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Severe burn injuries are defined by a prolonged hypermetabolic response characterized by increases in resting energy expenditure, systemic catabolism, and multi-organ dysfunction. The sustained elevation of catecholamines following a burn injury is thought to significantly contribute to this hypermetabolic response, leading to changes in adipose tissue such as increased lipolysis and the browning of subcutaneous white adipose tissue (WAT). Failure to mitigate these adverse changes within the adipose tissue has been shown to exacerbate the post-burn hypermetabolic response and lead to negative outcomes. Propranolol, a non-selective β-blocker, has been clinically administered to improve outcomes of pediatric and adult burn patients, but there is inadequate knowledge of its effects on the distinct adipose tissue depots. In this study, we investigated the adipose depot-specific alterations that occur in response to burn injury. Moreover, we explored the therapeutic effects of β-adrenoceptor blockade via the drug propranolol in attenuating these burn-induced pathophysiological changes within the different fat depots. Using a murine model of thermal injury, we show that burn injury induces endoplasmic reticulum (ER) stress in the epididymal (eWAT) but not in the inguinal (iWAT) WAT depot. Conversely, burn injury induces the activation of key lipolytic pathways in both eWAT and iWAT depots. Treatment of burn mice with propranolol effectively mitigated adverse burn-induced alterations in the adipose by alleviating ER stress in the eWAT and reducing lipolysis in both depots. Furthermore, propranolol treatment in post-burn mice attenuated UCP1-mediated subcutaneous WAT browning following injury. Overall, our findings suggest that propranolol serves as an effective therapeutic intervention to mitigate the adverse changes induced by burn injury, including ER stress, lipotoxicity, and WAT browning, in both adipose tissue depots. KEY MESSAGES: Burn injury adversely affects adipose tissue metabolism via distinct changes in both visceral and subcutaneous adipose depots. Propranolol, a non-selective β-adrenergic blocker, attenuates many of the adverse adipose tissue changes mediated by burn injury., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Hypermetabolic reprogramming triggered by thermal injury causes substantial morbidity and mortality. Despite the therapeutic potential of targeting this response, the underlying mechanisms remain poorly understood. Interestingly, protein S-acylation is a reversible posttranslational modification induced by metabolic alterations via DHHC acyltransferases. While this modification aids in the regulation of cellular functions, deregulated S-acylation contributes to various diseases by altering protein structure, stability, and localization. However, whether and how S-acylation may impact morbidity and mortality during postburn hypermetabolism is unknown. In this study, we discovered that alterations in the acyl proteome play a key role in mediating adverse outcomes that occur after burn injury. Using a murine model, we show that burn injury induces profound changes in the expression of various DHHC isoforms in metabolic organs central to regulating postburn hypermetabolism, the adipose tissue, and liver. This was accompanied by increased levels of S-acylated proteins in several pathways involved in mediating the adverse hypermetabolic response, including ER stress, lipolysis, and browning. In fact, similar results were also observed in adipose tissue from severely burned patients, as reflected by increased S-acylation of ERK1/2, eIF2a, ATGL, FGF21, and UCP1 relative to nonburn controls. Importantly, pharmacologically targeting this posttranslational modification using a nonselective DHHC inhibitor effectively attenuated burn-induced ER stress, lipolysis, and browning induction in an ex vivo explant model. Together, these findings suggest that S-acylation may facilitate the protein activation profile that drives burn-induced hypermetabolism and that targeting it could potentially be an effective strategy to restore metabolic function and improve outcomes after injury., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Najath Abdul Kareem,1 Ayesha Aijaz,1 Marc G Jeschke1– 4 1Sunnybrook Research Institute, Toronto, ON, Canada; 2Department of Surgery, Division of Plastic Surgery, University of Toronto, Toronto, ON, Canada; 3Department of Immunology, University of Toronto, Toronto, ON, Canada; 4Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, ON, CanadaCorrespondence: Marc G JeschkeRoss Tilley Burn Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Rm D704, Toronto, ON, M4N 3M5, CanadaTel +1 416-480-6703Fax +1 416-480-6763Email marc.jeschke@sunnybrook.caAbstract: Burn injuries affect approximately 11 million people annually, with fatalities amounting up to 180,000. Burn injuries constitute a global health issue associated with high morbidity and mortality. Recent years have seen advancements in regenerative medicine for burn wound healing encompassing stem cells and stem cell-derived products such as exosomes and conditioned media with promising results compared to current treatment approaches. Sources of stem cells used for treatment vary ranging from hair follicle stem cells, embryonic stem cells, umbilical cord stem cells, to mesenchymal stem cells, such as adipose-derived mesenchymal stem cells, bone marrow-derived mesenchymal stem cells, and even stem cells harvested from discarded burn tissue. Stem cells utilize various pathways for wound healing, such as PI3/AKT pathway, WNT-β catenin pathway, TGF-β pathway, Notch and Hedgehog signaling pathway. Due to the paracrine signaling mechanism of stem cells, exosomes and conditioned media derived from stem cells have also been utilized in burn wound therapy. As exosomes and conditioned media are cell-free therapy and contain various biomolecules that facilitate wound healing, they are gaining popularity as an alternative treatment strategy with significant improvement in outcomes. The treatment is provided either as direct injections or embedded in a natural/artificial scaffold. This paper reviews in detail the different sources of stem cells, stem cell-derived products, their efficacy in burn wound repair, associated signaling pathways and modes of delivery for wound healing.Keywords: stem cells, burn injury, exosomes, conditioned media, wound healing

Background: With advancements in burn treatment and intensive care leading to decreased mortality rates, a growing cohort of burn survivors is emerging. These individuals may be susceptible to frailty, characterized by reduced physiological reserve and increased vulnerability to stressors commonly associated with aging, which significantly complicates their recovery process. To date, no study has investigated burns as a potential risk factor for frailty. This study aimed to determine the short-term prevalence of frailty among burn survivors' months after injury and compare it with that of the general population., Methods: A post hoc analysis was conducted on the Randomized Trial of Enteral Glutamine to Minimize the Effects of Burn Injury (RE-ENERGIZE) trial, an international randomized-controlled trial involving 1200 burn injury patients with partial- or full-thickness burns. Participants who did not complete the 36-Item Short Form Health Survey (SF-36) questionnaire were excluded. Data for the general population were obtained from the 2022 National Health Interview Survey (NHIS). Frailty was assessed using the FRAIL (Fatigue, Resistance, Ambulation, Illness, Loss of weight) scale. Due to lack of data on loss of weight, for the purposes of this study, malnutrition was used as the fifth variable. Illness and malnutrition were based on admission data, while fatigue, resistance, and ambulation were determined from post-discharge responses to the SF-36. The burn cohort and general population groups were matched using propensity score matching and compared in terms of frailty status. Within the burn group, patients were divided into different subgroups based on their frailty status, and the differences in their (instrumental) activities of daily living (iADL and ADL) were compared. A multivariable analysis was performed within the burn cohort to identify factors predisposing to frailty as well as compromised iADL and ADL., Results: Out of the 1200 burn patients involved in the study, 600 completed the required questionnaires [follow-up time: (5.5 ± 2.3) months] and were matched to 1200 adults from the general population in the U.S. In comparison to the general population, burn patients exhibited a significantly higher likelihood of being pre-frail (42.3% vs. 19.8%, P < 0.0001), or frail (13.0% vs. 1.0%, P < 0.0001). When focusing on specific components, burn patients were more prone to experiencing fatigue (25.8% vs. 13.5%, P < 0.0001), limited resistance (34.0% vs. 2.7%, P < 0.0001), and restricted ambulation (41.8% vs. 3.8%, P < 0.0001). Conversely, the incidence rate of illness was observed to be higher in the general population (1.2% vs. 2.8%, P = 0.03), while no significant difference was detected regarding malnutrition (2.3% vs. 2.6%, P = 0.75). Furthermore, in comparison with robust burn patients, it was significantly more likely for pre-frail and frail patients to disclose compromise in ADL and iADL. The frail cohort reported the most pronounced limitation., Conclusions: Our findings suggest a higher incidence of post-discharge frailty among burn survivors in the short-term following injury. Burn survivors experience compromised fatigue, resistance, and ambulation, while rates of illness and malnutrition were lower or unchanged, respectively. These results underscore the critical need for early identification of frailty after a burn injury, with timely and comprehensive involvement of a multidisciplinary team including burn and pain specialists, community physicians, physiotherapists, nutritionists, and social workers. This collaborative effort can ensure holistic care to address and mitigate frailty in this patient population., (© 2024. The Author(s).)

Objective and Background: Propranolol, a nonselective beta-receptor blocker, improves outcomes of severely burned patients. While the clinical and physiological benefits of beta-blockade are well characterized, the underlying metabolic mechanisms are less well defined. We hypothesized that propranolol improves outcomes after burn injury by profoundly modulating metabolic pathways., Methods: In this phase II randomized controlled trial, patients with burns ≥20% of total body surface area were randomly assigned to control or propranolol (dose given to decrease heart rate <100 bpm). Outcomes included clinical markers, inflammatory and lipidomic profiles, untargeted metabolomics, and molecular pathways., Results: Fifty-two severely burned patients were enrolled in this trial (propranolol, n=23 and controls, n=29). There were no significant differences in demographics or injury severity between groups. Metabolomic pathway analyses of the adipose tissue showed that propranolol substantially alters several essential metabolic pathways involved in energy and nucleotide metabolism, as well as catecholamine degradation ( P <0.05). Lipidomic analysis revealed that propranolol-treated patients had lower levels of proinflammatory palmitic acid ( P <0.05) and saturated fatty acids ( P <0.05) with an increased ratio of polyunsaturated fatty acids ( P <0.05), thus shifting the lipidomic profile towards an anti-inflammatory phenotype after burn ( P <0.05). These metabolic effects were mediated by decreased activation of hormone-sensitive lipase at serine 660 ( P <0.05) and significantly reduced endoplasmic reticulum stress by decreasing phospho-JNK ( P <0.05)., Conclusion: Propranolol's ability to mitigate pathophysiological changes to essential metabolic pathways results in significantly improved stress responses., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: The analysis of the single-cell transcriptome has emerged as a powerful tool to gain insights on the basic mechanisms of health and disease. It is widely used to reveal the cellular diversity and complexity of tissues at cellular resolution by RNA sequencing of the whole transcriptome from a single cell. Equally, it is applied to discover an unknown, rare population of cells in the tissue. The prime advantage of single-cell transcriptome analysis is the detection of stochastic nature of gene expression of the cell in tissue. Moreover, the availability of multiple platforms for the single-cell transcriptome has broadened its approaches to using cells of different sizes and shapes, including the capture of short or full-length transcripts, which is helpful in the analysis of challenging biological samples. And with the development of numerous packages in R and Python, new directions in the computational analysis of single-cell transcriptomes can be taken to characterize healthy versus diseased tissues to obtain novel pathological insights. Downstream analysis such as differential gene expression analysis, gene ontology term analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, cell-cell interaction analysis, and trajectory analysis has become standard practice in the workflow of single-cell transcriptome analysis to further examine the biology of different cell types. Here, we provide a broad overview of single-cell transcriptome analysis in health and disease conditions currently applied in various studies., Competing Interests: Conflict of interest: The authors report no conflicts of interest., (Copyright © 2023 by the Shock Society.)

Background: Despite the growing prevalence of burn survivors, a gap persists in our understanding of the correlation between acute burn trauma and the long-term impact on psychosocial health. This study set out to investigate the prevalence of long-term pain and symptoms of anxiety and depression in survivors of extensive burns, comparing this to the general population, and identify injury and demographic-related factors predisposing individuals to psychosocial compromise., Methods: RE-ENERGIZE was an international, double-blinded, randomized-controlled trial that enrolled 1200 patients with partial- or full-thickness burns that required surgical treatment. For the post hoc analysis, we excluded participants who did not complete the Short Form Health Survey (SF-36) questionnaire. Normative data were taken from the 2021 National Health Interview Survey dataset. Propensity score matching was performed using the nearest-neighbor 1-to-1 method, and the two cohorts were compared in terms of chronic pain, and symptoms of anxiety and depression. A multivariable analysis was performed on the burns cohort to identify factors predicting post-discharge pain and symptoms of anxiety and depression., Results: A total of 600 burn patients and 26,666 general population adults were included in this study. Following propensity score matching, both groups comprised 478 participants each, who were predominately male, white, overweight and between 20 and 60 years old. Compared to the general population, burn patients were significantly more likely to report the presence of moderate and a lot of pain (p = 0.002). Symptoms of anxiety were significantly higher in the burn population in two of four levels (most of the time; some of the time; p < 0.0001 for both). Responders in the burn population were significantly less likely to report the absence of depressive symptoms (p < 0.0001). Burn patients were also significantly more likely to report that their mental health affects their social life. TBSA, history of depression, and female sex were identified as independently associated factors for pain, anxiety, and depressive symptoms. The presence of chronic pain and anxiety symptoms independently predicted for symptoms of depression., Conclusions: Analyzing the largest multicenter cohort of patients with extensive burns, we find that burn injury is associated with chronic pain, and symptoms of anxiety and depression. In addition, TBSA-burned and history of depression directly correlate with the prevalence of chronic pain, and symptoms of anxiety and depression. Finally, pain, and symptoms of anxiety and depression are interrelated and may have interactive effects on the process of recovery following burn injury. Burn patients would, therefore, benefit from a multidisciplinary team approach with early mobilization of pain and mental health experts, in order to promptly prevent the development of psychosocial challenges and their consequences., (© 2024. The Author(s).)

Background: Dermal scaffolds have created a paradigm shift for burn and wound management by providing improved healing and less scarring, while improving cosmesis and functionality. Dermal regeneration template (DRT) is a bilayer membrane for dermal regeneration developed by Yannas and Burke in the 1980s. The aim of this review is to summarize clinical evidence for dermal scaffolds focusing on DRT for the management and reconstruction of burn injuries and complex wounds., Methods: A comprehensive search of PubMed was performed from the start of indexing through November 2022. Articles reporting on DRT use in patients with burns, limb salvage, and wound reconstruction were included with focus on high-level clinical evidence., Results: DRT has become an established alternative option for the treatment of full-thickness and deep partial-thickness burns, with improved outcomes in areas where cosmesis and functionality are important. In the management of diabetic foot ulcers, use of DRT is associated with high rates of complete wound healing with a low risk of adverse outcomes. DRT has been successfully used in traumatic and surgical wounds, showing particular benefit in deep wounds and in the reconstruction of numerous anatomical sites., Conclusions: Considerable clinical experience has accrued with the use of DRT beyond its original application for thermal injury. A growing body of evidence from clinical studies reports the successful use of DRT to improve clinical outcomes and quality of life across clinical indications at a number of anatomical sites., Competing Interests: SG is former consultant for Integra LifeSciences Corporation. NM is former consultant for Integra LifeSciences Corporation (≥5 years ago). JPF received research funding from the National Institutes of Health, and is consultant for 3M, AbbVie, Becton Dickinson, Baxter, Integra LifeSciences Corporation, and Gore. CEA is former consultant for Integra LifeSciences Corporation (≥5 years ago). MGJ received research funding and consulting fees from Integra LifeSciences Corporation. PT is an employee of Integra LifeSciences Corporation and owns common stock of Integra LifeSciences Holdings Corporation, its parent corporation. DPO received research funding and consulting fees from Integra LifeSciences Corporation., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Abstract: Background: Interleukin (IL)-6 is a multifunctional cytokine with both a proinflammatory and anti-inflammatory role. In many studies, IL-6 increases rapidly after burn injury and is associated with poor outcomes. However, there are two aspects to IL-6; it can signal via its soluble IL-6 receptor (sIL-6R), which is referred to as trans-signaling and is regarded as the proinflammatory pathway. The role of sIL-6R postburn injury has yet to be explored in its entirety. We hypothesized that patients with a lower ratio of IL-6 to sIL-6R would have worse outcomes. Methods: Patients admitted to our burn center within 7 days of injury were included in this study. Patients were divided into two groups based on IL-6 and sIL-6R levels measured within the first 7 days postburn injury. Patients were in the high ratio group if their IL-6/sIL-6R ratio was ≥0.185. Clinical outcomes included organ biomarkers, morbidities, and hospital length of stay. Groups were compared using Student's t test, Mann-Whitney U , and Fisher's exact test as appropriate; a P value of <0.05 was considered statistically significant. Results: We studied 86 patients with a median age of 50 years (36-66 years) and a median total body surface area burn of 18% (10-31). There were 40 patients categorized with a low IL-6/sIL-6R ratio and 46 patients with a high IL-6/sIL-6R ratio. Patients in the high IL-6/sIL-6R ratio group had a significantly greater total body surface area burn ( P < 0.001) and a significantly greater proportion of patients with inhalation injury ( P = 0.001). Levels of IL-6 were significantly higher in patients with a high IL-6/sIL-6R ratio ( P < 0.0001). However, levels of sIL-6R were not significantly different among the low and high groups ( P = 0.965). Mortality was significantly greater in the high IL-6/sIL-6R ratio group (3% vs. 26%; P = 0.002). Conclusions: Interestingly, patients with a higher ratio of IL-6/sIL-6R had significantly greater mortality. Using sIL-6R as a marker for the proinflammatory immune response, we expected patients with a lower IL-6/sIL-6R ratio to have poor outcomes, typically associated with a hyperinflammatory or exaggerated immune response. However, the absolute value of sIL-6R did not differ. This suggests that classical signaling of IL-6 via its membrane-bound receptor, with an anti-inflammatory function, is important., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by the Shock Society.)

Objectives: Evidence supporting glutamine supplementation in severe adult burn patients has created a state of uncertainty due to the variability in the treatment effect reported across small and large randomized controlled trials (RCTs). We aimed to systematically review the effect of glutamine supplementation on mortality in severe adult burn patients., Data Sources: MEDLINE, Embase, CINAHL, and Cochrane Central were searched from inception to February 10, 2023., Study Selection: RCTs evaluating the effect of enteral or IV glutamine supplementation alone in severe adult burn patients were included., Data Extraction: Two reviewers independently extracted data on study characteristics, burn injury characteristics, description of the intervention between groups, adverse events, and clinical outcomes., Data Synthesis: Random effects meta-analyses were performed to estimate the pooled risk ratio (RR). Trial sequential analyses (TSA) for mortality and infectious complications were performed. Ten RCTs (1,577 patients) were included. We observed no significant effect of glutamine supplementation on overall mortality (RR, 0.65, 95% CI, 0.33-1.28; p = 0.21), infectious complications (RR, 0.83; 95% CI, 0.63-1.09; p = 0.18), or other secondary outcomes. In subgroup analyses, we observed no significant effects based on administration route or burn severity. We did observe a significant subgroup effect between single and multicenter RCTs in which glutamine significantly reduced mortality and infectious complications in singe-center RCTs but not in multicenter RCTs. However, TSA showed that the pooled results of single-center RCTs were type 1 errors and further trials would be futile., Conclusions: Glutamine supplementation, regardless of administration, does not appear to improve clinical outcomes in severely adult burned patients., Competing Interests: Dr. Hill received funding from Fresenius Kabi; she disclosed that she is currently supported by the Medical Faculty Rheinisch-Westfälische Technische Hochschule Aachen University (“Habilitationsstipendium”). Dr. Jeschke received support for article research from the National Institutes of Health. Dr. Cancio disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Alan D Rogers, Marc G Jeschke Ross Tilley Burn Centre, Division of Plastic and Reconstructive Surgery, Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada Abstract: Encountered regularly by health care providers across both medical and surgical fields and an increasing socioeconomic burden globally, wound care is severely neglected. Practice is heavily influenced by anecdote rather than evidence-based protocols and industry-biased literature rather than robust randomized controlled trials. Burn units are well placed to address this considerable need, as a result of their infrastructure, their multispecialty staffing, and their need to evolve in light of the declining incidence of major burn injury in developed countries. The aim of this review is to evaluate some of the ideological and practical challenges facing wound practitioners and burn surgeons while managing chronic and complex wounds. It also includes an approach to wound assessment and how to conceptualize and implement dressing strategies and new and existing multimodal therapies. Keywords: negative pressure wound therapy, instillation, antiseptic solutions, dressings, multidisciplinary wound care, stem cells, surgery, autograft, allograft, reconstructive ladder

Severe burns induce a chronic hypermetabolic state that persists well past wound closure, indicating that additional internal mechanisms must be involved. Adipose tissue is suggested to be a central regulator in perpetuating hypermetabolism, although this has not been directly tested. Here, we show that thermogenic adipose tissues are activated in parallel to increases in hypermetabolism independent of cold stress. Using an adipose tissue transplantation model, we discover that burn-derived subcutaneous white adipose tissue alone is sufficient to invoke a hypermetabolic response in a healthy recipient mouse. Concomitantly, transplantation of healthy adipose tissue alleviates metabolic dysfunction in a burn recipient. We further show that the nicotinic acetylcholine receptor signaling pathway may mediate an immune-adipose crosstalk to regulate adipose tissue remodeling post-injury. Targeting this pathway could lead to innovative therapeutic interventions to counteract hypermetabolic pathologies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Scar development remains a common occurrence and a major healthcare challenge affecting the lives of millions of patients annually. Severe injuries to the skin, such as burns can lead to pathological wound healing patterns, often characterized by dermal fibrosis or excessive scarring, and chronic inflammation. The two most common forms of fibrotic diseases following burn trauma are hypertrophic scars (HSCs) and keloids, which severely impact the patient's quality of life. Although the cellular and molecular mechanisms are similar, HSC and keloids have several distinct differences. In this review, we discuss the different forms of fibrosis that occur postburn injury, emphasizing how the extent of burn influences scar development. Moreover, we highlight how a systemic response induced by a burn injury drives wound fibrosis, including both the role of the inflammatory response, as well as the fate of fibroblast during skin healing. Finally, we list potential therapeutics aimed at alleviating pathological scar formation. An understanding of the mechanisms of postburn fibrosis will allow us to effectively move studies from bench to bedside.

Objective: We conducted a large-scale investigation of the systemic and adipose tissue-specific alterations in a clinical population of burn patients to identify factors that may influence hypermetabolism., Background: Previous research has identified chronic disturbances in adipose tissue inflammation, lipolysis, and browning, which may drive the perpetuation of hypermetabolism following the severe adrenergic stress of a burn injury. Given that adipose tissue is thought to be a central node in the regulation of systemic metabolism, we believe that systematically delineating the pathologic role of adipose tissue postburn, will lead to the identification of novel interventions to mitigate morbidity and mortality from severe burns., Methods: This was a single-institution cohort study, which obtained plasma and subcutaneous adipose tissue samples from severely burn adult patients over various time points during acute hospitalization. Whole-body clinical, metabolic, and inflammatory mediators were assessed in plasma, while genetic analyses through RT-qPCR and single-nuclei RNA sequencing were conducted in adipose tissue., Results: Systemic inflammation and adrenergic stress increase IL-6 signaling, lipolysis, browning, and adipokine dysfunction in the adipose tissue of adult burn patients, which may further propagate the long-term hypermetabolic response. Moreover, using single-nuclei RNA sequencing, we provide the first comprehensive characterization of alterations in the adipose tissue microenvironment occurring at acute and chronic stages postburn., Conclusion: We provide novel insight toward the effect of burns on adipokine release, inflammatory signaling pathways, and adipose heterogeneity over the trajectory of acute and chronic stages., Competing Interests: D.B. is a recipient of the Frederick Banting and Charles Best Canada Graduate Scholarship (CGS-D). A.A. is a recipient and supported by the Banting Postdoctoral Fellowships program through the Canadian Institutes of Health Research. The remaining authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Sepsis has become the leading cause of death in burn patients. Furthermore, sepsis and septic complications result in significant morbidities and longer hospitalization, which has profound impacts on the healthcare system. Despite this, sepsis in burn patients is surprisingly poorly understood and characterized. This retrospective, single-institution cohort study aimed to increase our understanding of the septic response after burns. We hypothesized that different sepsis definitions will results in distinctive septic trajectories and biochemical patterns after injury. Sepsis was defined by our burn center-specific prospective definition, the American Burn Association criteria, Sepsis-3 criteria, and the Mann-Salinas criteria. Applying these definitions, we compared clinical, metabolic, and inflammatory markers in septic and nonseptic burn patients. We found that the Sepsis-3 criteria are the most reliable screening tool used before clinical diagnoses for detecting sepsis trajectories and biochemical patterns. Moreover, we characterized distinct temporal alterations in biomarkers during the pre- and post-septic periods in burn patients, which may be incorporated into future sepsis definitions to improve the accuracy of a sepsis diagnosis in burn patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 by the Shock Society.)

Wound healing occurs as a response to disruption of the epidermis and dermis. It is an intricate and well-orchestrated response with the goal to restore skin integrity and function. However, in hundreds of millions of patients, skin wound healing results in abnormal scarring, including keloid lesions or hypertrophic scarring. Although the underlying mechanisms of hypertrophic scars and keloid lesions are not well defined, evidence suggests that the changes in the extracellular matrix are perpetuated by ongoing inflammation in susceptible individuals, resulting in a fibrotic phenotype. The lesions then become established, with ongoing deposition of excess disordered collagen. Not only can abnormal scarring be debilitating and painful, it can also cause functional impairment and profound changes in appearance, thereby substantially affecting patients' lives. Despite the vast demand on patient health and the medical society, very little progress has been made in the care of patients with abnormal scarring. To improve the outcome of pathological scarring, standardized and innovative approaches are required., (© 2023. Springer Nature Limited.)

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, severe mucocutaneous adverse reactions. Severity prediction at early onset is urgently required for treatment. However, previous prediction scores have been based on data of blood tests., Objective: This study aimed to present a novel score that predicts mortality in patients with SJS/TEN in the early stages based on only clinical information., Methods: We retrospectively evaluated 382 patients with SJS/TEN in a development study. A clinical risk score for TEN (CRISTEN) was created according to the association of potential risk factors with death. We calculated the sum of these risk factors using CRISTEN, and this was validated in a multinational survey of 416 patients and was compared with previous scoring systems., Results: The significant risk factors for death in SJS/TEN comprised 10 items, including patients' age of ≥65 years, ≥10% body surface area involvement, the use of antibiotics as culprit drugs, the use of systemic corticosteroid therapy before the onset, and mucosal damage affecting the ocular, buccal, and genital mucosa. Renal impairment, diabetes, cardiovascular disease, malignant neoplasm, and bacterial infection were included as underlying diseases. The CRISTEN model showed good discrimination (area under the curve [AUC] = 0.884) and calibration. In the validation study, the AUC was 0.827, which was statistically comparable to those of previous systems., Conclusion: A scoring system based on only clinical information was developed to predict mortality in SJS/TEN and was validated in an independent multinational study. CRISTEN may predict individual survival probabilities and direct the management and therapy of patients with SJS/TEN., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

High levels of plasma lactate are associated with increased mortality in critically injured patients, including those with severe burns. Although lactate has long been considered a waste product of glycolysis, it was recently revealed that it acts as a potent inducer of white adipose tissue (WAT) browning, a response implicated in mediating postburn cachexia, hepatic steatosis, and sustained hypermetabolism. Despite the clinical presentation of hyperlactatemia and browning in burns, whether these two pathological responses are linked is currently unknown. Here, we report that elevated lactate plays a causal signaling role in mediating adverse outcomes after burn trauma by directly promoting WAT browning. Using WAT obtained from human burn patients and mouse models of thermal injury, we show that the induction of postburn browning is positively correlated with a shift toward lactate import and metabolism. Furthermore, daily administration of l-lactate is sufficient to augment burn-induced mortality and weight loss in vivo. At the organ level, increased lactate transport amplified the thermogenic activation of WAT and its associated wasting, thereby driving postburn hepatic lipotoxicity and dysfunction. Mechanistically, the thermogenic effects of lactate appeared to result from increased import through MCT transporters, which in turn increased intracellular redox pressure, [NADH/NAD + ], and expression of the batokine, FGF21. In fact, pharmacological inhibition of MCT-mediated lactate uptake attenuated browning and improved hepatic function in mice after injury. Collectively, our findings identify a signaling role for lactate that impacts multiple aspects of postburn hypermetabolism, necessitating further investigation of this multifaceted metabolite in trauma and critical illness. NEW & NOTEWORTHY To our knowledge, this study was the first to investigate the role of lactate signaling in mediating white adipose tissue browning after burn trauma. We show that the induction of browning in both human burn patients and mice is positively correlated with a shift toward lactate import and metabolism. Daily l-lactate administration augments burn-induced mortality, browning, and hepatic lipotoxicity in vivo, whereas pharmacologically targeting lactate transport alleviates burn-induced browning and improves liver dysfunction after injury.

Abstract: Severe burns are characterized by the magnitude and duration of the hypermetabolic response thereafter, and demarcated by the loss of lean body mass and catabolism of fat stores. The aim of the present study was to delineate the temporal and location-specific physiological changes to adipose depots and downstream consequences post-burn in a murine model of thermal injury. C57BL/6 mice were subjected to a 30% total body surface area burn and body mass, food intake, and tissue mass were monitored for various time points up until 60 days postinjury. Mitochondrial respirometry was performed using a Seahorse XF96 analyzer. Lipolytic markers and browning markers were analyzed via Western blotting and histology. A severe burn results in a futile cycle of lipolysis and white adipose tissue (WAT) browning, the sequelae of which include fat catabolism, hepatomegaly, and loss of body mass despite increased food intake. A dynamic remodeling of epididymal WAT was observed with acute and chronic increases in lipolysis. Moreover, we demonstrate that pathological browning of inguinal WAT persists up to 60 days post-burn, highlighting the magnitude of the β-adrenergic response to thermal injury. Our data suggests that adipose depots have a heterogeneous response to burns and that therapeutic interventions targeting these physiological changes can improve outcomes. These data may also have implications for treating catabolic conditions such as cancer cachexia as well as developing treatments for obesity and type II diabetes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Hypermetabolism is a hallmark of larger burn injuries. The hypermetabolic response is characterized by marked and sustained increases in catecholamines, glucocorticoids, and glucagon. There is an increasing body of literature for nutrition and metabolic treatment and supplementation to counter the hypermetabolic and catabolic response secondary to burn injury. Early and adequate nutrition is key in addition to adjunctive therapies, such as oxandrolone, insulin, metformin, and propranolol. The duration of administration of anabolic agents should be at minimum for the duration of hospitalization, and possibly up to 2 to 3 years postburn., Competing Interests: Disclosure The authors have no disclosures to report., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aims: Hemorrhagic shock-resuscitation (HSR) following trauma contributes to organ dysfunction by causing ischemia-reperfusion injury (IRI). We previously showed that 'remote ischemic preconditioning' (RIPC) exerted multi-organ protection from IRI. Maintenance of mitochondrial quality by clearance of dysfunctional mitochondria via mitophagy is vital in restoring organ integrity. We hypothesized that parkin-dependent mitophagy played a role in RIPC-induced hepatoprotection following HSR., Methods: The hepatoprotective effect of RIPC in a murine model of HSR-IRI was investigated in wild type and parkin-/- animals. Mice were subjected to HSR ± RIPC and blood and organs were collected, followed by cytokine ELISAs, histology, qPCR, Western blots, and transmission electron microscopy., Results: HSR increased hepatocellular injury, as measured by plasma ALT and liver necrosis, while antecedent RIPC prevented this injury; in parkin -/- mice, RIPC failed to exert hepatoprotection. The ability of RIPC to lessen HSR-induced rises in plasma IL-6 and TNFα, was lost in parkin -/- mice. While RIPC alone did not induce mitophagy, the application of RIPC prior to HSR caused a synergistic increase in mitophagy, this increase was not observed in parkin -/- mice. RIPC induced shifts in mitochondrial morphology favoring mitophagy in WT but not in parkin -/- animals., Conclusions: RIPC was hepatoprotective in WT mice following HSR but not in parkin -/- mice. Loss of protection in parkin -/- mice corresponded with the failure of RIPC plus HSR to upregulate the mitophagic process. Improving mitochondrial quality by modulating mitophagy, may prove to be an attractive therapeutic target in disease processes caused by IRI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Selective attention might be space-, feature-, and/or object-based. Clear support for the involvement of an object-based mechanism is rather scarce, possibly because the predictions of models from these different classes often overlap. Yet, only object-based models can account for a larger congruency effect (CE) in the Eriksen flanker task when flankers are more (vs. less) strongly grouped to the target, but spacing and other response-irrelevant features of target and flankers are held constant. Exactly this was observed by Kramer and Jacobson (1991). So far, this theoretically relevant finding has not been replicated closely. We replicated the finding in two web-based experiments. Specifically, CEs were larger when flanker lines were connected to the central target line (vs. to outer neutral lines). We also successfully fitted the Diffusion Model for Conflict tasks (DMC) to the experimental data. Critically, diffusion modeling (DMC) and distributional analyses (delta functions) revealed that object membership primarily affected target processing strength rather than strength or timing of flanker processing. This challenges the prominent attentional spreading (sensory enhancement) account of object-based selective attention and motivates an alternative target attenuation account.

Background: Multipotent mesenchymal stromal/stem cell (MSC) therapy is under investigation in promising (pre-)clinical trials for wound healing, which is crucial for survival; however, the optimal cell dosage remains unknown. The aim was to investigate the efficacy of different low-to-high MSC dosages incorporated in a biodegradable collagen-based dermal regeneration template (DRT) Integra®., Methods: We conducted a porcine study (N = 8 Yorkshire pigs) and seeded between 200 and 2,000,000 cells/cm 2 of umbilical cord mesenchymal stromal/stem cells on the DRT and grafted it onto full-thickness burn excised wounds. On day 28, comparisons were made between the different low-to-high cell dose groups, the acellular control, a burn wound, and healthy skin., Result: We found that the low dose range between 200 and 40,000 cells/cm 2 regenerates the full-thickness burn excised wounds most efficaciously, followed by the middle dose range of 200,000-400,000 cells/cm 2 and a high dose of 2,000,000 cells/cm 2 . The low dose of 40,000 cells/cm 2 accelerated reepithelialization, reduced scarring, regenerated epidermal thickness superiorly, enhanced neovascularization, reduced fibrosis, and reduced type 1 and type 2 macrophages compared to other cell dosages and the acellular control., Conclusion: This regenerative cell therapy study using MSCs shows efficacy toward a low dose, which changes the paradigm that more cells lead to better wound healing outcome.

Severely burned patients suffer from a hypermetabolic syndrome that can last for years after the injury has resolved. The underlying cause of these metabolic alterations most likely involves the persistent elevated catecholamine levels that follow the surge induced by thermal injury. At the cellular level, endoplasmic reticulum (ER) stress in metabolic tissues is a hallmark observed in patients following burn injury and is associated with several detrimental effects. Therefore, ER stress could be the underlying cellular mechanism of persistent hypermetabolism in burned patients. Here, we show that catecholamines induce ER stress and that adreno-receptor blockers reduce stress responses in the HepG2 hepatocyte cell line. Our results also indicate that norepinephrine (NE) significantly induces ER stress in HepG2 cells and 3T3L1 mouse adipocytes. Furthermore, we demonstrate that the alpha-1 blocker, prazosin, and beta blocker, propranolol, block ER stress induced by NE. We also show that the effects of catecholamines in inducing ER stress are cell type-specific, as NE treatment failed to evoke ER stress in human fibroblasts. Thus, these findings reveal the mechanisms used by catecholamines to alter metabolism and suggest inhibition of the receptors utilized by these agents should be further explored as a potential target for the treatment of ER stress-mediated disease.

Burn injuries are a severe form of skin damage with a significant risk of scarring and systemic sequelae. Approximately 11 million individuals worldwide suffer burn injuries annually, with 180,000 people dying due to their injuries. Wound healing is considered the main determinant for the survival of severe burns and remains a challenge. The surgical treatment of burn wounds entails debridement of necrotic tissue, and the wound is covered with autologous skin substitutes taken from healthy donor areas. Autologous skin transplantation is still considered to be the gold standard for wound repair. However, autologous skin grafts are not always possible, especially in cases with extensive burns and limited donor sites. Allografts from human cadaver skin and xenografts from pig skin may be used in these situations to cover the wounds temporarily. Alternatively, dermal analogs are used until permanent coverage with autologous skin grafts or artificial skins can be achieved, requiring staged procedures to prolong the healing times with the associated risks of local and systemic infection. Over the last few decades, the wound healing process through tissue-engineered skin substitutes has significantly enhanced as the advances in intensive care ensuring early survival have led to the need to repair large skin defects. The focus has shifted from survival to the quality of survival, necessitating accelerated wound repair. This special volume of JBCR is dedicated to the discoveries, developments, and applications leading the reader into the past, present, and future perspectives of skin tissue engineering in burn injuries., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

De novo beige adipocyte biogenesis involves the proliferation of progenitor cells in white adipose tissue (WAT); however, what regulates this process remains unclear. Here, we report that in mouse models but also in human tissues, WAT lipolysis-derived linoleic acid triggers beige progenitor cell proliferation following cold acclimation, β3-adrenoceptor activation, and burn injury. A subset of adipocyte progenitors, as marked by cell surface markers PDGFRα or Sca1 and CD81, harbored cristae-rich mitochondria and actively imported linoleic acid via a fatty acid transporter CD36. Linoleic acid not only was oxidized as fuel in the mitochondria but also was utilized for the synthesis of arachidonic acid-derived signaling entities such as prostaglandin D 2 . Oral supplementation of linoleic acid was sufficient to stimulate beige progenitor cell proliferation, even under thermoneutral conditions, in a CD36-dependent manner. Together, this study provides mechanistic insights into how diverse pathophysiological stimuli, such as cold and burn injury, promote de novo beige fat biogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abnormal scar formation during wound healing can result in keloid and hypertrophic scars, which is a major global health challenge. Such abnormal scars can cause significant physiological pain and psychological distress and become a financial burden. Due to the biological complexity of scar formation, the pathogenesis of such scars and how to prevent them from forming remains elusive. In this review paper, we delve into the world of "omics" approaches to study abnormal scars and provide examples of genomics, transcriptomics, proteomics, epigenomics, and metabolomics. The benefits of "omics" approaches are that they allow for high-throughput studies and the analysis of 100s to 1000s of genes and proteins with the accumulation of large quantities of data. Currently in the field, there is a lack of "omics" review articles describing pathological scars. In this review, we summarize genome-wide linkage analysis, genome-wide association studies, and microarray data to name a few omics technologies. Such data can provide novel insights into different molecular pathways and identify novel factors which may not be captured through small-scale laboratory techniques., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Nazihah Bakhtyar et al.)

Background: Glutamine is thought to have beneficial effects on the metabolic and stress response to severe injury. Clinical trials involving patients with burns and other critically ill patients have shown conflicting results regarding the benefits and risks of glutamine supplementation., Methods: In a double-blind, randomized, placebo-controlled trial, we assigned patients with deep second- or third-degree burns (affecting ≥10% to ≥20% of total body-surface area, depending on age) within 72 hours after hospital admission to receive 0.5 g per kilogram of body weight per day of enterally delivered glutamine or placebo. Trial agents were given every 4 hours through a feeding tube or three or four times a day by mouth until 7 days after the last skin grafting procedure, discharge from the acute care unit, or 3 months after admission, whichever came first. The primary outcome was the time to discharge alive from the hospital, with data censored at 90 days. We calculated subdistribution hazard ratios for discharge alive, which took into account death as a competing risk., Results: A total of 1209 patients with severe burns (mean burn size, 33% of total body-surface area) underwent randomization, and 1200 were included in the analysis (596 patients in the glutamine group and 604 in the placebo group). The median time to discharge alive from the hospital was 40 days (interquartile range, 24 to 87) in the glutamine group and 38 days (interquartile range, 22 to 75) in the placebo group (subdistribution hazard ratio for discharge alive, 0.91; 95% confidence interval [CI], 0.80 to 1.04; P = 0.17). Mortality at 6 months was 17.2% in the glutamine group and 16.2% in the placebo group (hazard ratio for death, 1.06; 95% CI, 0.80 to 1.41). No substantial between-group differences in serious adverse events were observed., Conclusions: In patients with severe burns, supplemental glutamine did not reduce the time to discharge alive from the hospital. (Funded by the U.S. Department of Defense and the Canadian Institutes of Health Research; RE-ENERGIZE ClinicalTrials.gov number, NCT00985205.)., (Copyright © 2022 Massachusetts Medical Society.)

Introduction: Renal failure is the most common organ failure in severely burned patients. However, defining acute kidney injury and renal failure is very challenging. This study was designed to determine the relationship between a biomarker commonly measured on admission, serum creatinine, and outcomes in burn patients., Methods: We conducted a retrospective cohort study of adult patients (≥ 18 years) with a burn ≥ 5% total body surface area (TBSA) and a serum creatinine level measured within the first 72 h after injury. Patients were admitted over an 11-year period and divided into two groups based on creatinine levels measured within the first 72 h after injury. Patients were categorized in the high creatinine group if they had a measured creatinine ≥107 μmol/L (≥1.21 mg/dL); this value was chosen as the threshold for creatinine based on our institution's reference range. Clinical outcomes included morbidities, hospital length of stay, and mortality. Multivariable logistic regression was used to model the association between high admission creatinine and each outcome, adjusting for patient and injury characteristics., Results: We studied 923 patients, mean age 47 ± 18 years and median 13% (IQR 8-24) TBSA burned. There were 718 patients categorized with low admission creatinine and 205 patients with high admission creatinine. After adjustment for patient and injury characteristics, high admission creatinine was associated with a significantly higher rate of sepsis (OR 3.44; 95% CI 2.11-5.59), pneumonia (OR 4.56; 95% CI 1.8-11.53), and mortality (OR 3.59; 95% CI 1.91-6.75)., Conclusions: Elevated creatinine on admission is associated with an increased risk of morbidity and mortality. We suggest that admission creatinine can be used as a "red flag" to identify patients at a higher risk for poor outcomes., (Copyright © 2021 Elsevier Ltd and ISBI. All rights reserved.)

Antimicrobial resistance is an increasing problem in hospitals worldwide; however, the prevalence of carbapenemase-producing Enterobacteriaceae (CPE) in our region is low. Burn patients are vulnerable to infection because of the loss of the protective skin barrier, thus burn centers prioritize infection prevention and control (IP&C). This report describes a CPE outbreak in a regional burn center. In a period of 2.5 months, four nosocomial cases of CPE were identified, three containing the Klebsiella pneumoniae carbapenemase (KPC) gene and one Verona integrin-encoded metallo-β-lactamase (VIM) gene. The first two cases were identified while there was no CPE patient source on the unit. CPE KPC gene was then isolated in sink drains of three rooms. In addition to rigorous IP&C practices already in place, we implemented additional outbreak measures including restricting admissions to patients with complex burns or burns ≥10% TBSA, admitting patients to other in-patient units, and not permitting elective admissions. We began cohorting patients using nursing team separation for CPE-positive and -negative patients and geographical separation on the unit. Despite aggressive IP&C measures already in place, hospital-acquired CPE colonization/infection occurred. Given that CPE contaminated sinks of the same enzyme were identified, we believe hospital sink drains may the source. This highlights the importance of sink design and engineering solutions to prevent the formation of biofilm and reduce splashing. CPE infections are associated with poor outcomes in patients and significant health system costs due to a longer length of stay and additional institutional resources., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Impaired wound healing is a major issue in the elderly population and is associated with substantial health and economic burden, which is exponentially increasing with the growing aging population. While the underlying pathobiology of disturbed skin healing by aging is linked to several genetic and epigenetic factors, little is known about the cell-cell interaction during the wound healing process in aged individuals, particularly the mesenchymal stem cell (MSCs)-macrophages axis. In this study, by using a thermal injury animal model in which we compared the wound healing process of adult and young mice, we found that the insufficient pool of MSCs in adult animals are deficient in migrating to the wound bed and instead are restricted to the wound edge. We identified a deficiency of a CD90-positive MSC subpopulation in the wounds of adult animals, which is positively correlated with the number of F4/80+ macrophages. In vitro , we found that CD90+ cells preferentially adhere to the myeloid cells forming doublet cells. Thus, our findings highlight that in adult mice subjected to a thermal injury, impaired wound healing is likely mediated by a disturbed cellular interplay between myeloid cells and mesenchymal cells., (Copyright: © 2022 Amini-Nik et al.)

Although sepsis in burn patients is a major contributor to mortality, treatments are not always effective and underlying mechanisms have yet to be completely elucidated. NLRP3 inflammasome orchestrates burn-induced, inflammatory-driven pathophysiologic processes. Here, we determined the mechanism of NLRP3 inflammasome activation on bacterial clearance and mortality in burn sepsis. We obtained tissue and blood from 30 wild-type and 30 Nlrp3 -/- mice. Mice were subjected to a two-hit model of 25-30% TBSA scald burn followed by Pseudomonas aeruginosa wound infection 72 hours after injury. We also obtained tissue from 34 adult burn patients (≥18 years of age) with early (0-11 days post-burn) and later (≥12 days post-burn) surgical time-points and ten healthy controls. Murine studies indicated that Nlrp3 -/- had 30% improved survival and bacterial clearance at the site of injury and is systemically relative to burn sepsis wild type. Greater macrophage and neutrophil infiltration occurred acutely after infection (12 hours) to the site of injury and adipose tissue. This was followed by increased macrophage and neutrophil infiltration to lymphoid organs and liver beyond the acute phase (24 and 72 hours). Interestingly, Nlrp3 ablation increased acute systemic inflammation (IL-6, TNF-α, IL-1β). Septic burn patients had persistently increased adipose NLRP3 by-product expression beyond the acute phase that was more pronounced in late-onset sepsis. Our findings suggest that Nlrp3 genetic ablation enhanced acute tissue-specific inflammatory responsiveness. Likely, this occurs by paradoxically increasing acute immune infiltration and inflammation with a non-persistent response. Clinically, persistent NLRP3-mediated inflammation occurs in septic versus normal burn patients and potentially detrimentally impacts patient outcomes., (© 2021 John Wiley & Sons Ltd.)

Diabetes mellitus is an increasingly prevalent chronic disease that leads to long-term health consequences. Some long-term clinical sequelae of diabetes include coronary artery disease, peripheral vascular disease, peripheral neuropathy, and impaired wound healing. These can increase hospital stay and complications such as wound infections and amputations among patients with lower extremity burns. A retrospective analysis was performed of all isolated lower extremity burns from a single tertiary burn care center from 2006 to 2017. Patients were stratified by diabetic status and the incidence of lower extremity amputations was the primary outcome. Multivariable regression was used to model the association between diabetes and amputations, adjusting for patient and injury characteristics. A total of 198 patients were identified as meeting inclusion criteria, 160 were nondiabetic and 38 were diabetic. Age was significantly different between nondiabetic and diabetic patients; mean age was 46 ± 18 vs 62 ± 17 years (P < .0001). Length of stay was also significantly different, median length of stay was 11 (interquartile range 7-15) vs 18 (interquartile range 12-24; P < .001), with diabetic patients staying longer. There was a significantly greater proportion of diabetic patients that had an amputation (control 4% vs diabetic 29%; P < .0001). After adjustment for patient and injury characteristics, there was a significant association between diabetes and amputation (P = .002). Among patients with isolated lower extremity burns, those with a preexisting condition of diabetes had a longer hospitalization and increased amputations, despite similar size of burn. Diabetes is an important risk factor to acknowledge in patients with these injuries to optimize care., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Burns are a severe form of trauma that account for 1.1 million cases necessitating medical attention and 4500 mortalities annually in the United States alone. Importantly, the initial trauma is succeeded by extensive, prolonged physiological alterations that detrimentally impact multiple organ systems. Given the complexity of post-burn pathophysiology, in vitro experiments are insufficient to model thermal injuries. Therefore, compatible animal burn models are essential for studying burn-related phenomena. In this chapter, we discuss commonly employed small animal burn models and their comparability and applicability to human studies. In particular, we compare post-burn wound healing between the species as well as relevant hypermetabolic and inflammatory characteristics, providing a better understanding of the pros and cons of utilizing a small animal surrogate for human burns. We further provide an overview of the rodent scald burn model methodology as well as a comparison between elderly, aged and young animals, providing a guide for tailoring animal model choice based on the relevant research question., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Burn injury results in a triad of inter-related adaptive responses: a systemic inflammatory response, a stress response, and a consequent hypermetabolic state which supports the former two. These pathological responses extend beyond the site of injury to affect distant organs and influence long-term outcomes in the patient. Animal models have proven valuable in advancing our understanding of mechanisms underlying the multifactorial manifestations of burn injury. While rodent models have been unprecedented in providing insights into signaling pathways, metabolic responses, protein turnover, cellular and molecular changes; small animal models do not replicate hypermetabolism, hyperinflammation, and wound healing after a burn injury as seen in humans. Herein, we provide a concise review of preferred large animal models utilized to understand burn pathophysiology based on organ systems and associated dysfunction. Additionally, we present a detailed protocol of contact burn injury in the Yorkshire pig model with a focus on preoperative care, anesthesia, analgesia, wound excision and grafting, dressing application, and frequency of dressing changes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: It is unknown whether lung-protective ventilation is applied in burn patients and whether they benefit from it. This study aimed to determine ventilation practices in burn intensive care units (ICUs) and investigate the association between lung-protective ventilation and the number of ventilator-free days and alive at day 28 (VFD-28)., Methods: This is an international prospective observational cohort study including adult burn patients requiring mechanical ventilation. Low tidal volume ( V T ) was defined as V T  ≤ 8 mL/kg predicted body weight (PBW). Levels of positive end-expiratory pressure (PEEP) and maximum airway pressures were collected. The association between V T and VFD-28 was analyzed using a competing risk model. Ventilation settings were presented for all patients, focusing on the first day of ventilation. We also compared ventilation settings between patients with and without inhalation trauma., Results: A total of 160 patients from 28 ICUs in 16 countries were included. Low V T was used in 74% of patients, median V T size was 7.3 [interquartile range (IQR) 6.2-8.3] mL/kg PBW and did not differ between patients with and without inhalation trauma ( p  = 0.58). Median VFD-28 was 17 (IQR 0-26), without a difference between ventilation with low or high V T ( p  = 0.98). All patients were ventilated with PEEP levels ≥5 cmH 2 O; 80% of patients had maximum airway pressures <30 cmH 2 O., Conclusion: In this international cohort study we found that lung-protective ventilation is used in the majority of burn patients, irrespective of the presence of inhalation trauma. Use of low V T was not associated with a reduction in VFD-28., Trial Registration: Clinicaltrials.gov NCT02312869. Date of registration: 9 December 2014., (© The Author(s) 2021. Published by Oxford University Press.)

BACKGROUNDThe incidence of burn injuries in older patients is dramatically increasing as the population of older people grows. Despite the increased demand for elderly burn care, the mechanisms that mediate increased morbidity and mortality in older trauma patients are unknown. We recently showed that a burn injury invokes white adipose tissue browning that leads to a substantially increased hypermetabolic response associated with poor outcomes. Therefore, the aim of this study was to determine the effect of age on the metabolic adipose response of browning after a burn injury.METHODOne hundred and seventy patients with burn injury admitted to the Ross Tilley Burn Centre were prospectively enrolled and grouped by age as older (≥50 years) and young (≤35 years). Adipose tissue and sera were collected and analyzed for browning markers and metabolic state via histology, gene expression, and resting energy expenditure assays.RESULTSWe found that older patients with burn injury lacked the adipose browning response, as they showed significant reductions in uncoupling protein 1 (UCP1) expression. This failure of the browning response was associated with reduced whole-body metabolism and decreased survival in older patients with burn injury. Mechanistically, we found that the adipose of both aged patients after burn trauma and aged mice after a burn showed impairments in macrophage infiltration and IL-6, key immunological regulators of the browning process after a severe trauma.CONCLUSIONTargeting pathways that activate the browning response represents a potential therapeutic approach to improve outcomes after burn trauma for elderly patients.FUNDINGNIH (R01-GM087285-01), Canadian Institutes of Health Research (grant no. 123336), and Canada Foundation for Innovation Leaders Opportunity Fund (no. 25407).

Background: Wound healing processes are influenced by macronutrient intake (protein, carbohydrate and fat). The most favourable diet for cutaneous wound healing is not known, although high-protein diets are currently favoured clinically. This experimental study investigates the optimal macronutrient balance for cutaneous wound healing using a mouse model and the Geometric Framework, a nutrient modelling method, capable of analyzing the individual and interactive effects of a wide spectrum of macronutrient intake., Methods: Two adjacent and identical full-thickness skin excisions (1 cm 2 ) were surgically created on the dorsal area of male C57BL/6 mice. Mice were then allocated to one of 12 high-energy diets that varied in protein, carbohydrate and fat content. In select diets, wound healing processes, cytokine expression, energy expenditure, body composition, muscle and fat reserves were assessed., Results: Using the Geometric Framework, we show that a low-protein intake, coupled with a balanced intake of carbohydrate and fat is optimal for wound healing. Mice fed a low-protein diet progressed quickly through wound healing stages with favourable wound inflammatory cytokine expression and significantly accelerated collagen production. These local processes were associated with an increased early systemic inflammatory response and a higher overall energy expenditure, related to metabolic changes occurring in key macronutrient reserves in lean body mass and fat depots., Conclusions: The results suggest that a low-protein diet may have a greater potential to accelerate wound healing than the current clinically used high-protein diets., (© The Author(s) 2021. Published by Oxford University Press.)