NUCLEAR FACTOR-ERYTHROID-2-RELATED FACTOR REGULATES SYSTEMIC AND PULMONARY BARRIER FUNCTION AND IMMUNE PROGRAMMING AFTER BURN AND INHALATION INJURY.

ABSTRACT: Major burn injury is associated with systemic hyperinflammatory and oxidative stresses that encompass the wound, vascular, and pulmonary systems that contribute to complications and poor outcomes. These stresses are exacerbated if there is a combined burn and inhalation (B+I) injury, which leads to increases in morbidity and mortality. Nuclear factor-erythroid-2-related factor (NRF2) is a transcription factor that functions to maintain homeostasis during stress, in part by modulating inflammation and oxidative injury. We hypothesized that the NRF2-mediated homeostasis after burn alone and combined B-I injury is insufficient, but that pharmacological activation of the NRF2 pathway has the potential to reduce/reverse acute hyper inflammatory responses. We found that, after burn and B+I injury, Nrf2 -/- mice have higher mortality and exhibit greater pulmonary edema, vascular permeability, and exacerbated pulmonary and systemic proinflammatory responses compared with injured wild-type (WT) controls. Transcriptome analysis of lung tissue revealed specific Nrf2 -dependent dysregulated immune pathways after injury. In WT mice, we observed that B+I injury induces cytosolic, but not nuclear, accumulation of NRF2 protein in the lung microenvironment compared with sham-injured controls. Bardoxolone methyl (CDDO-Me)-containing microparticles (CDDO-MPs) were developed that allow for dilution in saline and stable release of CDDO-Me. When delivered intraperitoneally into mice 1 hour after B+I injury, CDDO-MPs significantly reduced mortality and cytokine dysfunction compared with untreated B-I animals. These data implicate the role of NRF2 regulation of pulmonary and systemic immune dysfunction after burn and B+I injury, and also a deficiency in controlling immune dysregulation. Selectively activating the NRF2 pathway may improve clinical outcomes in burn and B+I patients.

Characterization of the Basal and mTOR-Dependent Acute Pulmonary and Systemic Immune Response in a Murine Model of Combined Burn and Inhalation Injury.

Severe burn injury leads to a cascade of local and systemic immune responses that trigger an extreme state of immune dysfunction, leaving the patient highly susceptible to acute and chronic infection. When combined with inhalation injury, burn patients have higher mortality and a greater chance of developing secondary respiratory complications including infection. No animal model of combined burn and inhalation injury (B+I) exists that accurately mirrors the human clinical picture, nor are there any effective immunotherapies or predictive models of the risk of immune dysfunction. Our earlier work showed that the mechanistic/mammalian target of rapamycin (mTOR) pathway is activated early after burn injury, and its chemical blockade at injury reduced subsequent chronic bacterial susceptibility. It is unclear if mTOR plays a role in the exacerbated immune dysfunction seen after B+I injury. We aimed to: (1) characterize a novel murine model of B+I injury, and (2) investigate the role of mTOR in the immune response after B+I injury. Pulmonary and systemic immune responses to B+I were characterized in the absence or presence of mTOR inhibition at the time of injury. Data describe a murine model of B+I with inhalation-specific immune phenotypes and implicate mTOR in the acute immune dysfunction observed.

Multiplexed Human Gene Expression Analysis Reveals a Central Role of the TLR/mTOR/PPARγ and NFkB Axes in Burn and Inhalation Injury-Induced Changes in Systemic Immunometabolism and Long-Term Patient Outcomes.

Burn patients are subject to significant acute immune and metabolic dysfunction. Concomitant inhalation injury increases mortality by 20%. In order to identify specific immune and metabolic signaling pathways in burn (B), inhalation (I), and combined burn-inhalation (BI) injury, unbiased nanoString multiplex technology was used to investigate gene expression within peripheral blood mononuclear cells (PBMCs) from burn patients, with and without inhalation injury. PBMCs were collected from 36 injured patients and 12 healthy, non-burned controls within 72 h of injury. mRNA was isolated and hybridized with probes for 1342 genes related to general immunology and cellular metabolism. From these specific gene patterns, specific cellular perturbations and signaling pathways were inferred using robust bioinformatic tools. In both B and BI injuries, elements of mTOR, PPARγ, TLR, and NF-kB signaling pathways were significantly altered within PBMC after injury compared to PBMC from the healthy control group. Using linear regression modeling, (1) DEPTOR, LAMTOR5, PPARγ, and RPTOR significantly correlated with patient BMI; (2) RPTOR significantly correlated with patient length of stay, and (3) MRC1 significantly correlated with the eventual risk of patient mortality. Identification of mediators of this immunometabolic response that can act as biomarkers and/or therapeutic targets could ultimately aid the management of burn patients.

Early expression of IL-10, IL-12, ARG1, and NOS2 genes in peripheral blood mononuclear cells synergistically correlate with patient outcome after burn injury.

BACKGROUND: No methods exist to rapidly and accurately quantify the immune insult created by burn injuries. The development of a rapid, noninvasive clinical biomarker assay that evaluates a burn patient's underlying immune dysfunction and predicts clinical outcomes could transform burn care. We aimed to determine a set of peripheral biomarkers that correlates with clinical outcomes of burn patients. METHODS: This prospective observational study enrolled two patient cohorts within a single burn center into an institutionally approved institutional review board study. Blood draws were performed <48 hours after injury. Initial unbiased immune gene expression analysis compared 23 burn patients and 6 healthy controls using multiplex immune gene expression analysis of RNA from peripheral blood mononuclear cells. We then performed confirmatory outcomes analysis in 109 burn patients and 19 healthy controls using a targeted rapid quantitative polymerase chain reaction. Findings were validated and modeled associations with clinical outcomes using a regression model. RESULTS: A total of 149 genes with a significant difference in expression from burn patients compared with controls were identified. Pathway analysis identified pathways related to interleukin (IL)-10 and inducible nitric oxide synthase signaling to have significant z scores. quantitative polymerase chain reaction analysis of IL-10, IL-12, arginase 1 (ARG1), and inducible nitric oxide synthase demonstrated that burn injury was associated with increased expression of ARG1 and IL-10, and decreased expression of nitric oxide synthase 2 (NOS2) and IL-12. Burn severity, acute lung injury, development of infection, failure of skin autograft, and mortality significantly correlated with expression of one or more of these genes. Ratios of IL-10/IL-12, ARG1/NOS2, and (ARG1-IL-10)/(NOS2-IL-12) transcript levels further improved the correlation with outcomes. Using a multivariate regression model, adjusting for patient confounders demonstrated that (ARG1-IL-10)/(NOS2-IL-12) significantly correlated with burn severity and development of acute lung injury. CONCLUSION: We present a means to predict patient outcomes early after burn injury using peripheral blood, allowing early identification of underlying immune dysfunction. LEVEL OF EVIDENCE: Prognostic/Epidemiological; Level II.

Peritraumatic Plasma Omega-3 Fatty Acid Concentration Predicts Chronic Pain Severity Following Thermal Burn Injury.

Chronic pain is a significant comorbidity of burn injury affecting up to 60% of survivors. Currently, no treatments are available to prevent chronic pain after burn injury. Accumulating evidence suggests that omega-3 fatty acids (O3FAs) improve symptoms across a range of painful conditions. In this study, we evaluated whether low peritraumatic levels of O3FA predict greater pain severity during the year after burn injury. Burn survivors undergoing skin autograft were recruited from three participating burn centers. Plasma O3FA (n = 77) levels were assessed in the early aftermath of burn injury using liquid chromatography/mass spectrometry, and pain severity was assessed via the 0 to 10 numeric rating scale for 1 year following burn injury. Repeated-measures linear regression analyses were used to evaluate the association between peritraumatic O3FA concentrations and pain severity during the year following burn injury. Peritraumatic O3FA concentration and chronic pain severity were inversely related; lower levels of peritraumatic O3FAs predicted worse pain outcomes (ß = -0.002, P = .020). Future studies are needed to evaluate biological mechanisms mediating this association and to assess the ability of O3FAs to prevent chronic pain following burn injury.

Plasma extracellular vesicles released after severe burn injury modulate macrophage phenotype and function.

Extracellular vesicles (EVs) have emerged as key regulators of immune function across multiple diseases. Severe burn injury is a devastating trauma with significant immune dysfunction that results in an ∼12% mortality rate due to sepsis-induced organ failure, pneumonia, and other infections. Severe burn causes a biphasic immune response: an early (0-72 h) hyper-inflammatory state, with release of damage-associated molecular pattern molecules, such as high-mobility group protein 1 (HMGB1), and proinflammatory cytokines (e.g., IL-1ß), followed by an immunosuppressive state (1-2+ wk post injury), associated with increased susceptibility to life-threatening infections. We have reported that early after severe burn injury HMGB1 and IL-1ß are enriched in plasma EVs. Here we tested the impact of EVs isolated after burn injury on phenotypic and functional consequences in vivo and in vitro using adoptive transfers of EV. EVs isolated early from mice that underwent a 20% total body surface area burn injury (burn EVs) caused similar hallmark cytokine responses in naïve mice to those seen in burned mice. Burn EVs transferred to RAW264.7 macrophages caused similar functional (i.e., cytokine secretion) and immune gene expression changes seen with their associated phase of post-burn immune dysfunction. Burn EVs isolated early (24 h) induced MCP-1, IL-12p70, and IFNγ, whereas EVs isolated later blunted RAW proinflammatory responses to bacterial endotoxin (LPS). We also describe significantly increased HMGB1 cargo in burn EVs purified days 1 to 7 after injury. Thus, burn EVs cause immune outcomes in naïve mice and macrophages similar to findings after severe burn injury, suggesting EVs promote post-burn immune dysfunction.

Peritraumatic 17ß-estradiol levels influence chronic posttraumatic pain outcomes.

ABSTRACT: Biologic factors that predict risk for and mediate the development of common outcomes of trauma exposure such as chronic posttraumatic pain (CPTP) are poorly understood. In the current study, we examined whether peritraumatic circulating 17ß-estradiol (E2) levels influence CPTP trajectories. 17ß-estradiol levels were measured in plasma samples (n = 254) collected in the immediate aftermath of trauma exposure from 3 multiethnic longitudinal cohorts of men and women trauma survivors. Chronic posttraumatic pain severity was evaluated 6 weeks, 6 months, and 1 year after traumatic stress exposure. Repeated measures mixed models were used to test the relationship between peritraumatic E2 levels and prospective CPTP. Secondary analyses in a nested cohort assessed the influence of participant body mass index on the E2-CPTP relationship. In women, a statistically significant inverse relationship between peritraumatic E2 and CPTP was observed (ß = -0.280, P = 0.043) such that higher E2 levels predicted lower CPTP severity over time. Secondary analyses identified an E2 * body mass index interaction in men from the motor vehicle collision cohort such that obese men with higher E2 levels were at greater risk of developing CPTP. In nonobese men from the motor vehicle collision cohort and in men from the major thermal burn injury cohort, no statistically significant relationship was identified. In conclusion, peritraumatic circulating E2 levels predict CPTP vulnerability in women trauma survivors. In addition, these data suggest that peritraumatic administration of E2 might improve CPTP outcomes for women; further research is needed to test this possibility.

Peritraumatic Vitamin D Levels Predict Chronic Pain Severity and Contribute to Racial Differences in Pain Outcomes Following Major Thermal Burn Injury.

Major thermal burn injuries result in approximately 40,000 hospitalizations in the United States each year. Chronic pain affects up to 60% of burn survivors, and Black Americans have worse chronic pain outcomes than White Americans. Mechanisms of chronic pain pathogenesis after burn injury, and accounting for these racial differences, remain poorly understood. Due to socioeconomic disadvantage and differences in skin absorption, Black Americans have an increased prevalence of Vitamin D deficiency. We hypothesized that peritraumatic Vitamin D levels predict chronic pain outcomes after burn injury and contribute to racial differences in pain outcomes. Among burn survivors (n = 77, 52% White, 48% Black, 77% male), peritraumatic Vitamin D levels were more likely to be deficient in Blacks vs Whites (27/37 [73%] vs 14/40 [35%], P < .001). Peritraumatic Vitamin D levels were inversely associated with chronic post-burn pain outcomes across all burn injury survivors, including those who were and were not Vitamin D deficient, and accounted for approximately one-third of racial differences in post-burn pain outcome. Future studies are needed to evaluate potential mechanisms mediating the effect of Vitamin D on post-burn pain outcomes and the potential efficacy of Vitamin D in improving pain outcomes and reducing racial differences.

The effect of neighborhood Area Deprivation Index on residential burn injury severity.

INTRODUCTION: Residential fires account for the majority of burn-related injuries and fatalities. Established risk factors for burn injury include male gender, racial minority, children and elderly individuals, poverty, and substandard housing characteristics. In North Carolina, the rate of residential fire injuries and deaths is higher than the national average. Therefore, we sought to describe residential fire hospitalizations at a large regional burn center and describe the neighborhoods in which they live. We hypothesized that patients living in areas with higher Area Deprivation Index (ADI) are more likely to have major residential burns. METHODS: We conducted a retrospective analysis of burn admissions from January 2002 to December 2015. We dichotomized patients into two cohorts: residential and non-residential burns and performed a bivariate analysis. Multivariate Poisson regression models were utilized to determine if ADI was associated with inhalation injury and ≥20% total body surface area burn. RESULTS: Of the 10,506 patients presented during the study period. Of these, 10,016 (95.3%) patients resided in North Carolina, and 7894 (78.8%) had a residential burn. Of the overall cohort, 6.0% (n=458) of patients had ≥20% TBSA burns and 6.4% (n=506) had inhalation injury. The majority of patients were in the highest (most disadvantaged) ADI quartile (n=3050, 39.5%), and only 6.8% of patients (n=525) were in the lowest (least disadvantaged) ADI quartile. In the Poisson multivariate regressions to determine if the ADI was associated with severe burns, patients in the highest ADI quartile had an increased relative risk of ≥20% TBSA burn (RR 1.31, 95% CI 1.02-1.68) and inhalation injury (RR 1.39, 95% CI 1.09-1.76) when compared to patients in the second-lowest ADI quartile when controlled for pertinent covariates. CONCLUSION: Residential structure fires represent the major source of burns and fatalities. People who reside in the highest ADI quartile are more like to present with higher burn injury severity in terms of burn size and the presence of inhalation injury. The use of the ADI to target neighborhoods for burn prevention is imperative.

Work-Related Burn Injuries in a Tertiary Care Burn Center, 2013 to 2018.

The features of work-related burn (WRB) injuries are not well defined in the literature and they vary depending on geographical location. We wanted to describe these characteristics among patients treated in the UNC Burn Center to evaluate the potential impact of commonly accepted prevention efforts. Adults of working age, admitted between January 1, 2013, and December 31, 2018, were identified using our Burn Center Registry. Demographic data, characteristics of injury, course of treatment, and patients' outcomes were described. Differences between work-related and non-work-related injuries were evaluated using the Chi-square test and Student t-test where appropriate. Three thousand five hundred and forty-five patients were included. WRB cases constituted 18% of the study population, and this proportion remained relatively stable during the study timeframe. Young white males were the majority of this group. When compared with non-WRB patients, they were characterized by fewer co-morbidities, decreased TBSA burns, decreased risk of inhalation injury, shorter time of intensive care treatment, shorter lengths of hospital stay, and lower treatment cost. In contrast to non-WRB, among which flame injuries were the main reason for admission, work-related patients most often suffered scald burns. They also had a dramatically increased proportion of chemical and electrical burns, making the latter the most common cause of death in that group. WRB are characterized by a characteristic patient profile, burn etiologies, and outcomes. Learning specific patterns at this group may contribute to optimize work safety regulations and medical interventions.

Acuity Is Seasonal in a Tertiary Care Burn Center.

Supply and demand dictate resource allocation in large academic institutions. Classic teaching is that burns is a seasonal specialty with winter being the "busiest" time of year. Resident allocation during the winter and summer months, however, is traditionally low due to the holidays and travel peaks. Our objective was to evaluate our acuity-defined as patient complexity-based on seasons, in order to petition for appropriate mid-level provider allocation. We performed a retrospective review of all admissions to an accredited, large academic burn center. All patients admitted between January 1, 2009 and December 31, 2018 were eligible for inclusion. Demographics, length of stay, injury characteristics, and mortality were evaluated. Thirteen thousand four hundred fifty-eight patients were admitted during this study period. Most patients were admitted during the summer. Patients admitted to the intensive care unit were more likely to be admitted in the winter, although this was not statistically significant. Winter admissions had the longest lengths of stay, and the highest incidence of inhalation injury. Female and elderly patients were more likely admitted during the winter. There was a significant difference in mortality between summer and winter seasons. Acuity is seasonal in our large academic burn center and resource allocation should align with the needs of the patients. This data may help large centers petition their institutions for more consistent experienced mid-level providers, specifically during critical seasons.

Sex-Based Differences in Inpatient Burn Mortality.

BACKGROUND: Among burn patients, research is conflicted, but may suggest that females are at increased risk of mortality, despite the opposite being true in non-burn trauma. Our objective was to determine whether sex-based differences in burn mortality exist, and assess whether patient demographics, comorbid conditions, and injury characteristics explain said differences. METHODS: Adult patients admitted with burn injury-including inhalation injury only-between 2004 and 2013 were included. Inverse probability of treatment weights (IPTW) and inverse probability of censor weights (IPCW) were calculated using admit year, patient demographics, comorbid conditions, and injury characteristics to adjust for potential confounding and informative censoring. Standardized Kaplan-Meier survival curves, weighted by both IPTW and IPCW, were used to estimate the 30-day and 60-day risk of inpatient mortality across sex. RESULTS: Females were older (median age 44 vs. 41 years old, p < 0.0001) and more likely to be Black (32% vs. 25%, p < 0.0001), have diabetes (14% vs. 10%, p < 0.0001), pulmonary disease (14% vs. 7%, p < 0.0001), heart failure (4% vs. 2%, p = 0.001), scald burns (45% vs. 26%, p < 0.0001), and inhalational injuries (10% vs. 8%, p = 0.04). Even after weighting, females were still over twice as likely to die after 60 days (RR 2.87, 95% CI 1.09, 7.51). CONCLUSION: Female burn patients have a significantly higher risk of 60-day mortality, even after accounting for demographics, comorbid conditions, burn size, and inhalational injury. Future research efforts and treatments to attenuate mortality should account for these sex-based differences. The project was supported by the National Institutes of Health, Grant Number UL1TR001111.

Burn recidivism: a 10-year retrospective study characterizing patients with repeated burn injuries at a large tertiary referral burn center in the United States.

BACKGROUND: Psychiatric and substance use disorders are common among trauma and burn patients and are known risk factors for repeat episodes of trauma, known as trauma recidivism. The epidemiology of burn recidivism, specifically, has not been described. This study aimed to characterize cases of burn recidivism at a large US tertiary care burn center and compare burn recidivists (RCs) with non-recidivists (NRCs). METHODS: A 10-year retrospective descriptive cohort study of adult burn patients admitted to the North Carolina Jaycee Burn Center was conducted using data from an electronic burn registry and the medical record. Continuous variables were reported using medians and interquartile ranges (IQR). Chi-square and Wilcoxon-Mann-Whitney tests were used to compare demographic, burn, and hospitalization characteristics between NRCs and RCs. RESULTS: A total of 7134 burn patients were admitted, among which 51 (0.7%) were RCs and accounted for 129 (1.8%) admissions. Of the 51 RCs, 37 had two burn injuries each, totaling 74 admissions as a group, while the remaining 14 RCs had between three and eight burn injuries each, totaling 55 admissions as a group. Compared to NRCs, RCs were younger (median age 36 years vs. 42 years, p = 0.02) and more likely to be white (75% vs. 60%, p = 0.03), uninsured (45% vs. 30%, p = 0.02), have chemical burns (16% vs. 5%, p <  0.0001), and have burns that were ≤ 10% total body surface area (89% vs. 76%, p = 0.001). The mortality rate for RCs vs. NRCs did not differ (0% vs. 1.2%, p = 0.41). Psychiatric and substance use disorders were approximately five times greater among RCs compared to NRCs (75% vs. 15%, p <  0.001). Median total hospital charges per patient were nearly three times higher for RCs vs. NRCs ($85,736 vs. $32,023, p <  0.0001). CONCLUSIONS: Distinct from trauma recidivism, burn recidivism is not associated with more severe injury or increased mortality. Similar to trauma recidivists, but to a greater extent, burn RCs have high rates of comorbid psychiatric and medical conditions that contribute to increased health care utilization and costs. Studies involving larger samples from multiple centers can further clarify whether these findings are generalizable to national burn and trauma populations.

One-hit wonder: Late after burn injury, granulocytes can clear one bacterial infection but cannot control a subsequent infection.

OBJECTIVE: Burn injury induces an acute hyperactive immune response followed by a chronic immune dysregulation that leaves those afflicted susceptible to multiple secondary infections. Many murine models are able to recapitulate the acute immune response to burn injury, yet few models are able to recapitulate long-term immune suppression and thus chronic susceptibility to bacterial infections seen in burn patients. This has hindered the field, making evaluation of the mechanisms responsible for these susceptibilities difficult to study. Herein we describe a novel mouse model of burn injury that promotes chronic immune suppression allowing for susceptibility to primary and secondary infections and thus allows for the evaluation of associated mechanisms. METHODS: C57Bl/6 mice receiving a full-thickness contact burn were infected with Pseudomonas aeruginosa 14 days (primary infection) and/or 17 days (secondary infection) after burn or sham injury. The survival, pulmonary and systemic bacterial load as well as frequency and function of innate immune cells (neutrophils and macrophages) were evaluated. RESULTS: Following secondary infection, burn mice were less effective in clearance of bacteria compared to sham injured or burn mice following a primary infection. Following secondary infection both neutrophils and macrophages recruited to the airways exhibited reduced production of anti-bacterial reactive oxygen and nitrogen species and the pro-inflammatory cytokineIL-12 while macrophages demonstrated increased expression of the anti-inflammatory cytokine interleukin-10 compared to those from sham burned mice and/or burn mice receiving a primary infection. In addition the BALF from these mice contained significantly higher level so of the anti-inflammatory cytokine IL-4 compared to those from sham burned mice and/or burn mice receiving a primary infection. CONCLUSIONS: Burn-mediated protection from infection is transient, with a secondary infection inducing immune protection to collapse. Repeated infection leads to increased neutrophil and macrophage numbers in the lungs late after burn injury, with diminished innate immune cell function and an increased anti-inflammatory cytokine environment.

Evaluation of the Association Between Genetic Variants in Circadian Rhythm Genes and Posttraumatic Stress Symptoms Identifies a Potential Functional Allele in the Transcription Factor TEF.

Previous studies suggest that genetic variants within genes affecting the circadian rhythm influence the development of posttraumatic stress symptoms (PTSS). In the present study, we used data from three emergency care-based cohorts to search genetic variants in circadian pathway genes previously associated with neuropsychiatric disorders for variants that influence PTSS severity. The three cohorts used included a discovery cohort of African American men and women enrolled following motor vehicle collision (n = 907) and two replication cohorts: one of multi-ethnic women enrolled following sexual assault (n = 274) and one of multi-ethnic men and women enrolled following major thermal burn injury (n = 68). DNA and RNA were collected from trauma survivors at the time of initial assessment. Validated questionnaires were used to assess peritraumatic distress severity and to assess PTSS severity 6 weeks, 6 months, and 1 year following trauma exposure. Thirty-one genetic variants from circadian rhythm genes were selected for analyses, and main effect and potential gene*stress and gene*sex interactions were evaluated. Secondary analyses assessed whether associated genetic variants affected mRNA expression levels. We found that six genetic variants across five circadian rhythm-associated genes predicted PTSS outcomes following motor vehicle collision (p < 0.05), but only two of these variants survived adjustment for multiple comparisons (False Discovery Rate < 5%). The strongest of these associations, an interaction between the PAR-zip transcription factor, thyrotroph embryonic factor (TEF) variant rs5758324 and peritraumatic distress, predicted PTSS development in all three cohorts. Further analysis of genetic variants in the genetic region surrounding TEFrs5758324 (±125,000 nucleotides) indicated that this allele showed the strongest association. Further, TEF RNA expression levels (determined via RNA-seq) were positively associated with PTSS severity in distressed individuals with at least one copy of the TEFrs5758324 minor allele. These results suggest that rs5758324 genetic variant in TEF, a regulator of clock-controlled genes and key mediator of the core circadian rhythm, influence PTSS severity in a stress-dependent manner.

Postoperative outcomes of esophagectomy for cancer in elderly patients.

BACKGROUND: The number of elderly patients with esophageal cancer is expected to increase. We aimed to determine the postoperative outcomes of esophagectomy for esophageal cancer in elderly patients. MATERIAL AND METHODS: A retrospective, population-based analysis was performed using the National inpatient sample for the period 2000-2014. Adult patients ≥18 years old (yo) diagnosed with esophageal cancer who underwent esophagectomy during their inpatient hospitalization were included. Patients were categorized into <70 yo and ≥70 yo. Multivariable linear and logistic regressions were used to assess the potential effect of age on postoperative complications, inpatient mortality, and hospital charges. RESULTS: Overall, 5243 patients were included, with 3699 (70.6%) <70 yo and 1544 (29.5%) ≥70 yo. The yearly rate of esophagectomies among patients ≥70 yo did not significantly changed during the study period (28.4% in 2000 and 26.3% in 2014, P = 0.76). Elderly patients were significantly more likely to have postoperative cardiac failure (odds ratio 1.59, 95% confidence interval [CI] 1.21, 2.09, P = 0.0009) and inpatient mortality (odds ratio 1.84, 95% CI 1.39, 2.45, P < 0.0001). Among the elderly patients, hospital charges were, on average, $16,320 greater (95% CI $3110, $29,530) than patients <70 yo (P = 0.02). The predicted probability of mortality increased consistently across age (1.5% in 40 yo, 2.5% in 50 yo, 3.6% in 60 yo, 5.4% in 70 yo, and 7.0% in 80 yo). CONCLUSIONS: Elderly patients undergoing esophagectomy for cancer have a significantly higher risk of postoperative mortality and pose a higher financial burden on the health care system. Elderly patients with esophageal cancer should be carefully selected for surgery.

A Comparative Study of the ReCell® Device and Autologous Spit-Thickness Meshed Skin Graft in the Treatment of Acute Burn Injuries.

Early excision and autografting are standard care for deeper burns. However, donor sites are a source of significant morbidity. To address this, the ReCell® Autologous Cell Harvesting Device (ReCell) was designed for use at the point-of-care to prepare a noncultured, autologous skin cell suspension (ASCS) capable of epidermal regeneration using minimal donor skin. A prospective study was conducted to evaluate the clinical performance of ReCell vs meshed split-thickness skin grafts (STSG, Control) for the treatment of deep partial-thickness burns. Effectiveness measures were assessed to 1 year for both ASCS and Control treatment sites and donor sites, including the incidence of healing, scarring, and pain. At 4 weeks, 98% of the ASCS-treated sites were healed compared with 100% of the Controls. Pain and assessments of scarring at the treatment sites were reported to be similar between groups. Significant differences were observed between ReCell and Control donor sites. The mean ReCell donor area was approximately 40 times smaller than that of the Control (P < .0001), and after 1 week, significantly more ReCell donor sites were healed than Controls (P = .04). Over the first 16 weeks, patients reported significantly less pain at the ReCell donor sites compared with Controls (P ≤ .05 at each time point). Long-term patients reported higher satisfaction with ReCell donor site outcomes compared with the Controls. This study provides evidence that the treatment of deep partial-thickness burns with ASCS results in comparable healing, with significantly reduced donor site size and pain and improved appearance relative to STSG.

Colonization with Multidrug-Resistant Enterobacteriaceae is Associated with Increased Mortality Following Burn Injury in Sub-Saharan Africa.

BACKGROUND: Multidrug-resistant (MDR) bacteria are an emerging international concern in low- and middle-income countries that threaten recent public health gains. These challenges are exacerbated in immunocompromised hosts, such as those with burn injury. This study sought to describe the epidemiology and associated clinical outcomes of burn wound colonization in a Malawian tertiary burn center. METHODS: This is a prospective analysis of burn patients presenting to Kamuzu Central Hospital in Lilongwe, Malawi, within 72 h of burn injury. A swab of each patient's primary wound was collected at admission and each subsequent week. The primary exposure was burn wound colonization with MDR bacteria, particularly Enterobacteriaceae. The primary outcome was in-hospital mortality. A log binomial model estimated the association between the exposure and outcome, adjusted for confounders. RESULTS: Ninety-nine patients were enrolled with a median age of 4 years (IQR 2-12) and a male preponderance (54%). Median total body surface area burn (TBSA) was 14% (IQR 9-25), and crude in-hospital mortality was 19%. Enterobacteriaceae were the most common MDR bacteria with 36% of patients becoming colonized. Wound colonization with MDR Enterobacteriaceae was associated with increased in-hospital mortality with a risk ratio of 1.86 (95% CI 1.38, 2.50, p < 0.001) adjusted for TBSA, burn type (scald vs. flame), sex, age, length of stay, and methicillin-resistant Staphylococcus aureus colonization. CONCLUSION: MDR bacteria, especially Enterobacteriaceae, are common and are associated with worse burn injury outcomes. In resource-poor environments, a greater emphasis on prevention of MDR bacterial colonization, improved isolation precautions, affordable diagnostics, and antibiotic stewardship are imperative.

HMGB1/IL-1ß complexes in plasma microvesicles modulate immune responses to burn injury.

Modulating immune responses to sepsis and trauma remain one of the most difficult challenges in modern medicine. Large burn injuries (LBI) are a severe form of trauma associated with sepsis, immune impairment, and mortality. Immune dysfunction after LBI is complex, involving both enhanced and impaired immune activation. The release of Damage-Associated Molecular Patterns (DAMPs), such as HMGB1, and cytokines (e.g. IL-1ß) creates an environment of immune dysfunction often leading to end organ failure and death. Both HMGB1 and IL-1ß have been found to play critical roles in sepsis and post-burn immune dysfunction. HMGB1 and IL-1ß have been shown previously to form potent complexes in vitro. We recently identified the presence of HMGB1/IL-1ß heterocomplexes in human tissue. We now find HMGB1/IL-1ß complexes in human and mouse plasma, and identify a synergistic role of HMGB1/IL-1ß complexes in post-burn immune dysfunction. In both humans and mice, we found that HMGB1 was enriched in plasma microvesicles (MVs) after LBI. HMGB1 was found form complexes with IL-1ß. Using flow cytometry of mouse plasma MVs, we identified an increase in an HMGB1+/IL-1ß+ MVs. Using co-IP, HMGB1 was found to bind the pro-form of IL-1ß in mouse and human plasma. Pro-IL-1ß, which is traditionally considered inactive, became active when complexed with HMGB1. Human THP-1 monocytes treated with HMGB1-pro-IL-1ß complexes showed increased transcription of LBI associated cytokines IL-6 and IFNß along with suppression of iNOS, mimicking findings associated with LBI. These findings identify that HMGB1/IL-1ß complexes released after burn injuries can modulate immune responses, and microvesicles are identified as a novel reservoir for these immune mediators. These complexes might serve as novel immune targets for the treatment of systemic immune responses due to LBI or other causes of sepsis.

Hypertrophic Scar Severity at Autograft Sites Is Associated With Increased Pain and Itch After Major Thermal Burn Injury.

Approximately three quarters of major thermal burn injury (MThBI) survivors suffer from hypertrophic scarring (HTS) and over half experience chronic pain or itch. In survivors of MThBI, HTS and chronic pain or itch are considered one of the greatest unmet challenges of postburn injury care and psychosocial reintegration. Although scarring, itch, and pain have been clinically associated, there are no prospective, multisite studies examining tissue autograft site pain or itch and scar outcomes. The authors collected a representative cohort (n = 56) of MThBI survivors who received autografting within 14 days of injury and evaluated graft-site pain or itch severity (0-10 Numeric Rating Scale) and HTS using a validated scar photograph assessment scale 6 months following MThBI. Given that stress is known to influence wound healing, the authors also assessed the relationship between previous trauma exposure, peritraumatic stress, preburn overall health (SF-12), scarring, and chronic pain or itch severity using Spearman's correlation. Association between HTS and chronic pain or itch was significant in a linear regression model adjusted for age, sex, and ethnicity (ß = 0.2, P = .033 for pain, ß = 0.2, P = .019 for itch). Results indicate that prior trauma exposure is inversely correlated (r = -.363, P = .030) with scar severity, but not pain or itch severity 6 months after MThBI. Study results suggest that preburn chronic pain or itch is associated with pathological scarring 6 months following MThBI. Results also indicate that stress may improve scarring after MThBI. Further work to understand the mechanisms that underlie both HTS and chronic pain or itch and their relationship to chronic stress is critical to the development of novel therapies to assist burn survivors recover.