BJA/RCoA Project Grants

Background
The use of antibiotics to prevent surgical wound (surgical site) infection is an accepted cornerstone of modern healthcare. This type of infection occurs in or around the incision a surgeon makes and affects 1 in 20 patients after surgery. In the UK, we use around 7 million doses of antibiotics each year to prevent these infections. However, the evidence supporting this practice is relatively weak and predates the use of modern surgical and anaesthetic techniques that have reduced the risk of wound infections. At the same time, there is evidence that antibiotics may be causing harm, both to individual patients and to society. An estimated 1 in 50 surgical patients have a complication directly caused by antibiotics, including kidney damage, hearing loss and allergic reactions. As well as these well-known antibiotic harms, there are additional but poorly recognised problems in patients who report an antibiotic allergy. Up to 1 in 7 patients are labelled as allergic to an antibiotic, but the majority are not truly allergic to the antibiotic in question and therefore receive alternative antibiotics unnecessarily. The alternative antibiotic may be less effective in preventing surgical wound infection, while at the same time increasing the risk of side effects. For society, the widespread use of antibiotics leads to the development of bacteria that are resistant to these drugs, so-called antimicrobial resistance. This is recognised as a major global threat to public health. We urgently need to understand the risks and harms associated with preventive antibiotic use, so we can ensure the best possible use of these drugs, whilst minimising harm to patients.

Aims
To describe the relationships between preventive antibiotic use in surgery, surgical wound infection and antibiotic side effects we will:

• Assess any effect of preventive antibiotics on the frequency of wound infections after surgery
  
• Assess whether wound infections are more common for patients with antibiotic allergy labels
  
• Describe the frequency of side effects and harms of antibiotics

Methods
We will recruit 30,000 patients in 100 hospitals. Patients will be approached before surgery and asked to consent for their medical records to be examined. We will only observe what happens to patients; there will no changes to their treatment.

Expected outcomes
We expect to demonstrate:

• A weaker effect of antibiotics in preventing surgical wound infection than doctors currently expect
  
• A link between antibiotic allergy labels and increased infections of the surgical wound
  
• A significant level of harm associated with the use of antibiotics

Implications
Understanding the link between antibiotic use in surgery and patient outcomes is essential for doctors making decisions about antibiotic use for individual patients. We expect to identify important limitations in the practice of preventive antibiotic use. This work will tell us how to design a major clinical trial which would define the best way to balance the harms and benefits of antibiotics for surgical patients. It will also provide key data to demonstrate the need for such a trial to major public research funders.

Background
Opioid drugs are used to treat pain and to do that they interact with specific targets on cells; these are called opioid receptors. Typically these drugs include morphine that is used in operations and sometimes long term in end of life pain control. The problem with opioid drugs is that they produce serious side effects such as reduced breathing, nausea and vomiting and tolerance. We know that opioid receptors are members of a family; there are four members. Morphine interacts with a receptor called MOP and one of the other members called NOP is particularly important as it interacts with MOP and can modulate morphine actions. In addition there is now clinical development of a drug that targets NOP for use in pain. Opioids are commonly used in cancer surgery and in palliative care of cancer patients but there is evidence that these very drugs may enhance cancer spread. They depress immune function; the ability to kill off tumour cells, possibly stimulate cancer cells to grow and enhance blood vessel formation (angiogenesis); the tumour is trying to establish 'its own' blood supply. In this application we will examine if NOP (and MOP) activation causes blood vessels to form. Recently, studies in animals revealed the presence of opioid receptors in cells lining blood vessels called endothelial cells and these are variably increased by substances released from tumours. Activation of MOP receptors in some cases appears to increase vessel formation but this is not consistent. It varies with species studied and drug used. Moreover, there is no data with NOP. Our hypothesis is that cancer progression increases the expression of NOP and / or MOP in endothelial cells and stimulation of NOP and / or MOP influences blood vessel formation. To study this, we will expose human endothelial cells to extracts from human breast cancer cells and will mimic these extracts with known stimuli of angiogenesis (that are released from cancer cells). We will measure NOP and MOP expression (genetic message and receptor) with and without exposure. We will interrogate vessel formation in endothelial cells using two types of experiments; wound healing where migration mimics the early phase of vessel formation and tube formation where this migration organises into primitive tube (vessel) structures. We will examine how MOP and NOP drugs influence this process. We predict reduced wound healing and increased tube formation. Data from this work will serve two purposes, to pump prime data for a larger application and give some early indication of opioid drugs that are tumour 'beneficial' or 'detrimental'.

COVID-19 is a highly contagious virus, causing a global health emergency. A significant number (~17%) of hospitalised patients become severely unwell and require admission to an intensive care unit (ICU) due to lung failure (acute respiratory distress syndrome (ARDS and multi-organ failure (MOF). Sadly, 51.8% of COVID-ARDS patients develop kidney failure, which has a markedly increased risk of dying (61%). We have learned that kidney failure starts several days after lung failure, which suggest an initial viral "attack" on the lungs followed by kidney involvement several days later.

Cytokines are "signalling" molecules made by cells, which in healthy individuals help fight disease. It was initially thought that in COVID-19, lung cells release excessive cytokines (i.e. cytokine storm), which then cause kidney injury and MOF. However, research has demonstrated that cytokine levels in blood are actually very low and not enough to explain the extent of organ injury in COVID-19. This perhaps explains why treatment strategies aimed at specifically damping down the action of these particular cytokines in COVID-19 have failed. Consequently, there remains no cure for COVID-19 MOF, and whilst treatments such as steroids, manage symptoms, have a general anti-inflammatory effect and improve mortality, 30% of intensive care patients still die. Therefore, urgent research is needed to improve scientific knowledge of this condition and identify new therapies.

Microvesicles (MVs) are extremely small particles released by cells and carry various chemicals including cytokines, from inside the cell, packaged securely and safely within membranes (cellular envelopes). These vesicles act as 'postmen' delivering chemical messengers (e.g. cytokines) between cells and are important in various diseases where inflammation is implicated. We have demonstrated that MVs have a fundamental role in the development of organ failure in our laboratory models of non-COVID ARDS but we do not yet know the role of these vesicles in the development of ARDS/MOF in COVID-19.

We hypothesise that during COVID-19 infection of the lung, significant numbers of MVs are released within the lung (especially in severe COVID-19), which then "transmit" signals and inflammation to other organs via the bloodstream, causing organs to fail. Furthermore, as chemical messengers (e.g. cytokines) are hidden inside these vesicles, they are not measured by standard laboratory techniques and may explain why there are low cytokine levels in blood. This may also clarify why treatments inhibiting circulating cytokines (not hidden in vesicle membranes) have failed.

To explore these ideas, we aim to investigate MVs in blood and urine of ICU patients with severe COVID-19 (20mls blood (1 1/3 tablespoons); 10ml urine (3/4 tablespoon. We intend to examine which chemicals are present in these tiny vesicles and to relate this information to the clinical progress or otherwise of patients. These data will help us understand the chemical systems involved in severe COVID-19, tell us the significance of MVs and whether blocking MV signalling could lead to new treatments for COVID-19. Furthermore, analysis of these MVs may allow us to identify patients who are likely to become seriously ill, which would help in planning treatment.

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Background
In the western world one in 10 people will undergo surgery each year. Operations put significant stress on the body, and those over the age of 45 years often suffer serious problems after gut surgery. If these 'high-risk' patients develop a chest infection (pneumonia) after their operation they have not only an increased chance of dying, but also a much greater risk of failing to regain the quality of life they had before surgery. Currently we do not fully understand why chest infections occur in some people but not others, despite them having had a similar type of operation. Following surgery, recognising infection early is difficult and our options are limited to either waiting to treat suspected infection with antibiotics, or treatment with antibiotics in all patients to ensure everyone is covered. The latter will ultimately drive antibiotic resistance, with a devastating effect on the health of the population worldwide.

Aims
This project aims to describe the complex changes to the immune system that occur following surgery and to advance our understanding of why some people develop infections, but others remain infection free. We will analyse the levels of chemicals in the blood produced by our genes called RNA. These chemicals control the manufacture of proteins, including those that are vital for a healthy immune system. It is therefore essential that they function correctly following injury to the tissues and when there is a risk of infection, for example following surgery.

Methodology
This is a laboratory study testing blood samples previously obtained from a large population of 'high-risk' patients who have had major gut surgery. They have been followed to hospital discharge and their blood samples have already been stored and are ready for analysis in our laboratory. We will measure RNA in blood from these patients, collected before and after surgery, and compare patients who did, with those who did not develop a chest infection (pneumonia). We will use cutting edge scientific techniques at the Wellcome Centre for Human Genetics in Oxford. From this we will be able to understand not only how the body responds to the stress of surgery but also why some people cope better than others.

Expected outcomes
This work will produce a detailed and comprehensive understanding of our body's responses to major gut surgery and identify differences between people who do and do not develop infections. Ultimately it will help us to develop earlier and more precise ways to identify and treat different groups of patients, either with antibiotics or with medications designed to improve the patient's immune function.

Implications
The long-term objective is to develop personalised management for patients undergoing surgery. It will identify those most at risk and allow doctors in the future to treat them on an individual basis whilst monitoring their response, the ultimate objective being to reduce infections following major gut surgery. This will improve post-operative recovery, reduce unnecessary antibiotic use, and save the NHS money by preventing long, complex hospital stays.