Evidence of bacterial biofilms within acute wounds: a systematic review.

OBJECTIVE: The prevalence and role of biofilm formation in acute wounds has seldom been investigated. Understanding the presence of biofilm in acute wounds would allow earlier, biofilm-targeted management, thus decreasing the morbidity and mortality associated with wound infection, improving patient experience and potentially reducing healthcare costs. The purpose of this study was to summarise the evidence for biofilm formation within acute wounds. METHOD: We conducted a systematic literature review for studies which reported evidence of bacterial biofilm formation in acute wounds. An electronic search of four databases was carried out, without restrictions on date. The search terms included 'bacteria', 'biofilm', 'acute' and 'wound'. RESULTS: A total of 13 studies met the inclusion criteria. Of the studies, 69.2% showed evidence of biofilm formation within 14 days of acute wound formation, with 38.5% showing evidence of biofilm 48 hours after wound formed. CONCLUSION: The evidence from this review suggests that biofilm formation plays a greater role within acute wounds than previously considered.

Real-time detection of volatile metabolites enabling species-level discrimination of bacterial biofilms associated with wound infection.

AIMS: The main aim of this study was to investigate the real-time detection of volatile metabolites for the species-level discrimination of pathogens associated with clinically relevant wound infection, when grown in a collagen wound biofilm model. METHODS AND RESULTS: This work shows that Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyogenes produce a multitude of volatile compounds when grown as biofilms in a collagen-based biofilm model. The real-time detection of these complex volatile profiles using selected ion flow tube mass spectrometry and the use of multivariate statistical analysis on the resulting data can be used to successfully differentiate between the pathogens studied. CONCLUSIONS: The range of bacterial volatile compounds detected between the species studied vary and are distinct. Discrimination between bacterial species using real-time detection of volatile metabolites and multivariate statistical analysis was successfully demonstrated. SIGNIFICANCE AND IMPACT OF THE STUDY: Development of rapid point-of-care diagnostics for wound infection would improve diagnosis and patient care. Such technological approaches would also facilitate the appropriate use of antimicrobials, minimizing the emergence of antimicrobial resistance. This study further develops the use of volatile metabolite detection as a new diagnostic approach for wound infection.

Assessment of mutations induced by cold atmospheric plasma jet treatment relative to known mutagens in Escherichia coli.

The main bactericidal components of cold atmospheric plasma (CAP) are thought to be reactive oxygen and nitrogen species (RONS) and UV-radiation, both of which have the capacity to cause DNA damage and mutations. Here, the mutagenic effects of CAP on Escherichia coli were assessed in comparison to X- and UV-irradiation. DNA damage and mutagenesis were screened for using a diffusion-based DNA fragmentation assay and modified Ames test, respectively. Mutant colonies obtained from the latter were quantitated and sequenced. CAP was found to elicit a similar mutation spectrum to X-irradiation, which did not resemble that for UV implying that CAP-produced RONS are more likely the mutagenic component of CAP. CAP treatment was also shown to promote resistance to the antibiotic ciprofloxacin. Our data suggest that CAP treatment has mutagenic effects that may have important phenotypic consequences.

Designing a safe and sustainable pediatric neurosurgical practice: the English experience.

The 2001 Report of the Public Inquiry into children's heart surgery at the Bristol Royal Infirmary 1984-1995 stated that there must be standards for hospitals as a whole and that hospitals, which do not meet these standards, should not be able to offer services within the National Health Service (NHS). In 2013, agreed standards for pediatric neurosurgery were produced. Between 2001 and 2013 several key documents were published, which formed the background to the review that produced these standards:, the 'Safe and Sustainable' review. The process had the mission statement, 'Safe, sustainable and world class. Not ordinary, OK or just good enough.' In April 2013, the new commissioning structure of NHS England came into being. Clinical Reference Groups (reporting directly into the new structure) and pediatric neurosurgical operational delivery networks are taking the Safe and Sustainable pediatric neurosurgery standards and models of care into practice in England. Effective outcome data collection will allow us to assess whether these networks will improve equity of access for English children to world-class pediatric neurosurgical care and reduce the variation in outcomes seen at the present time.

Working Towards Holistic Scar Assessment and Improved Shared Decision Making in Global Burn Care.

Cutaneous burn scars impact various aspects of life. Scar treatment is mainly evaluated on scar characteristics. Consensus is needed on which other outcomes to capture, ensuring they are relevant to patients, clinicians, and researchers. The aim of this study was to identify, discuss and analyze outcomes related to cutaneous burn scarring, incorporating the voice of patients and views of healthcare professionals. For this, a Delphi process consisting of two survey rounds and a consensus meeting was initiated. Burn scar-related outcomes were identified from an existing comprehensive list of 100 outcomes by an international panel of patients, healthcare professionals and researchers. Fifty-nine outcomes were identified from the Delphi process as related to scarring (≥60% votes). Outcomes less impactful in relation to scar outcomes included psychosocial issues, sense of normality, understanding of treatment, costs and systemic issues. To represent a holistic assessment of outcomes related to cutaneous burn scarring, this Delphi process established a battery of outcomes currently included in scar quality assessment tools, and an expanded set of less frequently considered outcomes. Future work in this area must include the patient voice from developing countries. This is essential to identify globally applicable outcomes related to scarring.

Definitions, acceptability, limitations, and guidance in the use and reporting of surrogate end points in trials: a scoping review.

OBJECTIVE: To synthesize the current literature on the use of surrogate end points, including definitions, acceptability, and limitations of surrogate end points and guidance for their design/reporting, into trial reporting items. STUDY DESIGN AND SETTING: Literature was identified through searching bibliographic databases (until March 1, 2022) and gray literature sources (until May 27, 2022). Data were thematically analyzed into four categories: (1) definitions, (2) acceptability, (3) limitations and challenges, and (4) guidance, and synthesized into reporting guidance items. RESULTS: After screening, 90 documents were included: 79% (n = 71) had data on definitions, 77% (n = 69) on acceptability, 72% (n = 65) on limitations and challenges, and 61% (n = 55) on guidance. Data were synthesized into 17 potential trial reporting items: explicit statements on the use of surrogate end point(s) and justification for their use (items 1-6); methodological considerations, including whether sample size calculations were informed by surrogate validity (items 7-9); reporting of results for composite outcomes containing a surrogate end point (item 10); discussion and interpretation of findings (items 11-14); plans for confirmatory studies, collecting data on the surrogate end point and target outcome, and data sharing (items 15-16); and informing trial participants about using surrogate end points (item 17). CONCLUSION: The review identified and synthesized items on the use of surrogate end points in trials; these will inform the development of the Standard Protocol Items: Recommendations for Interventional Trials-SURROGATE and Consolidated Standards of Reporting Trials-SURROGATE extensions.

A framework for the definition and interpretation of the use of surrogate endpoints in interventional trials.

Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)-thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Secondary analysis of data from a core outcome set for burns demonstrated the need for involvement of lower income countries.

OBJECTIVE: To compare the views of participants from different income-status countries on outcome selection for a burn care Core Outcome Set (COS). METHODS: A retrospective analysis of data collected during a two round Delphi survey to prioritise the most important outcomes in burn care research. RESULTS: There was considerable agreement between participants from low- and middle-income countries (LMICs) and high-income countries (HICs) across outcomes. The groups agreed on 91% of 88 outcomes in round 1 and 92% of 100 in round 2. In cases of discordance, the consensus of participants from LMICs was to include the outcome and for participants from HICs to exclude. There was also considerable agreement between the groups for the top-ten ranking outcomes. Discordance in outcome prioritisation gives an insight into the different values clinicians from LMICs place on outcomes compared to those from HICs. Limitations of the study were that outcome rankings from international patients were not available. Healthcare professionals from LMICs were not involved in the final consensus meeting. CONCLUSION: COS developers should consider the need for a COS to be global at protocol stage. Global COS should include equal representation from both LMICs and HICs at all stages of development.

Use of core outcome sets was low in clinical trials published in major medical journals.

OBJECTIVES: To examine current practices in late-phase trials published in major medical journals and examine trialists' views about core outcome set (COS) use. STUDY DESIGN AND SETTING: A sequential multi-methods study was conducted. We examined late-phase trials published between October 2019 and March 2020 in JAMA, NEJM, The Lancet, BMJ, and Annals of Internal Medicine. The COMET database was searched for COS potentially relevant to trials not reporting using a COS; overlap of trial and COS outcomes was examined. An online survey examined awareness of, and decisions to search for and use a COS. RESULTS: Ninety-five trials were examined; 93 (98%) did not report using a COS. Relevant COS were identified for 31 trials (33%). Core outcomes were measured in 9 (23%) studies; all trials measured at least one core outcome. Thirty-one trialists (33%) completed our survey. The most common barrier to COS use was trialist's own outcome preferences and choice (68%). The most common perceived facilitator was awareness and knowledge about COS (90%). CONCLUSION: COS use in this cohort of trials was low, even when relevant COS were available. Increased use of COS in clinical trials can improve evaluation of intervention effects and evidence synthesis and reduce research waste.

Preventing venous thrombosis in critically ill children: what is the right approach?

BACKGROUND: The incidence of venous thromboembolic (VTE) events in children has increased in recent years (J Neurosurg, 101, 2004, 32; J Thromb Haemost, 1, 2003, 1443) yet there is currently no consensus as to what VTE prophylaxis, if any, should be applied to the pediatric population. OBJECTIVES/AIMS: Our aim was to audit current practice in pediatric VTE prophylaxis across England and Wales and to advocate simple measures for prevention. We illustrate the importance of the condition with a series of cases from the South West Paediatric Burns and Neurosurgical Services based in Bristol. METHODS: Every pediatric intensive care unit (PICU) and burns center admitting children in England and Wales was invited to participate in a structured telephone questionnaire designed to find out how VTE in children were being prevented. We performed a literature review of specific risk factors and management of these factors. RESULTS: Only one of the 24 units surveyed had written guidelines specific for children. Four other units used modified adult guidelines in older children. In the remaining 19 units that had no written guidelines, decisions regarding prophylaxis were based on individual cases and consultant-led. CONCLUSION: There is no consensus in England and Wales as to which VTE prophylactic measures should be applied in patients <18 years of age. The National Institute for Health and Clinical Excellence (NICE) guidelines apply to adults only. Given the rarity of VTE events in children, it is unlikely that randomized controlled trials will provide the answer. We therefore propose that simple empirical measures be formally implemented in critically ill children to reduce the risk of developing this important but under-recognized condition.

Multicentre observational study describing the systemic response to small-area burns in children.

BACKGROUND AND OBJECTIVES: Burns of less than 10% total body surface area (TBSA) are common injuries in children under five years of age. The inflammatory response to burn injury is well recognised for burns greater than 20% TBSA but has not been described for smaller burns. The aim of this study was to describe the systemic response to burn injury in young children with small-area burns. METHODS: The Morbidity In Small Thermal Injury in Children study (MISTIC) was a multicentre prospective observational cohort study that recruited 625 patients under five years of age with burns of less than 10% TBSA over eighteen months across three sites in England. Prospectively collected data included physical observations and laboratory blood tests taken in hospital as part of routine care. Additional information was sourced from temperature recordings taken at home following discharge. RESULTS: Elevated temperatures were observed in children with scald or contact burns between 2-10% TBSA, with a peak on day one after burn followed by a fall over days four to seven after burn. No temperature rise was seen in children with burns of <2% TBSA. Higher temperature readings were associated with larger burn size, age under two years and male sex. Heart rate and C-Reactive Protein levels showed a peak on day three after burn. CONCLUSIONS: An identifiable systemic inflammatory response to small-area burns in young children is reported. This knowledge can be used to aid in the diagnosis of children with a burn injury who re-present with a pyrexia, and no other symptoms to indicate clinical infection.

Systematic review of international Delphi surveys for core outcome set development: representation of international patients.

OBJECTIVES: A core outcome set (COS) describes a minimum set of outcomes to be reported by all clinical trials of one healthcare condition. Delphi surveys are frequently used to achieve consensus on core outcomes. International input is important to achieve global COS uptake. We aimed to investigate participant representation in international Delphi surveys, with reference to the inclusion of patients and participants from low and middle income countries as stakeholders (LMICs). DESIGN: Systematic review. DATA SOURCES: EMBASE, Medline, Web of Science, COMET database and hand-searching. ELIGIBILITY CRITERIA: Protocols and studies describing Delphi surveys used to develop an international COS for trial reporting, published between 1 January 2017 and 6 June 2019. DATA EXTRACTION AND SYNTHESIS: Delphi participants were grouped as patients or healthcare professionals (HCPs). Participants were considered international if their country of origin was different to that of the first or senior author. Data extraction included participant numbers, country of origin, country income group and whether Delphi surveys were translated. We analysed the impact these factors had on outcome prioritisation. RESULTS: Of 90 included studies, 69% (n=62) were completed and 31% (n=28) were protocols. Studies recruited more HCPs than patients (median 60 (IQR 30-113) vs 30 (IQR 14-66) participants, respectively). A higher percentage of HCPs was international compared with patients (57% (IQR 37-78) vs 20% (IQR 0-68)). Only 31% (n=28) studies recruited participants from LMICs. Regarding recruitment from LMICs, patients were under-represented (16% studies; n=8) compared with HCPs (22%; n=28). Few (7%; n=6) studies translated Delphi surveys. Only 3% studies (n=3) analysed Delphi responses by geographical location; all found differences in outcome prioritisation. CONCLUSIONS: There is a disproportionately lower inclusion of international patients, compared with HCPs, in COS-development Delphi surveys, particularly within LMICs. Future international Delphi surveys should consider exploring for geographical and income-based differences in outcome prioritisation. PROSPERO REGISTRATION NUMBER: CRD42019138519.

Cost-effectiveness and value of information analysis of a low-friction environment following skin graft in patients with burn injury.

BACKGROUND: Patients with burn injuries may receive a skin graft to achieve healing in a timely manner. However, in around 7% of cases, the skin graft is lost (fails to attach to the wound site) and a re-grafting procedure is necessary. It has been hypothesised that low-friction (smooth, more slippery) bedding may reduce the risk of skin-graft loss. A before and after feasibility study comparing low-friction with standard bedding in skin-grafted patients was conducted in order to collect proof of concept data. The resulting relative risk on the primary outcome (number of patients with skin graft failure) for the non-randomised study provided no evidence of effect but had a large standard error. The aim of this study is to see if an appropriately powered randomised control trial would be worthwhile. METHODS: A probabilistic decision-analytic model was constructed to compare low-friction bedding to standard care in a population of burn patients who have undergone skin grafting. Results from the before and after study were used as model inputs. The sensitivity of results to bias in the relative risk of graft loss was conducted. Low-friction bedding is considered optimal if expected incremental net benefit (INB) is positive. Uncertainty is assessed using cost-effectiveness acceptability curves. Expected Value of Perfect Partial Information (EVPPI) provides an upper bound for the potential net health benefits of new research for given model input. RESULTS: At a willingness to pay threshold of £20,000 per QALY, INB = £151 (95% Credible Interval (CrI) -142 to 814), marginally favouring low-friction bedding but with high uncertainty (probability of being cost-effective 70.5%). Expected value of perfect information (EVPI) per patient was £20.29, which results in a population EVPI of £174,765 over a 10-year lifetime for the technology (based on 1000 patients per year who would benefit from the intervention). The parameter contributing most to the uncertainty was the inpatient care cost, i.e. information that could be obtained from the audit of practice and without an expensive trial. These findings were robust to a wide-range of assumptions about the potential bias due to the observational nature of the comparative evidence. CONCLUSIONS: Our study results suggest that an RCT (randomised controlled trial) is unlikely to be worthwhile, but there may be value in a study to estimate the re-graft rates and associated costs in this population.

SPaCE Swab: Point-of-Care Sensor for Simple and Rapid Detection of Acute Wound Infection.

Wound infection is commonly observed after surgery and trauma but is difficult to diagnose and poorly defined in terms of objective clinical parameters. The assumption that bacteria in a wound correlate with infection is false; all wounds contain microorganisms, but not all wounds are clinically infected. This makes it difficult for clinicians to determine true wound infection, especially in wounds with pathogenic biofilms. If an infection is not properly treated, pathogenic virulence factors, such as rhamnolipids from Pseudomonas aeruginosa, can modulate the host immune response and cause tissue breakdown. Life-threatening sepsis can result if the organisms penetrate deep into host tissue. This communication describes the sensor development for five important clinical microbial pathogens commonly found in wounds: Staphylococcus aureus, P. aeruginosa, Candida albicans/auris, and Enterococcus faecalis (the SPaCE pathogens). The sensor contains liposomes encapsulating a self-quenched fluorescent dye. Toxins, expressed by SPaCE infecting pathogens in early-stage infected wounds, break down the liposomes, triggering dye release, thus changing the sensor color from yellow to green, an indication of infection. Five clinical species of bacteria and fungi, up to 20 strains each (totaling 83), were grown as early-stage biofilms in ex vivo porcine burn wounds. The biofilms were then swabbed, and the swab placed in the liposome suspension. The population density of selected pathogens in a porcine wound biofilm was quantified and correlated with colorimetric response. Over 88% of swabs switched the sensor on (107-108 CFU/swab). A pilot clinical study demonstrated a good correlation between sensor switch-on and early-stage wound infection.

Systematic review of clinical outcome reporting in randomised controlled trials of burn care.

INTRODUCTION: Systematic reviews collate trial data to provide evidence to support clinical decision-making. For effective synthesis, there must be consistency in outcome reporting. There is no agreed set of outcomes for reporting the effect of burn care interventions. Issues with outcome reporting have been identified, although not systematically investigated. This study gathers empirical evidence on any variation in outcome reporting and assesses the need for a core outcome set for burn care research. METHODS: Electronic searches of four search engines were undertaken from January 2012 to December 2016 for randomised controlled trials (RCTs), using medical subject headings and free text terms including 'burn', 'scald' 'thermal injury' and 'RCT'. Two authors independently screened papers, extracted outcomes verbatim and recorded the timing of outcome measurement. Duplicate outcomes (exact wording ± different spelling), similar outcomes (albumin in blood, serum albumin) and identical outcomes measured at different times were removed. Variation in outcome reporting was determined by assessing the number of unique outcomes reported across all included trials. Outcomes were classified into domains. Bias was reduced using five researchers and a patient working independently and together. RESULTS: 147 trials were included, of which 127 (86.4%) were RCTs, 13 (8.8%) pilot studies and 7 (4.8%) RCT protocols. 1494 verbatim clinical outcomes were reported; 955 were unique. 76.8% of outcomes were measured within 6 months of injury. Commonly reported outcomes were defined differently. Numbers of unique outcomes per trial varied from one to 37 (median 9; IQR 5,13). No single outcome was reported across all studies demonstrating inconsistency of reporting. Outcomes were classified into 54 domains. Numbers of outcomes per domain ranged from 1 to 166 (median 11; IQR 3,24). CONCLUSIONS: This review has demonstrated heterogeneity in outcome reporting in burn care research which will hinder amalgamation of study data. We recommend the development of a Core Outcome Set. PROSPERO REGISTRATION NUMBER: CRD42017060908.

A systematic review of core outcome set development studies demonstrates difficulties in defining unique outcomes.

OBJECTIVES: Core outcome set (COS) development often begins with a systematic review to identify outcomes. Reviews frequently show heterogeneity in numbers of outcomes reported across trials. Contributing to this is a lack of a uniform definition for an outcome. This study proposes a first working definition for a unique trial outcome to support reporting a quantitative assessment of outcome reporting heterogeneity (ORH). STUDY DESIGN AND SETTING: Eligible COS literature (development papers, protocols, and reviews) were identified using the COMET database, Ovid MEDLINE, and PubMed. Outcome numbers, definitions, timing, and grouping methodology were examined. RESULTS: One hundred and thirty two studies were included. 82 (88.1%) studies (excluding protocols) reported a total number of unique outcomes (median, 82; range, 12-5776; IQR, 261). Timing of assessment was reported in 32 (31.4%) studies. Methods to group similar outcomes were reported in 8 (7.8%) articles. No study defined how outcomes were agreed as different and how final numbers of unique outcomes were determined. It is proposed that a unique outcome requires original meaning and context. Thus ORH is suggested to be the reporting of multiple unique outcomes across trials related to one health care condition. CONCLUSION: This review identified inconsistencies in how authors define, extract, group, and count trial outcomes. Further work is needed to refine our proposed definitions to optimize COS development and allow a quantifiable measure of ORH.

Reaction-based indicator displacement assay (RIA) for the development of a triggered release system capable of biofilm inhibition.

Here, a reaction-based indicator displacement hydrogel assay (RIA) was developed for the detection of hydrogen peroxide (H2O2) via the oxidative release of the optical reporter Alizarin Red S (ARS). In the presence of H2O2, the RIA system displayed potent biofilm inhibition for Methicillin-resistant Staphylococcus aureus (MRSA), as shown through an in vitro assay quantifying antimicrobial efficacy. This work demonstrated the potential of H2O2-responsive hydrogels containing a covalently bound diol-based drug for controlled drug release.

Severe staphylococcal scalded skin syndrome in children.

Staphylococcal scalded skin syndrome (SSSS) is a rare toxin-mediated condition caused by Staphylococcus aureus, which causes blistering and desquamation of the skin. Between November 2005 and April 2006, four children were admitted to critical care beds in the South West Regional Paediatric Burns Unit because of SSSS affecting more than 50% of the body surface area. Details of these cases are presented, highlighting the potential severity of the condition. The cases also illustrate that fluid overload is a common complication of the condition, despite hypovolaemia being the more obvious risk, and that both hyponatraemia and leukopenia are frequent findings. These summaries clearly demonstrate the need for paediatric critical care in a tertiary burns unit for children with SSSS affecting a large proportion of the body surface area. The cluster of admissions prompted us to write a management protocol for children with severe SSSS and a summary of this is provided. Most children with SSSS will initially present to general paediatric units, where mild cases will be managed, but severe cases should be promptly referred to a tertiary paediatric burns unit for multi-disciplinary care in a critical care environment.