Tissue Inhibitors of Metalloproteinase 1 (TIMP-1) and 3 (TIMP-3) as New Markers of Acute Kidney Injury After Massive Burns.

BACKGROUND Acute kidney injury (AKI) is a common and serious complication after massive burn injury. One of the postulated etiologies is destruction of the extracellular matrix of nephrons, caused by a local imbalance between matrix metalloproteinases (MMPs) and specific inhibitors. The aim of this study was to analyze the dynamics of tissue inhibitors of metalloproteinases (TIMPs) during the first 5 days after massive thermal injury and the relationship with the risk of AKI. MATERIAL AND METHODS Thirty-three adults (22 men, 11 women) with severe burns were enrolled in the study. The values of TIMPs 1 to 4 were measured in blood serum and urine using the multiplex Luminex system. The associations between TIMPs and the risk of AKI were analyzed by using the generalized linear mixed models for repeated measurements. RESULTS Significant changes in serum and urine activities of TIMPs were confirmed, especially during the first 2 days after burn injury. Almost half of patients presented renal problems during the study. Significant differences between values of TIMPs in AKI and non-AKI status were also observed. However, a significant relationship between concentration of TIMPs and risk of AKI was confirmed only for urine TIMP-1 and serum TIMP-3. CONCLUSIONS The evaluation of TIMPs in the early stage after burn injury has potential benefits. The important roles of urine TIMP-1 and serum TIMP-3, as novel markers of the risk of AKI development, were confirmed. Other parameters require further analysis.

Identification of early coagulation changes associated with survival outcomes post severe burns from multiple perspectives.

Coagulation alterations manifest early after severe burns and are closely linked to mortality outcomes. Nevertheless, the precise characterization of coagulation changes associated with early mortality remains elusive. We examined alterations in indicators linked to mortality outcomes at both the transcriptomic and clinical characteristic levels. At the transcriptomic level, we pinpointed 28 differentially expressed coagulation-related genes (DECRGs) following burn injuries and endeavored to validate their causal relationships through Mendelian randomization. DECRGs tied to survival exhibit a significant association with neutrophil function, wherein the expression of CYP4F2 and P2RX1 serves as robust predictors of fatal outcomes. In terms of clinical indicators, early levels of D-dimer and alterations in serum calcium show a strong correlation with mortality outcomes. Coagulation depletion and fibrinolytic activation, stemming from the hyperactivation of coagulation pathways post-severe burns, are strongly linked to patient mortality. Monitoring these early coagulation markers with predictive value can effectively identify individuals necessitating priority critical care.

Association of inflammatory biomarkers with overall survival in burn patients: a systematic review and meta-analysis.

INTRODUCTION: The inflammatory response to burn injuries can lead to organ dysfunction that ultimately results in increased mortality and morbidity. This meta-analysis was conducted to determine the efficacy of inflammatory biomarkers, including the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), procalcitonin (PCT), and C-reactive protein (CRP) as predictive tools of mortality among burn patients. MATERIAL AND METHODS: The biomarker levels of survivors and non-survivors were consolidated according to guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Three main databases were searched electronically: PubMed, Web of Science, and Scopus, on December 8, 2022. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to evaluate and score the methodological quality of the included studies. The standard mean difference (SMD) with a 95% confidence interval (CI) was utilized. RESULTS: Twenty-four studies were included in our systematic review and meta-analysis, (3636 total burn patients), of whom 2878 survived. We found that deceased burn patients had elevated levels of NLR (SMD = 0.60, 95% CI; 0.19-1.00, P < 0.001), CRP (SMD = 0.80, 95% CI; 0.02-1.58, P = 0.04), and PCT (SMD = 0.85, 95% CI; 0.45-1.24, P < 0.001), compared to survivors. However, we found no association between PLR and mortality among burn patients (SMD = 0.00, 95% CI; -0.14-0.15, P < 0.001). In addition, CRP was significantly higher in non-survivors (SMD = 0.80, 95% CI; 0.02-1.58, P =0.04). Similar results were also found about PCT (SMD = 0.85, 95% CI; 0.45-1.24, P < 0.001). When we analyzed the PCT data, collected in the first 24-48 hours, we found similar results; the PCT level was significantly higher in non-survivors in the immediate postinjury-period (SMD = 0.67, 95% CI; 0.31-1.02, P < 0.001). There was no publication bias among studies on the role of NLR in burn (Egger's test P = 0.91). The based cut-off values for NLR (13), CRP (71), and PCT (1.77) yielded sensitivities of 69.2%, 100%, and 93.33%, and specificities of 76%, 72.22%, and 72.22% respectively. DISCUSSION/CONCLUSIONS: PCT is a marker of sepsis, therefore its elevated level is presumably associated with a higher incidence and severity of sepsis among non-survivors. In addition, NLR and CRP are promising biomarkers for predicting and guiding prevention against burn deaths in clinical settings.

Higher serum prealbumin levels are associated with higher graft take and wound healing in adult burn patients: A prospective observational trial.

INTRODUCTION: Nutritional support is essential in burn care. There are few studies investigating the effect of nutrition on burn healing. The purpose of this study was to determine the relationship between perioperative serum prealbumin levels and the probability of autologous skin graft take in burned patients. MATERIALS AND METHODS: A prospective observational study was carried out with burned adults recruited consecutively from April 2019 until September 2021. Serum prealbumin was determined perioperatively. The percentage of graft take was evaluated over the first 5 postoperative dressing changes. Time until full epithelialization (absence of wounds) was also registered. RESULTS: A total of 60 patients were recruited, mostly middle-aged people with moderate flame burns. Serum prealbumin levels and graft take had a weak-moderate, nonlinear, statistically significant correlation. They were also an independent predictor of full epithelialization on the fifth dressing change, together with burn depth. Higher perioperative serum prealbumin levels were significantly associated with a reduction in time until full epithelialization. CONCLUSIONS: Perioperative serum prealbumin levels are significantly correlated with the probability of split-thickness skin autograft take in burned patients and with a reduced time to achieve complete epithelialization. They were an independent predictor of full graft take.

The systemic inflammation indexes after admission predict in-hospital mortality in patients with extensive burns.

PURPOSE: To explore the clinical value of various complete blood count (CBC)-derived inflammation indicators to predict in-hospital mortality in patients with extensive burns. METHODS: Systemic inflammation indexes, including lymphocyte-platelet ratio (LPR), neutrophil-lymphocyte ratio (NLR), neutrophil-monocyte ratio (NMR), monocyte-lymphocyte ratio (MLR), neutrophil-to-lymphocyte * platelet (NLPR), systemic inflammation index (SII), and systemic inflammation response index (SIRI) on days 1, 3, and 7 after admission were calculated in 135 patients with extensive burns. RESULTS: We included 135 patients with extensive burns, including 97 survivors and 38 non-survivors. After adjusting for confounders, only the LPR on day 1, NLPR on days 3 and 7 were significantly associated with survival (OR= 1.237, 1.097, 1.104; 95 % CI: 1.055-1.451, 1.002-1.202, 1.005-1.212; respectively) in the analysis of multivariate logistic regression. The optimum cutoff values of the LPR on day 1 and NLPR on day 3 were 6.37 and 8.06, and the area under the curves (AUC) were 0.695 and 0.794, respectively. The AUC of NLPR on day 7 had the highest value, 0.814, and the optimum cut-off value was 3.84. The efficacy of LPR on day 1, NLPR on days 3 and 7 combined with the burn prognostic score index in predicting the prognosis of patients was higher than that of the burn index alone, and the three composite inflammatory indexes combined with PBI had the highest efficacy in predicting the prognosis (AUC = 0.994). Kaplan-Meier survival analysis showed poor prognosis in patients with higher LPR on day 1 and higher NLPR on days 3 and 7 (log-rank χ2 =9.623,31.564, 20.771, respectively; P < 0.01). CONCLUSIONS: LPR on day 1 and NLPR on days 3 and 7 after admission are reliable predictors of prognosis in patients with severe extensive burns. The combination of the burn prognostic score index, LPR on day 1, and NLPR on days 3 and 7 was superior to the burn indexes alone in predicting a patient's prognosis.

[Predictive value of D-dimer for deep venous thrombosis of lower extremity in adult burn patients].

Objective: To investigate the predictive value of D-dimer for deep venous thrombosis (DVT) of lower extremity in adult burn patients. Methods: A retrospective case series study was conducted. The clinical data of 3 861 adult burn patients who met the inclusion criteria and were admitted to the Department of Burns of Zhengzhou First People's Hospital from January 1, 2015 to December 31, 2019 were collected. The patients were divided into DVT group (n=77) and non-DVT group (n=3 784) according to whether DVT of lower extremity occurred during hospitalization or not. Data of patients in the two groups were collected and compared, including the gender, age, total burn area, D-dimer level, with lower limb burn and inhalation injury or not on admission, with sepsis/septic shock, femoral vein indwelling central venous catheter (CVC), history of surgery, and infusion of concentrated red blood cells or not during hospitalization. Data were statistically analyzed with independent sample t test, Mann-Whitney U test, and chi-square test. The indicators with statistically significant differences between the two groups were analyzed with multivariate logistic regression analysis to screen the independent risk factors for DVT of lower extremity in 3 861 adult burn patients. The receiver operating characteristic (ROC) curve of the independent risk factors predicting DVT of lower extremity in 3 861 adult burn patients were drawn, and the area under the curve (AUC), the optimal threshold value, and the sensitivity and specificity under the optimal threshold value were calculated. The quality of the AUC was compared by Delong test, and the sensitivity and specificity under the optimal threshold value were compared using chi-square test. Results: There were no statistically significant differences in gender, occurrence of sepsis/septic shock or history of surgery during hospitalization between patients in the two groups (P>0.05), while there were statistically significant differences in age, total burn area, D-dimer level, lower limb burn and inhalation injury on admission, and femoral vein indwelling CVC and infusion of concentrated red blood cells during hospitalization between patients in the two groups (t=-8.17, with Z values of -5.04 and -10.83, respectively, χ2 values of 21.83, 5.37, 7.75, and 4.52, respectively, P<0.05 or P<0.01). Multivariate logistic regression analysis showed that age, total burn area, and D-dimer level were the independent risk factors for DVT of lower extremity in 3 861 adult burn patients (with odds ratios of 1.05, 1.02, and 1.14, respectively, 95% confidence intervals of 1.04-1.06, 1.00-1.03, and 1.10-1.20, respectively, P<0.05 or P<0.01). The AUCs of ROC of age, total burn area, and D-dimer level for predicting DVT of lower extremity in 3 861 adult burn patients were 0.74, 0.67, and 0.86, respectively (with 95% confidence intervals of 0.68-0.80, 0.60-0.74, and 0.83-0.89, respectively, P values<0.01), the optimal threshold values were 50.5 years old, 10.5% total body surface area, and 1.845 mg/L, respectively, the sensitivity under the optimal threshold values were 71.4%, 70.1%, and 87.0%, respectively, and the specificity under the optimal threshold values were 66.8%, 67.2%, and 72.9%, respectively. The AUC quality and sensitivity and specificity under the optimal threshold value of D-dimer level were significantly better than those of age (z=3.29, with χ2 values of 284.91 and 34.25, respectively, P<0.01) and total burn area (z=4.98, with χ2 values of 326.79 and 29.88, respectively, P<0.01), while the AUC quality and sensitivity and specificity under the optimal threshold values were similar between age and total burn area (P>0.05). Conclusions: D-dimer level is an independent risk factor for DVT of lower extremity in adult burn patients, its AUC quality and sensitivity and specificity under the optimal threshold value are better than those of age and total burn area, and it has good predictive value for DVT of lower extremity in adult burn patients.

Severity of thermal burn injury is associated with systemic neutrophil activation.

Burn injuries elicit a unique and dynamic stress response which can lead to burn injury progression. Though neutrophils represent crucial players in the burn-induced immunological events, the dynamic secretion pattern and systemic levels of neutrophil-derived factors have not been investigated in detail so far. Serum levels of neutrophil elastase (NE), myeloperoxidase (MPO), citrullinated histone H3 (CitH3), and complement factor C3a were quantified in burn victims over 4 weeks post injury. Furthermore, the potential association with mortality, degree of burn injury, and inhalation trauma was evaluated. In addition, leukocyte, platelet, neutrophil, and lymphocyte counts were assessed. Lastly, we analyzed the association of neutrophil-derived factors with clinical severity scoring systems. Serum levels of NE, MPO, CitH3, and C3a were remarkably elevated in burn victims compared to healthy controls. Leukocyte and neutrophil counts were significantly increased on admission day and day 1, while relative lymphocytes were decreased in the first 7 days post burn trauma. Though neutrophil-derived factors did not predict mortality, patients suffering from 3rd degree burn injuries displayed increased CitH3 and NE levels. Accordingly, CitH3 and NE were elevated in cases with higher abbreviated burn severity indices (ABSI). Taken together, our data suggest a role for neutrophil activation and NETosis in burn injuries and burn injury progression. Targeting exacerbated neutrophil activation might represent a new therapeutic option for severe cases of 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.

Investigation of red cell distribution width as a prognostic criterion in severe burns.

This study was conducted to examine red cell distribution width (RDW) as a prognostic criterion in severe burns. The study is a descriptive correlational study and was carried out retrospectively. Patients with high RDW and low albumin values among severe burn injuries in the burn unit of a university hospital constituted half of the sample. Severe burns with RDW within normal range and a prognostic criterion for which albumin level normal and closest to normal accounted for the other half. RDW and albumin values were compared with the clinical results of patients with severe burns. IBM SPSS (Statistical Package for the Social Sciences) Statistics 25 was used for data analysis. Of the burn patients, 38.33% were between the age of 65-80, 51.67% were men, and 92.5% had third-degree burns. The mean albumin level of the patients was 2.39 ± 0.34 g/dL, and the mean RDW level was 18.47 ± 6.15%. The length of the stay in the intensive care unit was 13.45 ± 7.83 days, and the duration of central venous catheter use was 23.41 ± 8.25 days. High RDW and low albumin values were found to be associated with death, length of stay in the intensive care unit, and more blood transfusion. High RDW and hypoalbuminemia significantly affect the clinical results of severe burns. Both parameters are effective in determining the clinical course of burn patients, the length of hospital stay, presence of catheters and medication treatment protocol.

Association of the Circulating Supar Levels with Inflammation, Fibrinolysis, and Outcome in Severe Burn Patients.

BACKGROUND: Hyperfibrinolysis and pro/anti-inflammatory imbalance usually occur in the early stage of severe burns. Soluble urokinase-type plasminogen activator receptor (suPAR) is involved in fibrinolysis and inflammation. To date, the levels of circulating suPAR in non-survivors with severe burns remain unknown. This study aimed to investigate the early association between circulating suPAR levels and biomarkers of fibrinolysis, pro/anti-inflammatory, and prognosis. METHODS: Sixty-four consecutive Chinese patients with severe burns and 26 healthy volunteers were enrolled in a prospective observational cohort. Clinical characteristics and laboratory data were collected prospectively. Blood samples were collected at 48 h post-burn, and suPAR and biomarkers of pro/anti-inflammatory and fibrinolysis were detected by enzyme-linked immunosorbent assays. Important indicators between non-survivors and survivors were compared. Linear regression analysis was performed to screen variables associated with suPAR. Logistic regression analysis and receiver operating characteristic curve (ROC) analysis were performed to evaluate the prognostic value of suPAR. RESULT: Compared with the control group, the circulating suPAR levels in the survivors (P < 0.001) and non-survivors (P = 0.017) were higher. Compared with survivors, non-survivors had lower circulating suPAR levels at 48 h post-burn, and they showed a higher degree of fibrinolysis (higher D-dimer) and a lower TNF-α/IL-10 ratio. According to linear regression analysis, the variables independently associated with a lower suPAR level were lower platelet factor 4 (PF-4), urokinase-type plasminogen activator (uPA), and TNF-α/IL-10 levels and a higher D-dimer level. Logistic regression and ROC analyses indicated that a suPAR level ≤ 4.70 µg/L was independently associated with 30-day mortality. CONCLUSION: Low circulating suPAR levels at 48 h post-burn in severe burn patients may reflect decreased TNF-α/IL-10 ratio and increased hyperfibrinolysis. suPAR can predict 30-day mortality in patients with severe burn.

Drugs Interfering with Insulin Resistance and Their Influence on the Associated Hypermetabolic State in Severe Burns: A Narrative Review.

It has become widely accepted that insulin resistance and glucose hypermetabolism can be linked to acute pathologies, such as burn injury, severe trauma, or sepsis. Severe burns can determine a significant increase in catabolism, having an important effect on glucose metabolism and on muscle protein metabolism. It is imperative to acknowledge that these alterations can lead to increased mortality through organ failure, even when the patients survive the initial trauma caused by the burn. By limiting the peripheral use of glucose with consequent hyperglycemia, insulin resistance determines compensatory increased levels of insulin in plasma. However, the significant alterations in cellular metabolism lead to a lack of response to insulin's anabolic functions, as well as to a decrease in its cytoprotective role. In the end, via pathological insulin signaling associated with increased liver gluconeogenesis, elevated levels of glucose are detected in the blood. Several cellular mechanisms have been incriminated in the development of insulin resistance in burns. In this context, the main aim of this review article is to summarize some of the drugs that might interfere with insulin resistance in burns, taking into consideration that such an approach can significantly improve the prognosis of the burned patient.

Addition of admission lactate levels to Baux score improves mortality prediction in severe burns.

Risk adjustment and mortality prediction models are central in optimising care and for benchmarking purposes. In the burn setting, the Baux score and its derivatives have been the mainstay for predictions of mortality from burns. Other well-known measures to predict mortality stem from the ICU setting, where, for example, the Simplified Acute Physiology Score (SAPS 3) models have been found to be instrumental. Other attempts to further improve the prediction of outcome have been based on the following variables at admission: Sequential Organ Failure Assessment (aSOFA) score, determinations of aLactate or Neutrophil to Lymphocyte Ratio (aNLR). The aim of the present study was to examine if estimated mortality rate (EMR, SAPS 3), aSOFA, aLactate, and aNLR can, either alone or in conjunction with the others, improve the mortality prediction beyond that of the effects of age and percentage total body surface area (TBSA%) burned among patients with severe burns who need critical care. This is a retrospective, explorative, single centre, registry study based on prospectively gathered data. The study included 222 patients with median (25th-75th centiles) age of 55.0 (38.0 to 69.0) years, TBSA% burned was 24.5 (13.0 to 37.2) and crude mortality was 17%. As anticipated highest predicting power was obtained with age and TBSA% with an AUC at 0.906 (95% CI 0.857 to 0.955) as compared with EMR, aSOFA, aLactate and aNLR. The largest effect was seen thereafter by adding aLactate to the model, increasing AUC to 0.938 (0.898 to 0.979) (p < 0.001). Whereafter, adding EMR, aSOFA, and aNLR, separately or in combinations, only marginally improved the prediction power. This study shows that the prediction model with age and TBSA% may be improved by adding aLactate, despite the fact that aLactate levels were only moderately increased. Thereafter, adding EMR, aSOFA or aNLR only marginally affected the mortality prediction.

Intraoperative blood transfusions in burn patients.

BACKGROUND: Donated blood is a valuable and limited resource. Excision of burn wounds often leads to significant blood loss requiring transfusion. Accurately estimating blood loss is difficult, so examining the amount of blood products given intraoperatively is a clinically relevant way to measure utilization of this valuable resource. In this study, we examined the factors that influenced the amount of blood given intraoperatively during burn wound excisions. STUDY DESIGN AND METHODS: A retrospective analysis of patients admitted to a single burn center over 5 years who underwent excision of their burn wounds and received intraoperative blood products was performed. Patient and burn characteristics as well as pertinent surgical data and laboratory values on the day of surgery and postoperatively were gathered. A linear regression analysis examined factors influencing the number of units of products given and a predictive model was generated. RESULTS: A total of 563 operations performed on 166 patients were included. The amount of burn excised was the most influential variable on the amount of blood products given. Hemoglobin level, international normalized ratio, and platelet count on the day of surgery were associated with transfusion of different blood products. A predictive model was generated to aid in preoperative ordering of blood products. CONCLUSION: The amount of burn excised and common hematology and coagulation lab values were associated with the amount of different blood products administered during burn surgery. The predictive model generated needs to be validated prospectively to aid in preoperative planning for burn excisions.

Level of Decoy Receptor 3 for Monitoring Clinical Progression of Severe Burn Patients.

The clinical value of Decoy receptor 3 (DcR3) in severe burn is investigated. Ten patients with severe burns were monitored for DcR3, PCT, CRP, IL6, SOFA score, white blood cell (WBC), and platelet. The correlations were analyzed. DcR3 increased on day 1. The nonsurvivors had a steady high level of DcR3 while the survivors had a relatively low level of DcR3. The peak magnitude of DcR3 was high in five nonsurvivors and low in five survivors without overlap. Three patients had a continuously increasing DcR3 level and then died. In the other two nonsurvivors, DcR3 reached the peak and then decreased before death. DcR3 correlated well with PCT (ρ = 0.4469, P < .0001), less with CRP, platelet, IL6, SOFA score and WBC (ρ = 0.4369, 0.4078, 0.3995, 0.2631, 0.1504, respectively, all P < .001). To explore the mechanisms, the HaCaT or THP-1 cells were stimulated by the plasma of burn patients, 45°C, LPS or stimulators of TLRs or NOD2 (PGN, CL264, MDP, iE-DAP, Gardiquimod), and their DcR3 was increased, which could be reduced by GDC-0941 or BEZ235 (inhibitors of PI3K and mTOR). The levels of DcR3 appeared to be a useful biomarker for monitoring the clinical severity and a predictor of mortality of severe burns.

Burn-induced heterotopic ossification from incidence to therapy: key signaling pathways underlying ectopic bone formation.

Burn injury is one of the potential causes of heterotopic ossification (HO), which is a rare but debilitating condition. The incidence ranges from 3.5 to 5.6 depending on body area. Burns that cover a larger percentage of the total body surface area (TBSA), require skin graft surgeries, or necessitate pulmonary intensive care are well-researched risk factors for HO. Since burns initiate such complex pathophysiological processes with a variety of molecular signal changes, it is essential to focus on HO in the specific context of burn injury to define best practices for its treatment. There are numerous key players in the pathways of burn-induced HO, including neutrophils, monocytes, transforming growth factor-ß1-expressing macrophages and the adaptive immune system. The increased inflammation associated with burn injuries is also associated with pathway activation. Neurological and calcium-related contributions are also known. Endothelial-to-mesenchymal transition (EMT) and vascularization are known to play key roles in burn-induced HO, with hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) as potential initiators. Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and radiotherapy are effective prophylaxes for HO. Limited joint motion, ankylosis and intolerable pain caused by burn-induced HO can be effectively tackled via surgery. Effective biomarkers for monitoring burn-induced HO occurrence and bio-prophylactic and bio-therapeutic strategies should be actively developed in the future.

Circulating sFasL Levels Predict the Severity and Outcome of Burn Injury: A Prospective Observational Study.

BACKGROUND: Severe burn injury activates shock, inflammation, and blood cell system, but inappropriate reactions may lead to adverse outcomes. Soluble Fas ligand (sFasL) participates in apoptosis and inflammatory response. The circulating sFasL levels we investigated in association with the burn severity, shock, inflammation, blood cells, and mortality in patients with severe burns. METHODS: A total of 56 patients with severe burns were recruited. The levels of sFasL and the biomarkers reflecting shock, organ damage, inflammation, and blood cells at 48 h postburn were analyzed. We compared the practical situation of patients that stratified by median sFasL levels and investigated the predictive value of sFasL for mortality. RESULTS: High circulating sFasL levels were associated with the higher degrees of burn index, shock index, lactate, N-terminal probrain natriuretic peptide, total bilirubin, blood urea nitrogen, creatinine, tumor necrosis factor-α, interleukin-1ß, interleukin-8, intercellular adhesion molecule 1, and complement 3, and the lower degrees of oxygenation index, lymphocytes, and platelets. Multiple linear regression analysis showed that the higher tumor necrosis factor-α (P < 0.001) and the lower oxygenation index (P = 0.031) and lymphocytes (P = 0.043) were associated with the higher sFasL. High sFasL (a unit is 50 ng/L) (odds ratio [OR] 5.50 [95% CI 1.04-29.20], P = 0.045) was an independent predictor of increased mortality by multivariate logistic regression analysis. CONCLUSIONS: High circulating sFasL at 48 h postburn in patients with severe burns reflect shock, proinflammatory response, organ damage, and lymphocyte reductions and predict 30-day mortality.

STIM1 Regulates Endothelial Calcium Overload and Cytokine Upregulation During Sepsis.

BACKGROUND: Stromal interaction molecule 1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) is now recognized as the main mechanism of the majority of nonexcitable cell calcium influx. Calcium overload is a primary mechanism of endothelial cell injury during systemic inflammatory response and sepsis. Whether STIM1-mediated SOCE plays a role in calcium overload in vascular endothelial cell injury remains unclear. MATERIALS AND METHODS: To explore the role of STIM1-gated SOCE in vascular endothelial cell calcium overload and inflammation, we established a human septic serum or lipopolysaccharide (LPS)-induced human umbilical vein endothelial cell (HUVEC) experimental system and derived ribonucleic acid interference (RNAi)-mediated STIM1, ORAI1 (orai gene [HGNC: 25896 Entrez Gene: 84876] coding protein, ORAI Calcium Release-Activated Calcium Modulator 1), and transient receptor potential channel 1 (TRPC1) (core components of store-operated Ca2+[SOC]) downregulated HUVECs, as well as STIM1 overinduced HUVECs. RESULTS: Our results show that sepsis serum or LPS stimulation increased STIM1 in HUVECs and increased all cytokines except for VEGF and the inflammatory mediators tumor necrosis factor, intercellular cell adhesion molecule-1, and endothelin-1 in a time-dependent manner. RNAi-mediated knockdown of STIM1 significantly inhibited serum or LPS-induced inflammatory cytokine expression, and STIM1 overexpression in HUVECs promoted LPS-mediated induction of these cytokines. Meanwhile, similar to the blocking effect of the specific SOC inhibitors Gd3+ and La3+ on LPS-induced calcium influx, RNAi-mediated depletion of STIM1 or the SOC proteins TRPC1 and ORAI1 could significantly inhibit serum or LPS-induced extracellular calcium influx, as well as the expression of the inflammatory cytokines tumor necrosis factor, intercellular cell adhesion molecule-1, and endothelin-1. Simultaneous downregulation of the SOCE core units TRPC1 and ORAI1 inhibited LPS-induced calcium influx and cytokine expression, which could not be restored by inducing STIM1. Forced expression of nuclear factor-κB (NF-κB) in HUVECs significantly induced STIM1 expression, whereas RNAi-mediated depletion of NF-κB significantly inhibited STIM1 mRNA levels and significantly reduced the thapsigargin-mediated SOCE calcium influx, which was similar to results with the NF-κB inhibitor wogonin. CONCLUSIONS: Septic serum stimulates the expression of STIM1, cytokines, and inflammatory mediators in HUVECs. STIM1-mediated SOCE is required for Ca2+ influx induced by LPS or septic serum and contributes cytokines and inflammatory mediators in septic serum-stimulated HUVECs. In addition, STIM1-mediated SOCE on Ca2+ influx by septic serum or LPS involves NF-κB signaling.

Diagnostic Value of Neutrophil CD64 in Burn Patients With Infection in Chinese Population: A Systematic Review and Meta-analysis.

Infection is one of the leading causes of death in burn patients. Many researchers regard neutrophil CD64 (nCD64) as a biomarker in the early diagnosis of burn patients with infection. Nevertheless, the conclusions are controversial. A comprehensive analysis of the diagnostic value of nCD64 for burn infection was performed in China using a meta-analysis method. Pubmed, Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and China Wanfang databases were searched for studies on nCD64 as a diagnostic biomarker of burn patients with infection from the establishment of the databases to September 29, 2020. The data were analyzed by Stata 15.0 software. Six studies were identified. The results showed that the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.92 (95% confidence interval [CI]: 0.88~0.95), 0.82 (95% CI: 0.76~0.87), 5.10 (95% CI: 3.90~6.80), 0.10 (95% CI: 0.06~0.15), and 52 (95% CI: 29~94), respectively. The area under the curve was 0.94 (95% CI: 0.92~0.94). According to the analysis of the sepsis subgroup, it showed that nCD64 had good diagnostic value in the patients with burn sepsis in Chinese population. Neutrophil CD64 is highly efficient to diagnose burn infection in Chinese population. Therefore, nCD64 could be regarded as a valuable biomarker for the early diagnosis of burn infection in China, especially in patients with burn sepsis. Combined with other diagnostic indexes, nCD64 can be clinically used in the early diagnosis of burn infection to improve the sensitivity and specificity.