BJA/RCoA Project Grants

Queen Mary University of London

Title
Risks of AntiMicrobial Prophylaxis for Surgery (RAMPS)

Amount
£29,482

Scientific Abstract
Surgical site infection (SSI) affects 1 in 20 surgical patients and is an important cause of avoidable postoperative morbidity. The widespread use of antimicrobial drugs to prevent SSI is standard practice worldwide. However, the evidence supporting antimicrobial prophylaxis is relatively weak, and was generated before the introduction of modern surgical and anaesthetic techniques, which reduce rates of SSI. Antimicrobial use may also cause harm, with 1 in 50 surgical patients suffering complications directly attributable to antimicrobial drugs, including acute kidney injury, hearing loss and anaphylaxis. In addition, 1 in 7 patients carry a label of antimicrobial allergy, which results in the use of alternative antimicrobial drugs that are less effective and more toxic, potentially leading to more side effects. At a societal level, the widespread use of antimicrobial drugs is the principal cause of antimicrobial resistance, which represents a serious threat to global healthcare. We hypothesise that current practice for surgical antimicrobial prophylaxis may not be based on robust evidence of benefit versus risk. We will determine whether there are 1) associations between the number of doses of antimicrobial drugs and incidence of SSI, mortality and hospital re-admission within 30 days after surgery; and 2) associations between these outcomes and the presence of antimicrobial allergy labels.

University of Leicester

Title
Opioids and Tumour Angiogenesis; Emphasis on a role for the Nociceptin/Orphanin FQ receptor

Amount
£58,702

Scientific Abstract
Opioid receptors are classified as classical naloxone-sensitive MOP-(mu:μ), DOP-(delta:𝛿) and KOP-(kappa:κ) and the non-classical nociceptin/orphaninFQ (N/OFQ) receptor or NOP. All produce pain relief but with differences related to species and routes of administration. Several studies suggest that opioids influence angiogenesis, a critical process in tumour growth (reseeding), by acting on endothelial cells but the field is far from clear with positive and negative actions reported. Some of this variability likely results from species differences.
In this application we will use human tissues; umbilical vein endothelial cells (HUVEC) and breast cancer (MCF-7) cells. We will treat HUVEC cells with media from MCF-7 cells or use standard angiogenic stimuli (FGF/VEGF) and then determine NOP and MOP expression by PCR on HUVEC or protein using fluorescent receptor probes. We will then assess the effect of NOP and MOP activation in in vitro assays that model angiogenic processes; tube formation and wound healing. Our hypothesis is that breast cancer cells will secrete angiogenic stimuli (e.g. FGF/VEGF) to induce HUVEC NOP and MOP receptor expression. These receptors will reduce wound healing and increase tube formation (pro-angiogenic). This data will be used in a grant to examine mechanisms and identify opioids with reduced angiogenic potential.

Imperial College, London

Title
The role of microvesicles in the pathophysiology of organ failure in critically ill patients with COVID-19

Amount
£69,461

Scientific Abstract
A significant proportion (~17%) of hospitalised patients with COVID-19 require intensive care due to acute respiratory distress syndrome (ARDS) and multi-organ failure (MOF). Indeed, 51.8% COVID-19 ARDS patients develop acute kidney injury (AKI), which has a mortality of 61%. Management remains principally supportive and there remains an urgent need for research investigating mechanisms of respiratory/kidney failure in COVID-19 to identify novel diagnostic/therapeutic targets.

Microvesicles (MVs) are membrane-encapsulated extracellular particles (100-1000nm size), released from cells during injury/inflammation and carry a variety of molecular cargo, providing an alternative pathway for inter-cellular communication. We previously showed that MVs are important mediators of lung injury in murine models and are predictive of primary graft dysfunction in patients post-lung transplantation. We hypothesise that MVs released during viral infection of lung parenchyma, carry key pro-inflammatory mediators (e.g. IL-6/TNF), activating inflammatory pathways in recipient pulmonary endothelial cells and playing crucial roles in the evolution of COVID-19 ARDS. These MVs, released into the circulation, are fundamental to lung-to-kidney crosstalk, transmitting inflammation and producing AKI/MOF.

To investigate this, we will: 1) explore the diagnostic/biomarker potential of MVs, evaluating correlations of MV numbers/subtypes with clinical/laboratory parameters of lung/kidney injury; and 2) investigate molecular cargo within MVs and their biological activities.

Imperial College, London

Title
A transcriptomic-led approach to understand individual patient susceptibility to post-operative pneumonia following major abdominal surgery

Amount
£37,543

Scientific Abstract
In high-income countries, 1 in 10 adults undergo a surgical procedure each year. Over 20% of patients aged over 45 years undergoing major-abdominal surgery develop nosocomial infections; post-operative pneumonia is associated with a nearly five-fold increase in 30-day mortality. Current treatment of nosocomial infection is reactive and limited to antibiotic administration.

The immune changes following major abdominal surgery and their role in susceptibility to post-operative pneumonia are poorly understood. Transcriptomic analysis using RNA sequencing (RNA-Seq) provides an unbiased description of the complex and dynamic post-operative changes in immune function. In a previously recruited patient cohort we will define, using RNA-Seq, the specific regulatory and immune pathways activated post operatively, how these affect susceptibility to pneumonia and begin to investigate individual variability in the response to a homogeneous surgical insult.

The knowledge of context-specific pathways and networks generated from this project will provide valuable pilot-data for future larger-scale studies to: Validate our findings; further characterise inter-individual variation in the host response to a homogenous stimulus; identify potential biomarkers; guide the repurposing of existing drugs; provide insights into novel therapeutic targets. This programme of research will ultimately enable the development of a precision-medicine strategy for the prevention and management of post-operative nosocomial infections.