Centre for Clinical Research in Emergency Medicine


Student project opportunities 

Relationship between fluid resuscitation and the endothelium in sepsis-associated coagulopathy

Chief Supervisor: Professor Daniel Fatovich
Other supervisors: A/Prof. Glenn Arendts, Dr Erika Bosio
Project suitability: PhD
Essential qualifications: BSc (Hons) or equivalent, or Masters
Start date: 2017

Project outline

Sepsis is a dysregulated immune response to infection that results in organ failure. Sepsis accounts for 11% of ICU admissions, and has a high mortality (18% at 30 days). Despite its prevalence, identification and timely treatment are still the focus of intense research. Biomarkers for the specific diagnosis of sepsis have remained elusive. The hallmark of sepsis, and the principal driver of morbidity and mortality, is organ failure. The pathological mechanisms of this are complex. Work within our centre aims to better understand the immunological mechanisms underlying sepsis, and how these may be affected by treatment., e.g. fluid resuscitation. Our approach includes investigating novel biomarkers involved in leucocyte-endothelial cell signalling as tools for early sepsis diagnosis and potential future therapeutic targets. This project will focus on one aspect of sepsis, specifically the pathogenesis of coagulopathy and platelet dysfunction.

Aims

To investigate how intravenous fluid resuscitation in sepsis affects the function of endothelial cells, in particular activation of the coagulation cascade and platelets. The approach will include in vitro experiments involving blood samples obtained from patients undergoing resuscitation for sepsis. The relationship between intravenous fluids, degradation of the endothelial glycocalyx and up-regulation of endothelial cell pathways involved in coagulation and platelet binding will be explored. These findings will be correlated with a range of clinical measures of coagulopathy.

Recommended reading

  1. Kaukonen K-M, et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand 2000-2012. JAMA 2014;311:1308-16
  2. Angus DC, van de Poll T. Severe Sepsis and Septic Shock. N Engl J Med 2013;369:840-51
  3. Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity 2014; 40(4): 463-75.
  4. Prucha M, Bellingan G, Zazula R. Sepsis biomarkers. Clin Chim Acta 2015; 440: 97-103.
  5. Biron BM, Ayala A, Lomas-Neira JL. Biomarkers for Sepsis: What Is and What Might Be? Biomark Insights 2015; 10(Suppl 4): 7-17.
 
Anaphylaxis and Snakebite: Mechanisms of activation of immune cells by antivenoms

Chief Supervisor: Professor Daniel Fatovich
Other supervisors: Professor Simon Brown, Dr. Erika Bosio
Project suitability: PhD
Essential qualifications: BSc (Hons) or equivalent, or Masters
Start date: 2017

Project outline

Envenoming resulting from snakebites is a major public health problem in tropical and subtropical countries in Africa, Asia, Oceania and Latin America. A recent study estimates that there are at least 440,000 envenomings and 20,000 deaths due to snakebite annually. Early systemic reactions to equine polyvalent antivenoms, such as those used in Sri Lanka and other tropical countries, are a major problem, occurring in up to 75% of patients. Severe reactions (anaphylaxis) occur in up to 50% of those treated. We have demonstrated that envenoming itself, prior to antivenom, causes significant immune activation including mast cell degranulation with elevated concentrations of mast cell tryptase, IL-6, IL-10, C3a, C4a and C5a compared to healthy controls. The mechanism and potential for reconstituted antivenoms to activate immune cells will be examined using an in-vitro cell culture model with and without venom pre-incubation. The PhD Candidate will examine the ability of each freshly prepared antivenom to non-specifically trigger inflammatory pathways in fresh whole blood and an in vitro mast cell line (human Fc RI-transfected rat blast cells). The project will investigate the effects of serum or venom priming on the cellular responses to antivenom, with the aim of identifying the specific factors responsible for the activation of anaphylaxis. This model will also be used to investigate the efficacy of strategies to reduce antivenom contamination.

Aims

Understanding reactions to antivenom is essential for improving patient safety when antivenom is administered. These studies will help identify strategies to reduce the incidence of antivenom reactions and patients at risk who may benefit from closer monitoring or premedication, if shown to be effective.

Recommended reading

Kasturiratne A, et al. The global burden of snakebite: a literature analysis and modelling based on regional estimates of envenoming and deaths. PLoSMed 2008; 5(11): e218.

Fox S, et al. Underestimation of snakebite mortality by hospital statistics in the Monaragala District of Sri Lanka. Transactions of the Royal Society of Tropical Medicine and Hygiene 2006; 100(7): 693-5.

Isbister GK, Bawaskar HS. Scorpion envenomation. N Engl J Med 2014; 371(5): 457-63.

Gutierrez JM, et al. Assessing the preclinical efficacy of antivenoms: from the lethality neutralization assay to antivenomics. Toxicon 2013; 69: 168-79.

Contact details: daniel.fatovich@health.wa.gov.auerika.bosio@uwa.edu.au

 

MicroRNAs as biomarkers for the diagnosis of critical illness

Chief Supervisor:  Professor Daniel Fatovich
Other supervisors: Dr Erika Bosio, A/Professor Glenn Arendts
Project suitability: PhD
Essential qualifications: BSc (Hons) or equivalent, or Masters
Start date: 2017

Project outline

MicroRNAs are small (20-25 nucleotides) stable RNAs that play a role in the post-transcriptional regulation of genes, by binding to specific mRNAs. They can be found in serum and plasma, either as soluble components of the blood, or within circulating exosomes. Their levels change during disease, and for this reason they are popular candidate biomarkers. Furthermore, numerous studies assessing the gene regulatory functions of miRNA species have demonstrated novel therapeutic potential. Despite extensive work in the field, encompassing numerous diseases, their diagnostic potential has not yet been realised clinically. While it is becoming clear that miRNA technology is a viable and novel diagnostic option, the technology requires further research to become recognised and accepted by clinicians. If this technology is to become a mainstream diagnostic tool, the relevance and utility of miRNA footprints in diverse patient cohorts needs to be reliably demonstrated.

Our centre has collected an extensive biobank of thousands of samples from >1000 patients, recruited following presentation to Emergency Departments with critical illness. This project will involve a comparison of the miRNA libraries present in a range of different disease states, potentially including sepsis, cardiac arrest, stroke, trauma, dementia and diabetes with the scope of identifying candidate miRNA biomarkers that may define these illnesses.

Aims

  1. To investigate miRNA species present in different disease states.
  2. To identify candidate miRNA biomarkers present within specific patient cohorts.
  3. To validate these candidates with a view to developing a diagnostic test for use in the emergency department.

Recommended reading

  1. Wang J, Chen J, Sen S. MicroRNA as Biomarkers and Diagnostics. J Cell Physiol 2016; 231(1): 25-30.
  2. Bronze-da-Rocha E. MicroRNAs expression profiles in cardiovascular diseases. Biomed Res Int 2014; 2014: 985408.
  3. van Rooij E. The art of microRNA research. Circulation research 2011; 108(2): 219-34.

Contact details: erika.bosio@uwa.edu.au

 
Unravelling the association between delirium and attendance by older people from aged care to the emergency department

Chief Supervisor: A/Professor Glenn Arendts
Project suitability: PhD
Essential qualifications: BSc (Hons), BPsych (Hons) or equivalent, or Masters
Start date: 2017

Project outline

Delirium is an acute disturbance in brain function, characterised by defects in attention, orientation and other cognitive tasks. 8% of older people that attend ED have delirium on arrival, and at least that many again develop delirium whilst in hospital. Hospitalised patients with delirium have up to an eight fold increase in mortality after adjusting for covariates. The single greatest risk factor for delirium is pre-existing cognitive impairment.

Our centre has conducted prior cluster randomised trials that revealed that preventative interventions in aged care improve quality of life for residents but do not reduce the rate of transfer to hospital from facilities. One clear reason was the development of acute delirium in residents went undetected until secondary morbidity (e.g poor oral intake with dehydration, injurious falls, challenging behaviour) had become established. The PhD student will use this information to trial early detection strategies in aged care facilities to enable better recognition and management of acute delirium residents at an earlier stage. The strategies will have a clinical focus with some opportunity for basic laboratory analysis. Results will build on quality of life gains for older people already achieved, as well as reduce distressing hospital transfer, morbidity and mortality.

Aims

  1. To investigate the point prevalence of delirium in people attending emergency from aged care facilities.
  2. To experimentally trial brief screening instruments to improve delirium detection in aged care.
  3. To validate the chosen instrument in a cluster randomised trial.

Recommended reading

    • Hare M et al. Psychosomatics 2014;55:235-42
    • Arendts G et al. Arch Gerontol Geriatr. 2014;58(1):15-19

Contact details: glenn.arendts@uwa.edu.au

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