A Histological and Clinical Study of MatriDerm® Use in Burn Reconstruction.

Dermal substitutes are well established in the reconstructive ladder. MatriDerm® (Dr. Otto Suwelack Skin & Health Care AG, Billerbeck, Germany) is a single-layer dermal substitute composed of a bovine collagen (type I, III, and V) and elastin hydrolysate, that allows for immediate split-thickness skin grafting (SSG). The aim of this study was to histologically characterize the integration of MatriDerm® when used during burns surgery reconstruction. Eight subjects with nine burn scars and one acute burn wound underwent reconstruction with MatriDerm® and an immediate SSG. MatriDerm® integration and skin graft take were assessed with serial biopsies performed at weeks 1, 2, 3, and 4 and months 2, 3, 6, 9, and 12. Biopsies were assessed with standard special stains and immunohistochemistry, and representative slides were imaged with a transmission electron microscope. Patient satisfaction and clinical scar outcome were assessed with the Vancouver Scar Scale and a patient questionnaire. Histological analysis showed similar stages of wound healing as shown in other dermal templates but on a different timescale. There is early evidence of vascularization and an inflammatory infiltrate in the first 2 weeks. MatriDerm® is resorbed earlier than other dermal substitutes, with evidence of resorption at week 3, to be completely replaced by a neodermis at 2 months. The use of MatriDerm® in reconstruction with immediate skin grafting is supported histologically with early evidence of vascularization to support an epidermal autograft. Future histological studies may help further characterize the ideal dermal substitute.

Therapies for Long COVID in non-hospitalised individuals: from symptoms, patient-reported outcomes and immunology to targeted therapies (The TLC Study).

INTRODUCTION: Individuals with COVID-19 frequently experience symptoms and impaired quality of life beyond 4-12 weeks, commonly referred to as Long COVID. Whether Long COVID is one or several distinct syndromes is unknown. Establishing the evidence base for appropriate therapies is needed. We aim to evaluate the symptom burden and underlying pathophysiology of Long COVID syndromes in non-hospitalised individuals and evaluate potential therapies. METHODS AND ANALYSIS: A cohort of 4000 non-hospitalised individuals with a past COVID-19 diagnosis and 1000 matched controls will be selected from anonymised primary care records from the Clinical Practice Research Datalink, and invited by their general practitioners to participate on a digital platform (Atom5). Individuals will report symptoms, quality of life, work capability and patient-reported outcome measures. Data will be collected monthly for 1 year.Statistical clustering methods will be used to identify distinct Long COVID-19 symptom clusters. Individuals from the four most prevalent clusters and two control groups will be invited to participate in the BioWear substudy which will further phenotype Long COVID symptom clusters by measurement of immunological parameters and actigraphy.We will review existing evidence on interventions for postviral syndromes and Long COVID to map and prioritise interventions for each newly characterised Long COVID syndrome. Recommendations will be made using the cumulative evidence in an expert consensus workshop. A virtual supportive intervention will be coproduced with patients and health service providers for future evaluation.Individuals with lived experience of Long COVID will be involved throughout this programme through a patient and public involvement group. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Solihull Research Ethics Committee, West Midlands (21/WM/0203). Research findings will be presented at international conferences, in peer-reviewed journals, to Long COVID patient support groups and to policymakers. TRIAL REGISTRATION NUMBER: 1567490.

Multicentre, longitudinal, observational cohort study to examine the relationship between neutrophil function and sepsis in adults and children with severe thermal injuries: a protocol for the Scientific Investigation of the Biological Pathways Following Thermal Injury-2 (SIFTI-2) study.

INTRODUCTION: Burn-induced changes in the phenotype and function of neutrophils, cells which provide front-line protection against rapidly dividing bacterial infections, are emerging as potential biomarkers for the early prediction of sepsis. In a longitudinal study of adult burns patients, we recently demonstrated that a combined measurement of neutrophil phagocytic capacity, immature granulocyte (IG) count and plasma cell-free DNA (cfDNA) levels on the day of injury gave good discriminatory power for the prediction of later sepsis development. However, limited by a small sample size, single-centre design and focus on adult burns patients, these biomarkers require prospective validation in a larger patient cohort. The Scientific Investigation of the Biological Pathways Following Thermal Injury-2 study aims to prospectively validate neutrophil phagocytic activity, IG count and plasma cfDNA levels as early prognostic biomarkers of sepsis in thermally injured adult and paediatric patients. METHODS AND ANALYSIS: This multicentre, longitudinal, observational cohort study will enrol 245 paediatric and adult patients with moderate to severe burns within 24 hours of injury. Blood samples will be obtained at 19 postinjury time points (days 1-14, day 28, months 3, 6, 12 and 24) and analysed for neutrophil phagocytic activity, IG count and cfDNA levels. Patients will be screened daily for sepsis using the 2007 American Burn Association diagnostic criteria for sepsis. In addition, daily multiple organ dysfunction syndrome and Sequential Organ Failure Assessment Scores will be recorded relationships between neutrophil phagocytic activity, IG count and plasma cfDNA levels on day 1 of injury and the development of sepsis will be examined using logistic regression models. ETHICS AND DISSEMINATION: This study received ethics approval from the West Midlands, Coventry and Warwickshire Research Ethics Committee (REC reference:16/WM/0217). Findings will be presented at national and international conferences, and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04693442.

Ensuring that the outcome domains proposed for use in burns research are relevant to adult burn patients: a systematic review of qualitative research evidence.

BACKGROUND: There have been several attempts to define core outcome domains for use in research focused on adult burns. Some have been based in expert opinion, whilst others have used primary qualitative research to understand patients' perspectives on outcomes. To date there has not been a systematic review of qualitative research in burns to identify a comprehensive list of patient-centred outcome domains. We therefore conducted a systematic review of qualitative research studies in adult burns. METHODS: We searched multiple databases for English-language, peer-reviewed, qualitative research papers. We used search strategies devised using the SPIDER tool for qualitative synthesis. Our review utilized an iterative three-step approach: (1) outcome-focused coding; (2) development of descriptive accounts of outcome-relevant issues; and (3) revisiting studies and the broader theoretical literature in order to frame the review findings. RESULTS: Forty-one articles were included. We categorized papers according to their primary focus. The category with the most papers was adaptation to life following burn injury (n = 13). We defined 19 outcome domains across the 41 articles: (1) sense of self; (2) emotional and psychological morbidity; (3) sensory; (4) scarring and scar characteristics; (5) impact on relationships; (6) mobility and range of joint motion; (7) work; (8) activities of daily living and self-care; (9) treatment burden; (10) engagement in activities; (11) wound healing and infection; (12) other physical manifestations; (13) financial impact; (14) impact on spouses and family members; (15) analgesia and side effects; (16) cognitive skills; (17) length of hospital stay; (18) access to healthcare; and (19) speech and communication. We suggest that sense of self is a core concern for patients that, to date, has not been clearly conceptualized in the burns outcome domain literature. CONCLUSIONS: This outcome domain framework identifies domains that are not covered in previous attempts to outline core outcome domains for adult burn research. It does so with reference to existing theoretical perspectives from the sociology and psychology of medicine. We propose that this framework can be used as a basis to ensure that outcome assessment is patient-centred. Sense of self requires further consideration as a core outcome domain.

Loss of microbial diversity and pathogen domination of the gut microbiota in critically ill patients.

Among long-stay critically ill patients in the adult intensive care unit (ICU), there are often marked changes in the complexity of the gut microbiota. However, it remains unclear whether such patients might benefit from enhanced surveillance or from interventions targeting the gut microbiota or the pathogens therein. We therefore undertook a prospective observational study of 24 ICU patients, in which serial faecal samples were subjected to shotgun metagenomic sequencing, phylogenetic profiling and microbial genome analyses. Two-thirds of the patients experienced a marked drop in gut microbial diversity (to an inverse Simpson's index of <4) at some stage during their stay in the ICU, often accompanied by the absence or loss of potentially beneficial bacteria. Intravenous administration of the broad-spectrum antimicrobial agent meropenem was significantly associated with loss of gut microbial diversity, but the administration of other antibiotics, including piperacillin/tazobactam, failed to trigger statistically detectable changes in microbial diversity. In three-quarters of ICU patients, we documented episodes of gut domination by pathogenic strains, with evidence of cryptic nosocomial transmission of Enterococcus faecium. In some patients, we also saw an increase in the relative abundance of apparent commensal organisms in the gut microbiome, including the archaeal species Methanobrevibacter smithii. In conclusion, we have documented a dramatic absence of microbial diversity and pathogen domination of the gut microbiota in a high proportion of critically ill patients using shotgun metagenomics.

Pressure garment to prevent abnormal scarring after burn injury in adults and children: the PEGASUS feasibility RCT and mixed-methods study.

BACKGROUND: Eleven million people suffer a fire-related injury worldwide every year, and 71% have significant scarring. Pressure garment therapy (PGT) is a standard part of burn scar management, but there is little evidence of its clinical effectiveness or cost-effectiveness. OBJECTIVE: To identify the barriers to, and the facilitators of, conducting a randomised controlled trial (RCT) of burn scar management with and without PGT and test whether or not such a trial is feasible. DESIGN: Web-based surveys, semistructured individual interviews, a pilot RCT including a health economic evaluation and embedded process evaluation. SETTING: UK NHS burns services. Interviews and the pilot trial were run in seven burns services. PARTICIPANTS: Thirty NHS burns services and 245 staff provided survey responses and 15 staff participated in individual interviews. Face-to-face interviews were held with 24 adult patients and 16 parents of paediatric patients who had undergone PGT. The pilot trial recruited 88 participants (57 adults and 31 children) who were at risk of hypertrophic scarring and were considered suitable for scar management therapy. Interviews were held with 34 participants soon after recruitment, with 23 participants at 12 months and with eight staff from six sites at the end of the trial. INTERVENTIONS: The intervention was standard care with pressure garments. The control was standard care comprising scar management techniques involving demonstration and recommendations to undertake massage three or four times per day with moisturiser, silicone treatment, stretching and other exercises. MAIN OUTCOME MEASURES: Feasibility was assessed by eligibility rates, consent rates, retention in allocated arms, adherence with treatment and follow-up and completion of outcome assessments. The outcomes from interview-based studies were core outcome domains and barriers to, and facilitators of, trial participation and delivery. RESULTS: NHS burns services treat 2845 patients per annum (1476 paediatric and 1369 adult) and use pressure garments for 6-18 months, costing £2,171,184. The majority of staff perceived a need for a RCT of PGT, but often lacked equipoise around the research question and PGT as a treatment. Strong views about the use of PGT have the potential to influence the conduct of a full-scale RCT. A range of outcome domains was identified as important via the qualitative research: perceptions of appearance, specific scar characteristics, function, pain and itch, broader psychosocial outcomes and treatment burden. The outcome tools evaluated in the pilot trial did not cover all of these domains. The planned 88 participants were recruited: the eligibility rate was 88% [95% confidence interval (CI) 83% to 92%], the consent rate was 47% (95% CI 40% to 55%). Five (6%) participants withdrew, 14 (16%) were lost to follow-up and 8 (9%) crossed over. Adherence was as in clinical practice. Completion of outcomes was high for adult patients but poorer from parents of paediatric patients, particularly for quality of life. Sections on range of movement and willingness to pay were found to be challenging and poorly completed. LIMITATIONS: The Brisbane Burn Scar Impact Profile appears more suitable in terms of conceptual coverage than the outcome scales that were used in the trial but was not available at the time of the study. CONCLUSIONS: A definitive RCT of PGT in burn scar management appears feasible. However, staff attitudes to the use of pressure garments may lead to biases, and the provision of training and support to sites and an ongoing assessment of trial processes are required. FUTURE WORK: We recommend that any future trial include an in-depth mixed-methods recruitment investigation and a process evaluation to account for this. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34483199. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 36. See the NIHR Journals Library website for further project information.

Soluble GPVI is elevated in injured patients: shedding is mediated by fibrin activation of GPVI.

Soluble glycoprotein VI (sGPVI) is shed from the platelet surface and is a marker of platelet activation in thrombotic conditions. We assessed sGPVI levels together with patient and clinical parameters in acute and chronic inflammatory conditions, including patients with thermal injury and inflammatory bowel disease and patients admitted to the intensive care unit (ICU) for elective cardiac surgery, trauma, acute brain injury, or prolonged ventilation. Plasma sGPVI was measured by enzyme-linked immunosorbent assay and was elevated on day 14 after thermal injury, and was higher in patients who developed sepsis. sGPVI levels were associated with sepsis, and the value for predicting sepsis was increased in combination with platelet count and Abbreviated Burn Severity Index. sGPVI levels positively correlated with levels of D-dimer (a fibrin degradation product) in ICU patients and patients with thermal injury. sGPVI levels in ICU patients at admission were significantly associated with 28- and 90-day mortality independent of platelet count. sGPVI levels in patients with thermal injury were associated with 28-day mortality at days 1, 14, and 21 when adjusting for platelet count. In both cohorts, sGPVI associations with mortality were stronger than D-dimer levels. Mechanistically, release of GPVI was triggered by exposure of platelets to polymerized fibrin, but not by engagement of G protein-coupled receptors by thrombin, adenosine 5'-diphosphate, or thromboxane mimetics. Enhanced fibrin production in these patients may therefore contribute to the observed elevated sGPVI levels. sGPVI is an important platelet-specific marker for platelet activation that predicts sepsis progression and mortality in injured patients.

Prospective comparative evaluation study of Laser Doppler Imaging and thermal imaging in the assessment of burn depth.

INTRODUCTION: The accurate assessment of burn depth is challenging but crucial for surgical excision and tissue preservation. Laser Doppler Imaging (LDI) has gained increasing acceptance as a tool to aid depth assessment but its adoption is hampered by high costs, long scan times and limited portability. Thermal imaging is touted as a suitable alternative however few comparison studies have been done. METHODS: Sixteen burn patients with 52 regions of interests were analysed. Burn depth was determined using four methods LDI, thermal imaging, photographic and real-time clinical evaluation at day 1 and day 3. LDI flux and Delta T values were used for the prediction of outcomes (wound closure in <21 days). Photographic clinical evaluation of burn depth was performed by 4 blinded burn surgeons. RESULTS: Accuracy of assessment methods were greater on post burn day 3 compared to day 0. Accuracies of LDI on post burn day 0 and 3 were 80.8% and 92.3% compared to 55.8% and 71.2% for thermal imaging and 62.5% and 71.6% for photographic clinical assessment. Real-time clinical examination had an accuracy of 88.5%. Thermal imaging scan times were significantly faster compared to LDI. DISCUSSION: LDI outperforms thermal imaging in terms of diagnostic accuracy of burn depth likely due to the susceptibility of thermal imaging to environmental factors.

Neutrophil Dysfunction, Immature Granulocytes, and Cell-free DNA are Early Biomarkers of Sepsis in Burn-injured Patients: A Prospective Observational Cohort Study.

OBJECTIVE: The aim of this study was to measure neutrophil function longitudinally following burn injury and to examine the relationship between neutrophil dysfunction and sepsis. BACKGROUND: Sepsis prevalence and its associated mortality is high following burn injury, and sepsis diagnosis is complicated by the ongoing inflammatory response. Previous studies have suggested that neutrophil dysfunction may underlie high infection rates and sepsis postburn; however, neutrophil dysfunction has not been thoroughly characterized over time in burns patients. METHODS: Neutrophil phagocytosis, oxidative burst capacity, and neutrophil extracellular trap (NET) generation (NETosis) were measured from 1 day to up to 1 year postburn injury in 63 patients with major burns (≥15% total body surface area). In addition, immature granulocyte (IG) count, plasma cell-free DNA (cfDNA), and plasma citrullinated histone H3 (Cit H3) levels were measured. RESULTS: Neutrophil function was reduced for 28 days postburn injury and to a greater degree in patients who developed sepsis, which was also characterized by elevated IG counts. Plasma cfDNA and Cit-H3, a specific marker of NETosis, were elevated during septic episodes. The combination of neutrophil phagocytic capacity, plasma cfDNA levels, and IG count at day 1 postinjury gave good discriminatory power for the identification of septic patients. CONCLUSION: Neutrophil function, IG count, and plasma cfDNA levels show potential as biomarkers for the prediction/early diagnosis of sepsis postburn injury and neutrophil dysfunction may actively contribute to the development of sepsis. Targeting neutrophil dysfunction and IG release may be a viable therapeutic intervention to help reduce the incidence of nosocomial infections and sepsis postburn.

The Antibacterial Activity of Acetic Acid against Biofilm-Producing Pathogens of Relevance to Burns Patients.

INTRODUCTION: Localised infections, and burn wound sepsis are key concerns in the treatment of burns patients, and prevention of colonisation largely relies on biocides. Acetic acid has been shown to have good antibacterial activity against various planktonic organisms, however data is limited on efficacy, and few studies have been performed on biofilms. OBJECTIVES: We sought to investigate the antibacterial activity of acetic acid against important burn wound colonising organisms growing planktonically and as biofilms. METHODS: Laboratory experiments were performed to test the ability of acetic acid to inhibit growth of pathogens, inhibit the formation of biofilms, and eradicate pre-formed biofilms. RESULTS: Twenty-nine isolates of common wound-infecting pathogens were tested. Acetic acid was antibacterial against planktonic growth, with an minimum inhibitory concentration of 0.16-0.31% for all isolates, and was also able to prevent formation of biofilms (at 0.31%). Eradication of mature biofilms was observed for all isolates after three hours of exposure. CONCLUSIONS: This study provides evidence that acetic acid can inhibit growth of key burn wound pathogens when used at very dilute concentrations. Owing to current concerns of the reducing efficacy of systemic antibiotics, this novel biocide application offers great promise as a cheap and effective measure to treat infections in burns patients.

Antimicrobial dressings: Comparison of the ability of a panel of dressings to prevent biofilm formation by key burn wound pathogens.

UNLABELLED: Antimicrobial medicated dressings (AMD) are often used to reduce bacterial infection of burns and other wounds. However, there is limited literature regarding comparative efficacies to inform effective clinical decision making. OBJECTIVES: Following on from a previous study where we demonstrated good antibiofilm properties of acetic acid (AA), we assessed and compared the in vitro anti-biofilm activity of a range of AMDs and non-AMDs to AA. METHODS: Laboratory experiments determined the ability of a range of eleven commercial AMD, two nAMD, and AA, to prevent the formation of biofilms of a panel of four isolates of Pseudomonas aeruginosa and Acinetobacter baumannii. RESULTS: There is a large variation in ability of different dressings to inhibit biofilm formation, seen between dressings that contain the same, and those that contain other antimicrobial agents. The best performing AMD were Mepilex(®) Ag and Acticoat. AA consistently prevented biofilm formation. CONCLUSIONS: Large variation exists in the ability of AMD to prevent biofilm formation and colonisation of wounds. A standardised in vitro methodology should be developed for external parties to examine and compare the efficacies of commercially available AMDs, along with robust clinical randomised controlled trials. This is essential for informed clinical decision-making and optimal patient management.

Seeking the source of Pseudomonas aeruginosa infections in a recently opened hospital: an observational study using whole-genome sequencing.

OBJECTIVES: Pseudomonas aeruginosa is a common nosocomial pathogen responsible for significant morbidity and mortality internationally. Patients may become colonised or infected with P. aeruginosa after exposure to contaminated sources within the hospital environment. The aim of this study was to determine whether whole-genome sequencing (WGS) can be used to determine the source in a cohort of burns patients at high risk of P. aeruginosa acquisition. STUDY DESIGN: An observational prospective cohort study. SETTING: Burns care ward and critical care ward in the UK. PARTICIPANTS: Patients with >7% total burns by surface area were recruited into the study. METHODS: All patients were screened for P. aeruginosa on admission and samples taken from their immediate environment, including water. Screening patients who subsequently developed a positive P. aeruginosa microbiology result were subject to enhanced environmental surveillance. All isolates of P. aeruginosa were genome sequenced. Sequence analysis looked at similarity and relatedness between isolates. RESULTS: WGS for 141 P. aeruginosa isolates were obtained from patients, hospital water and the ward environment. Phylogenetic analysis revealed eight distinct clades, with a single clade representing the majority of environmental isolates in the burns unit. Isolates from three patients had identical genotypes compared with water isolates from the same room. There was clear clustering of water isolates by room and outlet, allowing the source of acquisitions to be unambiguously identified. Whole-genome shotgun sequencing of biofilm DNA extracted from a thermostatic mixer valve revealed this was the source of a P. aeruginosa subpopulation previously detected in water. In the remaining two cases there was no clear link to the hospital environment. CONCLUSIONS: This study reveals that WGS can be used for source tracking of P. aeruginosa in a hospital setting, and that acquisitions can be traced to a specific source within a hospital ward.

Hydrotherapy in burn care: a survey of hydrotherapy practices in the UK and Ireland and literature review.

INTRODUCTION: Hydrotherapy is widely used in burns management however there are risks associated with its use, in particular cross-infection. Data regarding indications and techniques in common use is deficient. This study aimed to investigate hydrotherapy practices in the UK and Ireland. METHODS: A survey of the hydrotherapy practice of major burn care providers was performed by e mail and where necessary, follow up telephone contact. RESULTS: The survey included 28 burn care providers. 27 reported using hydrotherapy. Only 11 (41%) had defined indication criteria with 4 (15%) implementing a specific protocol. Variations in hydrotherapy practice were seen. CONCLUSION: Hydrotherapy is used nationwide, however considerable variation in practice exists. One area worthy of further consideration is the need for appropriate standards of infection control.

Revised estimates of mortality from the Birmingham Burn Centre, 2001-2010: a continuing analysis over 65 years.

OBJECTIVE: The Birmingham Burn Centre has continued to publish mortality data over the last 65 years. It is one of the longest running cross-sectional cohort studies in the world. We present the latest data from the study, with a comparison to previous results. BACKGROUND: Results from the previous decade failed to show any improvement in mortality despite perceived advances in burn care. The aim of this update was to establish current mortality statistics and ascertain whether improvement had now been made. METHODS: Data were collected for a 10-year period on all burn-injured patients admitted to the Birmingham Burn Centre (Birmingham Children's Hospital, Selly Oak Hospital, and Queen Elizabeth Hospital Birmingham). Patients' age, percentage of burn, date of injury, and outcome were recorded and analyzed with both probit and logistic regression analyses. RESULTS: A total of 4577 patients were included in the analysis, with a mean total body surface area (TBSA) burn of 7.2% and a mean age of 22 years. Comparison of probit model results with previous results demonstrates improvement in predicted mortality and lethal area (LA50) of burns. Logistic regression produces similar results to the probit analysis. Trend analysis proved a statistically significant improvement in mortality. CONCLUSIONS: The last decade of burn care at Birmingham Burn Centre demonstrates an improvement in predicted mortality and LA50. This reflects our structured, multidisciplinary approach to burn-injured patients, early surgical excision and wound closure, and general advances in the intensive care of patients.

A pilot evaluation study of high resolution digital thermal imaging in the assessment of burn depth.

Thermal imaging is a tool that can be used to determine burn depth. We have revisited the use of this technology in the assessment of burns and aim to establish if high resolution, real-time technology can be practically used in conjunction with clinical examination to determine burn depth. 11 patients with burns affecting upper and lower limbs and the anterior and posterior trunk were included in this study. Digital and thermal images were recorded at between 42 h and 5 days post burn. When compared to skin temperature, full thickness burns were significantly cooler (p<0.001), as were deep partial thickness burns (p<0.05). Superficial partial thickness burns were not significantly different in temperature than non-burnt skin (p>0.05). Typically, full thickness burns were 2.3°C cooler than non-burnt skin; deep partial thickness burns were 1.2°C cooler than non-burnt skin; whilst superficial burns were only 0.1°C cooler. Thermal imaging can correctly determine difference in burn depth. The thermal camera produces images of high resolution and is quick and easy to use.