Discover: Response to Injury | NIHR SRMRC - Surgical Reconstruction and Microbiology Research Centre

Determination of accelerated ageing in trauma patients and the impact on rehabilitation

brownda — Tue, 30 Jul 2019 09:33:57 +0000

Background

Survivors of a major trauma, such as a road traffic accident or military conflict, have their lifespans shortened by up to 10 years. These patients also develop age-related diseases such as heart disease and cancer much earlier than people who have not been severely injured. One possible explanation is that the injury and subsequent large scale repair processes have resulted in an acceleration of the ageing process. Until very recently it was not possible to test this idea as we could not determine how rapidly someone was ageing, but now there are a range of biomarkers that can determine an individual’s biological age as opposed to their chronological age.

Method

This project will use three main methods to determine whether survivors of a major trauma show signs of accelerated ageing. Blood samples will be analysed at 1 week, 6 months and up to 8 years after injury in patients who were injured and had an injury severity score of 16 or higher. The early time points are from stored PBMCs and the 8 year follow up samples are being collected now. The samples will be assessed for three measures of ageing: Telomere length in PBMCs, DNA methylation at 350 CpG sites according to the Horvath and Hannum epigenetic clock algorithms and the IMM-AGE analysis of blood cell phenotype. The data taken together with clinical measures will reveal if the patients have evidence of accelerated ageing.

The gut microbiome response to trauma

brownda — Tue, 30 Jul 2019 09:33:38 +0000

Background

Long-stay patients in the intensive care unit (ICU) are among the sickest and most vulnerable in the hospital. Once in the ICU, they are subjected to numerous procedures and administration of many drugs. In healthy individuals, the human gut is home to a wide variety of bacteria and their genes (the human microbiome). However, in the long-stay ICU patient, there is a disruption in bacterial diversity. Indeed, studies using genetic detection of bacterial DNA have demonstrated that fewer types of bacteria are present and antibiotic-resistant bacteria may predominate. However, these genetic methods used have provided little information on the bacteria. Thanks to our recent groundbreaking experience of the direct genetic sequencing of DNA extracted from clinical samples we will explore bacteria in the gut of the ICU patient.

Method

Patients who are over 18 years of age and expected to stay on the ICU for more than 48 hours will be approached for participation in the study. Following consent, the first faecal sample passed on ICU and each calendar day thereafter will be collected until patient discharge from (or death on) the ICU. DNA extraction, quality control of extracted DNA, preparation of sequencing libraries and deep shotgun metagenomic sequencing will be carried out on these samples. From the sequence files, we will identify sequences that align to the human reference genome and exclude them from further analysis or deposition in public data repositories. We will then perform a range of analyses relevant to clinical microbiology and microbial ecology.

Tissue specific and cell derived biomarkers in the early management of traumatic and thermal injuries

brownda — Tue, 30 Jul 2019 09:28:53 +0000

Background

Although the major cause of death following severe trauma is bleeding, many patients die later following complications such as sepsis and organ failure. These patients, therefore, consume large amounts of critical care and hospital resources. Human experimental research is required to better understand the hyper-acute immune response to damage before early stratification, identification of potential targets, and therapeutic modulation are possible. The identification of reliable outcome predictors in severe sepsis is vital for the early diagnosis and prognosis and for stratifying patients onto various treatment regimes. Our studies, therefore, focus on the immunological, inflammatory and haematological responses following both severe burns and traumatic injury. This has not only increased our understanding of the physiological responses following injury but resulted in the identification of candidate biomarkers and novel therapies.

Method

We are collecting and storing vast numbers of blood and urine samples from our 2 main patient cohorts (e.g. Golden Hour and SIFTI studies). This involves close collaboration with both our trauma and burns clinical teams. Immune function (e.g. a Neutrophil function) and Haematological parameters are immediately measured within fresh samples. Inflammatory and ageing biomarkers (e.g. cytokines, extracellular vesicles, DNA methylation, Neutrophil Extracellular Traps, metabolites etc) are regularly measured in batches from thawed cellular, plasma and serum samples. Validated sample results are entered into large clinical databases to enable a statistical analysis to determine the relationship of the biomarkers with the clinical status and outcomes of individual patients. New research findings are presented at national and international meetings and published within leading scientific journals.