Electron Transport Chain Genes, Leads to ATP Loss and Caspase 3 Activation

BackgroundDoxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity.Methodology/principal findingsMice were treated with an acute dose of either doxorubicin (DOX) (15 mg/kg) or 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) (25 mg/kg). DMNQ is a more efficient redox cycling agent than DOX but unlike DOX has limited ability to inhibit gene transcription and DNA replication. This allowed specific testing of the redox hypothesis for cardiotoxicity. An acute dose was used to avoid pathophysiological effects in the genomic analysis. However similar data were obtained with a chronic model, but are not specifically presented. All data are deposited in the Gene Expression Omnibus (GEO). Pathway and biochemical analysis of cardiac global gene transcription and mRNA translation data derived at time points from 5 min after an acute exposure in vivo showed a pronounced effect on electron transport chain activity. This led to loss of ATP, increased AMPK expression, mitochondrial genome amplification and activation of caspase 3. No data gathered with either compound indicated general redox damage, though site specific redox damage in mitochondria cannot be entirely discounted.Conclusions/significanceThese data indicate the major mechanism of doxorubicin cardiotoxicity is via damage or inhibition of the electron transport chain and not general redox stress. There is a rapid response at transcriptional and translational level of many of the genes coding for proteins of the electron transport chain complexes. Still though ATP loss occurs with activation caspase 3 and these events probably account for the heart damage

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

A study of the interstellar medium towards the VHE gamma-ray sources HESS J1614-518 and HESS J1616-508

One of the most intriguing problems in galactic astronomy is the observation of the highest energy photons. Very high energy (VHE) gamma-ray telescopes such as HESS have located sources of TeV (10¹² eV) gamma-rays which are not associated with any known objects. Whilst these could be a new type of particle accelerator, it is more likely that they are related to supernova remnants (SNRs), pulsar wind nebula (PWN) or massive stellar regions. They may result from high energy cosmic-ray (CR) interactions with interstellar gas (ISM). This project used new radio data which provided information on molecular clouds to model the production of gamma-rays from CR interactions. The densities of protons in these clouds were used in models to determine if potential particle accelerators surrounding the two HESS sources, HESS J1616-508 and HESS J1614-518 were capable of producing the emission. The potential accelerators surrounding HESS J1616-508 were all found to have insufficient gas within their diffusion radius. Thus, it was not possible for those sources to produce gamma-rays through hadronic interactions despite only requiring modest CR energy budgets compared to that provided from a SNR. The same result was also found for WR 73-1 and PSR J1613-5211 near HESS J1614-518. However, Pismis 22 and WR 74 contained CO RoI CO1, CO2 and CO25 within their diffusion radii. The energy in CRs required for each region to generate the overlapping gamma-ray emission was compared to the available energy if a SNR was assumed to be the accelerator. The required energy was found to be less than the energy available. Thus, WR 74 and Pismis 22 could still generate the hadronic gamma-ray emission from HESS J1614-518.Thesis (M.Phil.) -- University of Adelaide, School of Physical Sciences, 2016

Understanding galaxies and their gas

The circumgalactic medium is a vast halo of gas surrounding galaxies comprised of accreting gas from the intergalactic medium, outflows from stellar winds and recycled gas. Understanding how these gas flows enter and exit galaxies is key to our understanding of galaxy evolution. We have found that the metal content of accreting or outflowing gas is similar, suggesting that metallicity is not a useful tracer of accretion. We have also investigated group environments and found that there is less highly ionized gas and its kinematically narrower than isolated environments. Furthermore, the metallicity of group environments is similar to isolated environments

Reporting radiographers and their role in thoracic CT service improvement: managing the pulmonary nodule

Objectives: The use of cross-sectional imaging in clinical medicine has been a major step forward in the management of many conditions but with that comes the increasing demand on resources and the detection of other potentially significant findings. This, in the context of a shortage of skilled radiologists, means that new ways of working are important. In thoracic CT, pulmonary nodules are a significant challenge because they are so common. Poor and inconsistent management can both cause harm to patients and waste resources so it is important that the latest guidelines are followed. The latter mandate the use of semi-automated volumetry that allows more precise management but is time-consuming. Methods: Reporting radiographers were iteratively trained in the use of semi-automated volumetry for pulmonary nodules by experienced thoracic radiologists. Once trained in this specific aspect, radiographers completed reporting of pulmonary nodules, checked by radiologists. Results: Radiographer reporting reduced radiologist time in reporting nodules and measuring their volume. Most of the volumetry was completed prior to the multidisciplinary meeting. This facilitated an increase in the number of patients discussed in 60 min from 15 to 22. Radiographers failed to detect few nodules, although a second read by radiologists is required in any case for other aspects of the reporting. Conclusion: Reporting radiographers, working with radiologists in a supportive setting, can deliver the radiology in a lung nodule pathway, reducing the time commitment from radiologists and the pulmonary nodule multidisciplinary team members, whilst using this as an opportunity to conduct research. </jats:sec